“Criteria for the award includes a lifelong commitment to collaboration amongst re-

search, clinical practice, and industry with a significant contribution to the field of veteri-
nary orthopedics and the VOS, including contributions educating countless veterinarians
about chronic pain and his work bringing innovative treatments for osteoarthritis to the
market.”
 Chronic Pain in
Small Animal
Medicine
Over the past decade, since publication of the first edition of Chronic Pain in Small Animal
Medicine, many advances have been made in the discipline of pain management, includ-
ing embracement under the One Medicine initiative to improve the health and well-being of
multiple species. Contributing significantly to this progress is the evidence base provided by
multimodal management of chronic diseases such as osteoarthritis, a leading cause of pet
euthanasia. These advances are explored in this updated edition, written for the veterinary
professional seeking a greater depth of knowledge in the mechanisms of pain accompanying
chronic disease states and the potential targets for treatment. Additional new sections describe
newer drugs that are now in wide use, the Canine Osteoarthritis Staging Tool (COAST), novel
approaches to cancer treatment, and cannabinoids and their functions.

The book goes beyond common protocols by focusing on the latest evidence and our under-
standing of ‘why and how to treat’. It describes and evaluates current physiological and bio-
chemical theories of pain transmission without losing sight of the practical need for such
information. Chronic Pain in Small Animal Medicine provides a foundation for advances in
animal care and welfare and is necessary reading for veterinarians in practice and training.

We’re living in an age of exciting, new discoveries, but these are only exciting if we are aware
of these offerings and their optimal indications for use. This book aims to open veterinarians’
eyes to the myriad new ways we can now treat chronic pain in small animals.
 SECOND EDITION

Chronic Pain in
Small Animal
Medicine

Steven M Fox
Surgical Specialist, New Zealand VMA
Independent Consultant, Albuquerque, New Mexico, USA
Adjunct Professor, College of Veterinary Medicine, University of Illinois, Urbana, USA
Program Chairman (2000–2002), President (2004), Veterinary Orthopedic Society
Second edition published 2024
by CRC Press
6000 Broken Sound Parkway NW, Suite 300, Boca Raton, FL 33487-2742

and by CRC Press

4 Park Square, Milton Park, Abingdon, Oxon, OX14 4RN

© 2024 Steven M Fox

CRC Press is an imprint of Taylor & Francis Group, LLC

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Library of Congress Cataloging-in-Publication Data

Names: Fox, Steven M., author.

Title: Chronic pain in small animal medicine / Steven M Fox.
Description: Second edition. | Boca Raton : CRC Press, 2023. | Includes bibliographical references and index.
| Summary: "Over the past decade, since publication of the first edition of Chronic Pain in Small Animal
Medicine, many advances have been made in the discipline of pain management, including embracement
under the One Medicine initiative to improve the health and well-being of multiple species. Contributing
significantly to this progress is the evidence base provided by multimodal management of chronic diseases
such as osteoarthritis, a leading cause of pet euthanasia. These advances are explored in this updated
edition, written for the veterinary professional seeking a greater depth of knowledge in the mechanisms of
pain accompanying chronic disease states, and the potential targets for treatment. Additional new sections
describe newer drugs that are now in wide use, the Canine OsteoArthritis Staging Tool (COAST), novel
approaches to cancer treatment, and cannabinoids and their functions. The book goes beyond common
protocols by focusing on the latest evidence and our understanding of 'why and how to treat'. It describes
and evaluates current physiological and biochemical theories of pain transmission, without losing sight of
the practical need for such information. Chronic Pain in Small Animal Medicine provides a foundation for
advances in animal care and welfare and is necessary reading for veterinarians in practice and training.
We're living in an age of exciting, new discoveries, but these are only exciting if we are aware of these
offerings and their optimal indications for use. This book aims to open veterinarians' eyes to the myriad new
ways we can now treat chronic pain in small animals"-- Provided by publisher.
Identifiers: LCCN 2023004838 (print) | LCCN 2023004839 (ebook) | ISBN 9781032453163 (hardback) | ISBN
9781032451442 (paperback) | ISBN 9781003376422 (ebook)
Subjects: MESH: Chronic Pain--veterinary | Pain Management--veterinary | Animals, Domestic | Chronic
Disease--drug therapy | Chronic Disease--veterinary | Veterinary Drugs--therapeutic use Classification: LCC
SF910.P34 (print) | LCC SF910.P34 (ebook) | NLM SF 910.P34 | DDC 636.089/60472--dc23/eng/20230510
LC record available at https://lccn.loc.gov/2023004838
LC ebook record available at https://lccn.loc.gov/2023004839

ISBN: 978-1-032-45316-3 (HB)

ISBN: 978-1-032-45144-2 (PB)
ISBN: 978-1-003-37642-2 (EB)

DOI: 10.1201/9781003376422

Typeset in Sabon LT Std

by KnowledgeWorks Global Ltd.
 Contents
Preface VIII CHAPTER 5: Nonsteroidal
Acknowledgments XI Anti-Inflammatory Drugs ........................... 174
Author XII
Contributors XIII CHAPTER 6: Nutraceuticals ........................ 200
Abbreviations XIV
Glossary XVI Section 3

Section 1 CHAPTER 7: Multimodal Management

of Pain ........................................................215
CHAPTER 1: Physiology of Pain ...................... 3
CHAPTER 8: Multimodal Management
CHAPTER 2: Pathophysiology of of Canine Osteoarthritis .............................231
Osteoarthritic Pain ...................................... 70
CHAPTER 9: Chronic Pain in Selected
CHAPTER 3: Pathophysiology Physiological Systems: Ophthalmic,
of Cancer Pain............................................102 Aural, and Dental Ophthalmic Pain............252

Case Reports 260

Section 2
Index 262
CHAPTER 4: Pharmacologics
(Drug Classes) ............................................127

VII
 Preface
To life, which is the place of pain… pain is not how long it persists, but whether
Bhagavad Gita it remains long after it should have disap-
(a 700-verse Hindu scripture) peared. As the father of pain medicine, John
Bonica, explains, ‘Acute pain is a symptom
There is no pain pathway! Pain is the result of of disease; chronic pain itself is a disease’.
a complex signaling network. The cognition The noxious stimuli that constitute pain
of pain, like cognition in general, requires can reconfigure the architecture of the ner-
sophisticated neurological hardware. vous system they invade. Lasting noxious
Pain has many definitions because it’s input can produce a neurobiological cycle of
an intensely subjective experience that is fil- chemical and electrical action and reactions
tered through our emotions as well as our that becomes an automatic feedback loop: a
anatomy. It’s any sensation amplified to an chronic, self-perpetuating torment that per-
uncomfortable level, and it’s a plethora of sists long after the original trauma has healed.
negative emotions called ‘suffering’. No one From the human healthcare experience,
patient feels pain the same – there is no sin- pain, and in particular chronic pain, is a major
gle accepted pain experience. Like the per- problem for which current treatments are often
ception of beauty, it’s very real, but only in inadequate. The tangible costs economically
the eye of the beholder. Yet pain is so fun- are in the many tens of billions of dollars, and
damental to our well-being that it is added the costs in terms of suffering are known all
to heart rate, respiratory rate, temperature, too well to practitioners who seek to help these
and blood pressure as the ‘fifth vital sign’. patients. In veterinary medicine we are experi-
Without a ‘pain thermometer’, people in pain encing a surge of increasing focus on measuring
must rely on their language skills to describe and resolving pain and suffering, and indeed,
what they are feeling. In human medicine, this aspect is central to the veterinarian’s oath.
pain is what the patient says it is; in veteri- This focus is being supported by an increased
nary medicine, pain is what the assessor says understanding of pain neurophysiology, discov-
it is! Trained as scientists, veterinarians are ery of novel treatment targets, a greater offering
schooled to assess responses based on the of innovative pharmacologics, and consumer
mean ± standard deviation, yet effective pain demand. The pharmaceutical industry has
management suggests we target the least- made important strides forward in bringing
respondent patient within the population, so new therapies to address the problem of chronic
as to ensure no patient is declined the relief pain, but to the suffering patient, this progress
of pain it needs and deserves. is glacially slow. Specific areas of exploration
In its simplest sense, pain protects us from include peripheral nervous system targets, cen-
bodily harm; hence the proposal that pain is tral nervous system targets, disease-specific
a teacher, the headmaster of nature’s survival targets, and development of measurement tools
school. Dangerous things are noxious things, and applications of new technologies.
and pain punishes us if we take excessive risks In the 1880s, Friedrich Bayer and Company
or push ourselves beyond our physical limits. commercialized Bayer Aspirin. When aspirin
Further, pain often forces us to observe ‘recov- (‘a’ for acetyl, part of its chemical composi-
ery time’. Another way of understanding pain tion; ‘spir’ from a plant that contained sali-
is that any stimulus – noxious or otherwise cin; and ‘in’, a popular medical suffix at the
– can become painful if the patient’s ability to time) went over the counter in 1915, the mass
cope with it has been diminished. production of pain alleviators for the general
A working definition of chronic pain is public was launched. Pain is the most com-
that, unlike acute pain, it lasts beyond the mon reason patients see a physician, while
time necessary for healing and resists normal pain and pain relief are among the most
treatment. The primary indicator of chronic robust areas of medical research.

VIII
 Preface IX

Realistically, new discoveries and innova- appears that it may be dangerous to interfere
tive drug formulations for veterinary patients with it. Does this mean taking an analgesic,
will continue to lag considerably behind those like acetaminophen (paracetamol), without
for humans, despite the fact that animals are blocking neutrophils may be better than tak-
often used for the development of human ther- ing an anti-inflammatory drug or steroid?
apies. This is a reality of present-day econom- Stay tuned for the third edition, wherein we
ics, appreciated as return on investment by the may have the answer.
pharmaceutical industry. Accordingly, there This text was created for the veterinary
are presently, and will likely in the future be, a healthcare professional seeking a greater
limited number of agents and techniques actu- depth of knowledge in mechanisms of pain
ally labeled for veterinary use. It is therefore accompanying chronic disease states and
incumbent on the veterinarian and veterinary potential targets for treatment. It aspires to
healthcare professional to understand both the go beyond the ‘cookbook protocols’ found in
neurobiology of chronic pain and the mode many offerings by providing contemporary
of action of various therapies so as to deter- understandings of ‘why and how to treat’.
mine if the therapeutic agent or technique is An attention-getting photo is that of the
likely to be safe and efficacious when utilized number of scientific medical publications in
‘off-label’. Such insights may not be readily the past couple of years placed adjacent to
available for the proposed target patient, but the number of scientific medical publications
would be ‘inferred’ from data obtained from in the previous couple of decades. The former
a different species. Herein comes the weighing intimidates the latter – the point being that
of ‘species specificity’ vs. ‘one science’ in the new information is drowning us like a tsu-
clinical decision-making process. nami, not only in volume but also in breadth.
So . . . what’s new? Medicine, in general, To offer our patients the ‘best care’, provid-
will always engender creativity and innova- ers need to be current in the knowledge of
tion, some of which challenges our dogmatic the ‘best medicine’. This requires a trilogy
propensity. For example, in a surprising dis- of synergism among researchers, publishers,
covery that flies in the face of conventional and clinicians. Herein publications such as
medicine, McGill University researchers this require occasional revisions. This sec-
report that treating pain with anti-inflam- ond edition attempts to meet segments of
matory medications, like ibuprofen or aspi- that challenge.
rin, may promote pain in the long term. Several new therapeutics are introduced as
Published in Science Translational Medicine, well as combination products. Also, new deliv-
the authors suggest that inflammation, a ery systems are revealed together with their
normal part of injury recovery, helps resolve effectiveness and safety, together with drivers
acute pain and prevents it from becoming for development. New discoveries regarding
chronic (from Emily Shiffer. How We Treat the role of macrophages is presented, particu-
Acute Pain Could Be Wrong. Medscape: 17 larly as related to osteoarthritis.
June 2022). It might be proposed that block- There is a new section on the use of radio-
ing that inflammation may interfere with synoviorthesis as well as anti–nerve growth
this process, leading to harder-to-treat pain. factor (NGF) monoclonal antibodies. This sec-
Further, “What we’ve been doing for decades ond edition also contains a section on recogni-
not only appears to be mis-guided but is 180 tion and assessment of pain in different species
degrees out. We should not be blocking inflam- and reveals a staged approach to the treatment
mation. We should allow inflammation to play of osteoarthritis via the COAST scheme.
its role: nature’s way of obtunding chronic Additionally, commentary on acupunc-
pain”. Testing this concept, researchers ture and cannabinoids is included; however,
blocked neutrophils in mice, finding the pain the topics of product selection, dosing, and
lasted 2 to 10 times longer than normal. Anti- treatment protocols have intentionally been
inflammatory drugs, despite providing short- avoided due to the contentions of wide vari-
term relief, had the same pain-prolonging ability from which consensus is lacking –
effect, though injecting neutrophils into the topics for a different forum.
mice seemed to keep that from happening. The first edition (2010) of this text has been
Inflammation occurs for a reason, and it translated into several different languages
X Preface

and has sold more than 850 copies – testimo- Four decades ago, only 10% of graduating
nial to the increasing focus on chronic pain veterinarians were women. With the passing
management in veterinary medicine. I pro- of Title IX and the removal of gender bias
pose this can be attributed to several factors: in veterinary college admissions during the
(1) increases in pet owner demand, 1970s, approximately four out of five veteri-
(2) advances in scientific discoveries, (3) eco- nary students are now female. The number of
nomic entrepreneurship, and (4) (most signifi- female veterinarians now exceeds the number
cantly) the increased representation of female of male veterinarians (American Veterinary
veterinarians. I personally feel that women Medical Association [AVMA] members). In
are more empathetic to pain and are synergis- companion animal practice, the number of
tic to the scientific advances in driving patient women now exceed men by more than 30%.
relief from pain. The increased use of analgesics in veteri-
I would like to share an observation nary medicine certainly has a number of con-
before closing, an observation credible only tributing factors; however, I propose that the
from those of us active in clinical veterinary increased use of analgesics and increased per-
medicine over the past few decades. centage of female veterinarians are more than
Brakke Consulting estimates that of vet- coincidental. I believe there is an element of cau-
erinary-approved NSAIDs (the most common sality. It is my personal belief that, more often
scripted analgesic for dogs and cats) from than not, women bring to veterinary medicine
Pain Management Product reports, U.S. sales a greater empathy for pain than do males. In
figures at the manufacturer level are: such recognition, I believe women should be
proud of this significant contribution they have
Y2000: $75M brought to our collaborative profession.
Y2010: $205M
Y2020: $295M Steven M Fox
 Acknowledgments
It is said that fulfillment comes from (1) hav- With immense appreciation I acknowl-
ing something to do, (2) having something edge the role of Dr. Linda Contos and
to look forward to, and (3) having someone Dr. John Heidrich in making this initiative
to love. If that is true, then I am three times possible. I shall be forever grateful. I also rec-
blessed. I wish to recognize the contributors ognize Ms. J.L. Stone for her encouragement
to this work, who are noted international and support during the demanding times of
leaders in veterinary medicine. It is my good this undertaking. A heart-felt ‘shout-out’ is
fortune to learn from their collaboration made recognizing Dr. Rob and Judy Goring
and, more importantly, to embrace them as for their deep friendship and total support
personal friends and colleagues. to complete yet another project. Recognition
Creation of the International Veterinary is also due Ms. Sharon Francis for provid-
Academy of Pain Management (IVAPM) and ing an efficient office environment as well as
the International Association for the Study administrative support. In addition, I wish
of Pain: Non-human Special Interest Group to salute ‘my editor’, Ms. Alice Oven, with
(IASP:SIG) has made a framework through whom I have worked for a number of years.
which we can all collectively advance the Alice, you are the best of the best. Your pro-
science and practice of pain management. fessionalism is exemplary.
Congratulations to the visionaries who Finally, I want to commend CRC Press/
have invested their resources toward the Taylor & Francis for their recognition of con-
creation of these organizations, and thanks temporary veterinary issues, servicing their
to their membership who have recognized readers’ interests with quality resources,
a forum for the promotion of our common and providing a congenial framework for
interests. collaboration.

The best doctor in the world is the veterinarian. He can’t ask his
patients what is the matter – he’s got to just know.

Will Rogers

XI
 Author
Steven M Fox, MS, DVM, specialist at Pfizer Animal Health, and as
MBA, PhD, is the inaugu- director of pain management for Novartis
ral recipient of the endowed Animal Health. Dr. Fox played a key role
Dr. Steve Fox Lifetime in the development and launch of both the
Achievement Award by Rimadyl and Deramaxx branded nonste-
the Veterinary Orthopedic roidal anti-inflammatory drugs (NSAIDs).
Society (2022). He is a former president of the Veterinary
Orthopedic Society, is a council member of
the Association for Veterinary Orthopedic
Research and Education, and is a certi-
“Criteria for the award includes a lifelong
fied small animal surgical specialist in New
commitment to collaboration amongst
research, clinical practice, and industry with Zealand. Dr. Fox is an adjunct assistant pro-
a significant contribution to the field of vet- fessor at the University of Illinois, as well
erinary orthopedics and the VOS, including as adjunct associate professor at Massey
contributions educating countless veterinar- University, advisor to the University of
ians about chronic pain and his work bring- Tennessee Pain Center, founding member of
ing innovative treatments for osteoarthritis to the Companion Animal Pain Management
the market.” Consortium Leadership Council, and fellow
of the New Zealand Institute of Management.
Experience and diversity are the hallmarks Dr. Fox has also served as educational man-
of Dr. Fox’s professional background. He has ager for the Western Veterinary Conference
served as president of Securos Surgical for held annually in Las Vegas, Nevada.
six years and is now active as a private con- He enjoys dual citizenship in the United
sultant for several prominent animal health States and New Zealand. In addition,
companies and specialty organizations. Dr. Fox has authored more than 80 profes-
Dr. Fox received his MS (nutritional biochem- sional publications, five textbooks, seven
istry) and DVM degrees from the University textbook chapters, and two interactive CD/
of Illinois and both MBA (entrepreneurialism DVDs. He is a popular international speaker
and new ventures) and PhD (pain manage- on the subjects of pain management, musculo-
ment) degrees from Massey University in New skeletal diseases, and excellence in speaking.
Zealand. He completed his surgical residency Before beginning his career in veterinary
at the University of Florida and practiced in medicine, he graduated with a BS degree in
surgical referrals for 15 years. mechanical engineering from the U.S. Naval
He has served on the Veterinary Teaching Academy and flew more than 300 combat
Hospital faculty at Mississippi State missions as a naval aviator in Vietnam, flying
University, as product manager at Pioneer the A6 Intruder, while serving concurrently
Hi-Bred International, as senior lecturer as officer of the deck aboard the nuclear-
in companion animal orthopedic surgery powered aircraft carrier, USS Enterprise
at Massey University, as senior veterinary (CVN-65).

XII
 Contributors
James (Jimi) L. Cook, DVM, PhD, DACVS B. Duncan X. Lascelles, BSc, BVSc, PhD, FRCVS,
Director of the Comparative Orthopaedic CERTVA, DSAS(ST), DECVS, DACVS
Laboratory Professor of Translational Pain Research
William and Kathryn Allen Distinguished and Management
Professor in Orthopaedic Surgery College of Veterinary Medicine
School of Medicine North Carolina State University
University of Missouri Raleigh, NC
Columbia, MO
Bob Menardi, DVM
James Duncan, PhD Chief Veterinary Officer
Independent Consultant Exubrion Therapeutics
Kennewick, WA Buford, GA

William Muir, DVM, MS, PhD, DACVAA, DACVECC

Nicole Ehrhart, VMD, MS, DACVS Professor and Associate Dean
Professor of Surgical Oncology Basic Sciences and Research
College of Veterinary Medicine and Lincoln Memorial University
Biomedical Sciences Harrogate, TN
Ross M. Wilkins Limb Preservation
Chair in Musculoskeletal Biology and Sheilah A. Robertson, BVMS, PhD, DACVAA,
Oncology DECVAA , DACAW, DECAWBM (WSEL), CVA , MRCVS
Colorado State University Professor of Anesthesia, Pain Management
Fort Collins, CO and Animal Welfare
College of Veterinary Medicine
Steven M Fox, MS, DVM, MBA, PhD University of Florida
Surgical Specialist and
New Zealand VMA Senior Medical Director
and Lap of Love Veterinary Hospice
Independent Consultant Gainesville, FL
Albuquerque, NM
and William J. Tranquilli, DVM, MS, DACVA
Adjunct Professor Professor Emeritus
College of Veterinary Medicine University of Illinois
University of Illinois Urbana, IL
Urbana, IL

XIII
 Abbreviations
5-HT 5-hydroxytryptamine fMRI functional magnetic resonance
AA arachidonic acid imaging
ACE angiotensin-converting enzyme GABA gamma aminobutyric acid
ADE adverse drug event GAG glycosaminoglycan
ADP adenosine diphosphate GAIT Glucosamine/Chondroitin
ALA alpha-linolenic acid Arthritis Intervention Trial
ALT alanine aminotransferase GCMPS Glasgow Composite Measure of
AMA American Medical Association Pain Scale
AMP adenosine monophosphate GDNF glial-derived neurotrophic factor
AMPA alpha-amino-3-hydroxy- HA hyaluronic acid
5-methyl-4-isoxazole HCN hyperpolarization-activated
propionic-acid cyclic nucleotide-gated
ARS acute radiation score HIV human immunodeficiency virus
ASIC acid-sensing ion channel HRQoL health-related quality of life
ASU avocado/soybean unsaponifiables HVA high-voltage activated
ATL aspirin-triggered lipoxin IASP International Association for the
ATP adenosine triphosphate Study of Pain
BDNF brain-derived neurotrophic factor IBS irritable bowel syndrome
BUN blood urea nitrogen IC interstitial cystitis
cAMP cyclic adenosine monophosphate IKK IkB kinase
CCK cholecystokinin IL interleukin
CCL cranial cruciate ligament iNOS inducible NOS
CCLT cranial cruciate ligament KCS keratoconjunctivitis sicca
transection LOX lipoxygenase
CGRP calcitonin gene–related peptide LT leukotriene
CIPN chemotherapy-induced peripheral LVA low-voltage activated
neuropathy mAb monoclonal antibody
CMPS composite measure pain scale MFPS multifactorial pain scales
CNS central nervous system MMP matrix metalloproteinase
COX cyclooxygenase NAVNA North American Veterinary
CrCLD cranial cruciate ligament Nutraceutical Association
deficiency NE norepinephrine
CRI continuous rate infusion NF-κB nuclear factor kappa B
DHA docosahexaenoic acid NGF nerve growth factor
DJD degenerative joint disease NMDA N-methyl-D-aspartate
DMOAA disease-modifying osteoarthritic nNOS neuronal NOS
agent NNT number needed to treat
DMOAD disease-modifying osteoarthritic NO nitric oxide
drug NOS nitric oxide synthase
DRG dorsal root ganglion NPY neuropeptide Y
ELISA enzyme-linked immunosorbent NRS numeric rating scales
assay NSAID nonsteroidal anti-inflammatory
eNOS endothelial NOS drug
EPA eicosapentaenoic acid OA osteoarthritis
ERK extracellular signal-regulated OTM oral transmucosal
kinase P2X ionotropic purinoceptor
FDA Food and Drug Administration P2Y metabotropic purinoceptor

XIV
 Abbreviations XV

PDN painful diabetic neuropathy TGF transforming growth factor

PG prostaglandin TIMP tissue inhibitor of
PHN postherpetic neuralgia metalloproteinase
PNS peripheral nervous system TNF tumor necrosis factor
PSGAG polysulfated glycosaminoglycan TRP transient receptor potential
RSO radiosynoviorthesis TRPV transient receptor potential
SAMe S-adenosylmethionine vanilloid
SAP serum alkaline phosphatase TTX tetrodotoxin
SDS simple descriptive scales TX thromboxane
SERT serotonin transporter VAS visual analog scale
SNL spinal nerve ligation VDCC voltage-dependent calcium
sP substance P channel
SSRI selective serotonin reuptake VGSC voltage-gated sodium channel
inhibitor VR vanilloid receptor
TENS transcutaneous electrical nerve VRS verbal rating scale
stimulation WDR wide dynamic range
 Glossary
Ap fiber afferents: nociceptors can be acti- Aggrecan: a major proteoglycan of articular
vated by mechanical stress resulting from cartilage, consisting of the proteoglycan
direct pressure, tissue deformation, or monomer that aggregates with hyaluronan.
changes in osmolarity. Based upon sensory Aggrecanase: an enzyme that degrades
modality and electrical response, mamma- aggrecan.
lian mechanosensory neurons can be classi- Agonist (opioid): this binds to one or more
fied into four groups: receptor types and causes certain effects.
Agonist-antagonist (opioid): this simultane-
• Aa fibers are proprioceptors that detect ously binds to more than one type of recep-
muscle tension or joint position. tor, causing an effect at one receptor but no
• Ap fibers include touch receptors that are or a lesser effect at another receptor.
activated by low pressure. Allodynia: this is pain due to a stimulus
• AS and C fibers are nociceptors that that does not normally provoke pain. A
respond to strong mechanical, thermal, mechanism of touch-evoked pain1 places
electrical, or chemical stimulation. the emphasis of a mechanistic model on
presynaptic interactions between A and
Action potential: this is the means by which C fibers, with enhancement of the inflam-
information signals are transmitted in matory response resultant from release
nerves; abrupt pulselike changes in the of vasoactive peptides (sP and CGRP)
membrane potential. An action potential from the terminal endings of afferent AS
can be elicited in a nerve fiber by almost and C fibers by antidromic action poten-
any factor that suddenly increases the per- tials (neurogenic inflammation or axon
meability of the membrane to sodium ions, reflexes).
such as electrical stimulation, mechani- Analgesia: this is absence of pain sensation.
cal compression of the fiber, application Angiogenesis: the development of blood
of chemicals to the membrane, or almost vessels, e.g., the induction of blood ves-
any other event that disturbs the normal sel growth from surrounding tissue into
resting state of the membrane. a tumor by a diffusible chemical factor
Adenosine: an endogenous nucleotide released by the tumor cells.
that generally serves inhibitory func- Antagonist (opioid): it binds to one or more
tions and it acts as a depressant in the receptor types but causes no effect at
central nervous system (CNS). It can those receptors; by competitive displace-
be progressively phosphorylated to gener- ment, reverses the effect of an agonist.
ate the high-energy molecules of adenos- Apoptosis: a process including coagulative
ine monophosphate, diphosphate, and necrosis and shrinkage. Programmed cell
triphosphate (AMP, ADP, and ATP), and death as signaled by the nuclei in normally
from ATP, may be further modified to functioning human and animal cells when
generate the intracellular second-messen- age or state of cell health and condition
ger cyclic AMP (cAMP). dictates. Cells that die by apoptosis do not
Adjunct: this efers to a drug, agent, or ther- usually elicit the inflammatory responses
apy that is added to a ‘baseline’ protocol, that are associated with necrosis, though
e.g., addition of tramadol to a nonste- the reasons are not clear. Cancerous cells,
roidal anti-inflammatory drug (NSAID) however, are unable to experience the
protocol or acupuncture added to a drug normal cell transduction or apoptosis-
therapy. driven natural cell death process.
Afferent: an incoming or conducted toward Arachidonic acid pathway: a metabolic path-
the central nervous system (CNS). way giving rise to a variety of eicosanoids,

XVI
 Glossary XVII

including prostaglandins from cyclooxy- release. These channels thus provide a

genase (COX) and leukotrienes via lipoxy- major link between neuronal excitability
genase (LOX). and synaptic transmission.
Aspirin-triggered lipoxin (ATL): this is Calcitonin gene–related peptide: CGRP is
15-epi-LXA4. Under normal circum- found in a number of tissues, including
stances, prostaglandins (PGs) produced nervous tissue. It is a vasodilator that
by COX-1 and COX-2 contribute to many may participate in the cutaneous triple
aspects of mucosal defense. response. Co-localizes with substance P in
Aspirin suppresses PG synthesis via neurons. It occurs as a result of alternative
both COX-1 and COX-2, thereby impair- processing of messenger RNA (mRNA)
ing mucosal defense and leading to hem- from the calcitonin gene. The neuropep-
orrhagic erosion formation. Aspirin also tide is widely distributed in neural tissue
triggers generation of ATL, which par- of the brain, gut, perivascular nerves, and
tially counteracts the detrimental effects other tissue. The peptide produces mul-
of PG suppression. ATL is produced via tiple biological effects and has both cir-
COX-2 but not via COX-1. culatory and neurotransmitter actions. In
Inhibition of COX-2 activity by any particular, it is a potent endogenous vaso-
NSAID removes the formation of ATL dilator. Intracerebral administration leads
by aspirin. In the absence of the protec- to a rise in noradrenergic sympathetic
tive effects of ATL, the extent of gastric outflow, a rise in blood pressure, and a
damage is likely increased. Therefore, the fall in gastric secretion.
combined use of aspirin together with any Capsaicin: this is trans-8-methyl-n-vanillyl-
other NSAID may accentuate the gastric 6-nonenamide. Cytotoxic alkaloid from
damage of aspirin. various species of capsicum (pepper,
ASU: this is avocado/soybean unsaponifi- paprika), of the solanaceae; causes pain,
ables – a nutraceutical compound. irritation, and inflammation, due to sub-
Biomarkers: a specific biochemicals in the stance P depletion from sensory (affer-
body with a well-defined molecular fea- ent) nerve fibers; used mainly to study
ture that makes them useful for diagnos- the physiology of pain and in the form of
ing a disease, measuring the progress of capsicum as a counterirritant and gastro-
a disease, or determining the effects of a intestinal stimulant.
treatment. Cartesian model: it refers to Rene Descartes’
Blotting: a general term for the transfer of theory of the early 1600s; a fixed relation-
protein, RNA, or DNA molecules from ship between the magnitude of stimulus
a relatively thick acrylamide or agarose and subsequent sensation.
gel or to a paper-like membrane (usually Central sensitization: this denotes aug-
nylon or nitrocellulose) by capillarity or mentation of responsiveness of central
an electric field, preserving the spatial pain-signaling neurons to input from
arrangement. Once on the membrane, the low-threshold mechanoreceptors; plays a
molecules are immobilized, typically by major role in secondary hyperalgesia.
baking or by ultraviolet irradiation, and C-fos: a proto-oncogene that encodes
can then be detected at high sensitivity nuclear proteins that act as transcrip-
by hybridization (in the case of DNA and tional regulators of target genes. C-fos
RNA) or antibody labeling (in the case is considered an immediate-early gene
of protein). Northern blot is a technique (IEG), a class of genes that respond to a
to study gene expression by detection of variety of stimuli by rapid but transient
RNA (or isolated mRNA); Western blots expression. The nomenclature originates
detect specific proteins; Southern blots in virology, where viral genes are defined
detect specific DNA sequences. as ‘early’ or ‘late’, depending on whether
Calcium channels: it is activated by rela- their expression occurs before or after
tively strong membrane depolarization, replication of the viral genome. Further,
they permit calcium ion influx in response a set of viral genes is expressed rapidly
to action potentials. Consequential sec- or ‘immediately’ after infection of a cell,
ondary actions include neurotransmitter even in the presence of protein synthesis
XVIII Glossary

inhibitors. Thus, the term ‘viral immedi- afferent fibers into the spinal dorsal horn:
ate-early gene’ (e.g., v-fos) was adopted may become a source for ectopic or spon-
and modified to ‘cellular immediate-early taneous electrical signal generation fol-
gene’ (e.g., c-fos) for cellular genes that are lowing axonal injury.
rapidly induced in the presence of protein Dysesthesia: a spontaneous pain.
synthesis inhibition. C-fos is activated in Eburnation: a late stage of osteoarthritis
the brain and spinal cord under various (OA), where all cartilage is eroded and
conditions, including seizures and nox- the exposed subchondral bone takes on a
ious stimulation, and C-fos expression ‘polished ivory’ appearance.
may be a marker for neuroaxis excitation. Ectopic discharge: this can arise from the
Chondrocyte: the only cellular element of dorsal root ganglion (DRG) following
articular cartilage. peripheral axotomy. A direct relationship
Chondroprotectant: an agent that ‘spares’ exists between ectopic afferent firing and
cartilage degradation. allodynia in neuropathic pain.
Chronic pain: this results from sustained Efferent: an outgoing; conducted away from
noxious stimuli such as ongoing inflam- the central nervous system (CNS).
mation or may be independent of the incit- Eicosanoid: it is the generic term for com-
ing cause. It extends beyond the period of pounds derived from arachidonic acid.
tissue healing and/or with low levels of Includes leukotrienes, prostacyclin, pros-
identified pathology that are insufficient taglandins, and thromboxanes. Eico-
to explain the presence and/or extent of sanoid activity is tissue dependent.
pain. It is maladaptive and offers no use- Eicosapentaenoic acid (EPA): a precursor
ful biological function or survival advan- for the synthesis of eicosanoids, derived
tage. Accordingly, chronic pain may be from alpha-linolenic acid and/or doco-
considered a disease per se. sahexaenoic acid. Eicosanoids produced
Convergence: where somatic and visceral from EPA appear to be less inflammatory
afferents come together on the same dorsal than those formed from the more com-
horn neuron within the spinal cord; as a mon precursor, arachidonic acid.
result, ‘referred’ pain is sensed in each soma ELISA: the enzyme-linked immunosorbent
although the stimulus is from the viscera. assay is a serological test used as a general
Coxib-class NSAIDs: a nonsteroidal anti- screening tool for the detection of anti-
inflammatory drug designed to suppress bodies. Reported as positive or negative.
cyclooxygenase-2–mediated eicosanoids Since false-positive tests do occur (for
only and spare cyclooxygenase-1–mediated example, a recent flu shot), positives may
eicosanoids. require further evaluation using the West-
Cytokines: a heterogeneous group of poly- ern blot. ELISA technology links a mea-
peptides that activate the immune system surable enzyme to either an antigen or an
and mediate inflammatory responses, act- antibody. In this way, it can then measure
ing on a variety of tissues, including the the presence of an antibody or an antigen
peripheral nervous system (PNS) and cen- in the bloodstream.
tral nervous system (CNS). Enantiomer: a pair of chiral isomers (stereo-
Cytokines act at hormonal concentra- isomers) that are direct, nonsuperimpos-
tions, but in contrast to circulating endo- able mirror images of each other.
crine hormones, they exert their effects Endbulb: a terminal swelling at the proxi-
on nearby cells over short extracellular mal stump when an axon is severed.
distances at low concentrations, and thus, Enthesophytes: a bony proliferation found
serum levels may not reliably reflect local at the insertion of ligaments, tendons, and
activation. Models of painful nerve injury joint capsule to bone.
reveal changes in cytokine expression in Ephaptic cross-talk: these are the excitatory
the injured nerve itself, in the dorsal root interactions among neighboring neurons,
ganglion (DRG), in the spinal cord dorsal amplifying sensory signals and causing
horn, and in the CNS. sensation spread.
Dorsal root ganglion (DRG): a collection Epitope: that part of an antigenic molecule
of neuronal cell bodies that send their to which the T-cell receptor responds; a
 Glossary XIX

site on a large molecule against which an Glycosaminoglycans (GAGs): these are

antibody will be produced and to which hydrophilic ‘bristles’ attached to the hyal-
it will bind. uronan backbone, thereby forming the
Evidence-based: the conscientious, explicit, ‘bottle brush’ appearance of the cartilage
and judicious use of current best evidence aggrecan.
in making decisions. Glutamate: the predominant neurotransmit-
Excitability: this refers to the translation of ter used by all primary afferent fibers.
the generator potential into an impulse Hyperalgesia: an increased response to a
train, where sodium and potassium chan- stimulus that is normally painful.
nels play a major role. If excitability is IC50: the concentration of drug needed to
suppressed, the cell loses its ability to inhibit the activity of an enzyme by 50%.
respond to all stimuli. (IC80 is sometimes referenced.)
Excitation: this refers to the transduction Idiosyncratic: cause/etiology is unknown.
process, the ability of a stimulus to depo- Incisional pain (postoperative): a specific
larize a sensory neuron, creating a genera- form of acute pain, routinely lasting 2
tor potential. (mechanical stimulus) to 7 (heat stimulus)
Fibrillation: it is seen in the early stages of days.
osteoarthritis (OA), where the superficial Kinematic gait analysis (motion analy-
layer of the hyaline cartilage begins ‘flak- sis): it measures changes in joint angles
ing’ and is lost. with gait, the velocity and acceleration of
Force plate platform: a device for objective changes in joint angles, stride length, and
measurement of ground reaction forces; gait swing and stance times. Often used
frequently used to compare efficacy of dif- in conjunction with force platform gait
ferent treatment protocols. analysis, providing a powerful method of
GABA: the most abundant inhibitory neu- detecting musculoskeletal abnormalities
rotransmitter in the central nervous sys- and response to therapy.
tem (CNS) and plays a role in the control Ligand: any molecule that binds to another;
of the pathways that transmit sensory in normal usage, a soluble molecule such
events, including nociception. GABAergic as a hormone or neurotransmitter that
interneurons can be found in nearly all binds to a receptor. The decision as to
layers of the spinal cord, with the high- which is the ligand and which the receptor
est concentrations in laminae I–III. A is often a little arbitrary when the broader
decrease in GABAergic tone in the spinal sense of receptor is used (where there is
cord may underlie the state of allodynia. no implication of transduction of signal).
Gate theory: this was proposed by Melzack In these cases, it is probably a good rule
and Wall in 1965, suggesting that the cen- to consider the ligand to be the smaller of
tral nervous system (CNS) controls noci- the two.
ception: activity in large (non-nociceptive) Matrix metalloproteinase (MMP): a family
fibers can inhibit the perception of activ- of enzymes involved in the degradation of
ity in small (nociceptive) fibers and that cartilage matrix.
descending activity from the brain also Membrane remodeling: an inappropriate
can inhibit that perception, i.e., encod- distribution of membrane proteins such
ing of high-intensity afferent input to the as ion channels, transducer molecules,
CNS was subject to modulation. and receptors synthesized in the cell soma
Glasgow Pain Scale: a multidimensional and transported into the cell membrane of
scheme for assessing pain. It takes into endbulbs and sprouts by vesicle exocytosis
account the sensory and affective qualities following injury to afferent neurons. This
of pain in addition to its intensity. leads to altered axonal excitability.
Glial cells: these are astrocytes, oligodendro- Meta-analysis: a quantitative method of
cytes, and microglia. Microglia are resident combining the results of independent stud-
tissue macrophages of the central nervous ies (usually drawn from the published lit-
system (CNS) and, when activated, can erature) and synthesizing summaries and
release chemical mediators that can act on conclusions that may be used to evaluate
neurons to alter their function. therapeutic effectiveness or to plan new
XX Glossary

studies, with application chiefly in the injury states such as neuropathy may pro-
areas of research and medicine. It is often duce a prolonged activation of the NMDA
an overview of clinical trials. It is usually receptor subsequent to a sustained affer-
called a meta-analysis by the author or ent input that causes a relatively small but
sponsoring body and should be differenti- continuous increase in the levels of gluta-
ated from reviews of the literature. mate and enhances the evoked release of
Modulation: an alteration of ascending sig- the amino acid. NMDA receptors are not
nals initially in the dorsal horn and con- functional unless there has been a persis-
tinuing throughout the central nervous tent or large-scale release of glutamate.
system (CNS). Ketamine, memantine, and amantadine
Multimodal analgesia: the administration are common NMDA antagonists.
of a combination of different drugs from Nitric oxide synthase (NOS): it synthesizes
different pharmacological classes, as well nitric oxide (NO) from L-arginine; three
as different delivery forms and techniques. isoforms are known to exist: endothelial
Nerve fiber: it refers to the combination of NOS (eNOS), neuronal NOS (nNOS), and
the axon and Schwann cell as a functional inducible NOS (iNOS).
unit. Nociception: the physiological activity of
Neurogenic inflammation: these are driven transduction, transmission, and modula-
by events in the central nervous system tion of noxious stimuli; may or may not
(CNS) and not dependent on granulocytes include perception, depending on the con-
or lymphocytes as the classic inflam- scious state of the animal, i.e., the result
matory response to tissue trauma or of nociception in the conscious animal is
immune-mediated cell damage. Dendrite pain.
release of inflammatory mediators causes Nociceptive pain (physiological pain): an
action potentials to fire backward down everyday acute pain, purposeful, short-
nociceptors, potentiating transmission of acting, and relatively easy to treat.
nociceptive signals from the periphery. Nuclear factor kappa B (NF-κB): a transcrip-
Neuroma: it is formed by failed efforts of tion factor that regulates gene expression
injured peripheral nerve sprouts to re- of many cellular mediators influencing the
establish normal functional contact, immune and inflammatory response.
which can become ectopic generators of Number needed to treat (NNT): an estimate
neural activity. of the number of patients that would need
Neuropathic pain: it arises from injury to to be given a treatment for one of them
or sensitization of the peripheral nervous to achieve a desired outcome, e.g., the
system (PNS) or central nervous system number of patients that must be treated,
(CNS). after correction for placebo responders,
Neurotransmitter: any of a group of endoge- to obtain one patient with at least 50%
nous substances that are released on excita- pain relief. In a similar manner, number
tion from the axon terminal of a presynaptic needed to harm (NNH) is a calculation of
neuron of the central nervous system (CNS) adverse effects.
or peripheral nervous system (PNS) and Nutraceutical: a nondrug food additive that
travel across the synaptic cleft to either is given orally to benefit the well-being of
excite or inhibit the target cell. Among the the recipient.
many substances that have the properties OP1: opioid delta receptor.
of a neurotransmitter are acetylcholine, OP2: opioid kappa receptor.
norepinephrine, glutamate, epinephrine, OP3: opioid mu receptor.
dopamine, glycine, gamma-aminobutyrate, Osteoarthritis (OA): it is a degenerative joint
glutamic acid, substance P, enkephalins, disease (DJD) disorder of the total mov-
endorphins, and serotonin. able joints characterized by deterioration
NMDA (N-methyl-D-aspartate) receptor: it of articular cartilage; osteophyte forma-
has been implicated in the phenomenon tion and bone remodeling; pathology of
of windup and in related changes such as periarticular tissues, including synovium,
spinal hyperexcitability that enhance and subchondral bone, muscle, tendon, and
prolong sensory transmission. Persistent ligament; and a low-grade, nonpurulent
 Glossary XXI

inflammation of variable degree. Pain is Physical rehabilitation: these are the activi-
the hallmark clinical sign. ties involved in the goal to restore, main-
Osteophytes: a central core of bone fre- tain, and promote optimal function,
quently found at the junction of the optimal fitness, wellness, and quality of
synovium, perichondrium, and periosteum life as they relate to movement disorders
of arthritic joints. and health.
P2X: an ionotropic receptor for adenosine Plasticity: this refers to neuronal information
triphosphate (ATP). processing, which can change in a manner
Paresthesias: dysesthesia and hyperpathia dependent on levels of neuronal excitabil-
refer to odd, unnatural sensations like ity and synaptic strength, diversifying for
‘pins-and needles’, sudden jabs, or electric short periods (seconds) or prolonged peri-
shock–like sensations. These occur when ods (days), or perhaps indefinitely.
nerves are partially blocked (e.g., ‘my Preemptive analgesia: a presurgical block-
leg went to sleep’) or when there is nerve ade of nociception intended to prevent or
damage. lessen postsurgical pain or pain hyper-
Partial agonist (opioid): it binds at a given sensitivity. The best clinical application is
receptor causing an effect less pronounced actually ‘perioperative’, where analgesia is
than that of a pure agonist. administered long enough to last through-
Pathological pain (inflammatory pain, neu- out surgery and even into the postopera-
ropathic pain): it implies tissue damage, tive period.
nontransient, and may be associated with Primary hyperalgesia: a hyperalgesia at the
significant tissue inflammation and nerve site of injury, while hyperalgesia in the
injury. uninjured skin surrounding the injury is
Perception: it is the receipt and cognitive termed secondary hyperalgesia.
appreciation of signals arriving at higher Q-conotoxin: these are found in the
central nervous system (CNS) structures, venom of predatory marine snails that
thereby allowing the interpretation as blocks depolarization-induced calcium
pain. influx through voltage-sensitive calcium
Phenotype: the total characteristics dis- channels.
played by an organism under a particular Qi: a tenet of traditional Chinese medicine
set of environmental factors, regardless holding that qi is a fundamental and vital
of the actual genotype of the organism. substance of the universe, with all phenom-
Results from interaction between the gen- ena being produced by its changes. Tradi-
otype and the environment. tional Chinese medicine suggests that a
Peripheral nervous system (PNS): these are balanced flow of qi throughout the system is
the cranial nerves, spinal nerves with their required for good health, and acupuncture
roots and rami, peripheral components stimulation can correct imbalances.
of the autonomic nervous system, and Referred pain: a pain sensation felt at an
peripheral nerves whose primary sensory anatomical location different from its ori-
neurons are located in the associated dor- gin; most often associated with visceral
sal root ganglion. pain where the central nervous system
Postherpetic neuralgia (PHN): PHN is com- (CNS) is sensing a somatic input rather
monly used as a model for neuropathic than visceral nociception.
pain. PHN is a consequence of herpes Reversal of GABA/Glycinergic inhibition: a
zoster, where pain will continue long after microglial activity occurring only follow-
the rash has resolved, causing a great deal ing neuropathic injury but not peripheral
of suffering and disability. Herpes zoster inflammation, where reversing the direc-
results from activation of the varicella- tion of anionic flux in lamina I neurons
zoster virus, which has remained latent reverses the effect of GABA and glycine,
in the dorsal root ganglion since the first changing inhibition to excitation.
infection (usually chickenpox). The vari- Schwann cell: this plays a major role in
cella-zoster virus has a very narrow host nerve regeneration and axonal mainte-
range, and natural infection occurs only nance. Some cells produce myelin, a lipid-
in humans and other primates. rich insulating covering.
XXII Glossary

Secondary hyperalgesia: a hyperalgesia in myelinated axons that normally do not

the uninjured skin surrounding the injury, make sP, but become capable of manufac-
including two different components: (1) turing sP after a prolonged inflammatory
a change in the modality of the sensa- stimulus.
tion evoked by low-threshold mechano- Synergism: a response greater than the addi-
receptors, from touch to pain, and (2) an tive response, e.g., the effect of opioids
increase in the magnitude of the pain sen- combined with α 2-adrenoceptor agonists
sations evoked by mechanically sensitive is greater than the additive effect of each
nociceptors. class of drug individually.
Sensitization: a leftward shift of the stimu- Synovial fluid: a dialysate of plasma con-
lus-response function that relates magni- taining electrolytes and small molecules
tude of the neural response to stimulus in similar proportions as in plasma.
intensity. Synovial intima: a lining of the joint cap-
Silent afferents (sleeping nociceptors, mechan- sule, containing synoviocytes A and B.
ically insensitive nociceptors): these affer- Synovitis: an inflammation of the synovial
ents are ubiquitous and have been found intima.
in skin, joint, and viscera in rat, cat, and Tetrodotoxin (TTX): a toxin derived from
monkey2; 20%–40% of C fibers in skin, puffer fish, sensitivity to which is useful
30%–40% in muscle, 50%–75% in joints, for classifying sodium currents (sensitive
and possibly more than 90% of C fibers or resistant).
in the colon and bladder fail to respond to Tidemark: the upper limit of the calcified car-
acute noxious stimuli. In joints that have tilage layer (zone 4) of articular cartilage.
been artificially inflated, these previously Transcutaneous electrical nerve stimulation
silent afferents develop an ongoing dis- (TENS): a method of producing electro-
charge and fire vigorously during ordinary analgesia through current applied to elec-
movement. trodes placed in the skin.
Sodium channels: these are voltage-depen- Transduction: a conversion of energy from
dent sodium channels produce the inward a noxious stimulus into nerve impulses by
transmembrane current that depolarizes sensory receptors.
the cell membrane, and thus are critically Transmission: it is the transference of neu-
important contributors to action potential ral signals from the site of transduction
electrogenesis. Compelling evidence indi- (periphery) to the central nervous system
cates that sodium channels participate (CNS).
substantially in the hyperexcitability of Transmucosal (transbuccal): it is not to
sensory neurons that contributes to neu- be confused with oral administration,
ropathic pain. refers to placement of a drug for absorp-
Subchondral bone: a thin layer of bone that tion across the mucous membranes (as by
joins hyaline cartilage with cancellous placement in the guttural pouch). This
bone supporting the bony plate. Compli- route of absorption avoids hepatic first-
ance of subchondral bone to applied joint pass elimination because venous drainage
forces allows congruity of joint surfaces is systemic.
for increasing the contact area of load dis- TRPV (vanilloid or capsaicin) receptor: a
tribution, i.e., a shock absorber, thereby detector of noxious heat.
reducing peak loading and potentially Viscosupplementation: an intra-articular
damaging effects on cartilage. injection of a chondroprotectant intended
Substance P (sP): a vasoactive peptide found to increase the viscoelastic properties of
in the brain, spinal ganglia, and intestine the synovial fluid.
of vertebrates. Induces vasodilatation and Voltage-gated sodium and calcium chan-
salivation and increases capillary perme- nel: VGSCs are complex, transmembrane
ability. A tachykinin, released only after proteins that have a role in governing elec-
intense, constant peripheral stimuli. sP, trical activity in excitable tissues. The chan-
acting at NK1 receptors, plays an impor- nel is activated in response to depolarization
tant role in nociception and emesis. of the cell membrane that causes a voltage-
‘Phylogenetic switch’ is a term given to dependent conformational change in the
 Glossary XXIII

channel from a resting, closed conformation Windup: a form of activity-dependent

to an active conformation, which increases plasticity characterized by a progres-
membrane permeability. Gabapentin is sive increase in action potential output
thought to work via a voltage-dependent from dorsal horn neurons elicited dur-
calcium channel (VDCC). ing the course of a train of repeated low-
Wallerian degeneration: a form of degenera- frequency C fiber or nociceptor stimuli.
tion occurring in nerve fibers as a result of Resultant cumulative depolarization is
their division; so-called from Dr. Waller, boosted by recruitment of NMDA recep-
who published an account of it in 1850. tor current through inhibition of magne-
Washout: this refers to the time interval sium channel suppression.
between different nonsteroidal anti-inflam-
matory drug (NSAID) administrations pre-
sumed to reduce the risk for contributing
to adverse drug reactions. Empirically, rec-
ommendations range from 1 to 7 days in REFERENCES
healthy dogs.
WHO cancer pain ladder: the World Health 1. Cervero F, Laird JM. Mechanism of touch-evoked
pain (allodynia): a new model. Pain 1996;68:13–23.
Organization’s analgesic ladder provides 2. McMahon S, Koltzenburg M. The changing
clinical guidance from a severity-based role of primary afferent neurons in pain. Pain
pain classification system. 1990;43:269–272.
SECTION

1
 CHAPTER

1
Physiology of Pain
IN PERSPECTIVE Understanding the
Pain management has become one of the
Physiology of Pain
more inspiring contemporary issues in vet- Nociception is the transduction, conduc-
erinary medicine. It is an area of progressive tion, and central nervous system (CNS)
research, revealing new understandings on processing of signals generated by a nox-
an almost daily basis. Accordingly, ‘current’ ious insult. The conscious, cognitive pro-
insights into pain management is a relative cessing of nociception results in pain, i.e.,
term. In some respects, the management of pain infers consciousness. It is reason-
pain, especially in companion animal prac- able to assume that a stimulus considered
tice, is more thorough than in human medi- painful to a human, that is damaging or
cine. And although it is amusing to recognize potentially damaging to tissues and evokes
that most pain in humans is managed based escape and behavioral responses, would
on rodent data, considerable direction for also be painful to an animal because ana-
managing pain in animals is based on the tomical structures and neurophysiological
human pain experience. This is because processes leading to the perception of pain
many physiological systems are similar are similar across species.
across species, and large population studies The pain pathway suggests reference
often conducted in human medicine require to the simplistic nociceptive pathway of a
resources prohibitive in veterinary medicine. three-neuron chain, with the first-order neu-
Thus, evidence-based veterinary pain man- ron originating in the periphery and pro-
agement will likely always be under some jecting to the spinal cord, the second-order
degree of scrutiny. Since our maturation of neuron ascending the spinal cord, and the
understanding the complex mechanisms of third-order neuron projecting into the cere-
pain comes from studies in different species bral cortex and other supraspinal structures
with many physiological processes in com- (Figure 1.1).
mon, it is fitting to consider the study of pain ‘For every complex issue, there is an
as ‘one science’. answer that is simple, neat … and wrong!’
The frontier of discovery for treating There are no ‘pain fibers’ in nerves and no
pain is founded upon an understanding of ‘pain pathways’ in the brain. Pain is not a
physiology and neurobiology. Physiological stimulus. The experience of pain is the final
mechanisms underpin the evidence support- product of a complex information-process-
ing treatment protocols and provide insights ing network.
for new drug development. An overview of
pain physiology is intellectually intriguing,
but extensive. Therefore, the following syn-
opsis is presented to gain an appreciation of AFFERENT RECEPTORS
the complex mechanisms underlying chronic
pain and to encourage lateral thinking Peripheral sensory receptors are special-
about treatment modalities. Paraphrasing ized terminations of afferent nerve fibers
Albert Einstein, ‘Some things can be made exposed to the tissue environment, even
simple, but only so much so before they lose when the fiber is myelinated more cen-
meaning’. trally. Such receptors are plentiful in the

DOI: 10.1201/9781003376422-2 3
4 Chronic Pain in Small Animal Medicine

FIGURE 1.1 The pain pathway infers a three-

neuron chain. The first-order neuron originates
in the periphery and projects to the spinal cord.
The second-order neuron ascends the spinal
cord, and the third-order neuron projects into
the cerebral cortex and other supraspinal struc-
tures. (Adapted from Tranquilli WJ, et al. Pain
Management for the Small Animal Practitioner.
Teton NewMedia 2004, 2nd edition. With
FIGURE 1.2 Afferent receptors are widely dis-
permission.)
persed and serve different functions, allowing the
animal to sense its environment. (Adapted from
epidermis/dermis and display differenti- Tranquilli WJ, et al. Pain Management for the
ated functions (Figure 1.2): Small Animal Practitioner. Teton NewMedia 2004,
2nd edition. With permission.)
• Low-threshold mechanoreceptors: Aα and
Aβ in humans; Aα, Aβ, Aδ, and C in animals endings are also in close proximity to mast
• Displacement: Ruffini endings stretch; hair cells and small blood vessels. Contents of rup-
follicle with palisade endings of 10–15 dif- tured cells or plasma contents, together with
ferent nerve fibers each neurotransmitters released from activated
• Velocity: Meissner corpuscle nerve terminals, create a milieu of proteins,
• Vibration: Pacinian corpuscle, fluid envi- allowing the free nerve endings, capillaries,
ronment with onion-like lamellae acting as and mast cells to act together as an evil tri-
high-pass filter umvirate to increase pain (Figure 1.3).
• Thermal receptors: Although there are no pain fibers or
• Cold: discriminates 0.5°C, 100 μm pain pathways, there are anatomically and
diameter field, Aδ physiologically specialized peripheral sen-
• Warm: mostly C fibers sory neurons – nociceptors – which respond
• Nociceptors: to noxious stimuli but not to weak stimuli
• Myelinated: Aδ, most conduct in 5–25 (Table 1.1). These are mostly thinly myelin-
m/s range, 50–180 μm field, 10–250 ated Aδ and unmyelinated C afferents, and
receptors/mm 2 they end as free, unencapsulated peripheral
• C polymodal nociceptors, pain nerve endings in most tissues of the body,
including skin, deep somatic tissues like
As terminations of afferent nerve fibers, muscles and joints, and viscera. (The brain
peripheral sensory receptors allow the recep- itself is not served by these sensory fibers,
tor to transduce or translate specific kinds of which is why cutting brain tissue does not
energy into action potentials. Most periph- hurt.) Thickly myelinated Aβ afferents typi-
eral receptors act either by direct coupling of cally respond to light tactile stimuli. They
physical energy to cause changes in ion chan- also respond to noxious stimuli, but they do
nel permeability or by activation of second not increase their response when the stimulus
messenger cascades. Chemoreceptors detect changes from moderate to strong, i.e., they
products of tissue damage or inflammation do not encode stimuli in the noxious range.
that initiate receptor excitation. Free nerve Although Aβ afferents do respond to painful
 Chapter 1 Physiology of Pain 5

FIGURE 1.3 A milieu of inflammatory mediators results in receptor excitation that transduces or trans-
lates specific forms of energy into action potentials. Such action potentials become the nociceptive
messengers for pain.

TABLE 1.1 Nociceptors and fiber types

Nociceptors Fiber type and response
Aδ • Small-myelinated fibers
• Slowest conducting are nociceptors
AMH type I • Respond to mechanical stimuli
(A mechano-heat) • Have heat threshold of 53°C, but sensitize rapidly to heat
• Most common
AMH type II • Respond to mechanical stimuli
• Threshold 47°C, also respond to noxious cold
AM • Respond only to noxious mechanical stimulation
CMH • Most common C (polymodal nociceptor)
• Responds to mechanical stimuli
• Thermal threshold 45°–49°C
• Noxious cold ≤4°C
CH • Responds to heat only
• Thermal threshold 45°–49°C
CMC • Like CMH, responds to noxious cold instead of heat
CC • Responds to noxious cold only
Silent nociceptors • Do not fire in absence of tissue injury
6 Chronic Pain in Small Animal Medicine

ingredient in chili peppers. The principal

action of capsaicin and other vanilloids on
the sensory neuron membrane is to pro-
duce a nonselective increase in cation (+)
permeability, associated with the opening
of a distinct type of cation channel. The
inward current responsible for depolariza-
tion and excitation of the neurons is carried
mainly by sodium ions, but the channel is
also permeable to divalent cations, includ-
ing calcium. The vanilloid receptor VR1
(also called TRPV1) shows a remarkable
characteristic of heat sensitivity (and also
acidic pH), with robust channel opening in
response to increases in ambient tempera-
ture. The physiological effects of capsaicin
are numerous:

• Immediate pain.
• Various autonomic effects caused by periph-
FIGURE 1.4 Receptor activation may allow ion eral release of substance P (sP) and calcito-
influx or trigger a second messenger pathway nin gene–related peptide (CGRP), inducing
that initiates an action potential. profound vasodilatation, while release of
sP promotes vascular leakage and protein
stimuli, electrical stimulation, even at high extravasation; components of the neuro-
frequency, normally produces a sensation genic inflammatory response: rubor (red-
not of pain, but of nonpainful pressure. ness), calor (heat), and tumor (swelling).
Convergence of large- and small-diameter • An antinociceptive effect of varying dura-
afferents of various sorts at the level of the tion, associated with the desensitization
dorsal horn, with further processing in the effect of capsaicin on the peripheral termi-
brain, gives rise to a variety of everyday nals of C fibers. The cellular mechanisms
sensations. underlying the neurodegenerative conse-
A change in temperature or an agonist quences of capsaicin likely involve both
binding to a membrane may cause a confor- necrotic and apoptotic cell death.
mational change in the shape of a receptor • A fall in body temperature: a reflex response
protein, allowing influx of ions or trigger- generated by thermosensitive neurons in the
ing second messenger pathways (Figure 1.4). hypothalamus following capsaicin activa-
When transient receptor potential (TRP) tion of primary afferent fibers.
(vanilloid or capsaicin) receptors are acti-
vated, they directly allow calcium ion cell Capsaicin acts on nonmyelinated periph-
influx, which can be sufficient to initiate eral afferent fibers to deplete sP and other
neurotransmitter release. transmitter peptides; the net effect is first to
Primary afferents will fire action poten- stimulate and then to destroy C fibers.1
tials at different adaptive rates. For example, A number of receptor systems reportedly
touch receptors or vibration detectors and play a role in the peripheral modulation of
hair follicle afferents fire at the beginning nociceptor responsiveness. The vanilloid
and sometimes at the end of a maintained receptor TRPV1 is present on a subpopula-
stimulus. They respond to the change (delta) tion of primary afferent fibers and is activated
of a stimulus. In contrast, nociceptors never by capsaicin, heat, and protons. Following
fully adapt and stop firing in the presence of inflammation, axonal transport of TRPV1
a stimulus. They are difficult to turn off once messenger RNA (mRNA) is induced, with
they are activated. the proportion of TRPV1-labeled unmyelin-
The term vanilloid refers to a group of ated axons in the periphery being increased
substances related structurally and phar- by almost 100%. 2 The inflammatory medi-
macologically to capsaicin, the pungent ator bradykinin lowers the threshold of
 Chapter 1 Physiology of Pain 7

nociceptors. sP and CGRP are peptide trans-

mitters of nociceptors. Ion channels exist
along the length of the primary afferent 1
fibers and functional receptors, while mech-
anisms to release at least some neurotrans-
mitters also prevail along the length of the
axon. Several neurotransmitters can exist in
a single neuron.
Depolarization induces the release of neu-
rotransmitters (Figure 1.6), and excesses of
released neurotransmitters (e.g., glutamate)
are recycled by the presynaptic terminal.
FIGURE 1.5 Neurotransmitters and modulators Further, it has been shown that calcium flow
are transported from the DRG both centrally and
through transient receptor potential vanilloid
peripherally.
(TRPV) receptors along the course of the axon
is sufficient to cause release of neurotransmit-
TRPV1-mediated heat-induced currents in ters, independent of axon depolarization.5
dorsal root ganglion (DRG) neurons and This implies that inflammatory mediators,
increases the proportion of DRG cells that heat, or changes in pH can cause release of
respond to capsaicin.3 potentially pain-producing substances along
In addition, there is a synergism between the entire length of a nerve. However, the
an acid pH and the capsaicin (VR1) recep- patient will sense the pain emanating from the
tor, such that transmembrane current is sig- peripheral terminations. It is also noted that
nificantly increased from the inflammatory the release of some neurotransmitters cannot
environment.4 To date, strong evidence exists be evoked by individual inflammatory media-
showing that nociceptor firing and human tors, such as prostaglandin (PG) E2; however,
perception of pain are correlated (the animal together with bradykinin, PGE2 can enhance
corollary is not yet validated). neurotransmitter release.
Cell bodies manufacture neurotransmit- Neurotransmitters are noted as such only
ters and modulators of all kinds, as well if they have a receptor for binding. Other
as receptors and ion channels. These are criteria include (1) synthesis in the neuron
transported from the DRG both centrally DRG, (2) seen in the presynaptic terminal
and peripherally (Figure 1.5). Glutamate (central or peripheral) and released in suffi-
is the major excitatory neurotransmitter of cient quantities to exert a defined action on

FIGURE 1.6 At the synapse, there is a chemical transmission of the nerve impulse.
8 Chronic Pain in Small Animal Medicine

FIGURE 1.7 Many different types of receptors may reside on primary afferent terminals. (Adapted from
Woolf CJ, Costigan M. Transcriptional and posttranslational plasticity and the generation of inflamma-
tory pain. Proc Natl Acad Sci 1999; 96: 7723–7730.)

the postsynaptic neuron or tissue, (3) exog- enhance pain and hypersensitivity through
enous administration mimics endogenously the response of the capsaicin/vanilloid recep-
released neurotransmitter, (4) a mechanism tor (TRPV1). sP and CGRP can be released
exists for its removal, and (5) it is released by from the peripheral terminals of activated C
neuronal depolarization in a Ca++-dependent fibers and contribute to neurogenic inflam-
fashion. Many different neurotransmitters mation by causing vasodilation. Affected tis-
exist, most notably glutamate, sP, and CGRP. sues are subsequently in a state of peripheral
Glutamate is the most prevalent neurotrans- sensitization. sP is an 11–amino acid peptide
mitter in the CNS and is synthesized not only neurotransmitter, often co-occurring with
in the cell body but also in the terminals. CGRP, which, when released in the spinal
Several receptors reside on primary affer- dorsal horn, activates second-order transmis-
ent terminals, which regulate terminal excit- sion neurons that send a nociceptive (‘pain’)
ability: serotonin, somatostatin, interleukin, signal to the brain.
tyrosine kinase, ionotropic glutamate, etc.
(Figure 1.7).
PLASTICITY ENCODING
Mediators of Pain René Descartes (1596–1650) proposed that
PGs are not the only chemical mediators ‘pain’ was transmitted from the periphery
of inflammation and hypersensitivity. The to a higher center through tubes of transfer
acidity and heat of injured, inflamed tissue (Figure 1.8). From the concept of Descartes
 Chapter 1 Physiology of Pain 9

quantitative phenomenon, is designed to

alert us to physical injury. Studying World
War II injuries, Henry Beecher observed that 1
some soldiers with horrendous injuries often
felt no pain, while soldiers with minor inju-
ries sometimes had severe pain. Beecher con-
cluded that Descartes’ theory was all wrong:
there is no linear relationship between injury
and the perception of pain.
It is now appreciated that there exists a
plasticity of pain encoding. A diminished
FIGURE 1.8 In the seventeenth century, René response (as with the analgesic morphine)
Descartes proposed that pain was transmitted to a given noxious stimulus can give rise to
through tubes of transfer. hypoalgesia/analgesia. On the other hand,
local injury can shift the stimulus-response
came the Cartesian model: a fixed relation- curve to the left, giving rise to the same pain
ship between the magnitude of stimulus and report with a lower stimulus: hyperalgesia.
subsequent sensation (Figure 1.9). If the curve is shifted such that a non-nox-
The Cartesian model has evolved over the ious stimulus becomes noxious, the state is
centuries through the contributions of many, referred to as allodynia (Figure 1.10).
including C.S. Sherrington (1852–1952), who Hyperalgesia to both heat and mechanical
coined the term ‘nociception’, stating that a stimulus that occurs at the site of an injury is
nociceptive stimulus will evoke a constella- due to sensitization of primary afferent noci-
tion of responses that define the pain state. ceptors.6,7 Mechanisms of the phenomenon
Nociception, per se, separates the detection have been studied in various tissues, includ-
of the event (noxious stimulus) from the pro- ing the joint, cornea, testicle, gastrointestinal
duction of a psychological or other type of tract, and bladder. Hyperalgesia at the site
response (pain). In a simple example, injury of injury is termed primary hyperalgesia,
in the legs of a paraplegic produces nocicep- while hyperalgesia in the uninjured tissue
tion from impulses in nociceptors, exactly surrounding the injury is termed secondary
as in a normal subject, but there is no pain hyperalgesia.
perceived. A common clinical example is
routine surgery, where neurobiological data
confirms nociception (response to the nox- GATE THEORY
ious stimulus), but pain is not experienced
while the patient is at an appropriate stage of The existence of a specific pain modulatory
anesthesia, i.e., there is no cognitive process- system was first clearly articulated in 1965
ing of the nociception. by Melzack and Wall8 in the gate control
The classic Cartesian view of pain theory of pain. This was the first theory to
stemmed from René Descartes’ ‘bell ringer’ propose that the CNS controls nociception.
model of pain in which pain, as a purely The basic premises of the gate control theory
of pain are that activity in large (non-noci-
ceptive) fibers can inhibit the perception of
activity in small (nociceptive) fibers and that
descending activity from the brain also can
inhibit that perception, i.e., interneurons
of the substantia gelatinosa regulate the
input of large and small fibers to lamina V
cells, serving as a gating mechanism. Most
simplistically: fast-moving action poten-
tials in myelinated fibers activate inhibitor
neurons that shut down second-order neu-
rons before slower-arriving signals reach
FIGURE 1.9 Cartesian model: psychophysical the inhibitor neurons via nonmyelinated
experience (pain report) = f (stimulus intensity). fibers (Figure 1.11). These signals from
10 Chronic Pain in Small Animal Medicine

FIGURE 1.10 Pain encoding is dynamic. An analgesic can provide hypoalgesia, while complementary
nociceptive agonists can result in hyperalgesia. A left shift in the stimulus-response curve can result in
allodynia, i.e., a normally non-noxious stimulus becomes noxious.

unmyelinated fibers would normally shut of high-intensity afferent input was subject
down inhibitor neurons, thereby allowing to modulation. Although their concept was
further transmission through second-order accurate, details of their explanation have
neurons. With the gate theory, Melzack and since been more accurately modified.
Wall formalized observations that encoding As an example, transcutaneous electri-
cal nerve stimulation (TENS) therapy is a
clinical implementation of the gate theory.
TENS is thought to act by preferential stim-
ulation of peripheral somatosensory fibers,
which conduct more rapidly than nocicep-
tive fibers. This results in a stimulation
of inhibitory interneurons in the second
lamina of the posterior horn (substantia
gelatinosa) that effectively blocks nocicep-
tion at the spinal cord level. Further, the
gate theory may explain why some people
feel a decrease in pain intensity when skin
near the pain region is rubbed with a hand
(‘rubbing it better’) and how a local area is
FIGURE 1.11 Melzack and Wall’s gate control the- ‘desensitized’ by rubbing prior to insertion
ory of pain; the first theory proposing that noci- of a needle. An additional example would
ception was under modulation by the CNS. be the shaking of a burned hand, an action
 Chapter 1 Physiology of Pain 11

that predominantly activates large nerve in neurotransmitter release, if sensory infor-

fibers. mation is to be conveyed from the periphery
to the second-order afferent neuron located 1
in the spinal cord dorsal horn.
ACTIVITY OF NOCICEPTORS Within the dorsal horn, the CNS ‘decides’
if the message lives or dies. The hypersensi-
Injured nerve fibers develop ectopic sensi- tization of windup is testimonial that the
tivity. A substantial proportion of C-fiber CNS dorsal horn is dynamic, and the impor-
afferents are nociceptors, and abnormal tant role of these voltage-gated ion channels
spontaneous activity has been observed in A makes them attractive targets for novel and
fibers and C fibers originating from neuro- selective analgesics. Voltage-gated calcium
nal-resultant nerve transections. In patients channels open when the membrane poten-
with hyperalgesic neuromas, locally anes- tial depolarizes and they cause intracellular
thetizing the neuroma often eliminates the calcium concentrations to rise. The calcium
pain.9 Nociceptor activity induces increased then causes contraction of muscle and secre-
sympathetic discharge. In certain painful tion of neurotransmitters and hormones from
patients, nociceptors acquire sensitivity to nerves. There are at least nine different types
norepinephrine (NE; noradrenalin) released of voltage-gated sodium channel (VGSC)
by sympathetic efferents. Pain caused by genes expressed in mammals11 and three cal-
activity in the sympathetic nervous system cium channel gene families.12 In the field of
is referred to as sympathetically maintained pain, calcium channel diversity is meaning-
pain. In human studies of stump neuromas ful because N-type channels (from subtypes
and skin,10 it is concluded that apparently L, N, P, R, and T) are critical for neurotrans-
sympathetically maintained pain does not mission in sensory neurons, but relatively
arise from too much epinephrine (adrenalin), less important for excitatory transmission in
but rather from the presence of adrenergic the CNS. Therefore, it is important that the
receptors that are coupled to nociceptors. In most effective analgesics – opiates – act upon
sympathetically maintained pain, nocicep- sensory neurons by inhibiting their N-type
tors develop α-adrenergic sensitivity such calcium channels. Voltage-gated potassium
that the release of NE by the sympathetic channels are not essential for the action
nervous system produces spontaneous activ- potential, but influence the shape of action
ity in the nociceptors. This spontaneous potentials and tune their firing time. When
activity maintains the CNS in a sensitized open, they steer the membrane potential
state. Therefore, in sympathetically main- toward the potassium equilibrium potential,
tained pain, NE that normally is released thereby decreasing the excitability of a cell.
from the sympathetic terminals acquires This makes them prime molecular targets
the capacity to evoke pain. In the presence for suppressing hyperactive neurons and sup-
of a sensitized central pain-signaling neu- pressing hyperalgesia.
ron (second order), pain in response to light Excitability of a neuron can be changed
touch is induced by activity in low-threshold by channels as well as receptors:
mechanoreceptors – allodynia. In this cir-
cumstance, α1-adrenergic antagonists lessen • Na +: Increased excitability with increased
nociceptor activity and the resultant hyper- permeability
algesia or allodynia. • K+: Increased excitability with decreased
permeability and vice versa
• Ca ++: Increased neurotransmitter release;
VOLTAGE-GATED ION increased second messenger action
• Cl-: Variable, depending on chloride equilib-
CHANNELS rium potential

Following thermal, mechanical, or chemical VGSCs are complex, transmembrane

stimulation of primary afferents, the excit- proteins that have a role in governing electri-
atory event must initiate a regenerative action cal activity in excitable tissue. The sodium
potential involving voltage-gated sodium, channel is activated in response to depolar-
calcium, or potassium channels, culminating ization of the cell membrane that causes a
12 Chronic Pain in Small Animal Medicine

DRG) or TTX-resistant (TTXr: Nav1.8 and

Nav1.9, which are exclusively expressed in
cells of the DRG and predominantly in noci-
ceptors). Loss-of-function mutation of the
gene that encodes Nav1.7 is associated with
the condition of insensitivity or indifference
to pain, e.g. hot-ember barefoot walkers. In
contrast, a gain-of-function mutation is the
major cause of erythromelalgia – a condi-
tion of heat allodynia in the extremities of
humans.
Accumulating evidence shows that upreg-
ulation of sodium channel subtypes takes
place in both neuropathic and inflammatory
models of pain.13 Many drugs used clinically
to treat human peripheral neuropathies,
including some local anesthetics (e.g. lido-
caine), antiarrhythmics (e.g. mexiletine), and
anticonvulsants (e.g. phenytoin and carbam-
azepine), are VGSC blockers.
FIGURE 1.12 Sequential events during the action In contrast to VGSCs, voltage-gated
potential showing the normal resting potential, potassium channels act as brakes in the sys-
development of a reversal potential during depo- tem, repolarizing active neurons to restore
larization, and re-establishment of the normal baseline membrane potentials. The hyperpo-
resting potential during repolarization. larization-activated cyclic nucleotide-gated
(HCN) channel is structurally homologous
voltage-dependent conformational change in to the potassium channel, prevails in cardiac
the channel from a resting, closed conforma- tissue and DRG neurons, and modulates the
tion to an active conformation, the result of rhythm and waveform of action potentials,
which increases the membrane permeability thereby also contributing to resting mem-
to sodium ions (Figure 1.12). Based on the brane potentials.14
sensitivity to a toxin derived from puffer fish, Calcium ions play an important role in
tetrodotoxin (TTX), sodium currents can be neurotransmission, being essential for trans-
subdivided as being either TTX-sensitive mitter release from terminals (Figure 1.13).
(TTXs: Nav1.7 channel, plentiful in the They also play a key role in neurons, linking

FIGURE 1.13 Neurohumoral transmission. The axonal action potential expresses a depolarization-
repolarization of the axon, characterized by an influx of sodium and efflux of potassium. Arriving at the nerve
terminal, the action potential facilitates an inward movement of calcium, which triggers the discharge of
neurotransmitters from storage vesicles into the junctional cleft. The neurotransmitters react with specialized
receptors on the postjunctional membranes and initiate physiological responses in the effector cell.
 Chapter 1 Physiology of Pain 13

receptors and enzymes, acting as intracel- isoforms are known to exist: endothe-
lular signals, forming a channel-gating
mechanism, and contributing to the degree
lial NOS (eNOS), neuronal NOS (nNOS),
and inducible NOS (iNOS). Of these iso- 1
of depolarization of the cell. The means by forms, eNOS and nNOS are constitutively
which calcium enters the neuron and termi- expressed, whereas the expression of iNOS
nal is via calcium channels, making calcium is induced in a wide cell range by immune
channel targets for a variety of neurotrans- or inflammatory stimuli. nNOS is not con-
mitters, neuromodulators, and drugs. Two fined to the CNS, but is the predominant
families of voltage-dependent calcium chan- form. NO may influence nociceptive process-
nels (VDCCs) exist: ing at many levels and may potentially have
different effects, depending on the site and
• Low threshold, rapidly activating, slowly concentration of NO.16 NO itself is a very
deactivating channels (low-voltage activated short-lived molecule (half-life of millisec-
[LVA] also referred to as T-type). onds to seconds); however, models of its dif-
• High-threshold, slowly activating, fast-deac- fusional spread suggest that a point source
tivating channels (high-voltage activated synthesizing NO for 1–10 seconds would
[HVA]). Ziconotide (a synthetic version of lead to a 200-μm sphere of influence: in the
a ω-conotoxin found in the venom of preda- brain this volume could encompass 2 mil-
tory marine snails) blocks depolarization- lion synapses.17 The main role of spinal NO
induced calcium influx through VDCC appears to be in mediating hyperalgesia. In
binding. the periphery, the antinociceptive actions of
opioids are mediated by NO and the analge-
Calcium channels include receptor- sic actions of endogenous opioids, acetylcho-
operated channels, stretch-operated chan- line, and α 2-adrenoreceptor agonists may all
nels, calcium channels operated by second involve NO in an antinociceptive role. There
messengers, and voltage-sensitive chan- also appears to be a link between NO and
nels (Table 1.2). The only channels that are the prostanoid pathway. Interleukin-1β (IL-
responsive to the current calcium channel 1β) can induce both NOS and cyclooxygen-
blockers are L-type calcium channels.15 ase (COX) expression, and NO can increase
The role of nitric oxide (NO) in nocicep- the synthesis and release of prostanoids.18
tion is unclear, although it appears to func- Within the body, the endogenous nucleo-
tion both centrally and peripherally. NO is tide adenosine performs multiple functions.
synthesized from L-arginine by the enzyme It can be progressively phosphorylated to
nitric oxide synthase (NOS), of which three generate the high-energy molecules adenosine

TABLE 1.2 Types of calcium channels

Types of calcium channels Activity stimulus
Receptor-operated channels Binding of a specific ligand, such as a neurohormone, to receptors
within the channel
Stretch-operated channels Vascular stretch
Second messenger– operated Intracellular second messengers, such as inositol phosphate
channels
Voltage-sensitive calcium Voltage change across the membrane, such as depolarization
channels
Neuronal (N-type) Are involved with transmitter release at synaptic junctions (as well as
P/Q channels)
Transient (T-type) Low-voltage activated channels that permit calcium flux at resting
membrane potentials, hence their role in pace making, neuronal
bursting, and synaptic signal boosting
Long lasting (L-type) Key determinants of membrane excitability (the only channels affected
by calcium channel–blocking agents)
14 Chronic Pain in Small Animal Medicine

monophosphate, diphosphate, and triphos-

phate (AMP, ADP, and ATP) and from ATP
PERIPHERAL NERVOUS
may be further modified to generate the intra- SYSTEM AND DORSAL
cellular second-messenger cyclic AMP (cAMP).
Generally, its effects are inhibitory, and it acts ROOT GANGLION
as a depressant in the CNS. Equilibrative
The peripheral nervous system (PNS) com-
transporters facilitate adenosine release across
prises nervous tissue outside the spinal canal
cell membranes into the extracellular space to
and brain. Nociception first undergoes
the extent that under severe hypoxic condi-
change in the PNS, followed by dynamic
tions, the concentration of adenosine may rise
changes in the dorsal horn of the spinal cord
100-fold.19 Species differences exist in adenos-
(Figure 1.14). Peripheral receptors (special-
ine receptor pharmacology, but early studies
ized axon terminals in the skin) transduce
suggest adenosine agonists were effective in
nociceptive and proprioceptive events for
antinociceptive tests, mainly by acting as gen-
processing by first-order sensory neurons in
eral CNS depressant agents.
the ipsilateral, segmental DRG, whose exten-
ATP can have diverse origins from which
sion terminates in the dorsal horn (substan-
to activate sensory nerve terminals. ATP can
tia gelatinosa) of the spinal cord.
be co-released with NE following sympa-
The PNS includes cranial nerves, spinal
thetic stimulation, possibly underlying the
nerves with their roots and rami, peripheral
maintenance of ‘sympathetic pain’, as well as
components of the autonomic nervous sys-
by antidromic stimulation of sensory nerves.
tem, and peripheral nerves whose primary
Painful stimulation can also be associated
sensory neurons are located in the associ-
with sympathetic activity – proposed as a
ated DRG, also a part of the PNS. Axons
contributor to arthritic pain. Purinoceptors
are extensions of the cell body and contain
for ATP fall into two broad groups: iono-
a continuous channel of neuronal cytoplasm.
tropic receptors, which are termed P2X, and
As a theory of electrical engineering,
metabotropic receptors, termed P2Y. P2X
there is a relationship between fiber size
receptors appear to be localized to noci-
and conduction velocity (Table 1.3); how-
ceptive nerve endings in the joint capsule. 20
ever, conduction velocity may be enhanced
Support for the role of P2Y receptors in
by Schwann cell activity or reduced by
pain is weak. There is, however, strong evi-
pathology.
dence that the ultimate breakdown product
Nearly all large-diameter myelinated Aβ
of ATP, adenosine, plays a role in nocicep-
fibers normally conduct non-noxious stimuli
tive processing, 21 and it may be that P2X
applied to the skin, joints, and muscles, and
and adenosine (P1) receptors act together as
thus these large sensory neurons usually
physiological regulators of nociceptive traf-
do not conduct noxious stimuli. 24 In con-
fic. Accordingly, the P2X receptor would
trast, most small-diameter sensory fibers,
be considered a candidate for pharmaco-
unmyelinated C fibers, and finely myelin-
logical intervention in treating nociceptive
ated A fibers are specialized sensory neurons
pain.
ATP is also sourced from damaged cells,
which could underlie the pain associated
with tissue trauma. Vascular endothelial
cells also appear to release ATP readily, with-
out any concomitant cellular lysis. 22
Adenosine receptor agonists can be highly
effective antinociceptive agents, where their
activity is similar to, but not identical with,
that of opioids. Both classes of compounds are
effective against thermal nociceptive stimuli;
opioids tend to be more efficacious against
mechanical nociception, whereas adenosine
agonists are more efficacious against inflam- FIGURE 1.14 Nociception is initially influenced by
matory and neuropathic pain. Their therapeu- first-order neurons in the PNS, prior to reaching
tic window is small, however.23 the dorsal horn of the spinal cord.
 Chapter 1 Physiology of Pain 15

TABLE 1.3 Relationship between fiber size and conduction velocity

Conduction velocity 1
Cutaneous nerve Muscle nerve in cat (m/s) Diameter (μm)
Aαβ 72–130 12–22
Group I
35–108 6–18
Group II 36–72 6–12
Aδ Group III 3–30 3–7
C Group IV 0.2–2 0.25–1.35

known as nociceptors, whose major function longitudinal course. This allows the nerve to
is to detect environmental stimuli that are stretch approximately 10% without injury,
perceived as harmful and convert them into and this compensatory design can be com-
electrochemical signals that are then trans- promised by scar formation within adjacent
mitted to the CNS. tissue. Endoneurial vessels are free of inner-
The term ‘nerve fiber’ refers to the com- vation, and blood flow is not modulated by
bination of the axon and Schwann cell as a sympathetic activity, but by local perfusion
functional unit. The Schwann cell (oligoden- pressure and vessel caliber. Since the endo-
drocytes are the corresponding CNS cell) neurial space can expand by edema or by the
significantly accelerates the speed of action influx of hematological or neuronal cells, the
potential propagation and acts as a first- perineurium can expand, pinching transperi-
line phagocyte. It also plays a major role in neurial vessels closed. At 50% compromise
nerve regeneration and axonal maintenance. to blood flow, neurological consequences can
All peripheral nerve axons are surrounded become apparent.
by segmental Schwann cells, although only
some Schwann cells produce a lipid-rich
insulation covering: myelin.
Myelin is formed by serial wrapping of
Schwann cell cytoplasm around an axon,
and sequential myelinated Schwann cells are
separated by nodes of Ranvier, a location of
high sodium channel concentration. Nodes
of Ranvier provide rapid axon saltatory
conduction. After nerve injury, new axonal
sprouts arise from a node of Ranvier. In the
perinodal region of the axon, high concen-
trations of potassium channels are exposed
during early phases of demyelination.
The most common cause of neuropa-
thy following axonal injury is associated
with Wallerian degeneration, named after
Augustus Waller, who in 1850 described a FIGURE 1.15 Wallerian degeneration includes (A)
pathological process following nerve tran- transection injury and degeneration in the dis-
section that included an initial reaction at the tal segment of the nerve (minimal degeneration
injury site, then degeneration and phagocy- proximally); (B) regeneration following degenera-
tosis of myelin and axons distal to the injury tion, as injured axons form many small sprouts
(Figure 1.15). Wallerian degeneration occurs that are guided by trophic factors to target tissue
(often following remnant basal lamina of Schwann
after axonal injury of any type, including
cells that have themselves degenerated); (C) the
crush and severe ischemia. axon size then increases, as the axon develops
The anatomy of nerve circulation influ- and remyelinates; and (D) occasionally a very
ences its homeostasis. Surface circulation painful neuroma forms when regeneration lacks
of a peripheral nerve is sinusoidal in its a terminal target.
16 Chronic Pain in Small Animal Medicine

There are other support cells in the PNS,

including mast cells, fibroblasts, endothelial
cells, and resident macrophages.

THE DORSAL HORN ACTS

AS A ‘GEAR BOX’ IN
FIGURE 1.16 DRG neurons are first-order sensory
neurons with axons branching both centrally and PAIN TRANSMISSION
peripherally.
In the early 1960s it became clear that pain
manifests several distinct perceptual com-
DRG neurons are the first-order sensory ponents. There is clearly a sensory-discrim-
neurons, with their distal axons connected inative feature that signals the intensity,
to sensory receptors or their free ends local- localization, and modality of the nocicep-
ized in tissue space (Figure 1.16). DRG axons tion, e.g. ‘I have a pain of 7, on a scale of
leave the cell body and then bifurcate into a 1–10, in my right index finger’. There is also,
central and peripheral process. clearly, an affective-motivational component
Axonal cell bodies ‘sense’ their environ- reflecting stimulus context and a variety
ment, which provides a ‘backflow’ to alter of higher-order functions such as memory
cell transcription and axonal protein flow and emotion, e.g. ‘The pain in my finger
(Table 1.4). Normally, the transcription makes life miserable, impacting everything
machinery is devoted primarily to making I do’. These different components are highly
neurotransmitters, but following peripheral integrated, involving distinct anatomical
nerve injury, the DRG senses the requirement systems.
for skeletal proteins for regeneration and shifts Complex networks of pathways from
its production for that purpose. The process various sites in the brain integrate together
of axonal transport is functional in all viable to modulate the spinal processing of sensory
axons, both myelinated and unmyelinated. information in a top-down manner. Higher-
order cognitive and emotional processes, such
as anxiety, mood, and attention, can influ-
TABLE 1.4 Classification of axoplasmic ence the perception of pain through a con-
proteins by transport rate vergence of somatic and limbic systems into
Velocity a so-called descending modulatory system,
Group (mm/day) Substances providing a neural substrate through which
I >240 Membrane constituents, the brain can control pain (Figure 1.17). The
transmitter vesicles, pharmacology of the descending systems is
glycoproteins, complex, but broadly, the two major defined
glycolipids, lipids, transmitters in the pathways from the brain
cholesterol, to spinal cord are the monoamines, NE, and
acetylcholine,
5-hydroxytryptamine (5-HT).
norepinephrine,
serotonin, sP, other An important tenet underlies the
putative transmitters, enhanced response of the CNS to mechanical
associated enzymes stimuli of cutaneous injury: ‘the peripheral
signal for pain does not reside exclusively
II 40 Mitochondrial
components, fodrin with nociceptors; under pathological circum-
stances, other receptor types, which are nor-
lll–IV 2–8 Actin, myosin-like mally associated with the sensation of touch,
proteins, glycolytic
acquire the capacity to evoke pain’. 25 This
enzymes, calmodulin,
clathrin, some additional principle applies to secondary hyperalgesia,
fodrin as well as to neuropathic pain states in gen-
eral. Central sensitization is the term denot-
V 1 Cytoskeleton proteins,
ing augmentation of the responsiveness of
neurofilament proteins
central pain-signaling neurons to input from
 Chapter 1 Physiology of Pain 17

FIGURE 1.17 The brain and spinal cord are able to ‘talk to one another’. The emotional center of the
brain is a series of nerves and tissue called the limbic system, which creates a rainbow of emotions.
The limbic system not only influences pain signals but also adds emotional texture to them. (PAG: peri-
aqueductal gray, RVM: rostral ventromedial medulla.)

low-threshold mechanoreceptors. It is cen- dorsal horn. 29 Neuronal information pro-

tral sensitization that plays the major role in cessing is not fixed, but is instead dynamic,
secondary hyperalgesia, not peripheral sen- changing in a manner that is dependent on
sitization. This underlies the value of local levels of neuronal excitability and synaptic
anesthetic blocks: when the CNS is spared strength, profoundly diversifying for either a
the input from nociceptors at the time of the short period (seconds) or prolonged periods
acute insult, hyperalgesia does not develop. 26 (days), or perhaps indefinitely.
The predominant neurotransmitter used In 1954 Rexed demonstrated that the
by all primary afferent fibers is glutamate, gray matter of the spinal cord can be divided
although other excitatory transmitters, nota- into cytoarchitecturally distinct laminae or
bly ATP, act to depolarize dorsal horn neu- layers (Figure 1.18). Physiological studies
rons directly or on presynaptic autoreceptors have since demonstrated an analogous, func-
to enhance glutamate release during action tional laminar organization. Lamina I (mar-
potential firing. 27 Primary afferents, unique ginal layer) is composed of cells that respond
in their capacity to release neurotransmit- primarily, and in some cases exclusively, to
ters peripherally and so underlie neurogenic noxious stimuli. Some also respond to innoc-
inflammation, convey information to the uous, i.e., noninjurious stimulation, includ-
CNS. In the dorsal horn, peptides such as ing moderate temperatures. Many lamina I
sP impact postsynaptic dorsal horn neurons, cells contribute axons to the spinothalamic
setting the gain or magnitude of the nocicep- tract. Lamina II (substantia gelatinosa) con-
tive response. 28 tains small interneurons, many responding
The dorsal horn of the spinal cord is to noxious inputs. Lamina II neurons modu-
organized into lamellae composed of dorsal late cells of laminae I and V. Laminae I and
horn neurons and the inhibitory and excit- II receive direct primary afferent input only
atory synaptic connections they receive and from small-diameter fibers. Laminae III and
make. Non-neural glial cells – the oligoden- IV cells respond to innocuous stimuli – hair
drocytes, astrocytes, and microglia – modu- brush and tactile skin stimulation – and do
late the operation of these neuronal circuits. not increase their response when noxious
A key feature of the somatosensory system, stimuli are presented. Lamina V cells respond
modifiability or plasticity, resides in the to noxious and non-noxious stimuli. They
18 Chronic Pain in Small Animal Medicine

FIGURE 1.18 The dorsal horn of the spinal cord is composed of lamellae, with characteristic afferents
and efferents.

are wide dynamic range (WDR) cells. They Different perceptions are elicited depending
also respond to noxious visceral stimuli. upon whether low- or high-threshold affer-
Spinal cord transmissions work as a ents have been activated because of the dif-
binary response: low-intensity stimuli are ferent central circuits engaged.
interpreted as innocuous or nonpainful, such Dorsal horn neurons consist primarily of
as touch, vibration, or hair movement, ver- projecting neurons, propriospinal neurons,
sus high-threshold stimuli that produce pain. and local interneurons (Figure 1.19). Their

FIGURE 1.19 Dorsal horn neurons consist of projecting neurons, propriospinal neurons, and local
interneurons.
 Chapter 1 Physiology of Pain 19

distribution as well as dendritic arboriza- example, flight or fight reactions in the pres-
tion determine which and how many inputs
each receives. Projection neurons transfer
ence of substantial injury. Inhibitory mecha-
nisms can be activated by peripheral inputs 1
sensory information to higher CNS levels of TENS, acupuncture, placebo, suggestion
and are also involved in the activation of (in humans), distraction, and cognition.
descending control systems. Propriospinal Further, endogenous inhibitory mechanisms
neurons transfer inputs from one segment of can be mimicked pharmacologically with
the spinal cord to another, and local inter- agents such as opiates, GABA-mimetics, and
neurons, comprising the majority of intrinsic α-adrenergic agonists.
dorsal horn neurons, serve as short-distance GABA exerts a powerful inhibitory tone
excitatory and inhibitory interneurons. Most within the spinal cord dorsal horn medi-
inhibitory interneurons contain gamma ated by both GABA A receptors (presynaptic
aminobutyric acid (GABA) and/or glycine and postsynaptic on primary afferents) and
as neurotransmitters and synapse both pre- GABA B receptors located principally on pre-
synaptically on primary afferent endings and synaptic sites. Although GABAergic inhibi-
postsynaptically on dorsal horn neurons. 30 tion may be upregulated during peripheral
Presynaptic inhibition decreases transmit- inflammatory states, GABAergic interneu-
ter release from primary afferent terminals, rons are subject to excitotoxic or apoptotic
while postsynaptic inhibition hyperpolarizes death following nerve injury, resulting in a
postsynaptic membranes. Many inhibitory loss of inhibitory tone, which, in turn, may
interneurons are spontaneously active, main- contribute to hyperalgesia and allodynia. 32
taining an ongoing tonic inhibitory control
within the dorsal horn.
Contributing to CNS plasticity is neuro-
Windup
nal capacity for structural reorganization of Windup is a form of activity-dependent plas-
synaptic circuitry. Schwann cells accrue and ticity characterized by a progressive increase
promote neuronal redevelopment, resulting in action potential output from dorsal horn
in deafferentation of injured and uninjured neurons elicited during the course of a train
fibers. The resultant collateral branching can of repeated low-frequency C fiber or nocicep-
lead to misdirected targeting of fibers and tor stimuli. 33 Repetitive discharge of primary
inappropriate peripheral innervation, so that afferent nociceptors results in co-release of
cutaneous areas once occupied by the lesioned neuromodulators such as sP and CGRP,
nerve become hyperinnervated by low- and together with glutamate (the main neu-
high-threshold fibers. Neurons may die, axon rotransmitter used by nociceptors synapsing
terminals may degenerate or atrophy, new with the dorsal horn) from nociceptor cen-
axon terminals may appear, and the structural tral terminals. These neuropeptides activate
contact between cells at the synapses may be postsynaptic G protein–coupled receptors,
modified. This can result in the loss of nor- which lead to slow postsynaptic depolariza-
mal connections, formation of novel abnormal tions lasting tens of seconds.34 The resul-
connections, and an alteration in the normal tant cumulative depolarization is boosted
balance between excitation and inhibition.31 by recruitment of N-methyl-D-aspartate
Structural reorganization and its functional (NMDA) receptor current through inhibi-
sequelae can result in changed sensory pro- tion of magnesium channel suppression.
cessing long after the initial injury has healed.
NMDA Receptor and Windup
The most involved receptor in the sensa-
WHAT MAKES THE CNS tion of acute pain, alpha-amino-3-hydroxy-
SO DYNAMIC? 5-methyl-4-isoxazole propionic-acid (AMPA),
is always exposed on afferent nerve termi-
nals. In contrast, those most involved in the
Afferent Signal Suppression sensation of chronic pain, NMDA receptors,
Spinal cord sensory transmissions can be are not functional unless there has been a
endogenously suppressed, as might be nec- persistent or large-scale release of glutamate
essary for survival value, enabling, for (Figure 1.20).
20 Chronic Pain in Small Animal Medicine

FIGURE 1.20 CNS windup involves the NMDA receptor.

Repeated activation of AMPA recep- Calcium entry by NMDA receptor activa-

tors dislodges magnesium ions that act like tion stimulates the neuronal isoform of NOS
stoppers in transmembrane sodium and (nNOS) localized within both primary affer-
calcium channels of the NMDA receptor ent nociceptors in the DRG and neurons of
complex. Calcium flowing into the cell acti- the spinal cord dorsal horn (primarily lami-
vates protein kinase C, the enzyme needed nae I–II and X). 36 NO, acting as a retrograde
for NOS production of NO. NO diffuses transmitter within the dorsal horn, thereby
through the dorsal cell membrane and syn- potentiates excitatory amino acid and neu-
aptic cleft into the nociceptor and stimu- rokinin release, contributing to central sen-
lates guanyl synthase–induced closure of sitization, and plays a key role in nociceptive
potassium channels. Since endorphins and processing.
enkephalins inhibit pain by opening these It is important to note that NMDA-
channels, closure induces opiate resistance. associated windup is a process where ‘nor-
NO also stimulates the release of sP, which mal’ underlying nociceptive signaling (much
by binding to neurokinin 1 (NK-1) recep- of which occurs in the spinothalamic tract)
tors in the dorsal horn membrane, trig- is facilitated by activity of the NMDA
gers c-fos gene expression and promotes receptor. When this facilitation is blocked
neural remodeling and hypersensitization. by an NMDA antagonist, the underlying
Accompanying this windup, less glutamate nociception signaling remains, which must
is required to transmit the pain signal and be treated with other analgesics. For this
more antinociceptive input is required for reason, NMDA antagonists serve best as
analgesia. Endorphins cannot keep up with adjuncts in a multimodal analgesic protocol
their demand and essentially lose their (Figure 1.21).
effectiveness. The clinical implications are Pain memories imprinted within the
underappreciated: inadequately treated CNS, mediated by NMDA receptors, pro-
pain is a much more important cause of duce hyperalgesia and contribute to allodynia
opioid tolerance than use of opioids them- (Figure 1.22). In several animal experiments,
selves. NMDA activation can also cause c-fos expression (the c-fos gene serves as a
neural cells to sprout new connective marker for cellular activation, i.e., nocicep-
endings. 35 tion), central sensitization, and windup do
 Chapter 1 Physiology of Pain 21

FIGURE 1.21 NMDA-mediated windup facilitates the underlying nociceptive signaling, resulting in a state
of hyperalgesia. Therefore, NMDA antagonists are administered as ‘adjuncts’ to a baseline protocol for
optimal results.

not occur if nociceptive blockade is applied patients who are unresponsive to surgical
prior to the nociceptive event. Such findings stimuli. This has been somewhat validated
suggest that presurgical blockade of nocicep- in the dog, 38,39 where (‘pain-induced dis-
tion may prevent postsurgical wound pain or tress’) cortisol spikes in response to noxious
pain hypersensitivity following surgery, i.e., stimuli of ovariohysterectomy during the
preemptive analgesia, as advocated by the anesthetic period suggest a link between
eminent pain physiologist, Patrick Wall. 37 surgical stimulus and neural responsiveness
Successful preemptive analgesia must meet during anesthetic-induced unconscious-
three criteria: (1) intense enough to block ness (Figure 1.23). As indicated by the
all nociception, (2) wide enough to cover expression of c-fos (early genomic expres-
the entire surgical area, and (3) prolonged sion), noxious stimuli still enter the spi-
enough to last throughout surgery and even nal cord during apparently adequate
into the postoperative period. anesthesia.40
It is important to note that adequate In 1988, Professor Patrick Wall intro-
levels of general anesthesia with a volatile duced the concept of preemptive analgesia
drug such as isoflurane do not prevent cen- to clinicians with his editorial in the journal
tral sensitization. The potential for central Pain.41 The emphasis of preemptive analgesia
sensitization exists even in unconscious is on preventing sensitization of the nervous
system throughout the perioperative period.
Pain is to be expected from an initial surgery
and the hypersensitivity that subsequently
develops. Analgesia administered after sen-
sitization may decrease pain somewhat, but
has little long-term benefit in addressing the
pain resultant from postsurgical inflamma-
tion. Analgesia administered before surgery
limits inflammatory pain and decreases
subsequent hypersensitivity. The most effec-
tive preemptive analgesic regimen occurs
when initiated before surgery and contin-
FIGURE 1.22 Stimulus-response curve of noxious ued throughout the postoperative period
insult. (Figure 1.24).
22 Chronic Pain in Small Animal Medicine

FIGURE 1.23 Changes in plasma cortisol concentrations from pretreatment values for control, anes-
thesia, analgesia, and surgery treatments; the curves demonstrate that although canine patients were
under the appropriate stage of gaseous anesthesia, nociception was apparent. Technically, these dogs
were not painful, because the nociception was not being cognitively processed.38

A review of preemptive analgesia, with a substantial role in perioperative pain

inclusion of suggested drugs (available in management45 because surgery cannot be
2001) and dosage has been provided else- performed without subsequent inflamma-
where.42 A logical preemptive drug proto- tion. Reducing the inflammatory response
col would include an opioid, α 2 -agonist ± in the periphery, and thereby decreasing
an NMDA antagonist,43 and a nonsteroidal sensitization of the peripheral nociceptors,
anti-inflammatory drug (NSAID).44 The should attenuate central sensitization.46
implementation of perioperative NSAIDs is It has also been recognized for some time
controversial based on their antiprostaglan- that NSAIDs synergistically interact with
din effect, which in the face of hypotension, both μ-opioid and α 2 -adrenoceptor ago-
might enhance the potential for acute renal nists.47–50 In human medicine, the use of
failure. This is why perioperative fluid sup- perioperative NSAIDs has reduced the use
port is such an important consideration. of patient-controlled analgesic morphine by
However, anti-inflammatory drugs play 40%–60%. 51,52

FIGURE 1.24 The most effective preemptive analgesia is initiated before surgery and continued through-
out the postoperative period.
 Chapter 1 Physiology of Pain 23

GLIAL CELLS glia is multidimensional because glia perform

By the early 1990s, a large body of literature

numerous functions. Responding to different
activation states, substances released by acti- 1
had accumulated with evidence that CNS vated glia include proinflammatory cytokines
proinflammatory cytokines (tumor necrosis (TNF, IL-1, IL-6), NO, reactive oxygen spe-
factor [TNF], IL-1, and IL-6) were critically cies, PGs, excitatory amino acids, and ATP. 59
involved in the generation of every sickness Microglia and astrocytes can synergize in
response studied. 53 Further, glia were recog- their functions, and so products released by
nized as a major source of these proinflam- one cell type can stimulate the release of pro-
matory substances. This built on the 1970s inflammatory substances from the other. A
data that CNS microglia and astrocytes shift from the basal state to active can occur
became activated following trauma to periph- quite rapidly, as microglia are extremely sen-
eral nerves.54 Further, the drug MK801, sitive to changes in their microenvironment.
which blocks neuropathic pain behaviors, Stimuli that trigger microglial activation
was demonstrated to block glial activation include CNS trauma, ischemia, tumors, neu-
as well, hence correlating neuropathic pain rodegeneration, and immune stimuli such as
and glial activation. Although microglia and bacteria or viruses.
astrocytes have become attractive treatment It is noteworthy that glia do not
targets for neuropathic pain, proinflamma- have axons. They cannot relay sensory
tory cytokines, for example, can also be pro- information from the spinal cord to the
duced by fibroblasts, endothelial cells, and brain. Accordingly, their role is indirect.
other types of glia and some neurons. 55 Conceptually, glia can be recognized as ‘vol-
The term ‘glia’ means glue, and the CNS ume controls’, where substances released by
contains three types of glial cells: astrocytes, activated glia cause incoming sensory affer-
oligodendrocytes, and microglia. Microglia ents to increase their release of neurotrans-
are the resident tissue macrophages of the mitter, thereby amplifying their ‘pain’
CNS and, as such, are thought to be the first message. It follows that preventing such glial
line of defense against injury or infection.56 alterations in the functioning of the ‘pain
Microglia cells, which outnumber neurons pathway’ can be conceptualized as ‘turning
by 10 to 1 in the CNS, play a central role down the gain on pain’.60
in the pathophysiology of neuropathic pain. The origin of microglia is uncertain; how-
Activated microglia release chemical media- ever, evidence suggests that microglia arise
tors that can act on neurons to alter their from mesodermal cells, probably of hemato-
function: expression and release of cytotoxic poietic lineage.61 After development, microg-
or inflammatory mediators, including IL-1β, lia can arise from two primary sources. First,
IL-6, TNF-α, proteases, and reactive oxygen resident microglial cells undergo mitosis and
intermediates, including NO. 57 therefore replenish their numbers through-
Normally, microglia are quiescent, hav- out life. Second, peripheral blood monocytes
ing no known basal function other than migrate into the CNS through the intact
surveillance for debris, pathogens, and CNS blood-brain barrier, and these cells subse-
‘clutter’. Astrocytes, on the other hand, reg- quently transform into resident microglia.
ulate extracellular ions, sequester extracel- In response to CNS immune challenge or
lular neurotransmitters, and perform other trauma, microglia are stimulated to actively
homeostatic functions. Astrocytes encap- proliferate.62 Further, CNS trauma and isch-
sulate synapses and actively participate in emia can lead to site-specific recruitment of
synaptic communication by responding to peripheral blood monocytes. Such mono-
synaptically released neurotransmitters by cytes can again mature into macrophages
releasing glial substances into the synapse as within the CNS that, over time, become
well.58 As such, astrocytes are ‘active’ but not morphologically identical to microglia. After
‘activated’. microglia maturation through three stages
Activation is a fundamentally different and clearance of immune challenges, microg-
phenomenon in neurons compared with that lia reverse their maturation toward the basal
in glia. For neurons, activation is unidimen- condition where they remain in a ‘primed’
sional, i.e., it relates to the production of state from which they can respond more rap-
action potentials. In contrast, activation of idly, as in an anamnestic response. Microglia
24 Chronic Pain in Small Animal Medicine

appear to be required for the development of

neuropathic pain, but not its maintenance.
Astrocytes appear to arise from dorsal
regions of the neural tube, comprise 40%–
50% of all glial cells, and outnumber neu-
rons. Multipotential neuroepithelial stem
cells are thought to give rise to astrocytes,
as well as to neurons and oligodendrocytes.63
Astrocytes have been divided into two
groups: protoplasmic astrocytes are predom-
inant in gray matter, while fibrous astrocytes
are primarily found within white matter.
Astrocytes are closely apposed to neu-
rons. They enwrap the majority of synapses
in the CNS and also ensheathe nonsynaptic
sites (neuronal cell bodies, dendrites, nodes of
Ranvier). In contrast to microglia, the basal
state of astrocytes is not quiescent, as they FIGURE 1.25 Representation of a tripartite syn-
perform a wide array of functions in the nor- apse in which the process of an astrocyte (gray)
mal CNS. Astrocytes provide neurons with wraps around a synaptic connection. Synaptic
energy sources and neurotransmitter pre- activity elicits postsynaptic potentials, while
GABA or glutamate can act on astrocytic recep-
cursors.64 They also play an important role
tors and trigger calcium release from internal
in trophic support via the release of growth stores to increase astrocytic calcium levels.
factors, regulation of extracellular ions and Elevated astrocytic calcium evokes the local
neurotransmitters, neuronal survival and release of the chemical transmitter glutamate,
differentiation, neurite outgrowth and axon which can modulate the synapse.
guidance, and formation of synapses.65 The
concept of the ‘tripartite synapse’ (instead of
the traditional two elements) is now widely response to these glial products, suggestive
accepted: the presynaptic terminal, the of a direct effect on neurons. IL-1 has been
postsynaptic terminal, and the surrounding demonstrated to enhance neuronal NMDA
astrocytes (Figure 1.25).66 conductance, including within the spinal
Synaptic activation of a low frequency or cord dorsal horn. TNF rapidly upregulates
intensity elicits no response by astrocytes. In membrane expression of neuronal AMPA
contrast, axonal activity of a high frequency receptors and also increases AMPA conduc-
or intensity activates astrocytes and induces tance. TNF also enhances neuroexcitability
oscillatory changes in intracellular calcium: in response to glutamate, and IL-1 induces
activation. Elevations in intracellular cal- the release of the neuroexcitant ATP via an
cium in astrocytes lead to glial release of var- NMDA-mediated mechanism. Additionally,
ious substances, including glutamate, PGE 2 , proinflammatory cytokines can induce the
and proinflammatory cytokines.67 These, in production of a variety of neuroexcitatory
turn, increase the synaptic strength of excit- substances, including NO, PGs, and reactive
atory synapses, increase the expression of oxygen species. Accordingly, proinflamma-
AMPA receptors by neurons, and induce an tory cytokines exert multiple effects, each of
increase in intracellular calcium and action which would be predicted to increase neu-
potential frequency in nearby neurons,68 at ronal excitation, and each of which would
least in part via glutamate-mediated activa- serve as a future target for analgesic drug
tion of extrasynaptic NMDA receptors. development.
The following summarizes mechanisms Astrocytes also communicate among
by which proinflammatory cytokines alter themselves. They do not generate action
neuronal excitability. Neurons, including potentials, but create calcium waves wherein
those in the spinal cord dorsal horn, express intracellular calcium elevations are propa-
receptors for proinflammatory cytokines. gated in a nondecremental fashion from
Neuronal excitability in the dorsal horn astrocyte to astrocyte. Calcium waves, by
and trigeminal nucleus increases rapidly in leading to the activation of distant astrocytes,
 Chapter 1 Physiology of Pain 25

FIGURE 1.26 Calcium waves within astrocytes provide bidirectional communication between astrocytes
and neurons.

result in the release of glial products at dis- amino acids, and classical immune media-
tant sites (Figure 1.26).66 Glial gap junctions tors, inducing spinal nociceptive facilita-
may also be involved in the spread of pain to tion.70 Considering that glial cells are not
distant sites.68 normally involved in pain processing and
Two interrelated points are worth noting: are only activated during excessive nervous
(1) the actions of glial products can syner- system activity, agents targeting these cells,
gize and (2) substances released by activated or their neuroactive products, hold analgesic
microglia can, in turn, activate astrocytes hope for the future (Table 1.5). Modulation
and vice versa. of the immune system is becoming the ‘new
Fractalkine is a neuron-to-glia signal69 approach’ to managing neuropathic pain.
that can trigger release of neurostimulat- Under the influence of ATP activation,
ing agents such as NO, ATP, excitatory P2X4 is upregulated with a time course that

TABLE 1.5 Different strategies targeting glial activity

Strategy Pros Cons Developments
Disrupt glial • If basal homeostatic • Disrupting basal glial Minocycline is being
activation functions of glia are left intracellular functions is explored as a
intact, could be promising not acceptable microglia-selective
• Drugs targeting microglia inhibitor in animal
alone may not be models
clinically effective in
reversing established
pain
Block • Proinflammatory • Proinflammatory Antagonists of TNF,
proinflammatory cytokines are involved in cytokines are IL-1, and IL-6 are
cytokine actions the initiation and redundant, as being assessed in
maintenance of pain unblocked cytokines animal models
facilitation may take over their
• This strategy is effective function: thus, blocking
for blocking as well as a single cytokine is
reversing pain facilitation unlikely to be clinically
effective
• Current compounds do
not cross the blood-
brain barrier
26 Chronic Pain in Small Animal Medicine

TABLE 1.5 Different strategies targeting glial activity (Continued)

Strategy Pros Cons Developments
Inhibit • If synthesis of all • No apparent Some thalidomide
proinflammatory proinflammatory disadvantage as long derivatives cross
cytokine synthesis cytokines could be as treatment is the blood-brain
blocked, pain problems reversible/controllable barrier and might
are predicted to be to allow expression of be worth
resolved cytokines under assessing for
conditions where they potential effects
would be beneficial on glial function
Disrupt cytokine • Broad-spectrum • P38 MAP kinase is not Efficacy of both p38
signaling and approaches to shut down the only cascade MAP kinase
synthesis creation or effectiveness involved inhibitors and
of key mediators of pain • It may be only IL-10 nonviral
facilitation transiently involved and gene therapy is
• Some p38 MAP kinase not restricted to glia being assessed in
inhibitors are orally active (expressed by neurons) animal models
and cross the blood-brain • Effect of inhibiting
barrier neuronal signaling is
• Intrathecal nonviral gene unknown
therapy (controllable by • IL-10 gene therapy
insertion of appropriate involves an invasive
control sequences) procedure (lumbar
reversibly generates IL-10 puncture)
site specifically, using a
safe and reliable
outpatient delivery system

Source: IASP meeting, Glasgow UK, 2008.

Notes:
IL-10 is an anti-inflammatory cytokine, does not cross the blood-brain barrier, and is effective in reversing pain facilitation; however, it
is very short-acting.
These pursuits and other clinical trials can be found at http://clinicaltrials.gov.

parallels that of the development of allo- GABA and glycine, changing inhibition to
dynia.71 P2X4 receptors are nonspecific cation excitation (Figure 1.27). Microglial activation
channels that are permeable to calcium ions. occurs only following C-fiber neuropathic
Apparently, ATP stimulation of these receptors injury and is not typically seen following
leads to calcium influx that activates signaling peripheral inflammation.
proteins leading to the release of factor(s) that
enhance transmission in spinal pain trans-
mission neurons. This could occur through DYNAMIC TRAFFICKING
enhanced glutamatergic synaptic transmis-
sion or through reversal of GABA/glyciner- A variety of pathological processes affect-
gic inhibition.72 In the rat peripheral nerve ing peripheral nerves, sensory ganglia, spinal
compression model, Coull et al.72 observed roots, and CNS structures can induce neu-
that reversing the direction of anionic flux in ropathic pain. When an axon is severed, the
lamina I neurons reverses the effect of GABA proximal stump (attached to the cell body)
and glycine. It is believed that increased cellu- seals off, forming a terminal swelling ‘end-
lar calcium impacts the capacity of neurons to bulb’. Within a day or two, numerous fine
pump chloride out of the cytoplasm through processes (‘sprouts’) start to grow out from the
the potassium chloride co-transporter, KCC-2. endbulb. Regenerating sprouts may elongate
Opening anion channels in the setting of within their original endoneurial tube, reform-
intracellular chloride accumulation results in ing connections, or they may become misdi-
chloride efflux instead of influx. Reversing the rected, forming a variety of different types
direction of anionic flux reverses the effect of of neuromas (Figure 1.15). Various neuroma
 Chapter 1 Physiology of Pain 27

FIGURE 1.27 Paradoxically, GABA/Glycinergic inhibition can be reversed to a state of excitation.

endings have been identified to give rise to Membrane remodeling also impacts
‘ectopic’ activity, which originates in axonal afferent hyperexcitability in neuropathy.
endbulbs, sprouts, patches of demyelination, Membrane proteins responsible for trans-
and in the cell soma, rather than at the usual duction and encoding are synthesized on
location, the peripheral sensory ending.73 ribosomes in the DRG cell soma. Thereafter,
Axotomy experiments have revealed that they are inserted into the local membrane in a
there are high levels of ectopic discharge in process called ‘vesicle exocytosis’ after being
dorsal roots following peripheral axotomy, loaded into the membrane of intracytoplas-
with activity apparently originating in the mic transport vesicles and vectorially trans-
DRG.74 When axons are cut close to the DRG, ported down the axon. Dynamic ‘trafficking’
75% of ectopic afferent activity originates in in normal neurons is closely regulated to
the DRG and 25% in the neuroma.75 When the ensure molecules arrive at their correct desti-
nerve is injured further distally, the neuroma nation in appropriate numbers. For example,
makes a relatively greater contribution. DRG the turnover half-life of sodium channels is
ectopia may be important in herniated inter- thought to be only 1–3 days.78 Various ion
vertebral disks in which the DRG is directly channels, transducer molecules, and recep-
impacted by the disease. A direct relation- tors are synthesized in the cell soma, trans-
ship exists between ectopic afferent firing and ported along the axon, and incorporated in
allodynia in neuropathic pain. Preventing the excess into the axon membrane of endbulbs
generation of ectopia, or blocking its access and sprouts associated with injured affer-
to the CNS, suppresses the allodynia, while ent neurons (Figure 1.28).79 This remodeling
enhancing ectopia accentuates allodynia. The
most convincing specific sign of spontaneous
neuropathic pain in animals (from rodents to
primates) is ‘autotomy’, their tendency to lick,
scratch, and bite numb (but presumably pain-
ful) denervated body parts.76
Other mechanisms, such as ephaptic
cross-talk, distort sensory signals in neu-
ropathy. Each sensory neuron normally con-
stitutes an independent signal conduction
channel; however, excitatory interactions
can develop among neighboring neurons,
amplifying sensory signals and causing sen- FIGURE 1.28 Injured afferent neurons can express
sation spread. an increased state of hyperexcitability. The cell
Thus, cross-excitation in the PNS may stoma synthesizes various ion channels, trans-
ducer molecules, and receptors that are trans-
contribute to windup. Ephaptic (electrical)
ported along the axon and incorporated in
cross-talk occurs when there is a sufficient excess into the axon membrane of the endbulbs
surface area of close membrane apposition and sprouts associated with the injury. (Adapted
between adjacent neurons in the absence of from Devor M. Nerve pathophysiology and mech-
the normal glial insulation.77 Different types anisms of pain in causalgia. J Auton Nerv Syst
of fibers are frequently coupled. 1983; 7: 371–384.)
28 Chronic Pain in Small Animal Medicine

appears to be a causative factor in altered Acute Pain

axonal excitability in some patients.
Neuronal hyperexcitability may also be Everyday acute pain, or ‘nociceptive pain’,
dependent upon intrinsic kinetic properties occurs when a strong noxious stimulus
of the ion channel. For example, cAMP- (mechanical, thermal, or chemical) impacts
dependent phosphorylation or dephosphor- the skin or deep tissue. Nociceptors, a spe-
ylation of the sodium channel molecule cial class of primary sensory nerve fibers, fire
regulates sodium ion current. Certain impulses in response to these stimuli, which
hormones, trophic factors, neuromodula- travel along the peripheral nerves, past the
tory peptides, and inflammatory mediators sensory cell bodies in the DRG, along the
(notably PGs) can activate dephosphorylat- dorsal roots, and into the spinal cord (or
ing enzymes that are positioned to affect brainstem). Thereafter, the conscious brain
afferent excitability by this mechanism. interprets these transmissions from popula-
That is to say, some diffusible mediators tions of second- and third-order neurons of
change sodium and potassium current den- the CNS. Acute pain is purposeful. It pro-
sity, regulating neuronal firing without nec- tects us from potentially severe tissue injury
essarily changing membrane potential.80 In of noxious insults from everyday activities
the understanding of neuropathic pain, it is (Figure 1.30). Acute pain is also short-acting
important to differentiate excitation from and relatively easy to treat.
excitability. Excitation refers to the trans- Physiological pain, a term synonymous
duction process, the ability of a stimulus with nociceptive pain, occurs after most
to depolarize a sensory neuron, creating a types of noxious stimulus and is usually pro-
generator potential. Excitability refers to tective. This type of pain plays an adaptive
the translation of the generator potential role as part of the body’s normal defensive
into an impulse train, where sodium and mechanisms, warning of contact with poten-
potassium channels play a major role. This tially damaging environmental insults, and
distinction has medical treatment implica- it initiates responses of avoidance. Dr. Frank
tions. Neuronal excitation can result from Vertosick states, ‘Pain is a teacher, the head-
a large number of physical and chemical master of nature’s survival school.’81 This
stimuli. Eliminate one, and many others protective system relies on a sophisticated
are still at play. In contrast, if excitability network of nociceptors and sensory neurons
is suppressed, the cell loses its ability to that encode for insult intensity, duration,
respond to all stimuli (Figure 1.29). quality, and location.

FIGURE 1.29 Relationships between peripheral nerve injury and spinal cord responses.
 Chapter 1 Physiology of Pain 29

FIGURE 1.31 Inflammatory pain is associated with

heat, redness, swelling, and loss of function.

symptom, whereas chronic pain can be con-

sidered a disease.

Inflammatory Pain
Inflammatory pain, often categorized along
with acute pain as ‘nociceptive’, refers to
FIGURE 1.30 Acute pain is a signal of life. It is pain and tenderness felt when the skin or
purposeful, of short duration, and most often other tissue is inflamed, hot, red, and swol-
responsive to treatment. len (Figure 1.31).
The inflammatory process is mediated
Physiological pain is rarely a clinical and facilitated by the local release of numer-
entity for treatment, but rather a state to ous chemicals, including bradykinin, PGs,
avoid. Pathological pain, inferring that tissue leukotrienes (LTs), serotonin, histamine, sP,
damage is present, is not transient, and may thromboxanes, platelet-activating factor,
be associated with significant tissue inflam- adenosine and ATP, protons, and free radi-
mation and nerve injury. It is often further cals. Cytokines, such as ILs and TNF, and
classified into inflammatory pain or neuro- neurotrophins, especially nerve growth fac-
pathic pain. From a temporal perspective, tor (NGF), are also generated during inflam-
recent pathological pain can be considered a mation (Figure 1.32).

FIGURE 1.32 Many different cell types and neuromodulators contribute to the pain associated with
inflammation.
30 Chronic Pain in Small Animal Medicine

When there is tissue injury and inflam- sensate; (2) visceral pain has poorer localiza-
mation, the firing threshold of the Aδ and C tion than superficial pain; and (3) visceral
nociceptive afferents in response to heating pain is more strongly linked to emotion than
of the skin is lowered into the non-noxious is superficial pain.
range. This is a result of PG production from A separate pathway for transmitting vis-
COX activity in the arachidonic acid cas- ceral input from the site of origin to the brain
cade, which acts directly on the peripheral does not exist. Every cell that has visceral
terminals of the Aδ and C fibers, lowering input has somatic input: visceral-somatic
their threshold to thermal (but not electrical) convergence. There are cells that receive
stimuli. somatic input only, but there are no cells that
receive visceral input only. During normal
activities, information is conducted from
Incisional Pain somatic origin, such as skin through the
Postoperative incisional pain is a specific spinothalamic tract, to CNS areas of inter-
and common form of acute pain. Studies pretation for nociception. With myocardial
in rodents have characterized the primary infarct/angina, for example, the same spino-
hyperalgesia to mechanical and thermal thalamic tract cells are activated, and the-
stimuli.82 Primary hyperalgesia to mechani- ory has it that the spinothalamic tract may
cal stimuli lasts for 2–3 days, while hyperal- have become ‘conditioned’ to the everyday
gesia to heat lasts longer – 6 or 7 days (after somatic responses, so it now ‘presumes’ it is
plantar incision). The secondary hyperalge- sensing a somatic input rather than visceral
sia is present only to mechanical, not ther- nociception (Figure 1.33).
mal, stimuli.83 A suggested mechanism for referred
Conversion of mechanically insensitive pain is that visceral and somatic primary
silent nociceptors to mechanically respon- neurons converge at common spinal neu-
sive fibers is thought to play an important rons (Figure 1.34). This is the convergence-
role in the maintenance of primary mechani- projection theory, which has considerable
cal hyperalgesia, while release of ATP from supporting experimental evidence.86
injured cells is considered to play an impor- To better explain ‘referred pain with
tant role in the induction of mechanical somatic hyperalgesia’, two theories have
allodynia following skin incision.84 The been proposed. The convergence-facilita-
incision-induced spontaneous activity in pri- tion theory proposes that abnormal vis-
mary afferent fibers helps to maintain the ceral input would produce an irritable
sensitized state of WDR neurons of the dor- focus in the relative spinal cord segment,
sal horn, in contrast to other forms of cuta-
neous injury (e.g. burns), where hyperalgesia
is NMDA dependent.

Visceral Pain
Healthy viscera are insensate or, at best, min-
imally sensate. Such observation dates back
to 1628 when Sir William Harvey exposed
the heart of a patient, and with pinching and
pricking determined that the patient could
not reliably identify the stimulus.85 This is in
contrast to the body surface, which is always
sensate. Injury to the surface of the body ini-
tiates the reflex response of fight or flight,
whereas visceral pain tends to invoke immo-
bility. In general, there is a poor correlation
between the amount of visceral pathology FIGURE 1.33 Neural mechanism underlying
and intensity of visceral pain. Clinical lore angina pectoris. The same spinothalamic cells
has it that (1) viscera are minimally sensate, are activated as by skin, and the ‘default’ source
whereas body surfaces are always highly is considered to be peripheral.
 Chapter 1 Physiology of Pain 31

GENDER AND VISCERAL PAIN

A review of the human literature89 dem- 1
onstrates that women are more likely than
men to experience a variety of recurrent
and visceral pain. Generally, women report
more severe levels of pain, more frequent
pain, and pain of longer duration than do
men. Reports of visceral pain in veterinary
patients is sparse. A report of veterinary out-
patients visiting the Ohio State University
showed that in the year 2002; 1,153 dogs
and 652 cats were presented.90 Twenty per-
cent of the dogs and 14% of the cats were
diagnosed as painful, with approximately
half of each species being diagnosed with
FIGURE 1.34 Convergence-projection theory: vis- visceral pain. No differences were noted
ceral and somatic primary neurons converge at related to gender; however, most animals
common spinal neurons.
presented were neutered or spayed. Studies
in rats show that visceral hypersensitivity
varies over the estrous cycle, where rats are
thus facilitating messages from somatic more sensitive during proestrus, and proes-
structures. The second theory postulates trus rats are more hypersensitive than male
that the visceral afferent barrage induces rats.91 Kamp et al. have shown that female
the activation of a reflex arc, the afferent mice are more sensitive to visceral pain than
branch of which is presented by visceral males in a colorectal distention model, but
afferent fibers and the efferent branch by have also shown that response varies with
somatic efferents as well as sympathetic the strain of mouse.92 There is a stunning
efferents toward the somatic structures overrepresentation of male subjects in the
(muscle, subcutis, and skin). The efferent study of pain (approximately 20:1),93 per-
impulses toward the periphery would then haps reflecting the concern of experimental
sensitize nociceptors in the parietal tissues variability with female subjects, supporting
of the referred area, thus resulting in the the case for inclusion of more female subjects
phenomenon of somatic hyperalgesia. in basic science studies of pain.
Visceral pain is also processed differ-
ently. Although primary afferents subserv-
ing visceral, cutaneous, and muscle pain
Visceral Pain Models
are mostly distinct, at the dorsal horn there A number of visceral pain models exist.
is considerable convergence of these path- Distention of hollow organs is a common
ways so that spinothalamic, spinoreticular, model. More often, distension of the distal
and spinomesencephalic tracts all contain gastrointestinal tract (colon, rectum) has
neurons that respond to both somatic and been used to evoke respiratory, cardiovas-
visceral stimuli. 87 Functional magnetic res- cular, visceromotor, behavioral, and neuro-
onance imaging (fMRI) reveals a common physiological responses in multiple species
cortical network subserving cutaneous and including horse, dog, cat, rabbit, and rat.
visceral pain that could underlie similarities Contemporary thinking is that viscera are
in the pain experience. However, differen- not insensate but are minimally sensate in
tial activation patterns within insular, pri- the healthy state and can become very sen-
mary somatosensory, motor, and prefrontal sitive following pathology that upregulates
cortices of the brain have been identified sensation from a subconscious state to the
that may account for the ability to distin- conscious state.
guish visceral and cutaneous pain as well as Strigo et al. have used psychophysical
the differential emotional, autonomic, and measures to directly compare visceral and
motor responses associated with different cutaneous pain and sensitivity.94 Healthy
sensations.88 human subjects evaluated perceptions evoked
32 Chronic Pain in Small Animal Medicine

FIGURE 1.35 In human studies, visceral pain is more unpleasant, diffuse, and variable than cutaneous
pain of similar intensity.

by balloon distention of the distal esopha- quantitatively fewer per unit area than simi-
gus and contact heat on the upper chest. For lar measures of cutaneous afferents. This may
esophageal distention, the threshold for pain suggest that increased activity is required to
intensity was higher than that observed for cross a threshold for perception. The large
unpleasantness, whereas for contact heat, proportion of silent afferents in viscera also
pain and unpleasantness thresholds did not help explain the variation of sensitization.
differ for either phasic or tonic stimulus Silent afferents have been frequently noted in
application. Results support that visceral visceral structures to form up to 50% of the
pain is more unpleasant, diffuse, and vari- neuronal sample.95
able than cutaneous pain of similar intensity, The mucosa, muscle, and serosa of hol-
independent of the duration of the presented low organs as well as the mesentery, but
stimuli (Figure 1.35). not the parenchyma, of solid organs con-
tain visceral receptors.96 Inflammation will
lower nociceptor firing thresholds, result-
VISCERAL STIMULI ing in a broader recognition of pain expe-
rienced at lower distension pressures. As
A lack of sensitivity in viscera at base- previously mentioned, inflammation also
line may relate to the sparse population of recruits ‘silent’ nociceptors, which fire at
visceral afferents themselves, which are lower thresholds or become sensitized by
 Chapter 1 Physiology of Pain 33

hypoxemia and ischemia.97 Acute pain is Poor Localization of Visceral Pain

the sum of high-threshold nociceptors acti-
vated at high pressures, where chronic nox- Much of our knowledge surrounding the
poor localization of visceral pain comes
1
ious stimuli recruit previously unresponsive
or silent nociceptors through hypoxemia or from clinical practice in humans. Visceral
inflammation. Pain sensations correlate with pain is not normally perceived as localized to
generated intracolonic or small bowel pres- a given organ, but to somatic structures that
sures and increased wall tension rather than receive afferent inputs at the same spinal seg-
intraluminal volume.98 Accordingly, patients ments as visceral afferent entry. The actual
may have ileus without pain. source of the visceral pain may only be local-
Stimulated visceral nociceptors release ized when manipulation or physical exami-
both sP and CGRP within synapses of the nation might stimulate the painful organ.
dorsal horn. Activation of visceral afferents Classically, visceral pain is considered either
also results in upregulation of NOS in the as wholly unlocalized pain or as referred
spinal cord dorsal horn and causes expres- pain, with two separate components: (1) the
sion of the oncogene c-fos.99 Kappa receptor diseased viscera sensation is transferred to
agonists bind to peripheral visceral afferents, another site (e.g. ischemic myocardium felt
suppressing the release of sP and expression in the neck and arm) or (2) hypersensitivity
of c-fos in the dorsal horn.100 at other sites from inputs directly applied to
Peripheral reduction in nociceptive those other sites (e.g. flank muscle becoming
thresholds leads to primary visceral hyper- sensitive to palpation concurrent with uro-
sensitivity. Secondary hypersensitivity is a lithiasis) – a phenomenon called secondary
central neuroplastic reaction to activated somatic hyperalgesia.
C fibers and convergence. Visceral central The very neuroanatomy of viscera sug-
hypersensitivity is maintained by glutamate gests their unique pain response (Figure 1.36).
release that binds to NMDA receptors, the The pattern of distribution for visceral pri-
activation of which leads to NOS expression, mary afferents differs markedly from that
NO production, and PG production.101 of cutaneous primary afferents. Visceral

FIGURE 1.36 The neuroanatomy of canine viscera suggests their unique pain response.
34 Chronic Pain in Small Animal Medicine

sensory pathways tend to follow perivascu- Collectively, there is an imprecise and dif-
lar routes that are diffuse in nature. Visceral fuse organization of visceral primary inputs
afferent pathways have peripheral sites of appearing consistent with an imprecise and
neuronal synaptic contact that occur with diffuse localization by the CNS.
the cell bodies of prevertebral ganglia such
as the celiac ganglion, mesenteric ganglion,
and pelvic ganglion. This architecture can VISCERAL
lead to alterations in local visceral function
outside central control. The gut is probably HYPERSENSITIZATION
an extreme example, where it functions by
its own ‘independent brain’ that regulates The bladder is one of the few viscera that have
the complex activities of digestion and recognized sensation when healthy and when
absorption. diseased. As with irritable bowel syndrome
DRG neurons innervating the viscera tend (IBS), hypersensitivity to somatic stimuli is
to follow the original location of structural noted in people with interstitial cystitis (IC).
precursors of the viscera during embryologi- Subjects with IC are significantly more sen-
cal development. Afferents of a given viscus sitive to deep tissue measures of sensation
may have cell bodies in the dorsal root gan- related to pressure, ischemia, and bladder
glia of 10 or more spinal levels, bilaterally stretch than healthy subjects, showing an
distributed. Further, individual viscerocep- upward and left shift of reported discomfort
tive afferent fibers branch once they enter the with bladder filling (Figure 1.38).103
spinal cord and may spread over a dozen or
more spinal segments, interacting with neu- Cross-Organ Communication:
rons in at least five different dorsal horn lam-
inae located bilaterally in the spinal cord.102
Visceral Organs
Upon further examination, spinal dorsal As many as 40%–60% of human patients
horn neurons with visceral inputs have mul- diagnosed with IBS also exhibit symptoms
tiple inputs, from the viscera, joints, muscle, and fulfill diagnostic criteria for IC; corre-
and cutaneous structures (Figure 1.37). spondingly, 38% of patients diagnosed with

FIGURE 1.37 Spinal dorsal horn neurons with visceral inputs have multiple inputs from the viscera, joints,
muscle, and cutaneous structures.
 Chapter 1 Physiology of Pain 35

FIGURE 1.39 Cross-organ convergence: conver-

gence of colonic and urinary bladder afferent
fibers onto a spinothalamic tract cell.

FIGURE 1.38 Human subjects with interstitial a result of the interaction between algogenic
cystitis (IC) show an upward and left shift of dis- conditions of more than one visceral organ
comfort with bladder filling compared to normal, (Figure 1.40).
healthy subjects. Single asterisk indicates sig-
nificant difference in subjects with IC vs. healthy
subjects ( p <0.05). Double asterisks indicate
significant difference in subjects with IC versus
healthy subjects ( p <0.01).103
VISCERAL PAIN AND
EMOTION
IC also have symptoms and fulfill diagnostic Human studies, as well as animal mod-
criteria for IBS.104,105 Because neural cross- els, have demonstrated that visceral pain is
talk exists under normal conditions, altera- strongly linked to emotion. The emotional
tions in neural pathways by disease or injury state frequently alters function of the vis-
may play a role in the development of over- cera,109 and the reverse is true – and is far
lapping chronic pelvic pain disorders and more pronounced than with equal intensity
pelvic organ cross-sensitization. of superficial pain. This tends to evoke an
Pezzone et al.106 have developed a rodent unending cycle of feedback between vis-
model for studying pelvic organ reflexes, ceral pain and anxiety. Therefore, it would
pelvic organ cross-talk, and associated stri- appear appropriate to include an anxiolytic
ated sphincter activity that has shown (1) in a pharmacotherapeutic regimen targeting
colonic afferent sensitization occurs fol- chronic visceral pain syndromes.
lowing the induction of acute cystitis and
(2) urinary bladder sensitization occurs
following the induction of acute colitis.
A possible explanation might be that the VISCERAL PAIN SUMMARY
inflamed colon and urinary bladder have a
common afferent axon that enters the spi- Visceral pain is unique for several reasons:
nal cord, resulting in the observed effect
(Figure 1.39). • There is a poor correlation between the
In the rat, approximately 14% of superfi- amount of tissue injury and visceral pain.
cial and 29% of deeper L6–S2 spinal neurons • Patterns of referred pain are a result of the
receive convergent inputs from both the uri- convergence of somatic and visceral affer-
nary bladder and colon.107 In cats, approxi- ents on the same dorsal horn neurons within
mately 30% of the sacral and thoracolumbar the spinal cord.
compound spinal interneurons have conver- • Clinical visceral pain is poorly localized (in
gent inputs from both the urinary bladder humans), midline, and perceived as deep
and colon, and both of these visceral organs because, in part, of poor representation
either excite or inhibit approximately 50% of within the primary somatosensory cortex.
the neurons.108 These facts suggest that pel- • More so than in somatic pain, visceral pain
vic pain conditions and disorders might be is accompanied by autonomic responses.
36 Chronic Pain in Small Animal Medicine

FIGURE 1.40 Pelvic pain severity is transmitted by the sum of activity from nonspecific sensory receptors
within mucosa, smooth muscle, and serosa. Further, convergence makes it difficult to identify a single
focus of input.

• Only a minority of visceral afferents are sen- Anatomical differences influencing vis-
sory, most relate to motor or reflex responses, ceral pain, where perception and psycho-
and few have specialized sensory terminals. logical processing are different from somatic
• Pain severity is transmitted by the sum of pain, include:
activity from nonspecific sensory receptors
within mucosa, smooth muscle, and serosa. • A low number of visceral nociceptors com-
pared with somatic nociceptors.
See Table 1.6. • Lack of specialization.
• Visceral polymodal nociceptors.
• Convergence with somatic afferents on dor-
sal horn laminae resulting in referred pain.
TABLE 1.6 Differences between visceral
and somatic pain processing • Hypersensitivity that is both peripherally
and centrally mediated, but not by windup
Superficial characteristic of somatic pain.
Visceral pain pain • Unique ascending tracts through the dorsal
Innervation Spinal + Vagal Spinal column; low and poor representation with
primary somatosensory cortex; rich input
Injury No Yes
through the medial thalamus to the limbic
Noxious Stretch Damage cortex, amygdala, anterior cingulate, and
Inflammation Threat of insular cortices.
Ischemia damage
• Close association with autonomic nerves.
Localization Poor Excellent
Referred pain The rule The exception Visceral sensitization mechanisms are:

Pathology Not related to Related to • Ongoing pain sensation.

intensity intensity
• Enhanced response to a given stimulation.
 Chapter 1 Physiology of Pain 37

TABLE 1.7 Potentially useful agents in the management of visceral pain

Agent Mode of action 1
Kappa opioid agonist Peripheral kappa receptor agonists on visceral afferents reduce sP and
CRGP
Mu and delta opioids Central mu and delta receptors reduce primary nociceptor activity and
central hypersensitivity through periaqueductal gray activity
NSAIDs Block spinal cord and peripheral PG and central hypersensitivity
Ketamine, methadone, Block dorsal horn NMDA receptors
amantadine
Corticosteroids Block expression of spinal cord NOS and reduce hypersensitivity
Gabapentin Reduce central glutamate levels and NMDA binding for hypersensitivity
α2-adrenoreceptor Facilitate descending inhibitory tracts through the periaqueductal gray
agonists
Tricyclic antidepressants Facilitate descending inhibitory tracts in periaqueductal gray
Anticholinergics Reduce colic and intestinal secretion
Somatostatin Inhibit vasointestinal peptide and decreases colic and intestinal secretion
and reduce central hypersensitivity

Peripheral mechanisms are: TACTILE ALLODYNIA

• Activation of visceral afferent fibers.
Tactile allodynia appears to be a sensory
response to impulse activity in low-threshold
Spinal mechanisms are:
mechanosensitive Aβ afferents abnormally
• Sensitization of spinal neurons.
• Expanded spatially distributed spinal input.
See Table 1.7.

NEUROGENIC INFLAMMATION
Release of sP and NGF into the periphery
causes a tissue reaction termed neurogenic
inflammation. Neurogenic inflammation is
driven by events in the CNS and does not
depend on granulocytes or lymphocytes,
as with the classic inflammatory response
to tissue trauma or immune-mediated cell
damage. Cells in the dorsal horn release
chemicals that cause action potentials to fire
backward down the nociceptors. The result
of this dorsal root reflex is that nociceptive
dendrites release sP and CGRP into periph-
eral tissues, causing degranulation of mast
cells and changing vascular endothelial cell
characteristics. The resultant outpouring of
potent inflammatory and vasodilating agents
causes edema and potentiates transmission FIGURE 1.41 Neurogenic inflammation varies from
of nociceptive signals from the periphery the classic inflammatory response, as it is driven
(Figure 1.41). by events in the CNS.
38 Chronic Pain in Small Animal Medicine

‘amplified’ by central sensitization. Aβ affer-

TABLE 1.8 Human conditions in which
ents normally signal touch and vibration, but neuropathic/neurogenic pain may appear
in neuropathy (and inflammation) they evoke
pain. ‘Aβ’ pain has opened new insights into Peripheral
the understanding of pain systems, displac- • Traumatic (including iatrogenic) nerve injury
ing Aβ and C fibers as the exclusive, and
• Ischemic neuropathy
perhaps even the most important, primary
afferent signaling channel for pathophysi- • Nerve compression/Entrapment
ological pain.
• Polyneuropathy (hereditary, metabolic, toxic,
Cervero and Laird110 proposed a model inflammatory, infection, paraneoplastic,
for the phenomenon of touch-evoked pain nutritional or in amyloids or vasculitis)
(allodynia), expanding on the gate the-
• Plexus injury
ory and neurogenic inflammation (axon
reflexes). Their model is based on the notion • Root compression
that Aβ mechanoreceptors can gain access
• Stump and phantom pain after amputation
to nociceptive neurons by means of a pre-
synaptic link, at the central level, between • Postherpetic neuralgia
low-threshold mechanoreceptors and noci- • Trigeminal and glossopharyngeal neuralgia
ceptors. Purportedly, excitation of nocicep-
tors provoked by a peripheral injury activates • Cancer-related neuropathy (i.e., due to neural
invasion of the tumor, surgical nerve damage,
the spinal interneurons that mediate primary
radiation-induced nerve damage, or
afferent depolarization between low-thresh- chemotherapy-induced neuropathy)
old mechanoreceptors and nociceptors.
Resultant from the increased and persistent • Scar pain
barrage driving these neurons, their excit- Central
ability is increased such that, when activated
Stroke (infarct or hemorrhage)
by low-threshold mechanoreceptors from •

areas surrounding the injury site, they pro- • Multiple sclerosis

duce a very intense primary afferent depolar-
• Spinal cord injury
ization in the nociceptive afferents capable
of generating spike activity. Such activation • Syringomyelia/Syringobulbia
is conducted antidromically in the form of
dorsal root reflexes, but would also be con-
ducted forward, activating the second-order is frequently difficult to treat (Figure 1.42),
neurons normally driven by nociceptors. The but may respond to certain anticonvulsants,
sensory consequence of this mechanism is tricyclic antidepressants (TCAs), and anti-
pain evoked by the activation of low-thresh- arrhythmics (Table 1.9). Local anesthetics
old mechanoreceptors from an area sur- applied systemically, topically, or to block
rounding an injury site (allodynia). nerves may also be effective. The separation
between inflammatory and neuropathic pain
does not exclude inflammatory components
Chronic Pain in neuropathic pain or neuropathic compo-
In contrast to acute pain, where the pain nents in inflammatory pain. There are no sys-
stops quickly after the noxious stimulus tematic studies in neuropathic pain patients
has been removed, the pain and tenderness on the correlation between the intensity of
of inflammation may last for hours, days, the symptoms and the nature and severity of
months, and years. Recognition of the poten- the nerve injury.
tial peripheral mediators of peripheral sensi- Chronic pain can result from sustained
tization after inflammation gives insight as noxious stimuli such as ongoing inflamma-
to the complexity of this process. Persistent, tion, or it may be independent of the incit-
or chronic, pain is often neuropathic pain, ing cause. Regardless of its etiology, chronic
which arises from injury to the PNS or CNS pain is maladaptive and offers no useful
(Table 1.8). biological function or survival advantage.
Chronic pain appears to have no purpose, The nervous system itself actually becomes
is characterized by extended duration, and the focus of the pathology and contributes
 Chapter 1 Physiology of Pain 39

FIGURE 1.42 Chronic pain appears to have no purpose, lasts beyond an expected normal physiological
response to the noxious insult, and is often difficult to treat.

TABLE 1.9 Mechanisms of neuropathic pain with corresponding drug targets

Mechanism Target Drug (human use)
Peripheral sensitization TRPV1 receptors Capsaicin
Altered expression, Voltage-gated K+ channels –
distribution, and function
of ion channels
Voltage-gated Na+ channels • Local anesthetics, e.g., lidocaine
• Antiepileptics, e.g., carbamazepine,
lacosamide, lamotrigine
• Antiarrhythmic agents, e.g., mexiletine
HCN channels –
P2X-receptor-gated channels –
Voltage-gated Ca2+ channels Ziconotide, gabapentin, pregabalin
Increased central excitation NMDA receptors Ketamine, ifenprodil
NK1 receptors –
Reduced spinal inhibition Opioid receptors Morphine, oxycodone, tramadol
GABA receptors Baclofen
Glycine receptors –
Deregulated supraspinal Monoamines • Tricyclic antidepressants, e.g.,
control amitriptyline, nortriptyline
• Serotonin and norepinephrine reuptake
inhibitors, e.g., duloxetine, tramadol
Immune system involvement Cytokines NSAIDs
TNF-α –
Microglia –
Schwann cell dedifferentiation Growth factors –
40 Chronic Pain in Small Animal Medicine

to patient morbidity. Effective treatment for involved, depending on the nature and time
chronic pain can be an enigma. Several stud- course of the originating stimulus.114
ies have shown that the longer a pain lingers, These three phases include (1) the pro-
the harder it is to eradicate. This is because cessing of a brief noxious stimulus; (2) the
pain can reconfigure the architecture of the consequences of prolonged noxious stimula-
nervous system it invades. tion, leading to tissue damage and periph-
Chronic pain was traditionally defined eral inflammation; and (3) the consequences
as pain lasting more than 3 or 6 months, of neurological damage, including periph-
depending on the source of the defini- eral neuropathies and central pain states
tion.111,112 More recently, chronic pain has (Figure 1.43).
been defined as ‘pain that extends beyond
the period of tissue healing and/or with low • Phase 1: acute nociceptive pain (physiologi-
levels of identified pathology that are insuffi- cal pain). Mechanisms underlying the pro-
cient to explain the presence and/or extent of cessing of brief noxious stimuli are fairly
pain’.113 There is no general consensus on the simple, with a direct route of transmission
definition of chronic pain. In clinical practice centrally toward the thalamus and cortex
it is often difficult to determine when acute resulting in the conscious perception of
pain has become chronic. pain, with the possibility for modulation
occurring at synaptic relays along the way.
It is reasonably easy to construct plausible
Acute to Chronic Pain and detailed neuronal circuits to explain the
Normally, a steady state is maintained in features of phase 1 pain.
which there is a close correlation between • Phase 2: inflammatory pain. If a noxious
injury and pain. Yet long-lasting or very stimulus is very intense or prolonged, lead-
intense nociceptive input or the removal of ing to tissue damage and inflammation,
a portion of the normal input can distort the it might be considered phase 2 pain, as
nociceptive system to such an extent that the influenced by response properties of vari-
close correlation between injury and pain can ous components of the nociceptive system
be lost. A progression from acute to chronic changing. These changes note that the CNS
pain might be considered as three major has moved to a new, more excitable state as
stages or phases of pain, proposing that dif- a result of the noxious input generated by
ferent neurophysiological mechanisms are tissue injury and inflammation. Phase 2 is

FIGURE 1.43 Progression of acute to chronic pain can be considered as phases of pain: brief (acute
nociceptive), persisting (inflammatory), and abnormal (neuropathic).
 Chapter 1 Physiology of Pain 41

characterized by its central drive, a drive

that is triggered and maintained by periph-
eral inputs. Patients experience spontaneous 1
pain and sensation changes evoked by stim-
ulation of the injured and surrounding area.
Such change is known as hyperalgesia –
a leftward shift of the stimulus-response
curve. Hyperalgesia in the area of injury
is termed primary hyperalgesia, and in the
areas of normal tissue surrounding the
injury site, secondary hyperalgesia. FIGURE 1.44 Integration of the physical dimen-
• Phase 3: neuropathic pain. This pain is sions of pain with the psychological factors,
abnormal pain, generally the consequence which are closely linked, gives insight into the
of either damage or altered neuroprocessing complexity of managing pain-induced distress
within peripheral nerves or within the CNS (suffering).
itself, characterized by a lack of correlation
between injury and pain. Clinically, phase
1 and 2 pain are symptoms of peripheral Neuropathic Pain
injury, whereas phase 3 pain is a symptom of Primary sensory neurons are able to signal
neurological disease. These pains are spon- specific sensory experiences because they
taneous, triggered by innocuous stimuli, or respond with electrical impulses to specific
are exaggerated responses to minor noxious types of stimuli (touch, pinch, heat, cold,
stimuli. A particular combination of mecha- vibration, etc.), and because they commu-
nisms responsible for each of the pain states nicate with second-order sensory neurons
is likely unique to the individual disease or in the spinal cord via specific synaptic con-
to a particular subgroup of patients. Phase nectivity using specific neurotransmitters.
3 pain may involve genetic, cognitive, or Maintaining these settings requires a com-
thalamic processing that has yet to be iden- plex biological process. If there has been
tified. Activation of these mechanisms may nerve injury, the electrical properties, neuro-
be abnormally prolonged or intense due to chemistry, and central connectivity of these
abnormal input from damaged neurons, or neurons can change, wreaking havoc on
simply because the regenerative properties normal sensory processing and sometimes
of neurons are very poor or ‘misdirected’. inducing severe chronic neuropathic pain.
Healing may never occur. Finally, there are The International Association for the
many mixed nociceptive-neuropathic pains, Study of Pain (IASP)115 defines neurogenic
not only in malignant disease, but also in pain as ‘pain initiated or caused by a pri-
conditions such as herniated intervertebral mary lesion or dysfunction or transitory
disk and postamputation (phantom) limb perturbation in the peripheral or central
pain. nervous system’. Due to potential vagaries
within this definition, simplistically, neuro-
Consideration of chronic pain as a disease pathic pain can be identified as pain due to a
per se, rather than a symptom, enables the primary lesion or malfunction of the PNS or
fundamental importance of the nonphysical CNS. Neuropathic pain is divided between
elements of pain to be considered. Integration diseases with demonstrable neural lesions in
of the physical dimensions of pain with the the PNS and CNS and those conditions with
psychological and social factors, which are no tangible lesion of major nerves and CNS.
closely linked together, allows a significant Therefore, there are ambiguities in identify-
and deliberate move away from traditional ing neuropathic diseases, and currently no
Cartesian dogma (Figure 1.44). tests are available that can unequivocally
As a result, treatment of one dimension diagnose neuropathic pain. Nevertheless, a
alone may not result in improvement at other large body of evidence validates the theory
levels, and the complexity of suffering (pain- of the physiological process underlying neu-
induced distress) (particularly in humans) ropathic pain.
is a challenge mandating a multifaceted Many kinds of nerve injury can induce
approach. electrical changes: trauma, viral or bacterial
42 Chronic Pain in Small Animal Medicine

infection, poor nutrition, toxins, autoim- The word ‘neuropathic’ is preferred

mune events, etc. Axon and myelin damage because it encompasses changes in func-
are known to cause a number of key changes tion as well as damage to a nerve as
in the functioning (‘phenotype’) of sensory possible causes of pain. Two major conse-
neurons, some of which lead to ectopic spon- quences for pain in neuropathy result from
taneous discharge. central sensitization. Input from residual
The relative role of peripheral and central uninjured Aβ touch afferents is rendered
mechanisms in neuropathic pain is not well painful. More than amplification, this is
understood and likely reflects different dis- a change in modality: from touch to pain.
ease states and genetic differences; however, Second, central sensitization may ren-
the abnormal input of neural activity from der spontaneous ectopic Aβ fiber activity
nociceptor afferents plays a dynamic and painful.
ongoing role in maintaining the pain state. An understanding of neuropathic pain
Two key concepts are critical to an under- is increasing with the realization that the
standing of neuropathic pain: (1) inappro- nervous system is not a ‘hard-wired, line-
priate activity in nociceptive fibers (injured labeled system’, but one that demonstrates
and uninjured) and (2) central changes occur ‘plasticity’, in that the function and struc-
in sensory processing that arise from these ture of the system alter with continuing
abnormalities. development, experience, or consequences
Neuropathic pain is caused by pathologi- of injury. The nervous system appears to
cal change or dysfunction in either the PNS retain a ‘memory of pain’, explained, per-
or CNS (Figure 1.45). Neurogenic pain, deaf- haps, by induction of the c-fos gene from
ferentation pain, and dysesthetic pain are all prolonged peripheral input leading to struc-
terms used to describe this entity. tural change.

FIGURE 1.45 Possible sites for neuropathic pain generation.

 Chapter 1 Physiology of Pain 43

CONTRIBUTION OF SCHWANN Animal models of neuropathic pain have

CELLS, GROWTH FACTORS,

largely focused on peripheral nerve injury:
trigeminal neuralgia,119 diabetic neuropa- 1
thy,120 and vincristine neuropathy,121 and can
AND PHENOTYPIC SWITCHES be broadly divided into peripheral mononeu-
TO NEUROPATHIC PAIN ropathic, peripheral polyneuropathic, and
central neuropathic pain, in line with the
The degree of primary afferent fiber myelina- human conditions. The spinal nerve ligation
tion is dependent on the integrity of envel- (SNL) model of peripheral mononeuropa-
oping Schwann cells that control sensory thy, where the L5 and L6 spinal nerves are
neuron development and function. Nerve unilaterally ligated close to their respective
injury can result in Schwann cell dedifferen- ganglia to produce a restricted partial dener-
tiation and a consequent switch from normal vation of the hindlimb, is favored by many
myelin production to the deregulated synthe- investigators.
sis of neurotrophic factors. Excessive growth In 1979, Wall et al.76 introduced a neu-
factors in the neuronal environment for a roma model where the sciatic and saphenous
prolonged time can adversely affect neigh- nerves of rats were transected and removed,
boring intact and injured neurons, contribut- thereby assessing pain that occurs following
ing to the pain phenomenon.116 complete nerve transection. From this model
Constitutive availability of growth fac- it is unclear if resultant autotomy (self-
tors in peripheral sensory neurons main- mutilation of the limb) is due to spontane-
tains the normal neuronal phenotype. For ous pain or complete absence of sensation.
example, NGF is taken up by free sensory Further, many pain conditions seen follow-
nerve endings and transported retrograde to ing nerve injury are due to partial, rather
the cell body, where it controls the expres- than complete, nerve injury. Accordingly,
sion of genes that are crucial for homeostatic several models of partial nerve injury have
sensory function. Such genes include those been developed, including chronic constric-
encoding neurotransmitters, receptors, and tion injury,122 partial nerve ligation,123 spinal
ion channels. One consequence of this dis- nerve transection124 or ligation,125 cryoneu-
ruption, as from nerve injury, is a downregu- rolysis,126 and sciatic nerve ischemia.127 In
lation of sP and CGRP in peptidergic fibers, these models input is preserved, allowing
with a concomitant upregulation of the usu- analysis of changes in mechanical and ther-
ally quiescent sP in Aβ fibers.117 Tissue NGF mal thresholds in addition to the guarding
can additionally drive peripheral and central and autotomy that are believed to be signs of
sensitization by upregulating neuronal con- spontaneous pain. Animal models are most
tent of brain-derived neurotrophic factor useful in gaining an understanding of the
(BDNF). Surrogate sources of BDNF have physiological processes involved in the devel-
potent neuroprotective effects on axoto- opment and maintenance of chronic pain, in
mized sensory neurons and can reverse some exploring and developing new treatments,
of the changes in sodium channel expression and in providing insights into clinical presen-
that are consequent to Schwann cell disorga- tations; however, it is extremely difficult to
nization and neuropathic pain.118 interpret the complex emotional, behavioral,
and environmental factors that impact the
overall disease state.
Models of Neuropathic Pain Postherpetic neuralgia (PHN), along with
Neuropathic pain can be broadly divided painful diabetic neuropathy (PDN), is one of
into central and peripheral neuropathic pain, the best models for the clinical investigation
depending on whether the primary lesion or of human neuropathic pain because numbers
dysfunction is situated in the CNS or PNS, of patients are adequate and the condition
and may be due to mechanical trauma, provides a stable chronic pain state and a
ischemia, degeneration, or inflammation. contralateral control. Trigeminal neuralgia is
A broad range of pathologies may result, also a model frequently cited when assessing
including transient ischemia, giving rise to drug response in humans.
a selective loss of specific neuronal type, or Information on the number needed to
perhaps complete denervation. treat (NNT) has provided insight into the
44 Chronic Pain in Small Animal Medicine

FIGURE 1.46 Numbers needed to treat in peripheral and central neuropathic pain. Circle size and related
numbers indicate number of patients who received active treatment.128

overall effect of drugs in groups of patients Generally, NNTs between 2 and 5 are
in different neuropathic pain states and indicative of effective analgesic treatments.
has become a common assessment param- Guidelines for the pharmacological treat-
eter. NNT is an estimate of the number of ment of neuropathic pain in humans have
patients that would need to be given a treat- been published (Figure 1.47).128,129
ment for one of them to achieve a desired out-
come; e.g. for postoperative pain, the NNT
describes the number of patients who have to TRACKING ELEMENTS
be treated with an analgesic intervention for
one of them to have at least 50% pain relief INVOLVED IN POST–TISSUE
over 4–6 hours and who would not have had
pain relief of that magnitude with placebo
INJURY PAIN STATES
(Figure 1.46). Damage to a peripheral nerve initiates a cas-
cade of peripheral nerve molecular events,
1 and tissue inflammation sensitizes the
NNT =
(Proportion of patients with at least 50% pain peripheral nerve to a more dramatic stimula-
relief from analgesic − Percentage of patients tion response. However, it is also recognized
with at least 50%pain relief with placebo) that inflammation or peripheral nerve injury
 Chapter 1 Physiology of Pain 45

stimuli) begin to express sP. Since sP is asso-

ciated with only small-diameter neurons
(which give rise to C fibers and transmit pain 1
and temperature) and transduction of nox-
ious information, this may lead to misinter-
pretation of light touch and proprioception
by the spinal cord and brain. Sprouting of the
Aβ nerves within the spinal cord may also
occur, with new contacts formed between
the Aβ (laminae III–IV) and C fibers (super-
ficial laminae). This may be a basis for the
development of chronic pain and allodynia.
Activity in sensory afferents is largely
absent under normal physiological condi-
tions, yet peripheral thermal and mechani-
cal stimuli will evoke intensity-dependent
increases in firing rates of lightly myelin-
ated (Aδ) or unmyelinated (C) afferent fibers
(Figure 1.48). As a result, the nervous system
maintains a specific intensity-, spatial- and
modality-linked encoding of the somatic
stimulus. In humans, the response parallels a
FIGURE 1.47 Treatment algorithm for peripheral psychophysical report of pain sensation, and
neuropathic pain in humans. Topical lidocaine in animals, it parallels the vigor of the escape
has been shown to be analgesic in patients with
response.
allodynia.128
In the event that tissue is not actually
injured, removal of the stimulus is accom-
will produce dramatic changes in the spinal panied by a rapid abatement of the afferent
cord. These include the release of neurotrans- input and pain sensation. Herein the ques-
mitters such as glutamate, sP, neurokinin A, tion arises, ‘why do we hurt after injury even
and CGRP. This is followed by activation of though the initiating stimulus is removed?’
certain receptors, such as the NMDA chan- There is no spontaneous activity of pri-
nel, which, in turn, initiate a further cascade mary afferents. Following tissue injury, there
of events within neurons. Such a cascade
includes the activation of second messengers
(calcium, PGs, and NO) and expression of
particular genes, such as c-fos. The amount
of protein product of the c-fos gene in the
spinal cord correlates with the initial stimu-
lus magnitude,40 but it also mediates some of
the adaptive responses of the spinal cord.
Neuropeptide levels in the spinal cord also
change. The levels of GABA fall, and the lev-
els of cholecystokinin, a neuropeptide with
anti-opioid actions, increase dramatically
with peripheral nerve damage. An increased
production of novel sodium channels medi-
ated by nerve injury and NGF adds further
to excessive spinal cord excitability. This can
result in a state of spinal cord disinhibition
and increased receptivity to incoming stimuli.
Following nerve injury and inflamma-
tion, profound changes occur in the neuronal
phenotype. Large-diameter primary affer- FIGURE 1.48 Activities associated with transient
ent neurons (which transmit non-noxious high-intensity stimuli.
46 Chronic Pain in Small Animal Medicine

is an ongoing sensory experience associ- ions released from inflammatory cells and
ated with primary hyperalgesia (extremely plasma extravasation products. These result
noxious sensation with moderate stimulus in stimulation and sensitization of free nerve
applied to the injury site) and secondary tac- endings that depolarize terminals, with the
tile allodynia (very unpleasant sensation with local release of sP and CGRP into the injured
mechanical stimulus applied adjacent to the tissues. Thus, mild damage to cutaneous
injury site), i.e., tissue injury–evoked afferent receptive fields results in significant increases
activity. When tissue injury involves trauma in the excitability of polymodal nociceptors
(crush) or an incision, such stimuli result in (C fibers) and high-threshold mechanorecep-
elaboration of active products that directly tors. Some C fibers have thresholds so high
activate afferent local terminals innervat- as to be activated only by intense physical
ing the injury region and facilitating their stimuli: these are silent nociceptors.
discharge to an ongoing afferent barrage Under the influence of the inflammatory
(Figure 1.49). In addition, after local injury, milieu, these silent nociceptors are sensitized
afferent terminals increase their response to such that they become spontaneously active,
any given stimulus. with activity that can be enhanced by rela-
Tissue injury leads to localized extravasa- tively mild physical stimuli.
tion of plasma and increased capillary wall Transduction of a physical stimulus
permeability. Such a physiological response occurs by terminal sensors (such as transient
is manifest as the ‘triple response’ of red- receptor potential [TRP] for temperature,
ness (local arterial dilatation), edema (from ATP and P2X for mechanical and hydrogen
capillary permeability), and hyperalgesia ions, and acid-sensing ion channels [ASICs]
(left shift of the stimulus-response curve). for chemicals), which convert the energy
Hormones, such as bradykinin, PGs, and to local terminal neuronal depolarization
cytokines (small secreted polypeptides/gly- (transduction) (Figure 1.50).
coproteins that mediate and regulate immu- The increasing stimulus intensity
nity, inflammation, and hematopoiesis), increases channel opening for the passage
bind to specific membrane receptors, which of sodium or calcium ions that then depo-
then signal the cell via second messengers, larize the membrane and lead to an action
often tyrosine kinases, to alter its function: potential: nerve conduction. The greater the
activate local release of effector molecules/ stimulus, the greater the depolarization and
gene expression or potassium or hydrogen the greater the frequency of discharge.

FIGURE 1.49 ‘Active’ factors generated from peripheral injury and effect of NSAIDs on stimulus fre-
quency (upper graph).
 Chapter 1 Physiology of Pain 47

FIGURE 1.50 Terminal sensors are activated by various physical stimuli, giving rise to terminal depolar-
ization. (ASIC: acid-sensing ion channel, Nav 1.8: TTX-resistant voltage-gated sodium channel, P2X:
subtype of ATP receptor, TRP: transient receptor potential.)

Due to the plasticity of the spinal cord, a given stimulus. This facilitation by repeti-
this linear (monotonic) relationship between tive C-fiber input, accordingly, increases the
peripheral activity and activity of neurons subsequent neuronal response to low-thresh-
that project out of the spinal cord to the old afferent input and facilitates the response
brain occurs as a nonlinear increase in spinal generated by a given noxious afferent input
output. (Figure 1.51).
A repetitive stimulation at a moderately An increased receptive field size reflects
fast rate given to WDR, afferent C fibers (but the contribution of sensory input converg-
not A fibers) results in a progressively facili- ing upon dorsal horn neurons from adjacent
tated discharge. The exaggerated discharge noninjured dermatomes. This is believed to
of (lamina V) WDR neurons is recognized as be due to the presence of subliminal excit-
windup, signaled by intracellular recording atory input between adjacent segments.
of a progressive and long sustained partial Afferents arriving at the spinal cord have col-
depolarization of the cell, allowing its mem- lateral projections up to four to six segments,
brane to be increasingly susceptible to affer- with a distal diminution of projection den-
ent input. sity (Figure 1.52). This neuroanatomy was
Hereafter, a natural stimulus applied over termed ‘long-ranging afferents’ by Patrick
a large area near the noxious insult displays Wall. After injury in a given receptive field,
the ability to activate the same WDR neuron. the primary associated neuron becomes sen-
The WDR discharge, projecting through the sitized. A collateral input from any long-
same spinal tracts, can augment response to ranging afferent might be able to initiate

FIGURE 1.51 With WDR neurons in a state of windup, nonpainful stimuli applied near the noxious insult
can activate the same WDR neuron, facilitating the nociceptive response.
48 Chronic Pain in Small Animal Medicine

FIGURE 1.52 Afferents arriving at the spinal cord FIGURE 1.53 ‘Long-ranging afferents’ influence
have collateral projections up to four to six seg- the summation effect of excitatory activity.
ments, yielding a receptive field representing the
‘sum’ of afferents (see text for explanation). a facilitated state of processing in WDR
neurons and ongoing facilitation of nocicep-
sufficient excitatory activity to activate that tive perception. These observations support
neuron through synergism. Now the recep- speculation that afferent C-fiber bursts may
tive field of the original afferent is effectively initiate long-lasting events, changing the spi-
the sum of both afferents. Clearly, there is nal processing that alters a response to sub-
an enhanced excitability of dorsal horn sequent input. However, the windup state
neurons initiated by small afferent input reflects more than the repetitive activation of
(Figure 1.53). a simple excitatory system.
After tissue injury, inflammation and cel- The unique pharmacology of NMDA
lular/vascular injury lead to the local periph- antagonists first revealed the phenomenon
eral release of active factors producing a of spinal windup (Figure 1.54). Such drugs
prolonged activation of C fibers that evokes showed no effect upon acute pain behavior,

FIGURE 1.54 Pharmacology involved in spinal facilitation. (NK1: neurokinin 1, VSCC: voltage-sensitive
calcium channel.)
 Chapter 1 Physiology of Pain 49

FIGURE 1.55 Transmitter interaction at the dorsal horn neuron. (NK1: neurokinin 1, PLA2: phospholipase
A2, VSCC: voltage-sensitive calcium channel.)

but reduced the facilitated states induced of several proteins, including the NMDA
after tissue injury. Under normal resting receptor and p38MAP kinase.
membrane potentials, the NMDA receptor p38MAP kinase phosphorylates phospholi-
is in a state of ‘magnesium block’, where pase A 2 that initiates the downstream release
occupancy by the excitatory amino acid glu- of arachidonic acid (AA) and provides the
tamate will not activate the ionophore. With substrate for COX to synthesize PGs. It also
a modest depolarization of the membrane (as activates a variety of transcription factors
during repetitive stimulation secondary to (e.g. NF-κB), which activates synthesis of a
the activation of AMPA and sP receptors), variety of proteins, including COX-2. COX
the magnesium block is removed, glutamate derivatives and NOS products are formed
now activates the NMDA receptor, and the and released that diffuse extracellularly
NMDA channel permits the passage of cal- and facilitate transmitter release (retrograde
cium ions (Figure 1.55). Increased intracel- transmission) from primary and nonprimary
lular calcium serves to initiate downstream afferent terminals.
components of the excitatory and facilitator Released PGs act presynaptically to
cascade. enhance the opening of voltage-sensitive
Primary afferent C fibers release pep- calcium channels that augment transmit-
tides and excitatory amino acids that evoke ter release. Additionally, PGs can act post-
excitation in second-order neurons. Afferent synaptically to block glycinergic inhibition
barrage induces additional excitation via (Figure 1.57).
product release of glutamate and prostanoids The reduction in activation of inhibitory
that markedly increase intracellular calcium glycine or GABA leads to interneuron regu-
and activation of various phosphorylating lation, resulting in a potent facilitation of
enzymes, including protein kinases A and C, dorsal horn excitability. It appears that the
as well as mitogen-activated kinases, including excitatory effect of large afferents is under a
p38MAP kinase and extracellular signal-reg- presynaptic GABA A /glycine modulatory con-
ulated kinase (ERK) (Figure 1.56). Increased trol, with removal resulting in a behaviorally
intracellular calcium leads to phosphorylation defined allodynia.
50 Chronic Pain in Small Animal Medicine

FIGURE 1.56 Persistent small afferent input contributes to spinal facilitation. (PKC: protein kinase C,
PLA2: phospholipase A2, VSCC: voltage-sensitive calcium channel.)

Intrinsic interneurons containing pep- Spinal facilitation is also believed to be

tides, such as enkephalin; inhibitory amino under the influence of the bulbospinal sero-
acids or bulbospinal pathways containing tonergic pathway (Figure 1.58). Bulbospinal
monoamines (norepinephrine, serotonin); NE (arising from the locus coeruleus/lateral
and peptides (enkephalin, neuropeptides Y medulla) acts as an inhibitory link upon the
[NPY]) may be activated by afferent input α 2 receptors, which are presynaptic and post-
and exert (reflex) a modulatory influence synaptic to the primary afferent. Serotonin
upon the release of C-fiber peptides and (5-HT, from the caudal raphe) may be inhibi-
postsynaptically hyperpolarize projection tory or excitatory on inhibitory interneurons
neurons. (GABA).

FIGURE 1.57 PGs act both presynaptically and postsynaptically to facilitate the cascade of afferent
transmission. (EP: prostaglandin receptor, NK1: neurokinin, PLA2: phospholipase A2, VSCC: voltage-
sensitive calcium channel.)
 Chapter 1 Physiology of Pain 51

FIGURE 1.58 Dorsal horn influence from bulbospinal pathways.

The CNS contains a variety of non-neuro- ATP, sP) can overflow from synaptic clefts to
nal cells, including astrocytes and microglia. adjacent non-neuronal cells, leading to their
Microglia are resident macrophages that are activation (Figure 1.59).
present from development. Primary afferent In the process of ‘neuroinflammation’,
and intrinsic neuron transmitters (glutamate, neurons may activate microglia by the

FIGURE 1.59 Activation of microglia is associated with the release of various neurotransmitters.
52 Chronic Pain in Small Animal Medicine

specific release of membrane chemokine The post–tissue injury pain state reflects
(fractalkine), which is expressed extracellu- sensitization of the peripheral terminal
larly on neurons and freed by neuronal exci- responding to the release of various factors
tation (constitutively), which subsequently that initiate spontaneous activity, as well as
binds to spinal microglia. Astrocytes may sensitize the peripheral terminal. Potent cen-
communicate over a distance by the spread tral (spinal) sensitization leads to facilitated
of excitation through local nonsynaptic responsiveness from the dorsal horn neurons
contacts of ‘gap junctions’ and may com- that receive ongoing small-afferent traffic
municate with microglia by the release of a (Figure 1.61). Sequential cascades lead to an
number of products, including glutamate/ enhanced response to injured receptive field
cytokines. Non-neuronal cells can influence input, but also enlarge the peripheral fields
synaptic transmission by release of various that are now capable of activating those
active products such as ATP and cytokines. neurons with originally ineffective sublimi-
They regulate extracellular parenchymal nal input. Augmentation reflects not only
glutamate by their glutamate transporters, local synaptic circuitry (glutamate/sP) but
which can serve to increase extracellular neu- also spinobulbospinal linkages (5-HT)
ronal glutamate receptors. Additionally, fol- and by-products released from local non-
lowing injury and inflammation, circulating neuronal cells.
cytokines (i.e., LL-1β/TNF-β) can activate The common symptom of pain following
perivascular astrocytes/microglia. Although tissue injury and inflammation disappears
these cells are constitutively active, they can consequential to the healing process. In con-
be upregulated after peripheral injury and trast, after a variety of injuries to the periph-
inflammation (Figure 1.60). eral nerve over time, a shower of painful

FIGURE 1.60 Following injury and inflammation, perivascular non-neuronal cells, including astrocytes
and microglia, contribute to nociceptive processing.
 Chapter 1 Physiology of Pain 53

FIGURE 1.61 Overview of nociceptive processing from injury to responsive behavior. Graph represents
relative responses to the pain state following sensitization of inflammation.

events ensues, including tactile allodynia – with the original target and, as if in frustra-
abnormal painful sensations in response to tion, proliferate significantly with the forma-
light tactile stimulation of the peripheral tion of neuromas. This phenomenon gives
body surface. Tactile allodynia provides evi- rise to ectopic activity and alteration in trans-
dence that the peripheral nerve injury has led ported factors from the terminal sprouts to the
to a reorganization of central processing. DRG. Yang et al.130 have shown that within
The mechanisms underlying such sponta- 14 days following nerve injury, there is consid-
neous pain and the miscoding of low-thresh- erably increased expression of many proteins
old afferent input are poorly understood; in the spinal cord and DRG (Table 1.10).
however, increased spontaneous activity Neuromas, formed by failed efforts of
in axons of the injured afferent nerve and/ injured peripheral nerve sprouts, become
or the dorsal horn neuron and exaggerated ectopic generators of neural activity.
response of dorsal horn neurons to normally Additionally, the DRG cells of such axons
innocuous afferent input are recognized. begin to demonstrate ongoing discharge.
Dysesthesia (spontaneous pain) and allo- These discharges are believed to arise from
dynia (pain evoked by light touch) can result the overexpression of sodium channels and a
from various peripheral nerve injuries due variety of receptors, which sense the inflam-
to sectioning or stretching, as with trauma; matory products in the injured environment.
compression, as with tumor or mechanical There are multiple populations of sodium
insult; chemical, as with anticancer agents channels, differing in their current activation
and pesticides; radiation, as with plexopa- properties and structures. VGSCs mediate
thies; metabolic, as with diabetes; viral, as the conducted potential in both myelinated
with PHN or human immunodeficiency and unmyelinated axons. Following nerve
virus (HIV); and immune, as with paraneo- injury, there is an increased presence of vari-
plastic activity. ous VGSCs, particularly in a neuroma and
Following mechanical injury to a periph- the DRG of unmyelinated axons, which
eral nerve, there is an initial dying back of likely support the ectopic activity observed
the axon (retrograde chromatolysis) for some in regenerating fibers. When used at doses
distance, at which point the axon begins to that do not block conduction, lidocaine will
sprout growth cones that then proceed for- block ectopic activity in neuromas and the
ward. Growth cones often fail to make contact DRG, reducing neuropathic thresholds and
54 Chronic Pain in Small Animal Medicine

TABLE 1.10 Receptors and channels showing increased activity within 14 days following
nerve injury
Receptors
• 5-HT receptor 5B • GABAA receptor alpha-5 subunit
• Cholinergic receptor, nicotinic, alpha • Glutamate receptor, ionotropic, AMPA3
polypeptide 5
• Cholinergic receptor, nicotinic, beta • Glutamate receptor, ionotropic, 4
polypeptide 2
• CSF-1 receptor • Glycine receptor alpha-2 subunit
Channels
• Calcium channel, voltage-dependent, L-type, • Pyrimidinergic receptor P2Y
alpha 1E subunit
• Calcium channel, voltage-dependent, • G protein-coupled, scavenger receptor class B
alpha-2/Delta subunit 1
• Chloride channel, nucleotide-sensitive, 1A • Neurotrophic tyrosine kinase, receptor, type 2
• Sodium channel, non-voltage-gated 1, beta • Homolog to peroxisomal PTS2 receptor
(epithelial)
• Potassium channel KIR6.2, potassium • Prostaglandin D2 receptor
voltage-gated channel, SK1-related
subfamily, member 1
• Protein kinase C–regulated chloride channel • Purinergic receptor P2Y, G protein–coupled 1
• ATPase, Na+K+ transporting, alpha-2 • Vasopressin V2 receptor
• Calcium channel, voltage-dependent, • Cholinergic receptor, nicotinic, delta polypeptide
alpha-1C subunit
• Chloride channel protein 3 long form • C-kit receptor tyrosine kinase isoform
• Potassium channel KIR6.2, potassium • Interleukin 13 receptor, alpha-1
voltage-gated channel, Isk-related subfamily,
member 1
• Sodium channel, voltage-gated, type 1, • Neurotensin receptor
alpha polypeptide
• Sodium channel, voltage-gated, type 6, • Opioid receptor, kappa-1
alpha polypeptide
• Potassium channel KIR6.2, potassium related, • Opioid receptor–like
subfamily relationship not yet defined

Abbreviations: SK1: small conductance channel – a gene-specific delayed rectifier–type potassium channel.

behaviors.131,132 Injured nerves have also as macrophages, as well as Schwann cells,

shown a decreased expression of potassium release cytokines such as IL-1β and TNF-α
channels in axons and the DRG. Potassium (Figure 1.62).
channels contribute to membrane hyperpo- TNF-α binding protein attenuates nerve
larization, and a decreased expression would injury–induced allodynia. A clinical example
contribute to increased afferent excitability. would be an avulsed disk, where inflamma-
Following nerve injury, various amines, tory products, such as TNF-α, have been
lipid mediators (PGs), and proinflamma- shown to be released that activate adjacent
tory cytokines (IL-1β, TNF-α) influence DRGs and nerves (Figure 1.63).
an accentuated effect on neuromas and After peripheral injury, the DRG is
the DRG. Local inflammatory cells such markedly changed. There is activation of
 Chapter 1 Physiology of Pain 55

the clinical condition of an avulsed disk

fragment.
In summary, the concept of low-thresh- 1
old tactile stimulation yielding a pain state
is quite intriguing. Mechanisms proposed
to account for this linkage include (1) direct
interactions between large and small (noci-
ceptive) afferents; (2) altered connectivity of
the dorsal horn, such that Aβ afferents drive
nociceptive systems; and (3) altered excit-
ability of dorsal horn systems activated by
large afferents. Afferents in the DRG and in
the neuroma develop a ‘cross-talk’ following
nerve injury. Depolarizing currents in one
axon generate a depolarizing voltage in an
adjacent quiescent axon. Thus, a large low-
threshold afferent would drive activity in
an adjacent high-threshold afferent. In the
presence of ongoing spontaneous activity
in large afferents, there is significant local
FIGURE 1.62 Overview of afferent activity resulting depolarization of afferent terminals in the
from nerve injury. dorsal horn initiating local release of GABA.
GABA/glycinergic terminals are frequently
immediate early genes, an increase in the presynaptic to the large central afferent
expression of various injury-related tran- terminal complexes, and these amino acids
scription factors, activation of local satellite normally exert an important tonic or evoked
(glial) cells, and a massive alteration in DRG inhibitory control over the activity of Aβ pri-
neuron protein expression of receptor chan- mary afferent terminals and second-order
nels and enzymes. Further, the DRG neuron neurons in the spinal dorsal horn. Following
is mechanically sensitive to local compres- nerve injury, spinal neurons regress to a neo-
sion that will lead to ectopic activity, as in natal phenotype in which GABA A activation

FIGURE 1.63 TNF-α in back pain.

56 Chronic Pain in Small Animal Medicine

FIGURE 1.64 Influence of spinal chloride transporters on allodynia.

becomes excitatory. This results from a ganglia of injured axons, forming baskets
reduction in the expression of the chloride of terminals around the ganglion cells. To
transporter protein in dorsal horn neurons paraphrase Albert Einstein, ‘The significant
following afferent nerve injury. problems that we face today cannot be solved
Normally, transmembrane chloride is at at the level of thinking that we were at when
equilibrium or just negative to resting mem- we identified them’.
brane potentials. Increasing membrane chlo-
ride permeability by activation of GABA A or Common Questions
glycine receptors normally yields hyperpolar-
ization and inhibition. Following peripheral Related to Chronic Pain
nerve injury, there is a loss of chloride trans- What Is the Difference between
porter, which normally exports chloride.
Pain and Suffering?
This leads to an intracellular accumulation
of chloride. Under such conditions, increas- Pain is a sensation plus a reaction to that sen-
ing chloride permeability, as by opening the sation. Suffering is more global. Suffering is an
GABA A or glycine receptor ionophore, does overall negative feeling that impairs the suf-
not lead to an inhibitory effect, but instead, ferer’s quality of life. Both physical and psy-
an excitatory effect on the second-order neu- chological issues are involved in suffering, and
ron may occur (Figure 1.64). pain may be only one component. Arguably,
After nerve injury, there is a significant clinical suffering depends less upon the magni-
enhancement in resting spinal glutamate tude of the hurting and more upon the uncer-
secretion, with glutamate having a major tainty over how long the hurting will last.
impact on the NMDA receptor, which in
turn, is a major player in windup. Following What Is Nociceptive Pain?
peripheral nerve injury, there is an increased Nociceptive pain results from the activation
expression of the peptide dynorphin. of nociceptors (Aδ and C fibers) by noxious
Dynorphin can initiate the concurrent release stimuli that may be mechanical, thermal,
of spinal glutamate and a potent tactile allo- or chemical. Nociceptors may be sensitized
dynia. Also, a significant increase in activa- by endogenous chemical stimuli (algogens)
tion of spinal microglia and astrocytes occurs such as serotonin, sP, bradykinin, PGs, and
in the ipsilateral spinal segments receiving histamine.
input from injured nerves. These cells play
a powerful constitutive role in the increase
of synaptic excitability through release of a
Under Normal Circumstances, Where
variety of active factors. Particularly in bone Are Algogenic Substances Found?
cancer, these cells are active. It is also noted Serotonin, histamine, potassium ions, hydro-
that there is an ingrowth of postganglionic gen ions, PGs, and other members of the ara-
sympathetic terminals into the dorsal root chidonic acid cascade are in tissues: kinins
 Chapter 1 Physiology of Pain 57

are in plasma, and sP is in the nerve termi- serves no useful biological purpose. Many of
nals of primary afferents. Histamine is found
in the granules of mast cells, in basophils,
us were schooled to believe that chronic pain
is simply acute pain of extended duration. 1
and in platelets. Serotonin is present in mast Our present understanding of pain physi-
cells and platelets. ology has demonstrated that this is not the
case. Acute pain is as different from chronic
What Are the Most Widely Used pain as Mars is from Venus.
Classifications for Pain?
What Is the Advantage of
The most recognized categories are based
on inferred neurophysiological mecha-
Classifying Pain?
nisms, temporal aspects, etiology, or region It provides the clinician with information
affected. about the possible origin of the pain. More
importantly, it steers the clinician toward
a proper pharmacological treatment plan.
What Is Meant by an Etiological
For example: neuropathic pain generally
Classification? responds to adjuvant medications, whereas
This classification pays more attention to nociceptive pain states are often controlled
the primary disease process in which pain by NSAIDs alone or in combination with
occurs, rather than to the pathophysiology opioids.
or temporal pattern. Examples include can-
cer pain and arthritis.
NOCICEPTOR SIGNALING:
What Is the Basis of the Regional
Classification of Pain? THERAPEUTIC TARGETS
The regional classification is strictly topo- Nociceptors express mechanically gated
graphic and does not infer pathophysiology channels that, upon excessive stretch, initiate
or etiology. It is defined by the part of the a signaling cascade. These cells also express
body affected, then subdivided into acute several purinergic receptors capable of sens-
and chronic. ing ATP, released from cells during excessive
mechanical stimulation. In sensing noxious
What Is the Temporal Classification of chemical stimuli, nociceptors express a wide
range of receptors that detect inflammation-
Pain, and What Are Its Shortcomings?
associated factors released from damaged
Temporal classification is based on the time tissues, including protons, endothelins, PGs,
course of symptoms and is usually divided bradykinin, and NGF.
into acute, chronic, and (perhaps) recurrent.
The major shortcoming is that the division
between acute and chronic is often arbitrary.
CYCLOOXYGENASE
What Is Acute Pain? Tumor cells and tumor-associated cells
Acute pain is temporally related to injury secrete a variety of factors that sensitize or
and resolves during the appropriate healing directly excite primary afferent neurons:
period. It often responds to treatment with PGs, endothelins, IL-1 and IL-6, epidermal
analgesic medications and treatment of the growth factor, transforming growth fac-
precipitating cause (e.g. treatment of bacte- tor (TGF), and platelet-derived growth fac-
rial infection with antibiotics). tor. Identification of these factors provides
potential blocking strategies for treatment.
One such strategy is focused on COX-2.
What Is Chronic Pain? COX-2 inhibitors (coxib-class NSAIDs) are
Chronic pain is often defined as pain that currently used to inhibit inflammation and
persists for more than 3 months or that out- pain. Further, experiments suggest coxibs
lasts the usual healing process. Some authors may have the added advantage of reducing
choose 6 months as a cutoff. Chronic pain the growth and metastasis of cancer.133
58 Chronic Pain in Small Animal Medicine

ENDOTHELIN follows that different patients with the same

cancer may have vastly different symptoms.
Endothelin-1 is a second pharmacological
target for cancer pain. Clinical studies in
humans have shown a correlation between PAIN ASSESSMENT
prostatic cancer pain and plasma levels of
endothelins.134 Similar to PGs, endothelins Pain management is a cardinal example of
that are released from tumor cells are also integrating the science of veterinary medi-
thought to be involved in regulating angio- cine with the art of veterinary practice. New
genesis and tumor growth.135,136 graduate veterinarians are well schooled in
the science, whereas the art comes only with
experience. This is particularly true in man-
aging pain because pain is a subjective phe-
ACID-SENSING ION nomenon. In man, pain is what the patient
CHANNELS says it is, whereas in animals, pain is what
the assessor says it is! Because pain is sub-
A hallmark of tissue injury is local acidosis, jective, an abstract, multiattribute construct
and tumor cells become ischemic and apop- similar to intelligence or anxiety, pain man-
totic as the tumor burden exceeds its vas- agement does not lend itself to a ‘cookbook’
cular supply. Two major ASICs expressed approach. For example, following surgery,
by nociceptors, TRPV1 and ASIC-3, are if the dog is lying quietly in its cage, is it
sensitized by the acidic tumor environment. doing so because it is very content or because
This is likely accentuated by osteolytic it is too painful to move? Further, trained
tumors, where there is a persistent extra- as scientists, veterinarians are schooled to
cellular microenvironment of acidic pH at assess responses based on the mean ± stan-
the osteoclast and mineralized bone inter- dard deviation, yet effective pain manage-
face. Further, studies showing that osteo- ment suggests we target the least-respondent
protegerin137 and a bisphosphonate,138 both patient within the population, so as to ensure
of which induce osteoclast apoptosis, are no patient is denied the relief it needs and
effective in decreasing osteoclast-induced deserves. There are many clues the attentive
bone cancer pain. assessor may note to suggest an animal is in
pain (Table 1.11).
As a rule of thumb, any change in behav-
SENSORY NEURON ior can signal pain; however, the most reli-
able indicator of pain is response to an
DYNAMICS analgesic. Physiological parameters, includ-
ing heart rate, respiratory rate, blood pres-
To appreciate the complexity of cancer sure, and temperature, are not consistent
pain is to understand that the biochemical or reliable indicators of pain. Various acute
and physiological status of sensory neurons pain assessment measures have been used by
is a reflection of factors derived from the researchers to quantify pain. These include
innervated tissue, and therefore changes in verbal rating scales (VRSs), simple descrip-
the periphery associated with inflamma- tive scales (SDSs), numerical rating scales
tion, nerve injury, or tissue injury influence (NRSs), and visual analog scales (VASs), all
changes in the phenotypes of sensory neu- of which have their limitations. Historical
rons. NGF and glial-derived neurotrophic limitations of scales used to assess pain have
factor (GDNF) influence such changes. The been assessment of pain on intensity alone.
medley of growth factors to which the sen- Such limitations have led to development of
sory neuron is exposed will change as the multidimensional scales, taking into account
growing tumor invades the peripheral tissue the sensory and affective qualities of pain in
innervating the neuron. With the potential addition to its intensity. The Glasgow Pain
for changing phenotype and response char- Scale140 is such a multidimensional scheme,
acteristics, it is understandable that the same and although it is detailed, its ongoing
tumor in the same individual may be painful refinement may result in greater utilization.
at one site of metastasis but not at another. It Currently, there are no ‘scales’ to assess
 Chapter 1 Physiology of Pain 59

TABLE 1.11 Characteristics associated with pain in cats and dogs

Characteristic Example 1
Abnormal posture • Hunched up guarding or splinting of abdomen
• ‘Praying’ position (forequarters on ground, hindquarters in air)
• Sitting or lying in an abnormal position
• Not resting in a normal position
Abnormal gait • Stiff
• No to partial weightbearing on injured limb
• Slight to obvious limp
Abnormal movement • Thrashing
• Restless
• Inactivity when awake
• Escape behavior
Vocalization • Screaming
• Whining
• Crying
• None
Characteristic Example
Miscellaneous • Looking, licking, or chewing at painful area
• Hyperesthesia or hyperalgesia
• Allodynia
• Failure to stretch or ‘wet dog shake’
• Failure to yawn
• Failure to use litter box (cat)
*May also be associated with • Restless or agitated
poor general health • Trembling or shaking
• Tachypnea or panting
• Weak tail wag
• Low carriage of tail
• Depressed or poor response to caregiver
• Head hangs down
• Not grooming
• Decreased or picky appetite
• Dull
• Lying quietly and not moving for long durations
• Stupor
• Urinates or defecates without attempt to move
• Recumbent and unaware of surroundings
• Unwilling or unable to walk
• Bites or attempts to bite caregivers
*May also be associated with • Restless or agitated
apprehension or anxiety • Trembling or shaking
• Tachypnea or panting
• Weak tail wag
• Low tail carriage
• Slow to rise
• Depressed
• Not grooming
• Bites or attempts to bite caregiver
• Ears pulled back
• Restless
• Barking or growling
• Growling or hissing
• Sitting in back of cage or hiding (cat)
(Continued)
60 Chronic Pain in Small Animal Medicine

TABLE 1.11 Characteristics associated with pain in cats and dogs (Continued)
Characteristic Example
May be normal behavior • Eye movement, but reluctance to move head
• Stretching when abdomen touched
• Penile prolapse
• Licking a wound or incision
Physiological signs that may be • Tachypnea or panting
associated with pain • Tachycardia
• Dilated pupils
• Hypertension
• Increased serum cortisol and epinephrine

Source: Modified from Reference 139.

chronic pain. Several investigators have sug- a result of the pain and specific to the ani-
gested exploring this area of interest through mal and its home environment is defined.
creation of novel questionnaires as an instru- Activities are graded at the start of treatment
ment for measuring chronic pain in dogs and after analgesic treatment is started. A
through its impact on health-related quality left shift corresponds to pain relief.
of life (HRQoL).141–143 Current methods of classifying pain are
Expanding on the value of owner assess- considered unsatisfactory by some145 for sev-
ment, a client-specific outcome measures eral reasons. Foremost is that pain syndromes
scheme has been developed.144 In this scheme, are identified by parts of the body, duration,
five specific problems related to osteoarthri- and causative agents, rather than the mecha-
tis (OA) were identified and recorded, and nism involved. The argument holds that ana-
the intensity of the problem was monitored tomical differences should be disregarded
as treatment progressed. Because the ques- in favor of mechanisms that apply to either
tions are specific to the individual animal in particular tissues or all parts of the body,
its environment, this measurement system rather than a particular part of the body.
appears to be highly sensitive. For example, the term cancer pain relates
Table 1.12 shows an example of a spe- only to the disease from which the patient
cific questionnaire used at North Carolina suffers, not the mechanism of any pain the
State University Comparative Pain Research patient may experience. A mechanism-based
Laboratory to assess pain associated with approach is likely to lead to specific phar-
clinical OA in cats. Activity or behavior macological intervention measures for each
that is suspected to have become altered as identified mechanism within a syndrome.

TABLE 1.12 Client-specific outcome measures – activity

Problems in mobility
related to osteoarthritis A little Quite Severely
in your cat No problem Problematic problematic problematic impossible
1. Jumping ONTO sofa ∇ ✓
2. Jumping ONTO kitchen ∇ ✓
counter
3. Walking up steps on ∇ ✓
back deck
4. Jumping on bed ∇ ✓
5. Using litter tray ∇ ✓

✓: Start of treatment.
∇: After treatment.
 Chapter 1 Physiology of Pain 61

FIGURE 1.65 Proposed scheme for a clinical approach to a mechanism-based classification of pain.145

Advances in pain management are then con- of suffering. When treating pain, knowledge
tingent on first determining the symptoms is still the best weapon.
that constitute a syndrome and then finding
mechanisms for each of these. The clinical Recognition and Assessment
approach for a mechanism-based classifica-
tion of pain is illustrated in Figure 1.65.
of Chronic Pain
Figure 1.65 illustrates how a patient with Despite the challenges of confidently identi-
pain could be analyzed from a pain-mech- fying maladaptive pain in our patients, pain
anism perspective. It is the mechanism that recognition is the keystone of effective pain
needs to be the target for novel drugs, rather measurement and management. Because
than particular disease states. Herein lies the behavioral changes associated with chronic
greatest potential for advancement in pain pain tend to be gradual and subtle, they are
management (Table 1.13). most easily detected by someone quite famil-
Clearly, the mechanisms associated iar with the animal; hence, the importance of
with pain are complex. However, only owner anamnesis input. More work has been
through the understanding of these mech- done on dogs than on cats, yet some feline
anisms can we best manage our patients’ studies have assessed quality of life (QoL)
pain with an evidence-based confidence or HRQoL.146 There is a growing under-
(Figure 1.66). standing of behaviors and ‘body language’
The real mandate of medical care is not expression of feline pain.147–149 Presently,
the saving of lives, but the dispensing of broad categories of behaviors are focused
comfort. We cannot expect to extend life on general mobility, activity performance,
forever. Yet we can hope to extend lives free eating/drinking, grooming, resting, social
 62

TABLE 1.13 Summary of various pain states

Pain Pain Pain Potential Animal
categories conditions mechanisms drug/Targets models Proof of concept
1. Transient stimulus- Procedural pain (injections/ Nociceptor activation • VRs Thermosensitivity, Minor surgical
induced pain minor injuries) • Na+-TTXs mechanosensitivity, procedures
(nociceptive pain) • MOR, nAChR chemosensitivity
2. Tissue damage • Trauma/Postoperative • Nociceptor activation • COX-2, EPR, 5-HTR, Chemical irritants: • Dental postoperative
(inflammatory pain) pain • Peripheral P2x, BKR capsaicin, mustard oil, pain
Spontaneous and • Arthritis/Infection sensitization • IL-β TNR-α, TrkA, TrkB formalin • Abdominal
provoked pain • Central sensitization • Na+-TTXr, ASIC, α2, Experimental postoperative pain
• Phenotype switch MOR, DOR, A1, inflammation: • Thoracotomy
N-Ca++, NK1, nAChR, carrageen, UVB, • Joint replacements
NMDA-R, GluR5, Freund’s adjuvant, • Osteoarthritis
mGluR, PkCγ cytokines/growth
factors
Chronic Pain in Small Animal Medicine

3. Injury: primary • Peripheral nerve • Ectopic activity • Na+-TTXr/TTXs • Peripheral nerve • Diabetic neuropathy
afferent (neuropathic diabetic injury • Phenotype switch • α2, NMDA-R, N-Ca++, section (human)
pain) Neuropathy (human) • Central sensitization PKCγ NGF/GDNF • Partial nerve section • Postherpetic
Spontaneous and Toxic neuropathy • Structural • GABA, AEAs, • Loose ligatures neuropathy (human)
provoked pain • Postherpetic neuralgia reorganization gabapentin • Experimental • Radicular pain
(human) • Disinhibition • TCA, SNRIs diabetes, toxic
neuropathies
4. Injury: central neuron • Spinal cord injury • Secondary ectopic • GABA-R • Spinal cord injury Spinal cord injury
(neuropathic pain) • Stroke (humans) activity • Na+-TTXs • Ischemia
Spontaneous and • Disinhibition • AEAs • Central disinhibition
provoked pain • Structural • TCA, SNRIs (e.g., strychnine/
reorganization bicuculline)
5. Unknown mechanism • Irritable bowel ? Altered gain COX-2, NMDA-R, Na+ Irritable bowel
syndrome channels syndrome/
• Fibromyalgia (humans) Fibromyalgia

Abbreviations: α2: adrenergic receptors, 5-HTR: serotonin receptors, A1: adenosine receptors, AEAs: antiepileptic agents- GABA-ergic compounds, BKR: bradykinin receptors, DOR: delta opiate receptors,
EPR: prostaglandin receptors, GluR5: kainate receptors, mGluR: metabotropic glutamate receptors, MOR: μ-opiate receptors, N-Ca++: voltage-gated calcium ion channels, nAChr: nicotine acetylcholine
receptor, Na+-TTXr: tetrodotoxin-resistant sodium ion channels, NK1: neurokinin receptors, NMDA-R: N-methyl-D-aspartic acid receptors, P2x: ligand-gated purino receptors/ion channels, PKCγ: protein
kinase C gamma, SNRIs: serotonin and norepinephrine reuptake inhibitors, TCA: tricyclic antidepressants, TrkA: TrkB: high-affinity neurotrophin tyrosine kinase receptors.
 Chapter 1 Physiology of Pain 63

FIGURE 1.66 The moving target of pain management. Well-characterized receptors in the periphery are
activated by noxious stimuli, acute inflammation, and tissue injury, sending afferent information to the
dorsal horn of the spinal cord, where synaptic transmission to ascending pathways is subject to modu-
lation by descending pathways, local neuronal circuits, and a variety of neurochemicals. (A2: adenosine
A2 receptor, ATP: adenosine triphosphate, B1/2: bradykinin receptors 1 and 2, EAAs: excitatory amino
acids, EP: prostaglandin E receptor, H1: histamine H1 receptor, IGluR: glutamate ionotropic receptor,
IL-1R: interleukin 1 receptor, MGluR: glutamate metabotropic receptor, P2X3: purinergic receptor X3,
PKA: protein kinase A, PKC: protein kinase C, ROS: reactive oxygen species, TrkA: tyrosine receptor
kinase A.)

activities with people and other pets, and implemented.151 QoL measures used in vet-
temperament.150 erinary medicine vary from simple scales
In that dogs are living longer, there is an tied to certain descriptors of behaviors152
increase in the incidence of painful chronic to broad, unconstrained assessments.153–155
conditions, namely OA and cancer, where Questionnaires have been developed to assess
treatment is becoming a viable alternative to HRQoL in dogs with degenerative joint dis-
euthanasia. At present, several instruments ease (DJD), cardiac disease,156 cancer,157,158
have been described to evaluate chronic chronic pain,141,159 spinal cord injuries,160,161
pain in dogs. These have provided informa- and atopic dermatitis,162 while some assess-
tion about the range of alterations in the ments are less specific.163,164 Several instru-
demeanor, mood, and behavior of dogs as a ments focused mainly on functional
consequence of chronic pain. assessment (clinical metrology instruments
Owner observations are the main- [CMIs]) have been developed for canine OA
stay of the assessment for chronic pain in and have undergone a variable degree of val-
dogs. Functional assessment, QoL, and idation.143,146,153,165–169 Such questionnaires
HRQoL tools have been developed and typically include a semiobjective rating of
64 Chronic Pain in Small Animal Medicine

disease parameters such as ‘lameness’ and review comprising structured searches on

‘pain’ on either a discontinuous ordinal scale the topic of avian pain recognition. Emphasis
or a VAS. of the searches was based on the behavioral
At the present time, the most fully vali- and postural alterations that have thus far
dated instruments available are: been explored. Pain stimulus varied depend-
ing on species, although the vast majority of
• GUVQuest141,159 the pain stimuli involved welfare issues such
• Canine Brief Pain Inventory170 as beak trimming, limb abnormalities, and
• Helsinki Chronic Pain Index (available on keel bone fractures in chickens. This review
request to author) provides a more thorough understanding of
• Texas VAS Instrument (available on request behavioral indicators of pain in species such
to author) as chickens, turkeys, psittacines, pigeons,
• Liverpool Osteoarthritis in Dogs (available raptors, and select others.
on request to author) As pain becomes more chronic in dura-
• JSSAP Canine Chronic Pain Index (can be tion and remains largely unalleviated in
downloaded from the [Japanese] JSSAP avian species, behavioral aspects can become
website) affected. Such a situation is noted with social
interactions and mating behaviors of turkeys
GUVQuest is an owner-based question- that are adversely affected by degenerative
naire developed using psychometric princi- hip disease.172
ples for assessing the impact of chronic pain Clearly, the lack of validated methods
on the HRQoL of dogs and is validated in for measuring pain creates ambiguity when
dogs with chronic joint disease and cancer. trying to assess pain in an animal. If pain is
The Canine Brief Pain Inventory (CBPI) underestimated, then subsequent treatment
has been used to evaluate improvements in can be similarly suboptimal.
pain scores in dogs with OA and in dogs with
osteosarcoma.
The Helsinki Chronic Pain Index (HCPI)
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CHAPTER

2
Pathophysiology of
Osteoarthritic Pain
OVERVIEW
In late 2003, a special report entitled
‘Usefulness, completeness, and accuracy of
Web sites providing information on osteo-
arthritis in dogs’ appeared in the Journal
of the American Veterinary Medical
Association.1 Five popular search engines
(AltaVista, Google, Lycon, Netscape, and
Microsoft Network) were searched with the
key words dog, degenerative joint disease,
canine, and osteoarthritis. From this exer-
cise, the authors concluded that although
most of the sites conveyed some conven-
tional information with reasonable accu-
racy, the information was incomplete, of
FIGURE 2.1 Prevalence of canine osteoarthritis in
minimal use, and often considered counter-
the United States (1999).
productive. Further, those veterinarians and
clients seeking information about osteoar-
thritis (OA) may have access to faulty or The demographics of dogs with OA are
misleading information. broad-reaching. Although the condition
Cranial cruciate ligament deficiency tends to be overrepresented in older, heavy
(CrCLD) in dogs is only one of many etiologies dogs, it can be a clinical problem in any
for OA; however, Wilke et. al. estimate that dog. The ‘poster child’ for OA in dogs is the
dog owners spent approximately $1.32 bil- middle-aged to older (>4 years), large breed
lion for the treatment of CrCLD alone in (>25 kg) dog that is overweight to obese. OA
the United States in 2003. 2 These insights is often secondary to either abnormal forces
reveal the prominence OA has in veterinary on normal joints (e.g., trauma, instability) or
medicine. OA affects more than 80% of normal forces on abnormal joints (e.g., dys-
Americans over age 553 and approximately plasias, development disorders). In the case
one in five adult dogs in America.4 It is the of obesity, which is often seen in older dogs,
number one cause of chronic pain in dogs, abnormal stress on the joints is accentuated.
and approximately 10–12 million dogs in the Cats, being light and agile, can compensate
United States show signs of OA. for fairly severe orthopedic disease, including
In 1999 the ‘average’ veterinary prac- musculoskeletal conditions such as OA. They
tice saw approximately 45 arthritic dogs are noted for hiding signs of lameness in the
per month, 21% of which were considered veterinarian’s office. Clinical signs of chronic
‘severe’, 38% were considered ‘moderate’, pain at home, as reported by owners, include
and 41% were considered ‘mild’ as assessed change of attitude (e.g., grumpiness, slowing
by their clinical presentation (Figure 2.1). 5 down) and disability (decreased grooming,

70 DOI: 10.1201/9781003376422-3
 Chapter 2 Pathophysiology of Osteoarthritic Pain 71

missing the litter box on occasion, and inabil- in the radiographs, and only mild sclerosis
ity to jump on to counters), rather than overt
signs of lameness. Prevalence of radiographic
was identified in joints with severe cartilage
damage. Although OA is a commonly recog- 2
signs of feline degenerative joint disease (DJD) nized disease in dogs, it is frequently under-
ranges from 22% to 90% of investigated pop- diagnosed in cats. However, it is now being
ulations.6–8 Freire et al. reported that 74% of recognized as a disease of senior-aged cats.11
100 cats selected randomly from a database
of 1,640 cats in a single practice had DJD
somewhere in the skeleton.9 Freire et al. also
reported that radiographic appearance does DEFINITION
not accurately predict whether or not feline
joints show lesions associated with DJD.10 In OA can be defined as a disorder of movable
the latter report, 31 of 64 joints (elbow, hip, joints characterized by deterioration of artic-
stifle, and hock) assessed from eight post- ular cartilage; osteophyte formation and bone
mortem, euthanized animal shelter cats had remodeling; pathology of periarticular tis-
radiographic signs of DJD. The absence of sues, including synovium, subchondral bone,
osteophytes did not predict appearance of muscle, tendon, and ligament; and a low-
cartilage pathology, with 35 joints showing grade, nonpurulent inflammation of variable
no radiographic signs of osteophytosis, but degree. OA is differentiated from rheumatoid
showing macroscopic cartilage lesions. There arthritis (RA), which is the classic example of
was no agreement between cartilage damage a primary immune-mediated systemic condi-
and the presence of sclerosis in the radio- tion characterized by bone destruction and
graphs. In stifle, hock, and hip joints, no scle- articular cartilage erosion. RA is considered
rosis was identified, even in those joints with to be a more destructive, progressive, and
moderate and severe cartilage damage. The debilitating condition than OA.
best correlations and agreements between OA is not a single disease, and is often
radiographic osteophyte score and macro- misperceived as a disease of cartilage. Herein,
scopic osteophyte score were in the elbow and the joint can be considered an ‘organ’, where
hip. In the elbow, moderate cartilage damage all components of the ‘organ’ are affected by
was present before any sclerosis was identified the disease process (Figure 2.2).

FIGURE 2.2 Anatomy of the femoral-tibial joint. The arthritic joint is analogous to a totally diseased
‘organ’, with loss of cartilage, sclerosis of subchondral bone, inflammation of the synovial membrane,
osteophyte formation, and pain.
72 Chronic Pain in Small Animal Medicine

OA is a syndrome characterized by patho-

logical changes of the synovial or diarthro-
dial joint expressed by disability and clinical
signs of pain. It is a complex condition involv-
ing multiple biochemical and biomechanical
interactions. Often termed DJD, OA can be
classified by the joint involved and whether
it is primary or secondary. It appears to be
mechanically driven but chemically medi-
ated, with endogenous attempts at aberrant
repair.
OA and DJD are synonyms; however,
these two terms and arthritis, arthrosis,
rheumatism, and others are often used inter-
changeably and incorrectly. Historically
recognized as ‘noninflammatory’, OA is FIGURE 2.3 OA is a degradative cycle.
now recognized as an inflammatory condi-
tion, but the inflammation is not that clas-
sically mediated by neutrophils, as in other ETIOLOGY
types of arthritis.12 OA is associated with
destruction and loss of cartilage, remodel- Degradation and synthesis of cartilage
ing of bone, and intermittent inflammation. matrix components are related to the release
Changes in subchondral bone, synovium, of mediators by chondrocytes and synovio-
and ligaments are detectable at an early cytes, including the cytokines, interleukin
stage, and cartilage matrix synthesis occurs (IL)-1 and tumor necrosis factor (TNF),
concurrently with increased degradation. nitric oxide (NO), and growth factors.13
Synovial and cartilage-derived proteases Release of these mediators is related to joint
are major players in cartilage matrix deg- loading, nutrition, and matrix integrity
radation, with metalloproteases and aggre- (Figure 2.4). A minor injury could start the
canases seemingly key catabolic agents. disease process in a less resistant environ-
The vicious catabolic/anabolic cycle of ment, whereas in other individuals the joint
OA (Figure 2.3) is not yet comprehensively may be able to compensate for a greater
understood. insult. Although cartilage assuredly has the

FIGURE 2.4 Etiology of osteoarthritis. Damage may become irreversible when compensation fails.
 Chapter 2 Pathophysiology of Osteoarthritic Pain 73

potential for endogenous repair, damage in naturally occurring OA. Lascelles et al. 20
may become irreversible when compensation
is exhausted.
have investigated this area by comparing
the levels of COX-1, COX-2, and LOX pro- 2
tein in joint tissues (joint capsule/synovium,
osteophytes, and subchondral bone), as
INFLAMMATION well as levels of PGE 2 and leukotriene (LT)
B 4 in joint tissues (joint capsule/synovium
Inflammation in joints causes peripheral sen- and subchondral bone) between a limited
sitization, with an upregulation of primary number (three each) of normal vs. arthritic
afferent neuron sensitivity, and also cen- dogs. Results showed that significantly more
tral sensitization, with hyperexcitability of COX-2 protein was present in the hip joint
nociceptive neurons in the central nervous capsule from joints with OA than in nor-
system (CNS) (see Chapter 1).14 Peripheral mal joints. Further, there was a significantly
sensitization is produced by the action of greater concentration of LTB 4 from coxo-
inflammatory mediators such as bradykinin, femoral joints with OA compared to normal
prostaglandins (PGs), neuropeptides, and dogs. Significantly more COX-1, COX-2,
cytokines. Quantitative sensory testing in and LOX protein was present in subchon-
human OA patients shows that there is dif- dral bone from the femoral head of joints
fuse and persistent alteration of nociceptive in OA than in normal joints. There was no
pathways, irrespective of the level of sever- difference in PGE2 or LTB4 concentration
ity associated with the underlying disease.15 in normal femoral head tissue compared to
Inflammatory mediators play a role either femoral head from coxofemoral joints with
by directly activating high-threshold recep- OA. Overall, there was significantly more
tors or, more commonly, by sensitizing noci- PGE 2 and LTB 4 in the hip joint capsule than
ceptive neurons to subsequent daily stimuli. in femoral head samples.
Damaged joints and sensory nervous system
interactions may not only produce pain but
may actually influence the course of the
disease.
JOINT STRUCTURE
The inflammatory component is more INTERACTIONS
prevalent at different phases of the disease.
The synovial fluid of most OA patients shows Cartilage is void of vessels, lymphatics, and
increased numbers of mononuclear cells and nervous tissue. It derives its nutrition from
increased levels of immunoglobulins and the diffusion of synovial fluid. The diffusion
complement. The synovial membrane shows of synovial fluid into the hyaline cartilage
signs of chronic inflammation, including (and evacuation of cartilage waste products)
hyperplasia of the lining with infiltration is enhanced by the loading and unloading of
of inflammatory cells. Inflammation likely cartilage by daily activities. This is analo-
plays an important role in the painful symp- gous to the movement of water in and out
toms of OA.16 of a sponge while being squeezed within a
The discovery of cyclooxygenase bucket of water.
(COX)-2 was linked to the finding that it was The synovial intima (lining layer) of the
upregulated as a result of inflammatory stim- joint capsule is normally only one to two
uli. As a consequence, COX-2 inhibitors are cell layers thick and contains type A and
marketed on the premise that they may be B synoviocytes. Type A synoviocytes are
more effective for the treatment of OA pain. macrophage-like cells that have a role in
This is supported by the assumption that removing debris from joints and processing
COX-2 activity is upregulated in the joint antigens. Type B synoviocytes are fibroblast-
tissues of dogs suffering from OA and is the like cells that are responsible for the produc-
primary COX enzyme responsible for pain tion of hyaluronan, but also are capable of
in OA. Although this is corroborated within producing degradative enzymes. Both types
the human literature,17–19 there is sparse of synoviocytes produce cytokines and other
evidence for this assumption in naturally mediators. 21 Therefore, as inflammatory
occurring canine OA, and nothing is known mediators and cytokines are released into
about the expression of lipoxygenase (LOX) the joint fluid, they stimulate synoviocytes
74 Chronic Pain in Small Animal Medicine

FIGURE 2.5 As matrix metalloproteinases (MMPs) are released from diseased cartilage, they stimulate
the generation of additional inflammatory mediators and cytokines from synoviocytes located in the
synovial intima. (GAGs: glycosaminoglycans.)

in the synovial intima to produce additional abnormal loading; and (likely) physical stim-
degradative enzymes that find their way ulation of muscle, tendon, and ligaments.
back into the cartilage by diffusion, and the
catabolic cycle becomes self-perpetuating
(Figure 2.5). The subsynovial layer, lying
immediately below the intima, contains free
JOINT COMPONENTS
nerve endings. With such close proximity of AND PHYSIOLOGY
these nociceptors within the subsynovium
to inflammatory mediators in the synovial Cartilage is a physiologically complex, yet
fluid, the process of noxious stimulation is structurally simple tissue. It is composed
practically intuitive. mostly of water. Type II collagen contributes
OA pain is the result of a complex inter- to structural integrity, the functional cell is the
play between structural change, biochemical chondrocyte, and the aggrecan aggregate of
alterations, peripheral and central pain pro- proteoglycans forms the functional unit. The
cessing mechanisms, and individual cogni- term aggrecan has been given to the proteogly-
tive processing of nociception. Bony changes can monomer that aggregates with hyaluronan
at the joint margins and beneath areas of and is found in articular cartilage (Figure 2.6).
damaged cartilage can be major sources of It is the major proteoglycan by mass of
OA pain. Chondrophyte and osteophyte hyaline cartilage. The aggrecan has a ‘bottle
growth result in elevation and stretching of brush’ appearance with a hyaluronan back-
richly innervated periosteum, which is also bone and ‘bristles’ of hydrophilic glycosami-
a common origin of expansile bone tumor noglycans (GAGs) that retain the water. An
pain. Human OA patients report pain, even aggrecan aggregate may contain over 100
at rest, associated with raised intraosseous aggrecan monomers (Figure 2.7).
pressure. 22 Cartilage exists in three forms: hyaline,
So, what is the source of pain in OA? The fibrocartilage, and elastocartilage. Hyaline
source of pain in the joint ‘organ’ is multi- cartilage is an avascular, aneural, and alym-
focal: direct stimulation of the joint capsule phatic tissue found at the end of long bones.
and bone receptors by cytokines/ligands of It is a perfect example of the structure-func-
inflammatory and degradative processes; tion relationship, where compromise of one
physical stimulation of the joint capsule directly affects the other.
from distention (effusion) and stretch (laxity, The chondrocyte is the cellular element
subluxation, abnormal articulation); physi- of articular cartilage. Chondrocytes are
cal stimulation of subchondral bone from metabolically active cells responsible for the
 Chapter 2 Pathophysiology of Osteoarthritic Pain 75

matrix. 23 Chondrocytes make up 5% of the

tissue volume by composition.
Collagen exists in 19 different forms. 24 2
Collagen type II is the predominant form
of collagen in articular cartilage. Type IX
collagen is thought to link collagen type II
fibrils together and limit their separation by
proteoglycan swelling, to limit fibril diam-
eter, and also possibly to bind proteoglycan
molecules to collagen type II. 25 The deepest
collagen fibers of hyaline cartilage, which
are embedded in the zone of calcified car-
tilage immediately above the subchondral
bone, appear to help in securing the carti-
lage to the bone. These fibers are arranged
perpendicular to the subchondral bone and
constitute the radial zone. The most super-
ficial fibers form a thin layer parallel to the
articular surface and comprise the tangential
zone. Between these is an intermediate zone
in which the fibers appear to have a random
oblique orientation (Figure 2.8).
These zones of collagen orientation produce
FIGURE 2.6 Aggrecan refers to the proteogly- an arcade-like arrangement and correspond to
can monomer that aggregates with hyaluronan, the distribution of chondrocytes seen in histo-
appearing as a ‘bottle brush’. logical sections of normal articular cartilage.
The arrangement of collagen fibers within the
production, organization, and maintenance matrix accounts for the physical properties of
of the extracellular matrix. 23 This cell type the cartilage (elasticity and compressibility).
exists within a lacuna, which together with
its perilacunar rim comprises the structural
and functional entity called the chondron.
The chondrocyte not only synthesizes extra-
cellular matrix components but also gen-
erates the proteinases that degrade these
extracellular matrix components, dependent
on changing properties of the surrounding

FIGURE 2.8 The three zones of collagen orienta-

tion account for the elasticity and compressibility
FIGURE 2.7 The aggrecan aggregate is the ‘func- of cartilage, allowing cartilage to more evenly dis-
tional unit’ of cartilage, containing over 100 tribute forces to the underlying, shock-absorbing
aggrecan monomers. subchondral bone.
76 Chronic Pain in Small Animal Medicine

The triple helices of collagen types II, IX, and

X are susceptible to collagenase cleaving by
matrix metalloproteinases (MMPs): MMP-1
and MMP-3 (stromelysin).26
Hyaluronan is a GAG, although it is not
sulfated and does not bind to a core protein
like chondroitin and keratan sulfate. It is an
important component of both the articular
cartilage matrix and synovial fluid.
Hyaluronan found in the extracellular
matrix is produced by chondrocytes, whereas
hyaluronan found in synovial fluid is pro-
duced by type B synoviocytes. Synovial fluid
hyaluronan functions as both a lubricant and
molecular barrier. Due to its steric configura-
tion, hyaluronan acts as a molecular sieve,
excluding macromolecules from its space.
Proteoglycans comprise most of the
extracellular matrix that is not collagen
and make up 22%–38% of the dry weight
of adult articular cartilage. 27 The common
GAGs of articular cartilage are chondroitin
sulfate, keratan sulfate, and dermatan sul-
fate. They are chains of variable length made
up of repeating disaccharide subunits cova-
lently attached to a protein core (Figure 2.9).
The GAGs are negatively charged due to
FIGURE 2.9 Proteoglycans (chondroitin sulfate,
the carboxyl and sulfate groups of these sub- keratan sulfate, and dermatan sulfate) are chains
units. This negative charge causes the GAGs of variable length covalently attached to a protein
to remain separated, thereby occupying a core.
large volume. The anionic charge also contrib-
utes to the hydrophilic properties of cartilage. phase. The hydraulic pressure increases as
Adult cartilage is 75%–80% water by weight. the compressive force increases. This is due
Retention of water by proteoglycan within the to decreased pore size as the solid matrix is
extracellular matrix creates a swelling pres- compressed, causing increased resistance to
sure and turgidity that are integral to normal fluid flow until an equilibrium is reached with
articular cartilage function. Proteoglycans can the compressive force, resulting in a ceasing
occupy a volume up to 50 times their dry weight of cartilage deformation. Further contribut-
volume when hydrated.28 Their expansile ing to this equilibrium is the increasing nega-
potential is limited to 20% of their potential by tive charge density within the matrix as water
the collagen framework. This constraint keeps is extruded from the matrix in response to
the cartilage turgid, helping to resist deforma- increasing compression.
tion when a compressive load is applied. Upon removal of the compression, water
There are no covalent links between col- and nutrients re-enter the cartilage matrix,
lagen and the proteoglycans.29 The size of the allowing the proteoglycans to swell and
hydrated proteoglycans ensures their reten- the cartilage to recover to its nondeformed
tion within the articular cartilage, with the configuration.
hydrophobic collagen network constraining Normal cartilage turnover and OA will
their escape. The interrelationship between result in proteoglycan fragment release.
the proteoglycans and collagen is also critical Further, susceptibility of the various pro-
to the ability of the articular cartilage matrix teoglycan monomers to cleavage at different
to respond to a compressive load (Figure 2.10). sites leads to diversity of fragments, some of
Upon loading, the compressive force placed which may serve as potential markers for dis-
upon the articular cartilage forces the fluid tinguishing the nature, cause, and severity of
phase to flow through the permeable solid proteoglycan cleavage.
 Chapter 2 Pathophysiology of Osteoarthritic Pain 77

FIGURE 2.10 The aggrecan aggregates, collagen, and water interact, allowing the articular cartilage
matrix to respond to compressive loads.

Subchondral bone is a thin layer of bone increased interosseous pressure, which may
that joins hyaline cartilage with cancellous contribute to chronic pain, particularly noc-
bone supporting the bony plate. The undulat- turnal pain.12
ing nature of the osteochondral junction allows OA frequently results in osteophyte for-
shear stresses to be converted into potentially mation (Figure 2.11). Osteophytes are a
less damaging compressive forces on the sub- central core of bone that blends in with the
chondral bone. The subchondral/cancellous
region has been found to be approximately 10
times more deformable than cortical bone and
plays a major role in the distribution of forces
across a joint.30 Compliance of subchondral
bone to applied joint forces allows congruity
of joint surfaces for increasing the contact area
of load distribution, thereby reducing peak
loading and potential damage to cartilage.31
Cartilage itself makes a poor shock absorber;
however, subchondral bone serves such a role
well. Thickening of the subchondral bone
plate and cancellous trabeculae occurs during
OA, thereby limiting the distribution of loads
across the joint.
Subchondral bone contains unmyelinated
nerve fibers, increasing in number with OA.32
Increased pressure on subchondral bone asso-
ciated with OA articular cartilage degradation
results in these nociceptors being stimulated.
This is thought to contribute to the vague but
consistent pain frequently associated with OA. FIGURE 2.11 Osteophytes are common sequelae
In humans OA is believed to be responsible for of OA.
78 Chronic Pain in Small Animal Medicine

subchondral bone. They are covered by hya-

line and fibrocartilage and are formed by a
process similar to endochondral ossifica-
tion. 33 Although they may occur centrally
in the joint, they are most frequently found
at the junction of the synovium, perichon-
drium, and periosteum. 34
Mechanical instability is believed to be
the predisposing cause of osteophyte forma-
tion; however, synovial membrane inflamma-
tion may play a role as well. Other etiologies
include venous congestion and blood vessel
invasion. Experimental models have dem-
onstrated osteophyte formation as early as
3 days to 1 week after creation of instability. 35
The periosteum of bone is richly inner-
vated with nociceptors, and stimulation of
these nociceptors with elevation of the peri-
FIGURE 2.13 OA is a ‘total joint disease’ and can
osteum by osteophytes is likely (Figure 2.12).
be found in a number of diarthrodial joints.
Additional stimulation of these nociceptors
is also likely as OA progresses and friction
between soft tissues and periosteum increases the pain of OA. Although ligamentous neu-
due to decreased boundary lubrication. roreceptors serve mainly to determine spatial
OA is a disease condition of the entire orientation of the joint, tissue strain incites
diarthrodial joint, including the articular the pain state. Muscle weakness accompa-
(hyaline) cartilage, synovial membrane, nying OA is also associated with pain and
synovial fluid, subchondral bone, and sur- disability. Stimulation of neuroreceptors
rounding supporting structures (muscles and within the damaged OA joint can stimulate
ligaments) (Figure 2.13). The term entheso- a reflex arc, resulting in constant stimulation
phytes refers to bony proliferations found of muscle tissue. Muscle spasm and muscle
at the insertion of ligaments, tendons, and fatigue may greatly contribute to the pain of
capsule to bone. Ligaments and muscles sur- OA. Mild muscle trauma thereafter likely
rounding the OA joint are contributors to releases inflammatory mediators, sensitizing

FIGURE 2.12 Bone periosteum is rich with nociceptors that are stimulated with stretching by osteo-
phytes or tumors. In the case of tumors, additional nociceptive mediators are also involved. (ET-1:
endothelin-1.)
 Chapter 2 Pathophysiology of Osteoarthritic Pain 79

muscle nociceptors to further mechanical increases.43 Chondroitin sulfate, the four-sul-

stimulation. Local tenderness often results
from the release of inflammatory mediators
fated compound, decreases, while the six-sul-
fated compound increases. The link proteins 2
such as bradykinin and PGE 2 . Nociceptors are also subject to proteolytic cleavage as
are found in muscle, fascia, and tendons, aging progresses.44 The end result of these
and since afferent nerve fibers from muscle normal age-related changes is a matrix with
distribute over a relatively large region of reduced capability to withstand the forces
the dorsal spinal horn, poor localization of associated with normal joint functioning.
muscle pain is common.
The synovium is composed of the syno-
vial lining, which contains both type A and B MORPHOLOGICAL CHANGES
synoviocytes. The subsynovial layer contains
fibroblasts, is vascular, contains free nerve The tangentially oriented collagen fibrils of
endings, and functions to enhance motion the superficial cartilage zone (Figure 2.8),
between the fibrous joint capsule and the along with relatively low proteoglycan con-
synovial membrane.36 Menisci in the stifle tent, have the greatest ability to withstand
are contiguous with the joint capsule and high tensile stresses, thereby resisting defor-
are composed of fibrocartilage.37 Pain from mation and distributing load more evenly
meniscal tearing and disruption comes from over the joint surface. Loss of this super-
stimulation of joint capsule pain receptors ficial layer, as occurs in the early stages of
and perhaps from stimulation of C fibers in cartilage fibrillation of OA, alters the biome-
the outer one-third of the meniscus.38 chanical properties of the articular cartilage.
Synovial fluid is frequently referred to One of the first changes of OA, recognized
as a dialysate of plasma, in that it contains microscopically, is fibrillation of the superfi-
electrolytes and small molecules in simi- cial cartilage layer.45 Fibrillation occurs as a
lar proportions as in plasma. The release of flaking of the superficial cartilage layers, fol-
inflammatory mediators results in synovial lowing the course of collagen fibrils parallel
vasculature increased permeability.39 This to the joint surface.
upregulates the synovial vasculature protein Once integrity of the stiff cartilage outer
content with resultant disturbance of the nor- layer is lost by the progression of fibrillation,
mal oncotic balance and change of synovial abnormal stresses give rise to fissures into
fluid volume. As the synovial membrane is the deeper layers (Figure 2.14). These fissures
distended and increased synovial blood flow
accompanies the synovitis of OA, there is an
increased exchange of small molecule pro-
teins across the synovial membrane. Proteins
are then cleared by joint lymphatic drainage.40
The increased rate of removal of these mole-
cules, along with variable rates of release from
cartilage, reflects the difficulty in using these
markers as indicators of disease severity.41

AGING CARTILAGE
Normal age-related changes occur in articu-
lar cartilage throughout life. Data from por-
cine articular cartilage has shown a decrease
in hydration, a decrease in collagen on a dry
FIGURE 2.14 Morphologically, arthritic hyaline car-
matter basis, a decrease in GAG concentra- tilage undergoes fibrillation (1) that progresses
tion – especially chondroitin sulfate – and to deep cartilage fissures (2) and is ultimately
a decrease in proteoglycan size with age.42 replaced with structurally inferior fibrocartilage
Although the total GAG concentration may (3). Joint mice (4) might be present if osteochon-
not vary much with increasing age, the ratio dritis dissecans fragments have maintained via-
of keratan sulfate to chondroitin sulfate bility from the synovial fluid.
80 Chronic Pain in Small Animal Medicine

develop in a vertical plane, again following

the orientation of mid-zone collagen fibrils.
Such fissures can extend to the subchondral
bone. Concurrently, chondrocytes become
larger and begin to cluster.

INFLAMMATORY MEDIATORS
OA-induced pathological changes in joints
include ulceration, fibrillation, softening, and
loss of articular cartilage. Excessive produc-
tion of MMPs by chondrocytes is one of the
major causes of altered cartilage homeostasis
and cartilage degradation.46 In OA cartilage,
proinflammatory cytokines, such as TNF-α, FIGURE 2.15 Synovitis is a common arthroscopic
IL-1, and IL-6, mediate the transcription finding in OA patients. The cauliflower-like red
of MMPs.36 Synovial lining cells are likely mass contained in the upper-right quadrant is
the primary source of these proinflamma- the characteristic intimal proliferation associated
tory cytokines, as these cytokines have been with synovitis.
demonstrated in the synovial membrane
and synovial fluid of OA joints.47,48 Studies blockade, and folate-mediated drug delivery
suggest that (under experimental condi- to macrophages.55
tions) transforming growth factor (TGF)-β, The release of free cartilage fragments
the synovial membrane, and synovial mac- initiates a synovitis (Figure 2.15) as they
rophages contribute to osteophyte forma- are phagocytized by type A synoviocytes. 56
tion.49,50 Inflammatory changes within OA This is followed by the release of additional
joints are proposed to be secondary to car- inflammatory mediators such as cytokines
tilage-soluble, cartilage-specific macromol- and PGs, which enhance the inflammatory
ecule degradation products. 51 Phagocytosis process to varying severity.57 Despite the
of these products by synovial macrophages increase of proteoglycan synthesis, catabo-
induces chronic inflammation of the synovial lism exceeds the anabolic rate. As collagen
membrane and joint capsule with subsequent breakdown progresses, proteoglycans are no
synthesis of proteases and proinflammatory longer constrained of their expansile poten-
cytokines such as TNF-α, IL-1, and IL-6.52 tial, and the water content of the cartilage
In addition to the role of synovial macro- increases. 58 One of the earliest changes seen
phages in osteophyte formation, synovial in OA is an increase in hydration (2%–3%).59
macrophages play an important role in the This hydration appears to be the result of
development and maintenance of synovial the cleavage of type II collagen by collage-
inflammation, as supported by the observa- nase. The functional collagen network is
tion that vascular endothelial growth factor disrupted, thereby permitting the proteogly-
(VEGF) derived from synovial macrophages cans, the hydration capacity of which is no
promotes VEGF immunoreactivity and longer restricted by the collagen network,
endothelial cell proliferation. 53 In a study54 to bind increased amounts of water, result-
of 17 dogs with naturally occurring rupture ing in the cartilage swelling.60 At this point
of the cranial cruciate ligament, macro- proteoglycans are lost into the synovial fluid.
phages and the cytokines TNF-α and IL-6 Cartilage at this stage is grossly softer than
were detected in the synovial membranes normal and more susceptible to mechanical
and joint capsule at concentrations reflecting injury.
the chronicity of the OA. Such observations Chondromalacia is an early sign of
have led to the development of therapeutic degeneration and is attributed to a decrease
agents for human rheumatoid patients, the in sulfated mucopolysaccharide content in
mechanism of action of which includes neu- the ground substance of the cartilage matrix.
tralization of cytokines, cytokine receptor As previously indicated, fibrillation is the
 Chapter 2 Pathophysiology of Osteoarthritic Pain 81

term applied to the exposure of the colla- are believed to be of great importance in this
gen framework through the loss of ground
substance (matrix) and is one of the earlier
process. Among other functions, cytokines
further stimulate chondrocytes and synovio- 2
pathological features of OA. As fibrillation cytes to produce and release more degrada-
progresses, the cartilage may fragment and tive enzymes.
erode. Erosion may continue until all the Proteoglycan and collagen breakdown
cartilage is worn away and the subchon- is mediated by an increase in MMPs, serine
dral bone is exposed. The subchondral bone proteases, lysosomal enzymes, and other
becomes sclerotic from mechanical pressure proteases at the articular surface early in
and/or the effect of the synovial fluid and the degenerative process. Extensive matrix
takes on the appearance of polished ivory, a degeneration is the consequence of these pro-
process called eburnation. teases. The production of metalloprotein-
With the progression of OA, chon- ases greatly exceeds the ability of heightened
drocytes undergo apoptosis and necrosis. TIMPs released to maintain homeostasis.
Extracellular matrix synthesis decreases Cytokines such as IL-1 and TNF-α further
while degradation increases. Chondrocyte stimulate metalloproteinase and serine pro-
activity is stimulated in part by release of tease chondrocyte synthesis that further
growth factors (e.g., insulin-like growth fac- degrade the extracellular matrix.64 IL-1
tor); however, the newly synthesized proteo- also stimulates chondrocyte and synovial
glycans have an abnormal composition, and cell release of PGE 2 , LTB 4, and thrombox-
newly synthesized proteoglycan subunits ane: arachidonic acid (AA) metabolites that
do not normally aggregate with hyaluronic enhance inflammation. IL-1 stimulates fibro-
acid (HA).61 The collagen network becomes blasts to produce collagen types I and III,
increasingly disorganized and disintegrated, which contribute to fibrosis of the joint cap-
with the content of collagen and proteogly- sule in the OA joint.65
cans reduced. The removal of functional
proteoglycans from the extracellular matrix
results in decreased water content of the car- SYNOVITIS
tilage and subsequent loss of biomechanical
properties. Mechanical stress and trauma to It is proposed that the chondrocyte is the
chondrocytes perpetuate the OA process. most active source of degradative protease
production; however, this is stimulated pri-
marily by cytokines and LTs produced by
MMP AND TIMP IMBALANCE the synovium.66 Yet it appears that syno-
vitis alone is insufficient as the sole etiol-
In the osteoarthritic cartilage an imbalance ogy of OA and that physical trauma is also
develops between active MMP levels and tis- necessary.67 Nevertheless, the impact strict
sue inhibitors of metalloproteinase (TIMPs), hemostasis makes on the development of
resulting in cartilage catabolism. Although degenerative articular change in the cruciate-
synoviocytes and some inflammatory cells deficient model (i.e., producing less inflam-
produce proteases, most are derived from matory stimulus) illustrates the importance
chondrocytes.62 MMPs exist as a number of the synovium in the development of OA
of different molecules and play a major role changes.68 It is therefore logical to assume
in cartilage destruction. Collagenases act that intervention in the inflammatory pro-
on collagen fibers to break down the carti- cess of OA will slow the disease process. This
lage framework, while stromelysin cleaves substantiates the legitimacy of nonsteroidal
the aggrecan, leading to the loss of matrix anti-inflammatory drug (NSAID) therapy in
proteoglycan. In the process OA cytokines, OA disease.
acting as chemical messengers to maintain
the chronic phase of inflammation and tis-
sue destruction, are upregulated. Whereas JOINT CAPSULE DYNAMICS
these degradative enzymes and cytokines are
normally found within chondrocytes, they Progressive alterations of the synovium
are normally inactive or only produced in include thickening of the synovial intima
response to injury.63 IL-1, IL-6, and TNF-α from one to two cell layers thick to three to
82 Chronic Pain in Small Animal Medicine

four cell layers thick, development of synovial

villi, and increased vascularity and infiltra-
INTRA-ARTICULAR
tion of the subsynovial stroma by lympho- STRUCTURE DEGRADATION
cytes.69 Apparently, changes in the synovium
precede changes in the articular cartilage. In Arachidonic Acid Cascade
the cruciate-deficient canine model, initial
change, including increased cellularity of the The inflammation associated with DJD
synovial lining layer and infiltration of the upregulates cytokines, such as IL-1 and
subsynovial layer by mononuclear cells, is TNF-α, which in turn activate the AA
noted as early as 1 week.70 Increased vascu- cascade. The AA cascade stimulates the
larity of the subsynovial layer and synovial synovium to produce various inflammatory
villi development were seen at the same time. mediators such as PGs, thromboxanes, LTs,
At 3–4 weeks following ligament transec- and kinins (Figure 2.16).72
tion, fibrosis of the joint capsule is observed, A major inflammatory mediator is PGE2,
most pronounced on the medial aspect of which influences vasodilatation and permeabil-
the joint. Phagocytosis of proteoglycan and ity of small blood vessels, leading to erythema;
collagen fragments in synovial fluid by syno- sensitizes peripheral nociceptors73; stimulates
vial intima macrophages may undermine the the formation of new blood vessels74; and stim-
synovium changes, 55 which may, in turn, ulates expression of MMPs via promotion of
stimulate synoviocytes to produce cytokines plasminogen activators.75 A primary group of
and metalloproteinases, perpetuating the MMPs active in the cleavage of type II collagen
cycle of further degeneration.71 are the collagenases (MMP-1, 8, and -13).

FIGURE 2.16 The arachidonic acid pathway produces a number of eicosanoids that impact the physiol-
ogy of joint inflammation.
 Chapter 2 Pathophysiology of Osteoarthritic Pain 83

PGE 2 in synovial fluid is believed to cytokines IL-1 and IL-6. A second group
originate from articular tissue, rather than
blood, since no relationship has been estab-
includes the degradation products of OA,
which may mimic the normal homeostatic 2
lished between PGE 2 concentrations and degradation products of cartilage. Herein, a
total leukocyte count in blood samples.76 differentiation might be made in the quan-
PGE 2 depresses proteoglycan synthesis by tity of degradative products and/or a quali-
chondrocytes, thereby accelerating GAG loss tative difference in proteoglycan fragments
from articular cartilage.77 associated with variations in proteoglycan
cleavage sites. OA-related molecules include
keratan sulfate, chondroitin sulfate, aggre-
Potential Biomarkers can fragment components, cartilage matrix
As OA progresses, numerous factors play glycoprotein, and cartilage oligomeric
consistent roles in the catabolic process, matrix protein. A third group of potential
offering potentially quantifiable markers OA markers includes anabolic components:
(Figure 2.17). Most investigators suggest specific types of chondroitin sulfates, link
that components that may serve as molecu- proteins, and collagen X. Currently, the
lar markers of OA can be categorized based synovial fluid is favored for measuring con-
on their origin and function during the centrations of potential OA markers, rather
process.78 The first group includes enzymes than serum or urine.68
released from periarticular macrophages or The Osteoarthritis Biomarkers Network
synoviocytes as well as degradative enzymes Consortium is developing and characteriz-
from chondrocytes: stromelysin (MMP-3), ing new biomarkers and redefining existing
collagenase (MMP-1), TIMPs, and the OA biomarkers.79 The scheme is represented

FIGURE 2.17 The catabolic process of OA is quite complex, offering several potential quantifiable
biomarkers.
84 Chronic Pain in Small Animal Medicine

which are considered ‘severe’, 38% are consid-

ered ‘moderate’, and 41% are considered ‘mild’
as assessed by their clinical presentation.5
This ‘cycle of inflammation’ provides an
overview for appreciation that OA is a pro-
cess rather than a disease entity. There can
be a number of causes for synovitis (which
is inflammation of the synovium): trauma,
which can be of a mechanical, chemical,
or thermal origin; joint instability; or idio-
pathic (of an unknown nature). The synovi-
tis is observed arthroscopically with various
degrees of inflammation and histologically
as hyperplastic and hypertrophic synovio-
FIGURE 2.18 The BIPED scheme, proposed by the cytes (demonstrated in the upper right por-
Osteoarthritis Biomarkers Network Consortium, tion of Figure 2.19). Additionally, there is
is designed to characterize OA biomarkers. marked angiogenesis of the synovium.
Noting that synoviocyte A’s are mostly
macrophages, an overproduction of proin-
by the acronym BIPED: Burden of disease, flammatory cytokines (such as MMPs, ILs,
Investigative, Prognostic, Efficacy of inter- and TNF-α) become part of the joint fluid
vention, and Diagnostic (Figure 2.18). milieu moving to and from synovial and car-
tilage tissues. MMPs, ADMTS (a disintegrin
• Burden of disease markers assess the sever- and metalloprotease with thrombospondin
ity or extent of disease, typically at a single motifs; aggrecanases that cleave the aggre-
point in time, among individuals with OA. can building blocks of cartilage), and NO (an
• An investigative marker is one for which important mediator in chondrocyte apopto-
there is insufficient information to allow sis) are particularly destructive to cartilage.
inclusion into one of the existing categories. Associated with cartilage catabolism comes
• The key feature of a prognostic marker is progressive inflammation, pain, and disabil-
the ability to predict the future onset of OA ity. The worse it gets – the worse it gets!
among those without OA at baseline or the OA is now well accepted as a low-grade
progression of OA among those with exist- inflammatory disease affecting the whole
ing disease. joint, evolving progressive destruction of
• An efficacy of intervention biomarker articular cartilage, synovial inflammation
chiefly provides information about the effi- (synovitis), subchondral bone remodeling,
cacy of treatment among those with OA or osteophyte formation, and meniscus, as well
those at high risk of developing OA. as ligament changes.81–84 Clearly, in addition
• Diagnostic markers are defined by the abil- to mechanical loading, inflammation (partic-
ity to classify individuals as either diseased ularly synovitis) contributes significantly to
or nondiseased. OA. Although it is generally of a lower grade
than that observed in RA, evidence supports
that synovitis directly contributes to several
Macrophages Regulate the clinical signs and symptoms of OA, includ-
ing pain, joint swelling, and effusion, and
Progression of Osteoarthritis synovitis reflects the structural progression
OA is predicted to be the single greatest cause of the disease85–87 (Figure 2.20).
of disability in the general population by 2030, The synovium consists of two distinct tis-
with an estimated 35% of people eventually sue layers and functions to produce and retain
suffering from this disease.80 OA is the num- synovial fluid in the joint. The intimal lining
ber one cause of chronic pain in dogs, and layer consists of two to three layers of mac-
approximately 10–12 million dogs (1 in 5 adult rophages and fibroblast-like synoviocytes:
dogs) in the United States show signs of OA.4 synoviocytes-A and synoviocytes-B, respec-
The ‘average’ veterinary practice sees approxi- tively. The outer layer is the synovial sub-
mately 45 arthritic dogs per month, 21% of lining layer, composed of fibrous connective
 Chapter 2 Pathophysiology of Osteoarthritic Pain 85

2.19

FIGURE 2.19 Osteoarthritis: an inflammatory ‘vicious’ cycle.

DRG neurons 2.20

Neurons

Schwann cells M2
Th2 cytokines

DAMPs
Microglia Astrocytes
Th1 cytokines
M1
Central sensitization
Neutrophils Macrophages Lymphocytes

Pro-inflammatory molecules
IL-1β, TNFα, CCL2, CCL3, etc. Pharmacological treatment

nAChR ligands (Nicotine, TC-2559, etc.)

Neuroinflammation Th2 cytokines (IL-4 and IL-13)
Inhibitors for cytokines/chemokines
Peripheral sensitization

FIGURE 2.20 Macrophage-driven inflammatory/neuropathic pain. (Adapted from Kiguchi N, Kobayashi

D, Saika F, Matsuzaki S, Kishioka S. Pharmacological regulation of neuropathic pain driven by inflam-
matory macrophages. Int J Mol Sci. 2017 Nov 1;18(11):2296 and Yu X, Liu H, Hamel KA, et al. Dorsal
root ganglion macrophages contribute to both the initiation and persistence of neuropathic pain. Nat
Commun. 2020 14;11(1):264.)
86 Chronic Pain in Small Animal Medicine

tissue and blood vessels, with few lympho- along with MMPs and aggrecanase, which
cytes and macrophages.88,89 The accumula- have destructive functions in OA.93 Using a
tion of polarized macrophages in the intimal collagenase-induced mouse model, Bondeson
lining is the principal morphological char- et al.93 identified several chemokines respon-
acteristic of synovitis and comprises mostly sible for the chemotaxis of macrophages in
proliferative synovial tissue.90 In OA, carti- the development of OA, including TGF-β
lage fragments, aggrecan, fibronectin, and and IL-1β. This same group also found that
intracellular proteins together with necrotic the selective depletion of lining macrophages
cells act as danger-associated molecular via the intra-articular injection of clodronate
patterns (DAMPs), which stimulate macro- liposomes ameliorated cartilage damage and
phage activation and produce inflammatory osteophyte formation. Such findings suggest
cytokines and chemokines.91,92 These media- that the activation of synovial macrophages
tors can not only recruit additional macro- is required for the production of MMPs that
phages and lymphocytes but also increase cause cartilage damage.
the synthesis of inflammatory cytokines Macrophages are remarkably plastic
and metalloproteinases by macrophages and cells, identified as classically activated M1
chondrocytes. Herein, macrophages play a macrophages or alternatively activated M2
pivotal role in innate immunity, and their macrophages that differ in response to micro-
polarized phenotypes correlate with the pro- environment stimuli.94,95 M1 macrophages
gression of OA. The polarized synovial mac- are activated by interferon-g, lipopolysac-
rophages appear to be a suitable therapeutic charide (LPS), or TNF-α. M1 macrophages
target for the early prevention and treatment secrete large amounts of proinflammatory
of OA (Figure 2.21). cytokines and mediators, such as TNF-α,
During OA development, synovial mac- IL-1, IL-6, IL-12, COX-2, and low levels of
rophages lose their stable state, mobilize, IL-10.96 M2 macrophages, which are also
and are activated in various ways. Therapies known as wound-healing macrophages, are
aimed at macrophages have shown the abil- polarized by the Th2 cytokines IL-4 and
ity to decrease inflammation and the pro- IL-13 and have been further divided into spe-
gression of OA. The removal of macrophages cific subtypes. Subtypes M2a, M2b, and M2c
from synovial cell cultures by anti-CD14– display an anti-inflammatory phenotype
conjugated magnetic beads resulted in the and contribute to tissue repair and remodel-
reduced production of IL-1 and TNF-α, ing.97,98 Although M1 and M2 macrophages

2.21 Tissue damage

MSC Differentiation,
TLR3 or
TLR4 ligand proliferation
Activation and activation
T cell
Promotes neutrophil
survival and activation
Survival and
proliferation
B cell

↑Antimicrobial ↑Cytokine
activity production

Macrophage NK cell

↑Maturation Via lymphatics

and activation (CCR7-dependent)
or circulation
Dendritic cell

FIGURE 2.21 Neutrophil-macrophage activation. (Reproduced with permission from Mantovani A,

Cassatella MA, Costantini C, Jaillon S. Neutrophils in the activation and regulation of innate and adap-
tive immunity. Nat Rev Immunol. 2011;11(8):519–531.)
 Chapter 2 Pathophysiology of Osteoarthritic Pain 87

are now regarded as polar extremes of a within the joint, macrophage-secreting

spectrum of in vitro macrophage activation
states, they do not adequately reflect tissue
inflammatory cytokines have a primarily
destructive impact on articular cartilage. 2
macrophages in vivo due to the complex The impact is multilevel and involves not
milieu surroundings. Macrophages accu- only the induction of aging and apoptosis
mulate and become polarized (M1 or M2) in chondrocytes but also decreases the syn-
in the synovium and articular cavity dur- thesis of key components of the extracellular
ing OA development.99 In addition to being matrix, such as proteoglycans, aggrecan, and
detected in the synovium, macrophages are type II collagen. In addition, inflammatory
also detected in synovial fluid and peripheral cytokines contribute to the increased synthe-
blood of OA patients.100 Liu et al.101 showed sis and release of many proteolytic enzymes
that the ratio of M1/M2 macrophages in that decompose articular cartilage, includ-
human synovial fluid and peripheral blood ing the metalloproteinase family MMPs
was markedly higher in knee OA patients and ADAMTS. The crucial role of IL-1β
compared to healthy controls. Studies indi- and TNF-α in macrophage-mediated OA
cated that failure to transform from the M1 progression has been confirmed. The spe-
to M2 subtype may play a larger role in the cific removal of synovial macrophages from
progression of OA than does the quantity synovial cell cultures has similar effects to
of activated macrophages. However, little is those observed in the neutralization of both
known about the regulatory mechanism of IL-1 and TNF- α. Not only do cells no lon-
macrophage polarization in the pathogenesis ger produce significant amounts of IL-1 and
and progression of OA (Figure 2.22). TNF-α but several cytokines are also down-
Activated and polarized macrophages in regulated, including IL-6, IL-8, MMP-1, and
the OA synovium secrete cytokines, growth MMP-3.16 Apart from driving inflamma-
factors, and MMPs, among other factors tory responses in OA, IL-1β and TNF-α can
that lead to inflammation and subsequent also promote osteoclast formation, which
cartilage degradation. Due to their effects contributes to bone resorption that, in turn,

2.22
Functions
M1 Macrophage • Pro-inflammatory
• Microbicidal
• Tumoricidal
• TH 1 response
• Antigen presentation capacity
• Killing of intracellular
pathogens
IFN-γ, LPS, • Tissue damage, etc.
GMCSF, etc.

IL4, IL13, IL10,

Macrophage MCSF, TGF-β, etc. Functions
• Anti-inflammatory
• Clearance of parasites
• Tumor promotion
• TH 2 response
• Immunoregulation
• Tissue remodelling
• Angiogenesis
M2 Macrophage
• Matrix deposition, etc.

FIGURE 2.22 Macrophages: M1 and M2.

88 Chronic Pain in Small Animal Medicine

stimulates osteoblasts to secrete MMPs and Ironically, articular cartilage is fre-

cytokines that adversely target bone and adja- quently the focus of studies in OA. However,
cent cartilage.102 Interestingly, macrophage- clinical treatment of the OA patient is most
derived TNF-α and IL-1β can regulate nerve often focused on the alleviation of pain.
growth factor (NGF) expression in synovial Appreciating that articular cartilage is
macrophages, which may cause OA pain.103 aneural, the focus of OA pain management
There is ample evidence that synovial macro- resides in the pathophysiology of periarticu-
phages are a key instigator of MMP overex- lar structures. No pain is elicited by stimula-
pression and upregulation in the production tion of cartilage, and stimulation of normal
of inflammatory cytokines with subsequent synovial tissue rarely evokes pain.106
cartilage degradation. Further, VEGF gener-
ated by synovial macrophages has been pro-
posed to exacerbate synovial angiogenesis
Nociceptors
and inflammation in OA.94 The major sources of clinical pain in deep
Compelling data suggest that besides the tissues such as joint structures are inflam-
autocrine mechanism, paracrine interactions matory disease, trauma, overload, and
between macrophages and chondrocytes degenerative diseases. Joint structures and
provide another mechanism for the initiation muscles are innervated by nociceptors that
and development of OA. Data indicates that are mostly activated under normal condi-
paracrine cross-talk between chondrocytes tions by nonphysiological painful stimuli
and synovial macrophages is required for such as overload, twisting, strong pressure,
continued cartilage destruction. Together, and ischemic contraction, which may cause
the paracrine effects of macrophages on deep structure damage. Most joint nocicep-
chondrocytes are exerted through factors tors are chemosensitive for inflammatory
secreted by synovial macrophages and sig- mediators such as bradykinin and PGs, and
naling activated in chondrocytes.104 in the presence of inflammation, joint and
In summary, targeting synovial mac- muscle nociceptors show pronounced sen-
rophages relieves pain and protects from sitization to mechanical stimuli. There are
synovitis, cartilage damage, and osteo- two types of second-order dorsal horn neu-
phyte formation during OA development. rons: nociceptive-specific and wide dynamic
Apparently, although macrophages accumu- range (WDR) neurons (see Chapter 1).107
late and tend to display the M1 polarized WDR neurons respond to various stim-
phenotype in OA synovium, the complete uli, whereas nociceptive-specific neurons
depletion of both M1 and M2 macrophages respond only to noxious stimuli. Spinal
does not inhibit the development of OA. cord neurons processing nociceptive input
from joint and muscle are often convergent
with inputs from skin and other deep tis-
THE PAIN OF sue (Figure 2.23). During inflammation in
muscle and joint, these convergent spinal
OSTEOARTHRITIS cord neurons develop pronounced hyperex-
citability, with enhanced mechanical stimu-
Pain is the clinical symptom most frequently lation from different foci and an expansion
associated with OA.105 The clinical mani- of the receptive field. Accordingly, these
festation of this pain is lameness. When an neurons are under strong descending inhibi-
animal presents with clinical lameness, a tion as well.
determination must be made whether the Although there is considerable sensory
animal is unable to use the limb or is unwill- information transmitted from muscle and
ing to use the limb. Inability to use the limb joint, most involves the sense of movement
may be attributable to musculoskeletal and position, evading consciousness. Pain
changes, such as joint contracture or muscle in the normal joint is commonly elicited by
atrophy. These anomalies are best addressed twisting or traumatizing the joint. Clearly,
with physical rehabilitation. On the other the processing of nociceptive inputs from
hand, unwillingness to use a limb is most deep tissues of muscle and joint differs from
often attributable to pain. Herein, lameness the processing of inputs from cutaneous
is an avoidance behavior. structures.108
 Chapter 2 Pathophysiology of Osteoarthritic Pain 89

Wyke111 has described four types of

sensory receptors associated with joints
(Figure 2.24, Table 2.1). Located in the joint 2
capsule, type I and II receptors respond to
mechanical stimuli such as pressure or ten-
sion and are therefore known as mechano-
receptors. Type I and II receptors are located
in the superficial layers and deep layers of
the capsule, respectively, and rapidly trans-
mit information via myelinated fibers. Type
II (mostly Aβ) receptors are more rapidly
adapting, thereby serving a more dynamic
function than the slowly adapting type I
receptors.76 In combination with other recep-
tors in the muscle and skin, type I and II
receptors allow recognition of limb and joint
orientation in space.112 Type III receptors are
FIGURE 2.23 The CNS is made up of hundreds not actually in the joint but are found on the
to thousands of neuronal pools. Each input fiber surface of ligaments. They are associated
(right) divides thousands of times, spreading over
a large area in the pool to synapse with dendrites
or cell bodies of neurons (left) in the pool. Each
input fiber arborizes such that large numbers of
its synaptic knobs lie on the centermost neurons
in its ‘field’, while fewer lie on adjacent neu-
rons. Therefore, an input stimulus can be either
an excitatory stimulus (threshold stimulus) or a
subthreshold stimulus to a neuron, depending
on the required knobs needed for stimulation. A
neuron made more excitable, but not to the point
of discharge, is said to be facilitated and can
reach threshold when complemented by input
from other input fibers. Subthreshold stimuli can
converge from several sources and summate at a
neuron to cause an excitatory stimulus.

Joint Afferents
Typical joint nerves contain thick myelin- FIGURE 2.24 Sensory receptors are end organs of
ated Aβ, thinly myelinated Aδ, and a high afferent nerves and belong to one of two main
physiological groups: (1) exteroceptors, which
proportion (˜80%) of unmyelinated C fibers.
detect stimuli that arise external to the body,
Articular Aβ fibers terminate as corpuscular and (2) interoceptors, which detect stimuli that
endings in fibrous capsule, articular liga- are within the body. Proprioceptors are a special
ments, menisci, and adjacent periosteum. class of interoceptors that signal conditions deep
Articular Aδ and C fibers terminate as non- within the body to the CNS. Proprioceptors are
corpuscular or free nerve endings in the located in skeletal muscles, tendons, ligaments,
fibrous capsule, adipose tissue, ligaments, and joint capsules. Free nerve endings act as
menisci, and periosteum.109 Within muscle, thermoreceptors and nociceptors (pain). Merkel
most of these endings are located in the wall endings are pressure-sensitive touch receptors.
of arterioles in the muscle belly and sur- Pacinian corpuscles respond to pressure and
are widely distributed throughout the dermis and
rounding connective tissue.110 The major
subcutaneous tissue, joint capsules, and other
neuropeptides in joint and muscle nerves pressure sites. Meissner corpuscles are highly
are substance P (sP), calcitonin gene–related sensitive to touch. Ruffini corpuscles in subcu-
peptide (CGRP), and somatostatin, although taneous connective tissue respond to tension.
these neuropeptides are not specific for deep Krause end bulbs are cold sensitive. See also
afferents. Table 2.1.
90 Chronic Pain in Small Animal Medicine

TABLE 2.1 Classification of articular receptor systems (see also Figure 2.24)
Parent nerve Behavioral
Type Morphology Location fibers characteristics
I Thinly encapsulated globular Fibrous capsule of Small myelinated Static and dynamic
corpuscles (100 μm × 40 joint (mainly (6–9 μm) mechanoreceptors
μm) in clusters of three to superficial layers) Low threshold,
six corpuscles slowly adapting
II Thickly encapsulated Fibrous capsule of Medium myelinated Dynamic
conical corpuscles (280 joint (mainly deeper (9–12 μm) mechanoreceptors
μm × 120 μm) in clusters layers) Low threshold,
of two to four corpuscles Articular fat pads rapidly adapting
III Thinly encapsulated Joint ligaments Large myelinated Dynamic
fusiform corpuscles (600 (intrinsic and (13–17 μm) mechanoreceptors
μm × 100 μm) extrinsic) High threshold, very
slowly adapting
IV Plexuses and free nerve Fibrous capsule, Very small myelinated Pain receptors
endings articular fat pads, (2–5 μm) High threshold,
ligaments, walls of Unmyelinated (<2 μm) nonadapting
blood vessels

with large-myelinated afferent (Aα) fibers,

allowing rapid transmission, and are inactive
during normal joint activity. Type III recep-
tors become active when a strong mechanical
stimulus threatens damage.76
In contrast to type I and II mechanore-
ceptors, type IV receptors are high-thresh-
old, slowly adaptive, polymodal free nerve
endings. These receptors also respond to
thermal and chemical stimuli associated
with inflammation. They are typically stim-
ulated by tension and pressure. Therefore,
they play a major role in discomfort associ-
ated with increased intra-articular pressure
of motion, increased synovial fluid volume
seen in chronic OA and cruciate ligament
rupture patients, and a relative increase due
to decreased atmospheric pressure associated
with weather changes. These receptors also
respond to subluxation of the joint, causing
tension in or pressure on the joint capsule.
Type IV receptors are found in all joint tis-
sues, including subchondral bone, but not
cartilage, which is aneural. Afferent sig-
naling from type IV receptors is via thinly
myelinated Aδ or unmyelinated C fibers.76
Some type IV receptors are considered to be
silent nociceptors,113 contributing to central
sensitization.
Joint afferents have been best described
in cat and rat stifle and tarsus joints, reveal-
ing proportions of different fibers in different
sensitivity classes (Figure 2.25). FIGURE 2.25 Mechanosensitivity of primary affer-
Many low-threshold Aβ and Aδ fibers in ent neurons supplying normal cats’ stifle joint.
the fibrous capsule and in ligaments, includ- The bar graphs show the proportion of fiber types
ing the anterior cruciate ligament, fire in the in the different sensitivity classes.73
 Chapter 2 Pathophysiology of Osteoarthritic Pain 91

TABLE 2.2 Chemosensitivity of Aδ and C fibers from normal joints

Mediator Resting activity Mechanosensitivity Source 2
Bradykinin ↑ ↑ 116–118
Prostaglandin E2 ↑ ↑ 118–121
Prostaglandin I2 ↓ ↓ 118, 120–123
Serotonin ↑ ↑ 124, 125
Capsaicin/anandamide ↓ 126, 127
NO ↓ 128
ATP ↑ 129, 130
Adenosine ↑ 130
Substance P (↑)↓ 131, 132
NK2 receptor agonist 133
Somatostatin ↓ 134
Galanin ↑↓ 135
Neuropeptide Y ↑↓ 136
Nociceptin ↑↓ 137

Note: Arrows represent influence of mediator on fiber chemosensitivity.

innocuous range, but they have their strongest Convergence May Amplify
response in the noxious range.114 An additional
group of sensory neurons is mechanoinsensi- Afferent Nociception
tive under normal conditions but becomes Nociceptive information from joint and mus-
mechanosensitive during inflammation: silent cle, which is transmitted to neurons in the
nociceptors. The mechanosensitivity of these superficial and deep dorsal horn, is processed
afferents changes during inflammation of the either from exclusively deep tissue input or
joint. Many low-threshold Aδ and C fibers, as neurons that exhibit convergent inputs from
well as a large proportion of high-threshold skin and deep structures. Some neurons may
afferents, respond to movements in the work- also input convergence from the viscera.
ing range of the joint. Noteworthy is the Neurons exclusively driven from deep tissue
recruitment of silent nociceptors for mecha- often include receptive fields of the joint and
nosensitivity, encoding for noxious events adjacent muscle. Some convergent neurons
during an inflammatory process.115 are excited by mechanical stimuli applied to
deep tissue (muscle, tendons, joint structures)
and by mechanical stimulation of the skin.
Inflammatory Mediators
A large proportion of Aδ and C fibers express
Neurogenic Inflammation
receptors for endogenous compounds asso- Once a stimulus is received by the second-
ciated with pathophysiological conditions order neuron in the dorsal spinal horn, an
(Table 2.2). The classical inflammatory ascending signal is sent to the third-order
mediators, bradykinin, PGE 2 and PGI 2 , and neuron in the brain, and a reflex arc back
serotonin, excite joint afferents and sensitize to the joint may also be initiated. The reflex
them to mechanical stimuli. Such mediators arc may result in stimulation of muscles sur-
affect Aδ and C fibers, but not Aβ fibers. rounding the joint and/or neurogenic inflam-
Although each mediator has its own profile mation (Figure 2.26).
of effect, they can interact and yield syner- Release of sP and NGF into the periphery
gistic responses.116 causes the tissue reaction termed neurogenic
92 Chronic Pain in Small Animal Medicine

FIGURE 2.27 Allodynia is an extreme left shift in

the pain-response curve.

those arising from Aβ fibers, normally con-

veying information such as position and
stress. Consistent with this phenomenon is
expansion of the receptive field, explaining
why tissues surrounding the joint are sensi-
tive to stimuli. For example, an affected joint
FIGURE 2.26 Neurogenic inflammation.
may show increased sensitivity to flexion
and extension but will also show sensitiv-
inflammation. Neurogenic inflammation is ity to light touch and with an exaggerated
driven by events in the CNS and does not response. This painful response to what
depend on granulocytes or lymphocytes, would normally be an innocuous stimulus
as with the classic inflammatory response is termed allodynia. Allodynia is, in fact, an
to tissue trauma or immune-mediated cell extreme left shift in the pain-response curve
damage. Cells in the dorsal horn release (Figure 2.27). (See Chapter 1 for further dis-
chemicals that cause action potentials to fire cussion and explanation.)
backward down the nociceptors. The result During joint or muscle inflammation, spi-
of this dorsal root reflex is that nociceptive nal cord neurons receiving deep tissue input
dendrites release sP and CGRP into periph- develop a state of hyperexcitability, contribut-
eral tissues, causing degranulation of mast ing to central sensitization (Figures 2.28 and
cells and changing vascular endothelial cell 2.29). Mense138 has illustrated the process of
characteristics. The resultant outpouring of central sensitization from input of the stifle.
potent inflammatory and vasodilating agents Initially, the monitored spinal cord neuron
causes edema and potentiates transmission responded only to noxious pressure applied
of nociceptive signals from the periphery. to the stifle and adjacent muscles. Response
to noxious compression of the stifle increased
Central Sensitization markedly after induction of inflammation by
injection of kaolin and carrageenan into the
at the Dorsal Horn stifle joint. Within 1 hour, the receptive field
Central sensitization refers to chronic activa- expanded from the knee such that the neuron
tion of primary afferent C fibers resulting in responded to pressure applied to the tarsus
increased excitability of neurons in the spi- and paw, and the previously high-threshold
nal cord. A consequence of central sensitiza- neuron was now activated by gentle innocu-
tion is an increase in the magnitude of the ous pressure.
response of postsynaptic ascending spinal Muscle fatigue and muscle spasm are
neurons to noxious stimuli and increased often seen as a contributing cause or resul-
response to low-threshold stimuli such as tant feature of OA139 and are frequently
 Chapter 2 Pathophysiology of Osteoarthritic Pain 93

FIGURE 2.28 Development of a spinal cord neuron hyperexcitability. Histogram shows spinal cord neu-
ron response to noxious pressure applied to the knee, ankle, and paw before and after the injection of
kaolin and carrageenan into the knee joint. Shaded areas on the animal show the receptive field of the
neuron before and during knee joint inflammation.138

associated with pain and disability.140 Spasm

can be part of the reflex arc neuroreceptor
stimulation. Muscle soreness may also be
a consequence of abnormal biomechanics
across an arthritic joint.

Role of Muscle Fatigue

and Spasm
Spinal cord neuron central sensitization from
muscle input appears to be similar to that of
deep joint tissue. The population of neurons
responding to stimulation of muscle expands
during inflammation. Studies have shown
the neurons in segments L3–6 of the cat are
increased from normal in the inflamed mus-
cle. It can be concluded that many synapses
are too weak to activate the neuron under
normal conditions; however, these synapses
are effective once the neuron becomes hyper-
FIGURE 2.29 Proportion of spinal cord neurons excitable. It has been proposed that such
that respond to gastrocnemius-soleus muscle spinal cord changes account for pronounced
electrical nerve stimulation in the normal and forms of referred pain from noxious stimu-
inflamed state.138 lation of deep tissue in humans.141 Central
94 Chronic Pain in Small Animal Medicine

sensitization can persist during chronic degenerative features. Joint degeneration,

inflammation, and deep input is particularly as a result of acutely altered biomechanics,
able to induce long-term changes in the noci- is perpetuated by inflammatory responses.
ceptive system. Spinal sensitization is also These responses are secondary to the
enhanced by upregulation of transmitters and inflammation from poor resistance to shear
mediators of synaptic activity. The intraspi- mechanical stress of hyaline cartilage and
nal release of glutamate is enhanced in joint due to the ligament endings in the joint trig-
inflammation, and antagonists of both the gering an inflammatory response.152–154 In
alpha-amino-3-hydroxy-5-methyl-4-isoxa- 53%–74% of CCLT dogs, medial menis-
zole propionic-acid (AMPA)/kinase and cal damage occurs,155 which itself is a driv-
N-methyl-D-aspartate (NMDA) receptors ing force of joint degeneration modeling.156
prevent the development of hyperexcitabil- Accordingly, the combination of CCLT and
ity and can reduce responses of the neurons meniscal damage constitutes a robust desta-
to mechanical stimulation of the joint after bilizing drive for development of OA.157 In
inflammation is established.142 Inflammation the CCLT model, permanent instability in
of the joint also impacts on the release of the knee joint is followed by degenerative
neuropeptides. Under inflammatory condi- changes in cartilage and changes in syno-
tions, a cocktail of transmitters and modula- vial tissue (representing secondary synovitis)
tors such as sP, neurokinin A, and CGRP is that, over the course of several years, lead to
released in large quantities that contribute to canine OA.153 Separating the two etiologies
synaptic processing,143 likely opening synap- (instability and cartilage damage), the canine
tic pathways such that more neurons respond ‘groove’ model of OA has been proposed to
to stimulation.107 PGE2 is also released within exclude the influence of instability.158
the dorsal and ventral horns during joint Though not objectively evaluated, it has
inflammation, likely a result of upregulation long been assumed that capsular thickening in
of spinal COX-2, seen within 3 hours after a CrCLD canine knee functions to stabilize the
induction of knee joint inflammation.144 joint over time.159–161 The goal of reconstruc-
tive surgical methods should be not only to
Osteoarthritis and alleviate the existing instability of the unstable
stifle joint but also to mimic normal kinemat-
Joint Instability ics as closely as possible. Extracapsular suture
DJD can simplistically be identified as con- techniques provide stifle joint stability through
sequential sequelae to cartilage degeneration static neutralization of the cranial drawer
and the persistent trigger from instability of without alteration of stifle joint anatomy.162
a joint. Surgically induced instability models The tibial plateau leveling osteotomy has been
of OA have been described in various animal used to provide dynamic stability to the stifle
species. Humans with a traumatic injury gen- joint by alteration of the tibial plateau angle.163
erally decrease use of the affected limb until Recently, the tibial tuberosity advancement
restabilization has occurred. In animals, technique has been proposed to stabilize the
where restabilization has not occurred, the stifle joint during weightbearing by neutraliz-
disease progression is usually much more ing cranial tibial thrust.164,165
rapid, making it much less amenable to thera- Studies indicate that passive hip joint lax-
peutic intervention.145,146 Surgically induced ity is the primary risk factor for development
models of OA, especially in rodents and rab- of DJD in dogs with hip dysplasia.166,167 It
bits, usually have rapid and severe cartilage is hypothesized that, in some dogs, passive
degeneration after the instability is created, joint laxity is transformed into functional
and generally, the greater the instability, the laxity during weightbearing, thereby expos-
greater the lesion.147 Surgical instability mod- ing the cartilaginous surfaces of the joint to
els of OA have been performed in rats, guinea excessive stresses. Such stresses cause carti-
pigs, rabbits, sheep, goats, and dogs.148–151 lage damage and microfracture, release of
The most frequently described canine inflammatory mediators, and, ultimately,
model of OA-related joint degeneration is the the changes associated with DJD. Functional
cranial cruciate ligament transection (CCLT) laxity appears to be both necessary and suffi-
model. In the CCLT model, joint instability cient for the development of DJD.168 Surgical
is the driving force in the development of management for hip dysplasia may involve
 Chapter 2 Pathophysiology of Osteoarthritic Pain 95

corrective osteotomies or arthroplasty tech- • Chronic shoulder luxation

niques, all designed to improve joint congru-
ency and stability. Total hip arthroplasty
• Osteochondrosis dissecans lesions
2
may be performed in adult dogs with chroni- Canine Osteoarthritis
cally painful hips that cannot be treated sat- Staging Tool (COAST)
isfactorily by other methods.
As with the knee and hip, instability is con- Canine OA is a gradually progressive degen-
sidered a primary etiological factor in elbow erative disease most commonly caused by
dysplasia.169 Elbow incongruity is the term to developmental abnormalities of the joints,
describe poor alignment of the elbow joint sur- such as hip dysplasia, elbow dysplasia, and
faces. Two illustrative features are as follows: osteochondrosis dissecans and also condi-
tions such as nontraumatic cranial cruciate
(1) An abnormal shape of the ulnar trochlear ligament failure.172,173 Traumatic joint injury
notch. is another important inciting factor.172,173
(2) A step between the radius and ulna, caused Pain, inflammation, impaired mobility, and
by either a short radius or a short ulna. functional as well as structural changes
characterize the disease and contribute to its
The suggestion is that both an elliptical progression.174,175 The ongoing nociceptive
notch and a step can cause increased local input into the CNS results in somatosensory
pressure within the joint, resulting in frag- system deterioration and central sensitiza-
mentation at different locations, clinically tion, which contribute to the overall percep-
recognized as an un-united anconeal process, tion of pain.176
fragmented coronoid process, and osteo- Early intervention has the greatest poten-
chondrosis dissecans of the humeral condyle. tial for providing the most effective manage-
Collectively, these lesions are referred to ment of OA since it provides an opportunity
as ‘elbow dysplasia’. Several surgical tech- to initiate an appropriate long-term care
niques have been proposed and are currently plan and disrupt the progressive, vicious
under development to restore joint congruity cycle of multidimensional deterioration.
and improve function.170 It is proposed that Unfortunately, greater than 50% of canine
incongruity worsens the prognosis after sur- arthritis cases are diagnosed in dogs aged
gery to remove loose fragments,171 account- between 8 and 13 years.177 The high percent-
ing for 30%–40% of postoperative patients age of first-time diagnosis in a more elderly
still showing lameness. age bracket is concerning given the known
link between OA and developmental ortho-
pedic disease in young dogs.173 It highlights
Surgical Intervention the probability of dogs living with unde-
It must be recognized that surgical intervention tected OA for a large proportion of their life!
is necessary for some patients. Surgery most As a result, veterinarians are frequently not
often involves extraction of inciting causes consulted until the dog’s behavioral changes
(e.g., ununited anconeal process, fragmented are more marked.
coronoid, joint mouse osteophytes, osteochon- The Canine Osteoarthritis Staging Tool
drosis dissecans lesions) and/or attempts to (COAST) has been developed by a group of
stabilize an affected joint. Clear indications for international specialists actively working in
surgery include but are not limited to: the fields of small animal orthopedics, anes-
thesia, and pain management to help vet-
• Cruciate ligament deficient stifle and/or erinarians with the proactive, stage-specific
meniscal tears diagnosis and monitoring of OA in dogs.178
• Symptomatic medial or lateral patellar Several potential benefits are envisaged
luxation through adopting such an approach:
• Fragmented medial coronoid process and
un-united anconeal process • Regular evaluation of preclinical dogs as
• Hip dysplasia that is nonresponsive to ‘con- well as those dogs clinically affected by OA,
servative management’ facilitating early detection of changes and
• End stage: tarsal or carpal disease, stifle dis- the timely implementation or adaptation of
ease, hip disease, and elbow disease their care plan.
96 Chronic Pain in Small Animal Medicine

• Improved understanding of the impact that

OA has on the dog as a whole through the
SUMMARY
use of multiple approaches to assessment. The pain associated with OA results from
• A consistent approach to evaluation and use a complex dynamic interaction of the mus-
of a common terminology. culoskeletal and nervous systems. Pain
• A multidisciplinary team approach to care, relief involves strategies for restoration of
encouraging better communication and mechanical integrity, suppression of periph-
understanding. eral inflammation, and exogenous modula-
tion of neurotransmission. This mandates a
The group recognized that a system multimodal approach.
defining the stages of OA, with guidance
on how to effectively utilize the system for
assessment and monitoring of dogs either
‘at risk’ or with clinical signs of the disease,
was a deficiency in veterinary medicine.
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CHAPTER

3
Pathophysiology of Cancer Pain
IN PERSPECTIVE • Pain intensity and time since onset of pain
• Etiology of pain
The word cancer means ‘crab’ and was given
to the disease because of its tenacity, a singular A distinct group of syndromes, therapies,
ability to cling to its victim like a crab’s claws and other etiologies of pain occur in cancer
clinging to its prey. The all-important reality patients3 such that neither the IASP nor any
of cancer pain is witnessed in John Steinbeck’s other diagnostic scheme distinguishes cancer
book, The Grapes of Wrath, where the char- pain from nonmalignant causes of chronic
acter Mrs. Wilson, who is dying of cancer, pain. Because the classification of cancer pain
states, ‘I’m jus’ pain covered in skin’. may have important diagnostic and therapeu-
Frank Vertosick, MD, states, ‘From the tic implications, a promising concept is a mech-
Darwinian point of view, cancer is an unim- anism-based treatment approach, determining
portant disease. Since it preferentially afflicts the sequence of analgesic agents based on the
animals beyond their child-bearing years, underlying etiopathology of cancer pain.
cancer poses no threat to animals in the wild,
since natural populations experience death in
other ways long before they are old enough SCHEMES FOR CLASSIFYING
for cancer to be a concern. We feel the sting of
advanced prostate cancer because we are for- CANCER PAIN
tunate enough to live into our seventh decade
and beyond, a feat rarely achieved even a hun- Table 3.1, the second column shows exam-
dred years ago. During the evolution of the ples/features of the respective classifications.
nervous system, we developed pain to help
us heal reversible insults: cracked vertebrae, TABLE 3.1 Classifications for cancer pain
pinched nerves, temporarily blocked colons,
Etiological • Primarily caused by cancer
broken legs. To our great sorrow, this same
classification • Treatment of malignancy
pain also works against us when irrevers- • Debility
ible diseases like cancer strike; consequently, • Concurrent pathology
death becomes a painful affair. We die with
Pathophysiological • Nociceptive (somatic,
all of our pain alarms impotently sounding. It
classification visceral)
is said that we are all born in another’s pain • Neuropathic
and destined to die in our own’.1 • Mixed pathophysiology
Location of cancer • Head and neck
pain syndromes Chest
TAXONOMY
•
• Vertebral and radicular pain
• Abdominal or pelvic
In 1994, the International Association for • Extremity
the Study of Pain (IASP) revised a classifi- Temporal • Acute
cation for chronic pain. 2 This classification classification • Breakthrough
includes five axes: • Chronic

• Location of the pain Severity-based • Mild

• Involved organ or tissue system classification • Moderate
• Temporal pattern of pain • Severe

102 DOI: 10.1201/9781003376422-4

 Chapter 3 Pathophysiology of Cancer Pain 103

the tumor develops, the body produces anti-

bodies to fight it by binding to and helping
the destruction of tumor cells. Such antibod- 3
ies may cross-react with epitopes on normal
nervous tissue, resulting in an attack on the
nervous system.
Neoplasms of the spinal cord may be
either intramedullary or extramedullary,
and primary tumors affecting the paraver-
tebral area may spread and compress the
FIGURE 3.1 Tumors may compress a nerve fiber. cord, particularly within the intervertebral
foramina (Figure 3.3). An enlarging cancer-
Etiological Classification ous lymph node can compress the cord, and
cancer that metastasizes to the vertebrae or
Four different etiologies of cancer pain are: surrounding tissues may also cause spinal
cord compression.
• That directly produced by the tumor Pain-generating mediators are often
• That due to the various treatment modalities released from certain tumors or from sur-
• That related to chronic debility rounding tissues involving invasion or
• That due to unrelated, concurrent disease metastasis, thereby producing pain itself.5
processes4 Paradoxically, various cancer therapies may
result in pain. Chemotherapeutic agents have
Identification of these etiologies is impor- been associated with peripheral neuropathies
tant, as they reflect distinct treatment options and acute pain in humans,6 and radiation
and prognoses. therapy may injure soft tissue or neuronal
A tumor may compress a nerve fiber structures. Furthermore, immunosuppres-
(Figure 3.1). Pain relief from debulking sive therapy may render some patients at
tumors suggests that mechanical distortion increased risk for secondary infection and
is a component of tumor pain. complications.
Compression of a peripheral nerve can Although the inclusion of psychogenic
cause local demyelination, Wallerian degener- pain in animals is controversial, nociceptive
ation of the nerve, secondary axon sprouting, and neuropathic types of cancer pain are
and neuroma formation. Physiological studies recognized. Stimulated afferent nociceptive
have demonstrated that dorsal root ganglion pathways in visceral or somatic tissue lead to
(DRG) compression can initiate a continuous nociceptive pain. Neuropathic pain is caused
afferent barrage that becomes self-sustaining. by dysfunction of, or lesions involving, the
When tumors are identified as a foreign peripheral nervous system (PNS) or central
body, they can give rise to paraneoplastic nervous system (CNS). Differentiating the
neuropathy (Figure 3.2). It is postulated that two may influence the selection of a spe-
expression of onconeuronal antigens by can- cific therapy. Nociceptive somatic cancer
cer cells results in an autoimmunity. When pain arises from soft tissue structures that

FIGURE 3.2 A paraneoplastic neuropathy can FIGURE 3.3 Spinal cord neoplasms may be intra-
arise from tumors recognized as a foreign body. medullary or extramedullary.
104 Chronic Pain in Small Animal Medicine

are non-neurological and nonvisceral in excitatory threshold of dorsal horn neurons,

origin, including skin, muscle, bone, and exaggerate their response to noxious stimuli,
joints, and often correlates with the extent and enlarge the size of their receptor fields
of tissue damage. Nociceptive visceral can- (secondary peripheral sensitization).
cer pain arises from the deep organs of the
abdomen, thorax, or pelvis and is often dif-
ficult to localize. Obstruction of hollow vis-
Sympathetically Dependent
cera, distension of organ walls, stretching of Cancer Pain
the pancreas or liver capsule, or extension Sympathetically mediated cancer pain may
of metastasis into the mesentery may induce result from direct or indirect involvement
visceral pain. of the sympathetic chain. This pain is per-
ceived in alignment with the pattern of sym-
Neuropathic Cancer Pain pathetic-vascular innervation, rather than
localization to the area of distribution for
Neuropathic pain affects the nervous system a specific peripheral nerve or dermatome.5
and may have multiple etiologies, including Although pathophysiological classification
nerve compression, deafferentation injury, of cancer pain is informative for treatment
and sympathetically induced origin.7 Nerve insight, one study in humans has shown that
compression has been identified as the 70% of patients showed two or more patho-
most common cause of neuropathic pain physiological classes of pain in the advanced
in human cancer patients (79%), followed stages of cancer.15
by nerve injury (16%) and sympathetically
mediated pain (5%).8 Neuropathic pain is
considered to be relatively less responsive to Anatomically Based Cancer Pain
opioids.9 Nonopioid adjuncts such as antiep- Anatomical classification of cancer pain has
ileptic, antidepressant, and antiarrhythmic limited applications since it lacks specificity
agents or combinations of these should be as to the mechanism of pain; however, it does
considered.10,11 provide guidance for certain invasive thera-
Noteworthy pain and neurological defi- pies such as external radiation, neurolytic
cits result from tumor infiltration or com- blocks, electrical stimulation, or perhaps,
pression of the PNS. This may include targeted drug delivery.
infiltration of spinal nerve roots, producing
radicular symptoms, and invasion of neu-
ronal plexuses. Such invasion or compres-
Severity-Based Cancer Pain
sion may involve a perineural inflammatory Severity-based classification of cancer pain
reaction that accentuates the nerve pain.12 reflects the extent of tissue destruction,
Degenerative changes and deafferenta- size of the tumor, or its location. In human
tion are consequences of prolonged tumor patients, metastatic bone lesions and injury
infiltration or compression.13 Resultant to nerves are typically more painful than soft
peripheral sensitization is associated with tissue tumors. The severity of cancer pain is
an increased density of sodium channels in dynamic, reflecting the course of the disease
the damaged axons and associated DRG.14 and different therapies administered; there-
Ectopic foci of electrical activity arise in fore, it is prudent to review the severity of the
injured axons, and stimulus thresholds are pain over time.
decreased. Activated peripheral nociceptors
release mediators for central sensitization,
i.e., the amino acid glutamate and neuro-
peptides, such as substance P (sP) and neu-
THE WHO CANCER
rokinin A. In turn, these neurotransmitters PAIN LADDER
cause an increase of intracellular calcium
and upregulation of N-methyl-D-aspartate In 1986, the World Health Organization
receptor (NMDA) receptors. Associated (WHO) developed a simple three-stage
with this increased intracellular calcium is analgesic ladder for treatment of cancer
activation of enzymatic reactions causing pain that relies on widely available and
expression of genes that ultimately lower the inexpensive analgesic agents.16 The WHO
 Chapter 3 Pathophysiology of Cancer Pain 105

TABLE 3.2 Annual crude incidence rates

of cancer per 100,000 population for
humans, dogs, and cats, Almeda County,
3
1960–196619
Cancer site Humans Dogs Cats
All sites 272.1 381.2 155.8
Skin, nonmelanoma 31.8 90.4 34.7
Malignant melanoma 8.3 25.0 ND
Digestive 74.5 25.2 11.2
Respiratory 32.9 8.5 5.0

FIGURE 3.4 The World Health Organization (WHO) Connective tissue 2.4 35.8 17.0
pain ladder was developed to give guidance for Mouth and pharynx 10.3 20.4 11.6
treating cancer pain in humans.
Breast 37.3 198.8 25.4

analgesic ladder provides clinical guidance Lymphoid tumors 13.3 25.0 48.1
from a severity-based pain classification Bone 1.2 7.9 4.9
system (Figure 3.4). Although the quality of
evidence for the WHO ladder approach has Testis 2.6 33.9 ND
been challenged, it has been globally dis-
tributed and is considered the standard for
cancer pain management in human patients. cancers are painful. Sensitivity to pain varies
Contemporary thinking, however, is to use between individuals, and the degree of pain
‘stronger’ analgesics earlier. may vary during the course of the cancer.
The most comprehensive effort to estimate
cancer incidence rates was a survey of veteri-
nary practices in Alameda and Contra Costa
MECHANISM-BASED counties (California) from 1963 to 196617
TREATMENT and remains the seminal study for estimat-
ing the incidence of canine and feline can-
A mechanistic-based treatment strategy for cers (see Table 3.2). This survey revealed an
managing cancer pain in humans has been annual incidence rate of 381/100,000 among
studied,15 i.e., neuropathic pain was treated dogs living in households that used veteri-
with antidepressants and anticonvulsants, nary services, while the incidence rate for
while opioids were integrated into the treat- cancer in cats was 156/100,000.
ment protocol only after these drugs were Intuitively, these data are only estimates,
considered ineffective. Interestingly, all as not all cases of cancer are diagnosed
human patients studied required concurrent equally, considering the many special proce-
therapy with a mean of three drug classes, dures, diagnostic tests, and costs involved.
including an opioid, to control their pain. In a study of 2,002 dogs that underwent
This illustrates the heterogeneity of cancer necropsy at the Angell Memorial Animal
pain mechanisms and the consequent value Hospital, cancer accounted for 20% of the
of a ‘balanced or multimodal analgesia’ deaths at 5 years and increased to over 40%
approach to treatment. in dogs 10 years of age.18

PREVALENCE OF PREVALENCE OF ANIMAL

CANCER IN ANIMALS CANCER PAIN
The frequency of cancer pain in animals is Currently, there are no estimates for the
difficult to identify, as is the prevalence of numbers of animals with cancer pain, and
cancer itself in the pet population. Not all there is sparse data on the efficacy of various
106 Chronic Pain in Small Animal Medicine

therapies. Cancer-related pain has been esti- • Lack of good or validated methods for
mated to afflict 30%–60% of human patients assessing animal pain.
at the time of diagnosis and 55%–95% of • Failure to include the owner’s input into
human patients during the advanced stages their pet’s ongoing assessment.
of disease. 20 Some authors have indicated • Failure to appreciate the high frequency
that approximately 28% of human cancer with which cancer patients experience pain.
patients die without adequate pain relief. 21 • Lack of knowledge regarding analgesic ther-
(Likely, this figure is less now than in 1984 apies and the probable need to alter these
when these data were published.) Several therapies during the course of the cancer.
authors22,23 have reported the underuse of
perioperative analgesics, suggesting the like- Considering that an overall average of
lihood that analgesic management of cancer about 70% of humans with advanced can-
pain in cats and dogs is quite low. Although cer suffer pain 24 and that many biological
inappropriate, undertreatment is not sur- systems are common between man and ani-
prising since the medical profession (both mals, a conservative estimate might be that
human and veterinary) has historically been 30% of animal cancers are painful. 25 As a
slow to administer analgesics. Reasons for rule, pain is more frequently associated with
this include the following: tumors arising in noncompliant tissue (e.g.,
bone) (Table 3.3).
• Underutilization of clinical staff for assess- It should not be overlooked that some
ing cancer pain during the course of the treatment therapies for cancer may create
disease. pain (Table 3.4).

TABLE 3.3 Tumors frequently associated with pain

Tumor Remarks
Bone • Noncompliant tissue tumors are typically painful
CNS • Tumors arising from neural tissue are not usually painful until
late into the course of the disease
• Extradural tumors are associated with pain
Cutaneous (invasive) • Ulcerative, invasive cutaneous tumors tend to be painful
Gastrointestinal • Distention of the esophagus, stomach, colon, and rectum are
painful
• Colonic and rectal pain often presents as perineal discomfort
Intranasal • Bone and turbinate destruction leads to pain
Intrathoracic and abdominal • Response to intracavity analgesics, such as local analgesics,
(e.g., mesothelioma, malignant suggests that these conditions are painful
histiocytosis)
Mammary carcinoma (inflammatory) • Dogs consistently show abnormal behavior considered to be
pain-induced
Oral and pharyngeal • Soft tissue tumors of the pharynx and caudal oral cavity are
particularly painful, perhaps due to constant irritation from
eating
• Soft tissue tumors of gingival origin are relatively nonpainful,
but become very painful with invasion of bone
Prostate • Quite painful, particularly with bone metastasis
Surgery • Postoperative pain associated with tumor removal can be
greater than anticipated, perhaps due to the presence of
neuropathic pain
 Chapter 3 Pathophysiology of Cancer Pain 107

TABLE 3.4 Chemotherapy-induced dysfunction and pain syndromes (humans)26

Chemotherapeutic agent Toxicity Impact on pain 3
Vinca alkaloids (vincristine, Neurological Peripheral neuropathy, autonomic
vinblastine) neuropathy
Paclitaxel/Docetaxel Bone marrow depression, Neutropenia, mucositis
neurological
Platinum complexes Renal, bone marrow Decrease creatinine clearance, peripheral
(cisplatin, carboplatin) depression, neurological neuropathy (cisplatin)
Etoposide Bone marrow depression Leukopenia, thrombocytopenia,
mucositis
Nitrogen mustards, Bone marrow depression Leukopenia, thrombocytopenia,
(mechlorethamine, hemorrhagic cystitis
chlorambucil, (cyclophosphamide)
cyclophosphamide,
ifosfamide)
Anthracycline antibiotics Bone marrow suppression, Leukopenia, thrombocytopenia/Anemia,
cardiac stomatitis, cardiac arrhythmias,
congestive heart failure
Mitoxantrone Bone marrow suppression Mucositis
Cytarabine Bone marrow suppression, Granulocytopenia/thrombocytopenia,
neurological peripheral neuropathy
Methotrexate Bone marrow suppression, Pancytopenia, mucositis, chronic renal
renal failure
Bleomycin Pulmonary Mucositis, lung fibrosis

CANCER PAIN ASSESSMENT in animals.30,31 Any change in an animal’s

normal behavior may be associated with
IN ANIMALS pain. Herein lies the value of integrating the
pet owner’s observations into the patient’s
The assessment of cancer pain in animals assessment on a continuum of follow-ups. In
is particularly challenging, and few reports fact, some studies show that the owner was a
have been made in this area. Yazbek and better assessor of their animal’s chronic pain
Fantoni 27 suggest that a simple questionnaire than a veterinarian.
may be useful in assessing health-related Certain behaviors are worth noting:
quality of life (HRQoL) in dogs with pain
secondary to cancer, in that dogs with can-
cer had significantly lower scores than did • Painful animals are less active.
healthy dogs. A number of animal pain scales • Animals in pain do not groom as frequently,
have been proposed (e.g., visual analog scale especially cats.
[VAS], numerical rating scale [NRS], simple • Dogs, in particular, may lick a painful area.
descriptive scale [SDS], multifactorial pain • Both painful dogs and cats may show
scales [MFPS], and composite measure pain decreased appetites.
scales [CMPS]); however, these are applied • Painful cats tend to seek seclusion.
to the assessment of acute pain, where some • Dogs in pain tend not to yawn, stretch, or
are more valid than others. Physiological ‘wet dog shake’.
variables such as heart rate, respiratory rate, • Animals in pain often posture differently.
cortisol levels, temperature, and pupil size
are unreliable measures for assessing acute One of the most reliable methods for
pain, 28,29 and behavioral changes are now identifying pain is the animal’s response to
considered the most reliable indicator of pain analgesic intervention.
108 Chronic Pain in Small Animal Medicine

cancer pain have been developed. In the

mouse femur model, bone cancer pain is
induced by injecting murine osteocytic sar-
coma cells into the intramedullary space
of the femur. These tumor cells prolifer-
ate, and ongoing, movement-evoked, and
mechanically evoked pain-related behaviors
develop that increase in severity over time
(Figure 3.6). These models have allowed elu-
cidation of how cancer pain is generated and
how the sensory information is processed
when the molecular architecture of bone is
changed by disease.

AFFERENT SENSORY
NEURONS
Primary afferent sensory neurons transfer
FIGURE 3.5 Bone marrow, mineralized bone, and
periosteum are highly innervated, sending sen- sensory information to the spinal cord and
sory input to the spinal cord. brain. Most small diameter sensory fibers –
unmyelinated C fibers and finely myelinated
A fibers – are specialized sensory neurons
BONE CANCER MODEL called nociceptors that express a diverse rep-
ertoire of transduction molecules that sense
Periosteum, mineralized bone, and bone mar- different forms of noxious stimuli (thermal,
row are highly innervated by Aβ, Aδ, and C mechanical, and chemical). To sense nox-
fibers, all of which conduct sensory input from ious chemical stimuli, nociceptors express
the periphery to the spinal cord (Figure 3.5). an array of receptors capable of detecting
Recently, the first animal models of bone inflammatory-related factors from damaged

FIGURE 3.6 Bone cancer changes the molecular architecture and bioneurological status of the diseased
bone. (ET-1: endothelin-1.)
 Chapter 3 Pathophysiology of Cancer Pain 109

tissue, i.e., protons, endothelins, prostaglan- types of cancer, in addition to blocking can-
dins (PGs), bradykinin, and nerve growth
factor (NGF).
cer pain, COX-2 inhibitors may have the
added advantage of reducing the growth and 3
Sensory neurons are also highly “plastic” – metastasis of tumors.
they can change their phenotype in response A PubMed search for the terms NSAID
to a sustained peripheral injury. Altering pat- and cancer conducted in February 2005
terns of signaling peptide and growth factor generated 7,513 abstracts. The same search
expression underlie peripheral sensitization, conducted in December 2007 generated
lowering the activation threshold and cre- 9,624 abstracts. A similar search for the
ating a state of hyperalgesia. Peripheral tis- terms NSAID and COX-2 revealed 1,907
sue damage also activates previously ‘silent’ abstracts in February 2005, compared to
nociceptors, which creates a state of hyperal- 3,529 abstracts in December 2007. The role
gesia and allodynia. of NSAIDs, and particularly coxib-class
In mice with bone cancer, normally NSAIDs, in cancer research is an area of
nonpainful palpation of the affected femur intense interest. 38
induces the release of sP from primary affer- Canine patient tumors expressing COX-2
ent fibers that terminate in the spinal cord. include the following:
sP in turn binds to and activates the neuro-
kinin-1 receptor that is expressed by a subset • Transitional cell carcinoma39
of spinal cord neurons.32 A similar activity • Renal cell carcinoma40
is noted with c-fos.33 Apparently, peripheral • Squamous cell carcinoma41
sensitization of nociceptors may be involved • Prostate carcinoma42
in the generation and maintenance of bone • Rectal polyps43
cancer pain. • Nasal carcinoma44
• Osteosarcoma45
• Mammary carcinoma46
NOCICEPTOR EXCITATION • Intestinal adenocarcinoma43
• Oral melanoma47
Tumor and tumor-associated cells, including
macrophages, neutrophils, and T lympho- In contrast to dogs, the absence of COX-2
cytes, secrete a wide variety of factors, includ- expression in most feline neoplasms might
ing PGs, endothelins, interleukin (IL)-1 and suggest that COX-2 inhibitors would have a
IL-6, epidermal growth factor, transforming lower potential as anticancer agents in this
growth factor (TGF), and platelet-derived species.48
growth factor, which directly excite pri- Peptide endothelin-1 is another phar-
mary afferent neurons. Each of these factors macological target for treating cancer pain.
may play an important role in the genera- A number of small unmyelinated primary
tion of pain associated with various cancers. afferents express receptors for endothelin,49
Pharmaceutical targeting of these factors and endothelins may well sensitize or excite
provides opportunities for pain relief, while nociceptors. Several tumors of humans,
anti-prostaglandin and anti-endothelins are including prostate cancer, express high lev-
already commercially available. els of endothelins, 50 and clinical studies have
Tumor-associated macrophages and shown a correlation between the severity of
several tumor cells express high levels of the pain in human patients with prostate
cyclooxygenase (COX)-2, producing large cancer and endothelin plasma levels. 51
amounts of PGs.34,35 Although all nonsteroi-
dal anti-inflammatory drugs (NSAIDs) are
anti-prostaglandins, the new COX-2 inhibi-
tors, or coxibs, preferentially inhibit COX-2
TUMOR-INDUCED
and avoid many of the COX-1 inhibition side LOCAL ACIDOSIS
effects. Additionally, some experiments have
suggested that COX-2 is involved in angio- Tumor burden often outgrows its vascular
genesis and tumor growth. 36,37 Although supply, becoming ischemic and undergoing
further research is required to characterize apoptosis. Subsequently, an accumulation
the effect of coxib-class NSAIDs on different of acid metabolites prevails, resulting in an
110 Chronic Pain in Small Animal Medicine

acidotic local environment. This is relevant to both the hematopoietic cells of the marrow
cancer pain, in that subsets of sensory neu- and the sensory fibers that normally innervate
rons have been shown to express different the marrow.59 This neuronal damage can give
acid-sending ion channels (ASICs)52 sensitive rise to neuropathic pain. Gabapentin is a drug
to protons or acidosis. Two major classes of originally developed as an anticonvulsant, but
ASICs expressed by nociceptors, both sensi- is effective in treating several forms of neu-
tive to decreases in pH, are TRPV1 and ASIC- ropathic pain and may be useful in treating
3. As tumors grow and undergo apoptosis, cancer-induced neuropathic pain.60
there is a local release of intracellular ions and Summarizing the contributors to bone
inflammatory-mediated protons that gives cancer pain:
rise to a local acidic environment. This neuro-
biological mechanism is particularly relevant • Release of cytokines, PGs, and endothelins
in bone cancer, where there is a proliferation from hematopoietic, immune, and tumor
and hypertrophy of osteoclasts. Osteoclasts cells
are multinucleated cells of the monocyte • Osteoclast activity 1 => lowered pH => acti-
lineage that resorb bone by maintaining an vation of TRPV1 and ASIC receptors
extracellular microenvironment of acidic pH • Bone erosion => release of growth factors
(4.0–5.0) at the interface between osteoclast e.g., NGF
and mineralized bone.53 Experiments in mice • Tumor growth => compression of afferent
have shown that osteoclasts contribute to the terminals
etiology of bone cancer pain54 and that osteo- • Neurochemical changes in DRG and spinal
protegerin55 and a bisphosphonate,55 both of cord
which induce osteoclast apoptosis, are effec-
tive in decreasing osteoclast-induced cancer
pain. TRPV1 or ASIC antagonists would act
similarly, but by blocking excitation of acid-
CENTRAL SENSITIZATION
sensitive channels on sensory neurons. If local neuropathic pain is a sequala to can-
cer, do the spinal cord and forebrain also
undergo significant neurochemical changes?
GROWTH FACTORS The murine cancer pain model revealed
extensive neurochemical reorganization
FROM TUMOR CELLS within the spinal cord segments receiving
input from primary afferent neurons inner-
Different patients with the same cancer may vating cancerous bone.61 Upregulation of the
have vastly different symptoms. Metastases pro-hyperalgesic peptide, dynorphin, and
to bone in the same individual may cause astrocyte hypertrophy contribute to the state
pain at one site but not at a different site. of central sensitization maintained by cancer
Small cancer deposits in one location may be pain.
more painful than large cancers at an unre-
lated site. Why the variability? One explana-
tion may be that changes in the periphery
associated with inflammation, nerve injury,
THE MOVING TARGET
or tissue injury are reflected by changes in OF CANCER PAIN
the phenotype of sensory neurons. 56 Such
changes are, in part, caused by a change As the cancer progresses, changing factors
in tissue levels of several growth factors may complicate the pain state. In the mouse
released from the local environment at the model of bone cancer, as the tumor cells
injury site, including NGFs57 and glial cell begin to proliferate, pain-related behaviors
line–derived neurotrophic factor (GDNF).58 precede any noticeable bone destruction.
Likely, the milieu of growth factors to which This is attributed to pro-hyperalgesic fac-
the sensory neuron is exposed will change as tors, such as active nociceptor response in
the developing tumor invades the tissue that the marrow to PGs and endothelin released
the neuron innervates. from growing tumor cells. At this point, pain
The murine sarcoma cell model has also might be attenuated by a coxib-class NSAID
demonstrated that growing tumor cells destroy or endothelin antagonist. With continued
 Chapter 3 Pathophysiology of Cancer Pain 111

tumor growth, sensory neurons innervating

the marrow are compressed and destroyed,
giving rise to neuropathic pain possibly respon- 3
sive to gabapentin. Once the tumor becomes
invaded by osteoclastic activity, pain might
be largely blocked by anti-osteoclastogenic
drugs, such as bisphosphonates or osteopro-
tegerin. As the intramedullary space becomes
filled with dying tumor cells, generating an
acidic environment, TRPV1 or ASIC antag-
onists may attenuate the pain. In the later
stages of bone destruction, antagonists to
the mechanically gated channels and/or ade-
nosine triphosphate (ATP) receptors in the
highly innervated periosteum may alleviate
movement-evoked pain. This scenario illus-
trates how a mechanistic approach to design-
ing more effective therapies for cancer pain
should be created based on the understanding
of how different stages of the disease impact
on tumor cell influence on nociceptors and
how the phenotype of nociceptors and CNS
neurons involved in nociceptive transmis-
sion changes during the course of advancing
cancer.
Clearly, the mechanisms associated with
cancer pain are complex. However, only
through the understanding of these mecha-
nisms can we best manage our patient’s pain
with evidence-based confidence. The murine
bone cancer model has given us insights
into the progressing, dynamic neurobiologi-
cal changes associated with cancer. These
insights further lead us to the conclusion that
effective treatment must be multimodal and
dynamic. FIGURE 3.7 Cancer can disrupt normal visceral
systems with resultant alterations that lead to
pain.
VISCERAL CANCER PAIN
Many cancers involve internal organs, Visceral pain can also result from treat-
and symptoms are silent until ischemia, ment damage of viscera and associated nerves
compression, or obstruction reach a given from surgery, chemotherapy, or radiation.
stage, at which time visceral pain is mani-
fest (Figure 3.7). Pain of visceral cancer ori-
gin can be divided into four groups: CHEMOTHERAPY
• Acute mechanical stretch of visceral Chemotherapy is a common treatment
structures. modality for cancer patients. Human can-
• Ischemia of visceral structures. cer patients can complain of a wide range
• Chemical stimuli from an infiltrating tumor of cancer-related side effects, such as pain,
or the body’s reaction to infiltration. fatigue, depression, nausea, vomiting, diar-
• A compressive form of neuropathic pain rhea, constipation, cardiac arrhythmias, vas-
that occurs due to direct invasion of nervous cular and pulmonary toxicity, skin changes,
structures involving the viscera. mucositis, and sensory-motor disturbances.62
112 Chronic Pain in Small Animal Medicine

Chemotherapy-induced peripheral neu- agents, which is a common practice, can

ropathy (CIPN) symptoms can present as aggravate or accelerate the induction of
pure sensory or motor disturbances or as neuropathic manifestations.
mixed sensory-motor neuropathy.63 Cranial
nerve neuropathy has been reported in
humans treated with cisplatin or carbopla- RADIATION THERAPY
tin.64 Muscle pain is a symptom reported in
human patients with CIPN and is occasion- Radiation kills cells by causing irrevers-
ally reported as muscle spasms. It is unclear ible DNA damage,72 and there is a direct
if the cramps are a direct toxic effect of the relationship between the amount of physi-
antitumor agent on the muscle fiber or mani- cal energy deposited, the degree of DNA
festations of a sensory neuropathy. To date, damage, the number of cells killed, and the
there is no specific drug or method for pre- extent of tissue injury. Cell death by radia-
vention of CIPN. tion is either by apoptosis or necrosis. With
apoptosis, cells break down into apoptotic
bodies and become resorbed by neighboring
CHEMOTHERAPEUTIC cells.73 With necrosis, cells break down into
fragments; release lysosomal enzymes; and
NEUROPATHIES generate inflammatory responses that can
lead to fibrosis, atrophy and ulceration at the
Several antitumor agents can lead to neu- local tissue level. Adverse response to radia-
ropathies.63 Paclitaxel (Taxol) has cyto- tion can be divided into early and late effects.
toxic activity through its ability to interfere Early effects are most often seen in cell pop-
with microtubule function by induc- ulations that have high turnover rates, e.g.,
ing the polymerization of tubulin65 and gastrointestinal, oropharyngeal, and esopha-
induces peripheral neuropathy in a dose- geal mucosa, bone marrow, and skin. Late
dependent manner.66 Platine-compound radiation effects more often involve tissues
cytotoxic agents (e.g., cisplatin and carbo- that are nonproliferating or slowly prolifer-
platin) also cause peripheral neuropathy ating, e.g., oligodendroglia, Schwann cells,
in a dose-dependent manner in humans, 67 kidney tubules, and vascular endothelium.
and apparently cisplatin is more neuro- Radiation-induced peripheral neuropathies
toxic than carboplatin.68 The prevalence of result from late effects of radiation treat-
platine-compound neuropathy is approxi- ment. The actual axons of peripheral nerves
mately 50% in human studies.69 Vincristine are less likely to be affected, but supporting
is a microtubule-interfering agent that is cells, such as Schwann cells, are vulnerable
administered to patients with hematological to ionizing radiation. Radiation can also
malignancies. The incidence of vincristine- affect tissues surrounding peripheral nerves,
induced peripheral neuropathy is between leading to development of fibrosis around
50% and 100% in humans.70 Ifosfamide is nerve trunks. This fibrosis with subsequent
a cyclophosphamide-related drug with toxic compression of nerve bundles is suspected to
effects on the CNS, and in humans these are be the primary etiology of peripheral radia-
manifest by hallucinations, confusion, and tion neuropathies.74
cranial nerve dysfunction.71 Carsten et al.75 have demonstrated that
These are but a few of the cytotoxic skin acute radiation score (ARS) in dogs with
drugs used to treat animals with cancer cancer of the forelimb undergoing curative-
whose neuropathic toxic potential has been intent radiation therapy was a highly statisti-
described in humans. Clinical manifesta- cally significant predictor of pain as reflected
tions of these drugs in veterinary patients in VAS and the Glasgow Composite Measure
may be more subtle or less severe since of Pain Scale, Short Form (GCMPS). Skin
many animals undergo therapy for a shorter ARSs increased prior to the increase in pain
period of time than humans. Nevertheless, scores, but not simultaneously. The investi-
these neuropathic consequences from cyto- gators concluded that it is optimal to com-
toxic agents should be understood by the bine daily ARSs with use of a pain scale to
caregiver, and it should be appreciated that achieve optimal pain management in the
administration of two or more cytotoxic radiation therapy patient.
 Chapter 3 Pathophysiology of Cancer Pain 113

directly into a tumor. The hydrogel is an

TABLE 3.5 Effects of therapy and disease
on tissue and nerve injury
yttrium-90 carrier at room temperature that
gels within the tumor interstitial spaces after 3
Iatrogenic Tissue injury Nerve injury injection to keep the radiation sources safely
Chemotherapy X in place. The short-range beta radiation from
yttrium-90 localizes the dose within the treat-
Radiation X
ment area so that normal organs and tissues
Surgery X X are not adversely affected.
Disease
Tumor X Biocompatibility of
compression
PLGA-PEG-PLGA Hydrogels
Release of X
active factors
Jim Duncan, PhD and Steven Fox, MS,
DVM, MBA, PhD
Immune X X
response The poly(lactic-co-glycolic acid) referred to
as PLGA is one of the main bioresorbable
polymers used in medicine. Initially, bio-
Although cancer pain is associated with resorbable polymers were used for surgical
both tissue injury/inflammation and nerve sutures. They have since been used in other
injury, it is unlikely that the pain is just the applications, such as implants to repair frac-
sum of these two mechanisms, but rather tures and drug release devices.76 The first
is a unique neurochemical pain state. See PLGA copolymer was made in the 1970s
Table 3.5. under the trade name of Vicryl®, which is a
synthetic absorbable suture coated with a lac-
tide and glycolide copolymer manufactured
NEW APPROACH TO by Ethicon, Inc., of Johnson & Johnson.
The PLGA polymer is synthesized through
CANCER TREATMENT WITH random ring-opening copolymerization of the
cyclic dimers of glycolic acid and lactic acid,
BIOCOMPATIBLE PLGA-PEG- and consecutive monomeric units are linked
PLGA HYDROGEL DELIVERY together by ester bonds. PLGA is soluble in
diverse solvents, including acetone, ethyl ace-
As discussed in this chapter, cancer pain is tate, and chlorinated solvents. PLGA biode-
the second most common chronic pain (next gradability can be manipulated by altering its
to pain from osteoarthritis) in companion composition: the higher the glycolide content
animal practice and a common cause for pet and/or the lower the molar mass, the faster
euthanasia. “We are all born in another’s the degradation rate.77–79 Accordingly, it is
pain and destined to die in our own”1 Cancer possible to synthesize materials with degrada-
affects 50% of dogs over age 10 and one in tion times ranging from weeks to years.
four dogs under age 10. Radiotherapeutics is Polymers derived from lactic and glycolic
an evolving treatment option for a number of acids have received attention from research on
cancer patients, with malignant cell death by alternative biodegradable polymers, as they
apoptosis or necrosis. have already received approval from the Food
One of the challenges with radiation and Drug Administration (FDA) for use as
treatment is physically positioning the ‘radia- drug release systems. Several studies have been
tion particles’ at a precise distance from the published demonstrating their low toxicity.80–82
target cells. Typically, ‘closer is better’; how- A major interest in the use of the PLGA
ever, source targeting must also spare nearby polymers is their ability to control both the
healthy, functional cells. Vivos, Inc., has mechanical and degradation time properties
developed a yttrium-90–based brachytherapy through monomer ratios.83 The copolymers
injectable device for the treatment of tumors can present linear and saturated chains, a
in both animals and humans. This device is constant rate of biodegradation, mechani-
a hydrogel liquid containing tiny yttrium-90 cal resistance, crystallinity, hydrophobicity,
phosphate particles that may be administered regular geometry of individual chains, and
114 Chronic Pain in Small Animal Medicine

3.8 O O

( )( )
CH3 O O O CH3 O CH3 O O
m +n
C CH O C CH O C CH2 O C CH2 O
O O m n
CH3
Poly(lactide) Poly(glycolide)
O O PLA PGA
lactide glycolide PLGA

FIGURE 3.8 Chemical structure of lactide and glycolide.

thermoplastic behavior. They possess an polymer. The subscripts m and n refer to

asymmetric center, presented by the lactic repeating units from the lactide and glycolide
acid (PLA) in a racemic mixture (D,L-PLA) starting reagents.
connected to the glycolic acid polymer (PGA). This configuration (Figure 3.9) allows for
The lactide and glycolide in Figure 3.8 is a a sol-gel effect of the polymer that is liquid
‘diblock’ copolymer. By the addition of poly- at room temperature and a phase change
ethylene glycol (PEG), the polymer becomes to a gel at higher (body) temperatures. This
a ‘triblock’ liner polymer. The addition of allows using a radioisotope placed directly in
an epoxy terminated PEG (EPEG) allows a tumor to be held in place for a requisite
for cross-linking and micelle formation.84 number of half-lives.
Note the EPEG is grafted on the monometh- The graph in Figure 3.10 shows an in
oxy PEG, thus referred to as a PLGA-g-PEG vitro hydrogel (30 weight % of PLGA-g-PEG

3.9 O
O O
O
X Y Z
O
O
M

FIGURE 3.9 Schematic drawing of the PLGA-g-PEG polymer (triblock linear polymer). The subscripts
x, y, z, and m refer to lactide, glycolide, PEG graphs, and the number of repeat units, respectively, of
ethylene glycol.

3.10 Percent 90Y activity Percent hydrogel

100 100
90 90
80 80
70 70
Percent activity Y-90

Percent hydrogel

60 60
50 50
Day 27
40 40
30 30
20 20
10 10
0 0
0 5 10 15 20 25 30 35 40 45
Time, days

FIGURE 3.10 Dissolution of hydrogel compared to Y-90 physical decay.

 Chapter 3 Pathophysiology of Cancer Pain 115

(A) (B) 3.11

H2O
Hydrophobic core
3
Micelle self-
assembly Hydrophilic shell

(C)

4°C 37°C

Heating

Cooling

Micelles in solution Aggregated micelle network

Sol state Gel state
(D)
Hydrophobic drug
H2O

Polymer
breakdown

Thermogel drug depot Sustained drug release

FIGURE 3.11 Triblock thermogel polymer. (A) Individual polymer subunit structure. (B) When in
the presence of water, individual polymer subunits self-assemble into micelles with hydropho-
bic PLGA cores and hydrophilic PEG shells. (C) At low temperature, micelles remain in aque-
ous solution. As the temperature is raised, cross-link formation between micelles results in
formation of a three-dimensional aggregated micelle network. (D) Hydrophobic drugs can
be incorporated into the micelle core and thus solubilized in the polymer solution. Hydrolytic
degradation of the polymer network results in slow, sustained release of drug from the micelle
cores.85

polymer to phosphate buffer saline) versus respectively. The degradation products are
yttrium-90 physical decay. At 27 days, the finally incorporated into the Krebs cycle and
yttrium-90 has decayed through 10 half- are ultimately expired as CO2 .
lives, at which time the radioactivity is at or Notably, the bulk degradation of both
below background (Figure 3.11). PLA and PGA does not immediately produce
a decrease in mass of the implant, which is
instead delayed to days, months, or years,
Degradation of PLGA until the molecular weight of the polymeric
Laycock et al.86 reported that the degrada- chains is reduced to an extent allowing
tion of polylactide (PLA) and polyglycolide them to freely leach out from the polymer
(PGA) mainly occurs by bulk hydrolysis, and matrix. At this point, the surrounding tis-
the hydrolysis rate is lowered by the crystal- sue may not be able to eliminate the acidic
linity. The lactic acid and glycolic acid are by-products of a rapidly degrading implant.
produced by the hydrolysis of PLA and PGA, Thus, an inflammatory or adverse response
116 Chronic Pain in Small Animal Medicine

3.12 PGA water soluble, nonreactive, and without any

specific receptors or targets in the body.88,89
hydrolysis
Accumulation of large PEG molecules
Glycolic acid (>20–30 kDa) remains a possible concern
PLA because of their increasingly low clearance
Urine elimination Glycine
hydrolysis with higher molecular size.90 Cellular vacuo-
lation in certain tissues and cell types, which
Serine Lactic acid has been observed in nonclinical toxicology
studies for ~50% of approved PEGylated
Pyruvic acid
drugs, is the only effect attributed to PEG
thus far noted.91,92 The pharmacokinetic
Tricarboxylic acid – Krebs Cycle
properties of PEGylated proteins are initially
CO2 + H2O driven by the two major parts of the mol-
ecule: the protein itself and its conjugated
FIGURE 3.12 Degradation pathways for polylac- PEG. When the PEG remains after protein
tide and polyglycolide. catabolism, its biodistribution and pharma-
cokinetic properties are governed by PEG-
related mechanisms93 (Figure 3.13).
may result due to a decrease in the micro- Bauman et al.93 concluded that following
environment pH levels. To overcome this single-dose administration of the 60-kDa
adversity, the incorporation of basic salts to PEG component of BAY 94-9027 ([prop-14C]
prevent a drop in the pH during the degra- BAY 1025662) to male rats, which approxi-
dation process is shown to be successful in mated the PEG dose that human patients
vitro87 (Figure 3.12). would receive with 30 years of BAY 94-9027
treatment, several conclusions can be drawn.
Primarily, results demonstrated that excre-
tion processes are in place for higher-molecu-
Degradation of PEG lar-weight PEGs, such as the PEG-60 moiety
Molecules of PEG have a simple, repetitive used in BAY 94-9027. Large PEG molecules
structure and are chemically inert with low (≥20 kDa) are continuously but slowly elimi-
toxicity. The linear structure is expressed as nated, resulting in long elimination half-lives
H-(O-CH 2-CH 2)n-OH. They are uncharged, in organs and tissues; thus, PEG accumulates

3.13
Receptor-mediated uptake
Blood of PEGylated protein PEGylated protein

Pinocytosis of PEGylated
protein and PEG Protein degradation
PEG
PEG
vacuole
PEG Exocytosis of PEG
(faster for PEG < 20–30 kDa) PEG release by cell
turnover and death

Small PEGylated Liver

proteins
Kidney

PEGylated proteins, A small proportion of

and PEG itself, can be some PEGs may be
eliminated via the liver degraded by oxidative
in feces metabolism

FIGURE 3.13 Distribution and excretion of PEG and PEGylated proteins.

 Chapter 3 Pathophysiology of Cancer Pain 117

with repeated dosing until a steady state is methodology. Among the various biocompat-
reached. Once a steady state is reached, the
PEG concentration in plasma, organs, and
ible polymers, PLGA has attracted attention
due to but not limited to: 3
tissues remains constant with no further
accumulation. The MPEG and EPEG used in • Biodegradability/biocompatibility
Vivos’s hydrogel is 750 daltons and 500 dal- • FDA and European Medicine Agency
tons, respectively. From the previously ref- approval in drug delivery systems97
erenced journal articles, the lower-Da PEGs
would be cleared quickly from mammalian
patients.
Several laboratory investigations using
ANALGESIA FOR
PLGA-based devices are reported in the lit- CANCER PAIN
erature, evidencing the biocompatibility and
biodegradability of this polymer.94,95 In a See Table 3.6 and Table 3.7.
study by Ma et al.,96 degradation and bio-
compatibility of 20 wt% PLGA-PEG-PLGA
hydrogels were reported. For the in vitro deg- NUTRITIONAL MANAGEMENT
radation study, the hydrogels were incubated
in phosphate buffered saline. Approximately Many types of cancer are influenced by
70% of the hydrogel degraded in 40 days. nutrition, diet, and nutritional status of
The in vivo biodegradation and biocompat- the patient. In humans cachexia is seen in
ibility of the PLGA-PEG-PLGA hydrogels 32%–87% of cases, commonly associated
(20 wt%) were subcutaneously injected into with cancers of the upper gastrointestinal
rats. The gels degraded gradually in the sub- tract.106 Weight loss can be detrimental to
cutaneous layer in 4 weeks and completely patient quality of life and prognosis, as well
disappeared after 5 weeks. as dramatically impacting on the pharmaco-
Hydrogels often display faster degrada- kinetics and pharmacodynamics of chemo-
tion in vivo than in vitro. Possible reasons are therapeutics and contributing to increased
that cells and enzymes in the subcutaneous treatment-related toxicity.107 Malnutrition
layer accelerate the degradation processes. is arguably one of the most common causes
Also, the accumulation of degradation inter- of death in people with cancer. Association
mediates in the subcutaneous layer may pro- between documented metabolic abnormali-
duce a slightly acid environment, which also ties, actual weight loss, and poor prognosis
accelerates the biodegradation.97 in cats or dogs with cancer has not been con-
vincingly demonstrated. One study from a
referral oncology practice showed that only
Summary 4% of the dogs were cachectic and 15% of
The PLGA-PEG-PLGA (PPP) triblock copo- the dogs had detectable and clinically signifi-
lymer is one of the most widely studied ther- cant muscle wasting.108 Nevertheless, nutri-
mosensitive hydrogels owing to its nontoxic, tional assessment of the cancer patient should
biocompatible, biodegradable, and thermo- be part of every treatment plan focusing on
sensitive properties. The PPP thermosensi- history, physical examination, and routine
tive hydrogels are investigated and used as in hematological and biochemical parameters.
situ gels due to the ability to be injected at The following five steps have been pro-
the target site as a carrier of pharmaceuticals posed to define the nutritional requirements
and converted into a gel, which remains in for dogs or cats with cancer109:
place. The different requirements of various
therapeutic applications are met by adjusting (1) Estimate fluid requirements
the properties of the hydrogel. These include (2) Estimate energy requirements
sol-gel transition temperature, gel window (3) Distribute calories (between protein, fat,
width, retention time, and drug release and carbohydrates)
time.98 (4) Evaluate remaining nutrients (e.g., vita-
Furthermore, drug diffusion–based release mins, minerals, essential nutrients)
systems are gaining attention due to cost- (5) Select a method of feeding (voluntary
effectiveness and relatively simple synthesis intake being preferred)
118 Chronic Pain in Small Animal Medicine

TABLE 3.6 Analgesics commonly used for cancer pain in the dog
Drug Dose (Dog) Remarks
Amantadine 1.0–4.0 mg/kg orally sid* • Available as tablet and elixir
Caution use with • NMDA antagonist
selegiline or sertraline • Effective as adjunct with other drug classes
until interactions are • Higher doses can produce gastrointestinal gas and
further elucidated loose stools
Amitriptyline 0.5–2.0 mg/kg orally sid* • Mode of action at (endogenous) descending
serotonergic system
• Moderate to weak analgesic activity
• Often used as adjunct to NSAID
• Toxicity in the dog not evaluated
Aspirin 10 mg/kg orally bid • NOT approved for use in the dog
• Toxicities include gastrointestinal, renal, and bleeding
• Better NSAID choices available
Butorphanol 0.2–0.5 mg/kg orally • Poor bioavailability per os
(sid–tid) • Weak analgesic
• Possible sedation at higher doses
• May be used as adjunct to NSAID
Codeine 0.5–2.0 mg/kg orally sid • Best bioavailability (−20%) among oral opioids
• Possible sedation at higher doses
Carprofen 2 mg/kg orally bid or • COX-2 preferential
4 mg/kg orally sid • Available as injectable, but with inferior
pharmacokinetics to the tablet
Deracoxib 1–2 mg/kg orally sid • COX-2–selective coxib-class NSAID
(extended use) • May be effective in altering the course of certain types
of COX-2–dependent cancer
Etodolac 5–15 mg/kg orally sid • COX-1 selective in the dog
• Associated with canine keratoconjunctivitis sicca (KCS)
Fentanyl 2–5 μg/kg/hr • Short-term use
(transdermal) • Variable absorption – systemic levels
• Expensive
Firocoxib 5.0 mg/kg sid • COX-2–selective coxib-class NSAID
• Questionable safety in dogs <7 months old
• No data in cancer dogs
Gabapentin 3–10 mg/kg orally • No analgesic data in dogs
sid–bid • Antiseizure effects
• Efficacy for neuropathic pain
• Rapidly metabolized in the dog
• Often used as adjunct with other analgesics
Glucosamine and Unestablished • Evidence base is weak
chondroitin • Often used as adjunct with other analgesics
sulfate • Product quality is widely variable
Lidocaine One (10 × 14 cm) patch • Clinical efficacy and toxicity not determined
(transdermal per 20 lb (9.1 kg) • Duration of effect approximately 3 days
patch) • Plasma steady state at 12–60 hours99
Meloxicam 0.2 mg/kg on day 1, • Preferential COX-2 inhibitor
then 0.1 mg/kg sid • Narrow safety profile
• Available as elixir and injectable only
Morphine (liquid) 0.2–0.5 mg/kg orally • Poor bioavailability (<20%)
tid–qid • Short duration of action
• Sedation and constipation may be seen at higher doses
 Chapter 3 Pathophysiology of Cancer Pain 119

TABLE 3.6 Analgesics commonly used for cancer pain in the dog (Continued)
Drug Dose (Dog) Remarks 3
Morphine 0.5–3.0 mg/kg orally Doses >0.5–1.0 mg/kg often reported to result in
(sustained tid–qid constipation
release)
Pamidronate 1–1.5 mg/kg, diluted in • Inhibits osteoclast activity as a bisphosphonate
250 mL saline, slowly • Effective where osteolysis from bone tumor contributes
IV (once monthly)* to pain
Paracetamol 10–15 mg/kg orally tid • Long-term: <10 mg/kg bid*
(acetaminophen) for 5 days • Known as acetaminophen in United States
• Lethal in cats
• Clinical toxicity not established in dogs
• Analgesic, but not anti-inflammatory
Piroxicam 0.3 mg/kg q48h* • Long-standing use as chemotherapeutic agent
• Narrow safety margin
Prednisolone 0.25–1 mg/kg orally • DO NOT use concurrently with NSAID
sid–bid, taper to q48h • Most effective in cases with pronounced inflammation
after 14 days
Tepoxalin 10–20 mg/kg orally on day • COX and LOX ‘dual pathway inhibitor’
1, then 10 mg/kg sid • No data in cancer patients
Tramadol 2–4 mg/kg orally • Codeine analog
bid–qid* • Norepinephrine/Serotonin reuptake inhibition
• No efficacy or toxicity data in dogs
• Often used as adjunct with other analgesics

Note: None have been assessed for dosage or efficacy in cancer; therefore, empirical doses and efficacy reflect dose
recommendations for osteoarthritic pain. Not all drugs are licensed in all countries.
* Empirical dose, based on personal experiences: pending further investigations.

TABLE 3.7 Analgesics commonly used for cancer pain in the cat
Drug Dose (Cat) Remarks
Amantadine 3.0 mg/kg orally sid • Toxicity studies not available in cats
• 100-mg capsules require recompounding for cats
• Often used as adjunct with other analgesics
Amitriptyline 0.5–2.0 mg/kg orally • Apparently well tolerated for up to 12 months with
sid daily dosing
• Occasional (<10%) drowsiness
• Often used as adjunct with other analgesics
Aspirin 10 mg/kg orally q48h • Associated with significant gastrointestinal
ulcerations
Buprenorphine 0.02 mg/kg • Same dose IV provides similar analgesia
transbuccal q6–7h • Readily accepted by the cat; therefore, acceptable
for home administration
• Anorexia may occur after 2–3 days100
Butorphanol 0.2–1.0 mg/kg orally • Weak analgesic
qid • May be more effective in visceral pain
• Limited bioavailability and duration of effect when
given orally101,102
Carprofen Undetermined • Insufficient data on extended use
Etodolac Undetermined • Insufficient data on extended use

(Continued)
120 Chronic Pain in Small Animal Medicine

TABLE 3.7 Analgesics commonly used for cancer pain in the cat (Continued)
Drug Dose (Cat) Remarks
Fentanyl (transdermal 2–5 μg/kg/hr • Not suggested for cats <4.5 kg
patch) • Do not cut or partially cover patches103,104
Flunixin meglumine 1 mg/kg orally as a • Insufficient data on extended use
single dose
Gabapentin 3–10 mg/kg orally • No analgesic data in cats
sid–bid • Antiseizure effects
• Efficacy for neuropathic pain
• Rapidly metabolized in the cat
• Often used as adjunct with other analgesics
Glucosamine/ Unestablished: • Evidence base is weak
chondroitin sulfate approximately • Often used as adjunct with other analgesics
combinations 15 mg/kg • Product quality is widely variable
CS orally sid–bid
Ketoprofen 1 mg/kg orally sid for a • Narrow safety range
maximum of 5 days • Possible use in ‘pulse therapy’ with a few ‘rest’
days between administrations
Lidocaine (transdermal One (10 × 14 cm) • Clinical efficacy and toxicity not determined
patch) patch for 5–9.1 kg • Duration of effect approximately 3 days
• Plasma steady state at 12–60 hours99
Meloxicam 0.2 mg/kg orally on day • Extended use is off-label
1, then 0.1 mg/kg • Easy dosing as an elixir
orally sid for 4 days, • Honey base syrup is well accepted105
then 0.05 mg/kg sid
for 10 days, then
0.025 mg/kg sid
Morphine (oral, liquid) 0.2–0.5 mg/kg orally • Limited bioavailability and duration of effect
tid–qid • Poor palatability
Morphine (oral, Tablets too large for •
sustained release) cats
Paracetamol Contraindicated • Lethal in cats
(acetaminophen)
Piroxicam 0.3 mg/kg sid • Decreased PCV in up to 30% of cats after 2–3
However, many use up weeks of daily therapy
to 1 mg/kg orally sid • Compounding may decrease drug activity
for up to 7 days
Every-other-day
dosing suggested for
long term
Prednisolone 0.25–0.5 mg/kg orally • DO NOT use concurrently with NSAID
sid • Most effective in cases with pronounced
inflammation
Tolfenamic acid 4 mg/kg orally sid for a • Not licensed in many countries
maximum of 3 days
Tramadol 4 mg/kg bid • Toxicity data not available in cats

Note: None have been assessed for dosage or efficacy in cancer; therefore, empirical doses and efficacy reflect dose
recommendations for other painful conditions and experience of the authors. Not all drugs are licensed in all countries.
 Chapter 3 Pathophysiology of Cancer Pain 121

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83. Jain RA. The manufacturing techniques of vari- 102. Carroll GL, Howe LB, Peterson KD. Analgesic
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co-glicolideo)(PLGA) devices. Biomaterials cam or butorphanol in onychectomized cats. J Am
2000;21:2475–2490. Vet Med Assoc 2005;226:913–919.
84. Tarasevich B, Gutowska A, Li XS, et al. The effect 103. Franks JN, Boothe HW, Taylor L, et al. Evaluation
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85. Gervais KJ. Evaluation of a biodegradable thermo- 104. Glerum LE, Egger CM, Allen SW, et al. Analgesic
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 2
SECTION
 CHAPTER

4
Pharmacologics (Drug Classes)
OPIOIDS cell body to nerve terminals. Inflammation
enhances the peripherally directed axonal
The analgesic effects of opium have been transport of opioid receptors, leading to an
known for over 5,000 years, but unfortunately, increase in their number (upregulation) at
abuse has limited the use of opioids. Society has peripheral nerve terminals. Further, preex-
attempted to find a balance between licit and isting, but possibly inactive, neuronal opi-
illicit use, therapeutic versus adverse effects, oid receptors may undergo changes in the
and medical needs with legal issues. Regardless inflammatory milieu (e.g., low pH), and
of the legal, administrative, and social obsta- become active. Ligands with a preference
cles, no other class of drugs has remained in for μ receptors are generally most potent,
use for the treatment of pain as long as opioids. but depending on the circumstances, all
three receptor types can be present and
functionally active in subcutaneous tissue,
OPIOID RECEPTORS viscera, or joints.

Knockout mice studies suggest that three

opioid receptor types regulate distinct pain
modalities1: CHOLECYSTOKININ
• Mu (μ) receptors (OP3) influence responses
AND OPIOIDS
to mechanical, chemical, and supraspinal Cholecystokinin (CCK) is one of the most
thermal nociception. (μ receptor densi- abundant of the neuropeptides present in
ties are not identical among individuals, as brain and spinal cord small neurons. CCK
shown by binding studies in human post- and the opioids tend to have opposite effects,
mortem brain samples.)2 suggesting that the CCK system may repre-
• Kappa (κ) receptors (OP2) modify spinally sent an ‘antiopioid’ or ‘antianalgesic’ mecha-
mediated nociception and chemical visceral nism. CCK antagonists not only enhance
pain. opioid responses but also reverse existing
• Delta (δ) receptors (OP1) increase mechani- morphine tolerance.3 Changes in the expres-
cal nociception and inflammatory pain. (To sion of the peptide CCK and its receptor
date there are no pure delta opiates commer- (CCK-2) on primary afferent neurons may
cially available.) play a key role in the alterations of pain sen-
sitivity and opioid responsiveness that occur
These receptors have several common
in chronic pain conditions.
properties:

• A total of 370–400 amino acids; two to five

glycosylation sites.
• Seven transmembrane spanning regions.
RESPONSE TO OPIOID
• All are negatively coupled through Gi pro- RECEPTOR ACTIVATION
tein to adenylate cyclase.
In common with spinal and supraspinal
Opioid receptors are synthesized in the opioid receptors, the binding of opioid ago-
dorsal root ganglia and transported from the nists results in potassium channel–mediated

DOI: 10.1201/9781003376422-6 127

128 Chronic Pain in Small Animal Medicine

FIGURE 4.1 Activity of spinal opiate analgesia.

neuronal hyperpolarization, attenuation of • Mesencephalon: lateral regions of the mes-

calcium entry through voltage-gated cal- encephalic reticular formation and medial
cium channels, and reduced cyclic adenosine region of the periaqueductal gray.
monophosphate (cAMP) availability, with • Medulla: rostral ventral medulla within
resultant reduction in nociceptor activity the midline structure corresponding to the
(Figure 4.1)4: raphe magnus.
• Spino/Medullary: substantia gelatinosa
regions of the spinal and medullary dorsal
• μ and δ (and to some degree κ) agonists induce
horn. The tenet that opioids are centrally
a membrane hyperpolarization through the
acting is long-standing. Yet direct applica-
activation of an inwardly rectifying potas-
tion of opioids to the peripheral nerve can
sium channel.
produce a local anesthetic-like action at high
• Inhibition of the opening of voltage-sensi-
concentrations, but this is not naloxone-
tive calcium channels that will subsequently
reversible. Models in which peripheral opi-
depress the terminal release of neurotrans-
oids appear to work are those that possess
mitter from the cell. Occupancy of the pre-
a significant degree of inflammation and are
synaptic μ and δ sites reduces the release
characterized by a hyperalgesic component.
of substance P (sP) and or calcitonin gene–
Mechanisms for this antihyperalgesic effect
related peptide (CGRP) in part by an inhi-
are currently unexplained, but injection of
bition of the opening of voltage-sensitive
morphine into the knee joint of humans
calcium channels.
after surgery has shown a powerful sparing
effect upon subsequent analgesic use.
That said, research over the last decade
suggests that morphine and other opioids do
Although controversial, studies suggest
not have fixed actions, but operate on recep-
neuropathic pain secondary to peripheral
tor mechanisms that are subject to alterations
nerve damage more often than not shows
by other transmitters and receptors.
reduced sensitivity to opioids. 5 This is attrib-
Supraspinal activity of opioids occurs at
utable to a reduction in spinal opioid recep-
several locations:
tors, nonopioid receptor–expressing Aβ
fiber–mediated allodynia, increased CCK
• Diencephalons: with active regions within antagonism of opioid actions, and N-methyl-
the basolateral amygdala. D-aspartate (NMDA)–mediated dorsal horn
• Mesencephalon: with active sites within the neuronal hyperexcitability, likely requiring a
substantia nigra. greater opioid inhibitory counter-effect.
 Chapter 4 Pharmacologics (Drug Classes) 129

OPIOID CLASSIFICATION central excitement. Urine production may

Opioids may be the best drugs available for

be decreased for several hours following
morphine administration; however, this 4
pain control, and one might argue that ‘seri- does not appear to be related to arginine
ous pain control’ cannot be implemented vasopressin (previously known as antidi-
without them. uretic hormone or vasopressin) concentra-
Morphine, oxymorphone, fentanyl, tions in the dog.6
hydromorphone, and meperidine are opi-
oid agonists acting mainly at the μ receptor,
where they have a high affinity. The agonist-
antagonists (butorphanol, nalbuphine, pen- OPIOID-ENHANCED PAIN
tazocine) are able to reverse some effects of
the pure agonists but can produce analgesia. The chronic nature of cancer pain often
Buprenorphine is a κ antagonist, with high requires prolonged opioid administration by
affinity for μ receptors, classified as a par- various routes, and doses are often escalated
tial agonist, while butorphanol acts at the κ over time, as the disease progresses. Clinical
receptor and acts as a μ antagonist. Opioid studies with humans report that opioids can
antagonists, including naloxone, naltrexone, unexpectedly produce hyperalgesia and
and nalmefene, reverse the actions of both μ allodynia, particularly during rapid opioid
and κ agonists. See Table 4.1. dose escalation.7,8 Preclinical human stud-
The reported ‘potency’ of different opi- ies have unexpectedly demonstrated that
oids can be misleading in that relative rank- opioids can paradoxically enhance pain.9,10
ing is based on affinity of the specific drug In a murine model of bone cancer, King
for binding to the receptor. The most com- et al.11 showed that in a dose-dependent
mon side effects seen with opioids include manner, morphine enhanced, rather than
respiratory depression, nausea and vomit- diminished, spontaneous and evoked pain.
ing, histamine release, constipation, and Additionally, morphine increased osteoclast
activity and upregulated interleukin (IL)-
1β within the femurs of sarcoma-treated
mice, suggesting enhancement of sarcoma-
TABLE 4.1 Classification of opioids based induced osteolysis. The authors proposed
upon binding activity that sustained morphine increases pain,
A pure opioid agonist An opioid-antagonist osteolysis, bone loss, and spontaneous frac-
binds to one or more binds to one or ture, as well as markers of neuronal dam-
types of receptors and more types of age in dorsal root ganglion (DRG) cells
causes certain effects, receptor, but causes and expression of proinflammatory cyto-
such as analgesia or no effect at those
kines. The observed osteoclastogenesis was
respiratory depression receptors
(e.g., morphine) By competitive attributed, in part, to intraosseous IL-1β
displacement, an levels. Although this data raises concern,
antagonist reverses the relevance must be considered in per-
the effect of an agonist spective. Subject mice in this study were
(e.g., naloxone given high doses of morphine delivered
reverses morphine) with minipumps. Bolus opioid administra-
A partial agonist binds An agonist-antagonist tion has been shown to effectively alleviate
at a given receptor, binds to more than bone cancer pain in humans as well as in
causing an effect less one type of receptor, animals, and all opioids are not the same.
pronounced than that causing an effect at Additionally, morphine is infrequently used
of a pure agonist one receptor but no
(e.g., buprenorphine or a lesser effect at
alone for cancer pain. In adherence to the
is less effective than another receptor World Health Organization’s (WHO)
morphine, as it is (e.g., butorphanol is cancer pain ladder, the patient should be
considered a partial considered a κ started on a nonsteroidal anti-inflamma-
agonist at the μ agonist and a μ tory drug (NSAID) and progress to the
receptor and an antagonist, with addition of an opioid, and then other drug
antagonist at the κ minimal effect at the
class agents, as appropriate. Nevertheless,
receptor) μ receptor)
sustained opioid delivery through patches
130 Chronic Pain in Small Animal Medicine

and controlled-release delivery systems is

becoming more commonly used for pain
OPIOID PATCH DELIVERY
management, and this data demonstrates The highly lipid-soluble opioid fentanyl lends
that prolonged morphine treatment may itself to transdermal delivery and is avail-
have unexpected antianalgesic effects. able in a patch containing a drug reservoir
(Duragesic®: Janssen Pharmaceutica, Inc.).
An ethylene-vinyl acetate copolymer mem-
brane controls the rate of delivery to the skin
ORALLY ADMINISTERED (Figure 4.2). (A recent development is the
Matrix ® adhesive delivery patch from Noven
OPIOIDS Pharmaceutical, Inc.)
Due in part to the differences in der-
Oral administration yields low (<30%; mor- mal vascularization, drug uptake varies
phine 5%) bioavailability12,13 because opi- between the dog and cat. Studies suggest it
oids are metabolized in the liver. Codeine takes 12–24 hours to reach peak effect in the
has the highest bioavailability, approaching dog,16,17 whereas peak values in the cat are
60%,14 and is often administered in combi- reached sooner (2–18 hours).18,19 Fentanyl
nation with acetaminophen (acetaminophen patches certainly have their place; however,
is lethal in cats). they are not without concerns, which include
Although morphine and hydromor- Class II Drug Enforcement Agency (DEA)
phone are available as suppositories, there accountability, expense, difficulty with
appears to be little difference in efficacy or maintaining placement, variable absorption,
bioavailability (~20%) from oral adminis- possible skin reaction, the need to shave
tration15; however, this delivery form is an the hair, and choosing an optimal location.
option if oral administration is unavailable. Following discharge, if a pet at home shows
See Table 4.2. hyperexcitability, the pet owner cannot dif-
ferentiate if the behavior is due to uncon-
trolled pain or excessive opioid absorption.
Patches may have their optimal use in chronic
TABLE 4.2 Available oral/rectal preparations conditions such as cancer. For postoperative
of morphine (for human use) in the United pain, one might consider a patient requir-
States ing opioid administration as an in-house
Duration Dosage
hospital patient, where it can be closely
of action Preparation formulation monitored and treated with cost-efficient
Immediate Tablet/Capsule 1.5, 30 mg
release
Soluble/ 10 mg
Sublingual
Solution 10 mg/5 mL
10 mg/
2.5 mL
20 mg/5 mL
Concentrate 20 mg/mL
Suppository 5, 10, 20, 30 mg
Controlled/ MS Contin 15, 30, 60, 100,
Sustained 200 mg
release
Oramorph SR 15, 30, 60, 100 mg
Kadian (food 20, 30, 50, 60,
sprinkles) 100 mg
Avinza (food 30, 60, 90, 120 mg
FIGURE 4.2 The fentanyl ‘patch’ provides trans-
sprinkles)
dermal delivery.
 Chapter 4 Pharmacologics (Drug Classes) 131

morphine, then discharging the patient only with a boxed warning, which is the strictest
when appropriate pain management can be
provided by oral medication, i.e., an NSAID
warning that can be issued for a drug.
The solution is applied to the skin at the 4
and/or an adjunct. base of the cat’s neck within 1 to 2 hours
before surgery, where it is rapidly absorbed
(within 30 minutes) into the layers of skin.
Application at this site is important for two
ZORBIUM reasons: (1) it negates oral ingestion and (2)
the dynamics of transdermal drug applica-
Ref: Freedom of Information Summary-
tions vary with the site of application. The
Original New Animal Drug Application.
area over the head is the least resisted exami-
NADA 141-547, Zorbium™ buprenorphine
nation area in cats. In a survey of veterinary
transdermal solution: cats (Elanco US Inc.)
examinations, cats resist examination in
Buprenorphine is classified as a partial mu rank order: the abdomen (30.6%), the tail
agonist, which means it doesn’t bind as (22.7%), the genital area (11.4%), the mouth
strongly to the receptor as full agonists (mor- (9.6%), the claws (7.4%), the ears (6.8%),
phine). It does have a high binding affinity for and over the head (4%). 26 The dose volume
various subclasses of opiate receptors, particu- is either 0.4 mL (8 mg) for cats weighing
larly mu, in the central nervous system (CNS). from 1.2 kg to 3 kg or 1 mL (20 mg) for cats
Buprenorphine slowly dissociates from the mu weighing >3 kg to 7.5 kg, which is a dose
receptor, resulting in prolonged analgesia. range of 2.7–6.7 mg/kg. Pain relief is pro-
There are limited opioid options to treat vided within 1–2 hours following adminis-
moderate-to-severe pain in conscious cats tration, and buprenorphine is continually
beyond the immediate postoperative period released into the cat’s body over a period of
because of inherent limitations of most opi- days. A single application provides pain relief
oids, to include poor oral bioavailability and to the cat for 4 days.
rapid elimination. 20 Buprenorphine admin- PK studies indicated that the rate of
istered by the oral transmucosal (OTM) elimination of TBS is faster than its rate of
route is approximately 30% bioavailable. 21 absorption from the skin (flip-flop kinetics),
It obviates the need for parenteral injections and the absorption determines the terminal
but requires frequent administrations for use half-life. The mean terminal half-life ranged
over extended periods. 22,23 between 78.3 and 91.2 hours.
To make available an approved, extended- During the days after clinical trial sur-
duration formulation of buprenorphine for the geries, the most common adverse reaction
control of postoperative pain in cats, a novel in ‘test subjects’ was increased body tem-
transdermal buprenorphine solution (TBS) perature. Additional findings observed in
has been developed. As a delivery method, cats administered the ‘test solution’ in safety
the transdermal route has several potential studies included dilated pupils; constipation;
strengths over oral and parenteral administra- and abnormal behavior such as hyperactiv-
tion. These include noninvasive dosing, avoid- ity, agitation, restlessness, and aggression.
ance of the gastrointestinal tract, and lack of A drying time study concluded that dose
first-pass metabolism.24 Freise et al.25 demon- volumes of 1.2 mL or less of the transdermal
strated that following a single topical appli- solution (without buprenorphine) applied to
cation of TBS, buprenorphine forms a depot the top of the cat’s neck at the base of the
in the skin, resulting in prolonged systemic skull dried completely within 30 minutes fol-
release with half-lives of 78.3–91.2 hours, lowing administration, while a human user
typical of flip-flop pharmacokinetics (PK). risk assessment concluded that following
The Food and Drug Administration complete drying of the solution (30 minutes),
(FDA) has previously approved an injectable there is no health risk to adults or chil-
buprenorphine for use in cats, as well as an dren associated with exposure to residual
NSAID (tablet and injection) for postopera- buprenorphine in the home environment.
tive pain in cats. The FDA has now (January TBS is supplied in single-use, unit-dose,
2022) approved the first TBS for the control and use-and-dispose applicator tubes. The
of postsurgical pain in cats. The solution is a success rate in TBS-treated cats was approxi-
DEA Schedule III opioid and was approved mately 80%. 27
132 Chronic Pain in Small Animal Medicine

INTRA-ARTICULAR In humans tramadol is able to reduce

the amount of sP in synovial fluid, as well
OPIOID DELIVERY as IL-6, which seems to correlate with the
stage of osteoarthritis (OA).33 The American
Morphine is also used for intra-articular College of Rheumatology and the American
analgesia, and several investigators suggest Medical Directors’ Association support the
that in combination with bupivacaine, mor- addition of tramadol to an NSAID for the
phine works best. 28 Because opioid recep- management of chronic pain in humans.34,35
tors are found in the spinal cord, opioids However, one meta-analysis on tramadol
can be applied directly to these receptors by concluded that tramadol or tramadol/acet-
epidural or intrathecal administration. This aminophen decreases pain intensity, pro-
takes advantage of smaller doses and central duces symptom relief, and improves function,
administration to minimize systemic uptake but these benefits were small. Adverse events,
and possible side effects associated with although reversible and not life-threatening,
higher dose recommendations. often caused human patients to stop taking
the medication and could limit its useful-
ness.36 Despite its wide use in humans, there
TRAMADOL is little to no safety or efficacy data on the role
of tramadol in veterinary patients. Published
The synthetic codeine analogue tramadol is data suggests caution with its cavalier use,
widely used (although not approved) in dogs. pending further studies assessing its effects
Approximately 40% of its activity is at the mu in cats and dogs. 37,38 Further, although tra-
receptor. Forty percent of tramadol activity madol effectiveness for treatment of canine
is as a norepinephrine reuptake inhibitor and chronic OA pain has been unsubstanti-
20% is as a serotonin (5-HT) reuptake inhib- ated, 37 the veterinary community continues
itor (SRI). Since tramadol has SRI features, to support the use of tramadol across a wide
its use can be associated with increased bleed- range of doses, spanning from 1 to 10 mg/kg
ing, especially when used in combination (0.45–4.5 mg/lb).31,39,40
with an NSAID. Since the majority of trama- Tramadol has become a very popular
dol activity is other than at the mu receptor, analgesic adjunct over the past decade, hav-
it is a poor substitute for the ‘pure’ opioids; ing gained a worldwide reputation as an
however, it can be used as an adjunct to an effective, safe, and well-tolerated drug for
opioid or an NSAID. 29 Tramadol’s activity inhibition of moderate pain in humans. It
has been attributed to a metabolite of trama- has come to fill the gap on the WHO anal-
dol, O-desmethyltramadol, known as M1, gesic ladder between the ‘weak analgesics’
although there are many other metabolites, (NSAIDs) and the strong opioids of the
but pharmacological effects have only been morphine type. The original compound
confirmed with one, O-desmethyltramadol, comprised S- and R-enantiomers that could
after routine tramadol administration. In easily be separated by solubility differ-
dogs, the systemic clearance of orally admin- ences of their compounds with an optically
istered tramadol is almost five times faster active compound. Pharmacological testing
than in humans, with at least 32 metabolites of the individual enantiomers showed the
identified. 30 The (+)-M1 is reported as hav- R-enantiomer to be the stronger analgesic,
ing 2–200 times more potency at mu receptor and erroneously this was further presumed
binding as (+)-tramadol.31 In humans, tram- to come from the trans-configuration; there-
adol is transformed to the active metabolite fore, the compound was named tramadol.
O-desmethyltramadol by CYP2D6, which Both enantiomers are required for full anal-
exists in various phenotypes. 32 The specific gesic activity. The S-enantiomer inhibits
CYP associated with tramadol metabolism serotonin reuptake and has weak affinity
to O-desmethyltramadol has not been iden- for opioid receptors, while the R-enantiomer
tified in dogs. In a study of young, healthy inhibits norepinephrine reuptake. Each
greyhounds orally dosed at 9.9 mg/kg, the enantiomer independently produces centrally
active metabolite O-desmethyltramadol was mediated analgesia, and the combination of
present in all dogs but at low concentrations, enantiomers produces a greater effect than
never exceeding 13.8 ng/mL.31 the additive effect of each enantiomer alone,
 Chapter 4 Pharmacologics (Drug Classes) 133

i.e., they are synergistic. Tramadol is not

approved for dogs or cats, and only prepa-
rations for oral administration are available 4
in the United States. There is no safety or
efficacy data in dogs or cats. Metabolism of
tramadol through hepatic demethylation to
O-desmethyl-tramadol (M1 demethylated
metabolite) is reported in several species
(including dog, where levels are quite low,
and cat), and O-desmethyl-tramadol has
been shown to bind to the μ-opioid receptor
with a much higher affinity than the parent
drug, likely providing an analgesic effect to
tramadol. Metabolic clearance is probably FIGURE 4.4 While traditional μ receptor agonists
through hepatic metabolism and renal excre- (morphine and codeine) show pronounced anal-
tion of unchanged drug. The lower clearance gesic reversal with the opioid-antagonist nalox-
in cats compared to dogs may reflect the cat’s one, tramadol does not – confirming that it is not
lower capacity of the liver to biotransform a ‘pure’ opioid.
tramadol. The unique characteristics of tra-
madol were identified by incomplete inhibi-
tion of intraperitoneal tramadol-induced that reduce seizure threshold, such as tricy-
antinociception by subcutaneous naloxone, clic antidepressants (TCAs), selective SRIs,
compared with the complete inhibition of monoamine oxidase inhibitors, or neurolep-
antinociception induced by codeine and mor- tics. Tramadol may also be associated with
phine in the mouse abdominal constriction gastrointestinal bleeding, exacerbated by the
test (Figures 4.3 and 4.4).41 concurrent use with an NSAID.
Tramadol does not inhibit cyclooxygen- One study44 in human patients dem-
ase (COX) activity. Seizure risk is cautioned onstrated that both tramadol and its M1
in human patients receiving CNS drugs demethylated metabolite penetrate into
synovial fluid, significantly reducing syno-
vial fluid concentrations of sP. IL-6 synovial
fluid concentrations were not significantly
decreased. In dogs the systemic clearance of
orally administered tramadol is almost five
times faster than in humans, with at least
32 metabolites identified.30 In a different
study,45 simulated oral dosing regimens at
5 mg/kg every 6 hours and 2.5 mg/kg every
4 hours were predicted to produce trama-
dol and M1 levels consistent with analgesia
in humans, noting that pharmacodynamic
studies are lacking to confirm the plasma
concentrations needed to provide analgesia
in dogs. In cats, tramadol is rapidly absorbed
after oral administration and eliminated rel-
FIGURE 4.3 Forty percent of the activity of trama- atively slowly.46 See Table 4.3.
dol is ‘opioid-like’ with activity at the μ receptor, Arguably, it is concerning how com-
while 60% of its activity is associated with sero- monly this drug is being used with virtually
tonergic and noradrenergic functions. The α2- no evidence base for its safety or efficacy
adrenoceceptor antagonist yohimbine partially
in veterinary patients. Most analgesic com-
reverses the antinociceptive effects of trama-
dol,42 supporting the role of α2-adrenoceceptors
bination products currently marketed for
in the antinociceptive effects of tramadol. Also, moderate-to-severe pain are mixtures of
the serotonin (5HT2a) receptor antagonist ket- codeine, hydrocodone, oxycodone, or pro-
anserin will partially reverse the antinociceptive poxyphene with aspirin, acetaminophen, or
effects of tramadol.43 ibuprofen.
134 Chronic Pain in Small Animal Medicine

TABLE 4.3 Pharmacokinetic parameters for orally administered tramadol

Tramadol O-desmethyl-tramadol
Dog Cat Dog Cat
Availability 65 ± 38% 93 ± 7%
T½ 2.18 ± 0.55 hr 4.82 ± 0.32 hr
Elimination
T½ ≤1.7 hr 3.4 hr
C max 1402.75 ± 696 ng/mL 914 ± 232 ng/mL
Tmax 1.04 ± 0.51 hr 0.42 hr

TAPENTADOL analyzing the chemistry and activity of tra-

madol, which had been created at the same
Tapentadol, common brand name Nucynta company in 1962. Tramadol has several enan-
(among others), is a centrally acting opioid tiomers, and each forms metabolites after
analgesic of the benzenoid class with a dual processing in the liver. These tramadol vari-
mode of action as an agonist of the μ-opioid ants have varying activities at the μ-opioid
receptor and as a norepinephrine reuptake receptor, the norepinephrine transporter, and
inhibitor (NRI). Analgesia in human patients the serotonin transporter, as well as differing
occurs within 32 minutes of oral administra- half-lives, with the metabolites having the best
tion and lasts for 4–6 hours. activity. Using tramadol as a starting point, the
It is similar to tramadol in its dual team aimed to discover a single molecule that
mechanism of action; namely, its ability to minimized the serotonin activity, had strong
activate the mu-opioid receptor and inhibit μ-opioid receptor agonism and strong norepi-
the reuptake of norepinephrine. Unlike tra- nephrine reuptake inhibition, and would not
madol, it has only weak effects on the reup- require metabolism to be active. The resultant
take of serotonin and is a significantly more discovery was tapentadol. Present commercial
potent opioid in humans, with no known preparations contain only the (R,R) stereoiso-
active metabolites. Tapentadol is not a pro- mer, which is the weakest isomer in terms of
drug and therefore does not rely on metabo- opioid activity.
lism to produce its therapeutic effects. This In 2009 tapentadol was classified by DEA
makes it a useful moderate-potency anal- as a Schedule II drug and entered the U.S.
gesic option for human patients who do market. Tapentadol was reported to be the
not respond adequately to more commonly “first new molecular entity of oral centrally-
used opioids due to genetic disposition (poor acting analgesics” class approved in the
metabolizers of CYP3A4 and CYP2D6), as United States in more than 25 years. It is not
well as providing a more consistent dosage- approved for veterinary use.
response range among the patient population. Chronic pain treatment represents one
The potency of tapentadol in human of the most complex clinical challenges, and
patients is somewhere between that of trama- even though opioids exhibit particular effi-
dol and morphine, with an analgesic efficacy cacy on nociceptive pain, their use must be
comparable to that of oxycodone, despite a controlled to avoid the risk of adverse reac-
lower incidence of side effects. Overall, in tions. A useful approach, aimed at maintain-
vivo data show that tapentadol is approxi- ing analgesia and mitigating side effects,
mately twice as potent as tramadol.47 It is is represented by the use of a new class of
occasionally regarded as a moderately strong analgesics endowed with μ-opioid (MOR)
opioid. Tapentadol was approved for human receptor agonism and NRI mechanisms.
use by the U.S. FDA in November 2008. Tapentadol is the progenitor of this new
Tapentadol was invented at the German class of drugs called MOR-NRI. A literature
pharmaceutical company Grünenthal in the review has been conducted to gain informa-
late 1980s. The investigative team started by tion about the human use efficacy and the
 Chapter 4 Pharmacologics (Drug Classes) 135

tolerability profile of tapentadol shifting from pain ladder and has about one-tenth of the
MOR agonism (acute pain) to NRI activity
(chronic pain). The tolerability and therapeu-
potency of morphine. Tramadol differs from
other traditional opioid medications in that 4
tic safety of tapentadol in neuropathic pain it doesn’t just act as a μ-opioid agonist but
models, as well as in clinical settings, have also affects monoamines by modulating the
been analyzed showing a good gastrointesti- effects of neurotransmitters involved in the
nal tolerability profile and a moderate effect modulation of pain such as serotonin and
on hormone levels (in healthy volunteers and norepinephrine, which activate descending
in patients) and on cognitive performance. pain inhibitory pathways. Tramadol’s effects
Tramadol is an opioid analgesic widely used on serotonin and norepinephrine mimic the
in human medicine to treat moderate to severe effects of other SNRI antidepressants such as
pain. It is metabolized by cytochrome CYP2D6 duloxetine. Tramadol has also been shown
into two major metabolites: pharmacologi- to affect a number of other pain modula-
cally active metabolite O-desmethyltramadol tors within the CNS as well as non-neuronal
(M1) and inactive N-desmethyltramadol inflammatory markers and immune media-
(M2). O-Desmethyltramadol (O-DSMT) is an tors. Due to the broad spectrum of targets
opioid analgesic and the main active metabolite involved in pain and inflammation, it’s not
of tramadol in humans (but not the dog or cat). surprising that evidence has shown that tra-
(+)-O-Desmethyltramadol is the most impor- madol is effective for a number of pain types,
tant metabolite of tramadol produced in the including neuropathic pain; postoperative
liver after tramadol is consumed. This metab- pain; lower back pain; and pain associated
olite is considerably more potent as a μ-opioid with labor, OA, fibromyalgia, and cancer.
agonist than the parent agent. Tramadol Due to its SNRI activity, tramadol also has
exists as a racemic mixture consisting of anxiolytic, antidepressant, and antishiver-
two pharmacologically active enantiomers ing effects, which are all frequently found
that both contribute to its analgesic property as comorbidities with human pain. Similar
through different mechanisms and are also to other opioid medications, tramadol poses
themselves metabolized into active metabo- a risk for development of tolerance, depen-
lites: (+)-tramadol and its primary metabolite dence, and abuse. If used in higher doses or
(+)-O-desmethyl-tramadol (M1) are agonists with other opioids, there is a dose-related
of the μ-opioid receptor, while (+)-tramadol risk of overdose, respiratory depression, and
inhibits serotonin reuptake and (–)-trama- death. However, unlike other opioid medi-
dol inhibits norepinephrine reuptake. These cations, tramadol use also carries a risk of
pathways are complementary and synergistic, seizure and serotonin syndrome, particularly
improving tramadol’s ability to modulate the if used with other serotonergic medications.
perception of and response to pain. Among its Unlike tramadol, the activity of tapentadol
metabolites, (+)-O-desmethyl-tramadol – the relies exclusively on its parent drug since it
(+)-M1 metabolite – has approximately 700- has no identified analgesic active metabolite.
fold greater affinity than (+)-tramadol for the The parent drug has approximately a 50-fold
mu-opioid receptors.47 Thus, when the parent lower affinity in vitro for mu receptors than
drug is metabolized, the contribution of sero- the (+)-M1 metabolite of tramadol, but an
tonin and noradrenaline reuptake inhibition equivalent mu-agonist analgesic effect based
decreases while the contribution of the mu- on in vivo data. This apparent inconsistency
agonist effect increases, resulting in a complex could be explained by the different diffusion
pattern of pharmacological activity dependent of these various active molecules in the CNS
on the rate and amount of active metabolites. or their ability to activate intracellular mecha-
Tramadol is a centrally acting synthetic nisms after binding to the receptors.
opioid analgesic and serotonin/norepinephrine Moreover, tapentadol has an activity simi-
reuptake inhibitor (SNRI) that is structurally lar to (–)-tramadol on noradrenergic reuptake
related to codeine and morphine. Due to and is approximately five times less active
its good tolerability profile and multimodal than (+)-tramadol on serotonergic reuptake.47
mechanism of action, tramadol is occasion- In vivo animal and human data confirmed
ally considered a lower-risk opioid option for that the noradrenergic and serotonergic
the treatment of moderate to severe pain. It activities of tramadol contribute to its anal-
is considered a Step 2 option on the WHO’s gesic effect,41,42 unlike tapentadol, where the
136 Chronic Pain in Small Animal Medicine

noradrenergic activity is dominant over the • Spinal cord: act in the substantia gelatinosa
serotonergic activity. Overall, in vivo data to block C-fiber release and hyperpolarize
show that tapentadol is approximately twice dorsal horn nociceptive neurons.
as potent as tramadol. Among tramadol’s • Periphery: act to alter the excitability in ter-
metabolites, (+)-O-desmethyl-tramadol – the minals located in an inflammatory milieu;
(+)-M1 metabolite – has approximately 700- only block hyperalgesia.
fold greater affinity than (+)-tramadol for the • Central: raise nociceptive thresholds.
mu-opioid receptors.47 Thus, when the par-
ent drug is metabolized, the contribution of
serotonin and noradrenaline reuptake inhibi-
OPIOIDS AT A GLANCE
tion decreases, while the contribution of the (SEE TABLE 4.4)
mu-agonist effect increases, resulting in a
complex pattern of pharmacological activity Meperidine (Pethidine, Demerol)
dependent on the rate and amount of active
metabolites. Ultimately, tapentadol is two to • Less sedation than morphine.
three times more potent than tramadol and • More likely to cause histamine release; intra-
two to three times less potent than morphine. venous administration can cause excitement
To summarize, tapentadol combines two in animals.
specific synergistic mechanisms of analgesic
action (mu-opioid receptor agonism and the TABLE 4.4 World Health Organization’s
inhibition of noradrenaline reuptake), whereas opioid classification
tramadol does not combine these two different
mechanisms of action in the same molecule. Strength Functional
Weak opioids Full agonists
• Codeine • Morphine
OPIOID OVERVIEW • Dihydrocodeine • Fentanyl
Opioids are relatively safe. Potential side • Dextropropoxyphene • Hydromorphone
effects include: • Tramadol • Codeine
• Sedation or CNS depression • Methadone
• Excitement or dysphoria
• Bradycardia Strong opioids • Tramadol
• Respiratory depression • Morphine • Meperidine
• Panting (pethidine)
• Laryngeal reflex depression • Methadone
• Histamine release (particularly with intra-
venous administration) • Fentanyl Partial agonists
• Vomiting and defecation (nausea) • Hydromorphone • Buprenorphine
• Constipation (longer-term use)
• Meperidine • Pentazocine
• Urinary retention (more common with epi- (pethidine)
dural administration)
• Hyperthermia (especially in cats with • Oxycodone • Butorphanol
hydromorphone) • Buprenorphine

Mechanistic summary of opioids • Levorphanol Agonists-antagonists

• Dextromoramide • Nalbuphine
• Act at μ, δ, and κ opioid receptors.
• Hyperpolarized by increased K+ conduc- • Oxymorphone • Nalorphine
tance; block transmitter release by blocking Full antagonists
calcium conductance. Act in brain, spinal
cord, and at peripheral afferent terminals. • Naloxone
• Brainstem: periaqueductal gray – activate • Naltrexone
several mechanisms, including increased
• Alvimopan
activity in descending/ascending pathways.
 Chapter 4 Pharmacologics (Drug Classes) 137

• Anticholinergic effects associated with Codeine

structural similarity to atropine.
• In humans, the metabolite normeperidine is • ‘International standard’ weak opioid. 4
a neurotoxic CNS stimulant associated with • Approximately 9% of Caucasians lack enzyme
adverse reactions.48 to provide analgesia50 – relevance in animals
• Very short acting (<2 hours in cats). unknown.
• Substantially improves analgesia of nonopi-
Oxymorphone oids (e.g., NSAIDs).

• Does not cause histamine release. Tramadol

• May induce panting.
• Forty percent activity at the μ receptor, 60%
Methadone as serotonin and norepinephrine neuronal
reuptake inhibitor (monoaminergic).
• Does not cause histamine release. • Reduces synovial fluid concentrations of sP
• NMDA and SRI activity. and IL-6 in human patients with knee OA.44
• Augments analgesia of opioids51 and
Hydromorphone NSAIDs. 52
• Bioavailability is about 65%, with a short
• More sedation than oxymorphone, but half-life (<1.7 hours) in dogs; bioavailability
shorter duration. is 93% with a half-life of 3.4 hours in the cat.
• No histamine release with intravenous • Simulated oral dosing regimens at 5 mg/kg
administration. q6h and 2.5 mg/kg q4h in the dog are pre-
• Hyperthermia in cats. dicted to produce tramadol and M1 levels
consistent with analgesia in humans.45
Fentanyl • Effective in neuropathic pain. 53
• Very low abuse potential.
• Rapid onset of action (2–3 minutes).
• Possible potentiation of bleeding, especially
• Short duration of action (thermal thresh-
when combined with an NSAID.
old testing revealed that 10 μg/kg IV lasts
• No efficacy or safety data in dog or cat.
approximately 2 hours in cats).

Butorphanol

• Agonist-antagonist. α2 AGONISTS
• Weak analgesic, with analgesic ceiling effect.
• Short duration of analgesia (~40 minutes The prototypical α 2-adrenergic agonist used
in the dog; approximately 90 minutes after in veterinary medicine has been xylazine.
intravenous dosing in cats). Since its introduction in 1962, xylazine
has been used, mostly in horses and rumi-
Buprenorphine nants, as a sedative-analgesic or anesthetic
adjuvant (it is not an anesthetic). The newer
• Agonist (strong for μ receptor)-antagonist (κ α 2-adrenergic agonist, medetomidine, has
receptor). gained acceptance in companion animal
• Slow onset (30–60 minutes), long acting practice. Medetomidine is an equal mixture
(8–12 hours). of two optical enantiomers, of which dextro-
• Affinity for μ receptor makes reversal more medetomidine is a potent α 2-agonist, while
difficult. levo-medetomidine is pharmacologically
• Most popular opioid used in small animal inactive. Medetomidine has a high affin-
practice in the UK, Australia, New Zealand, ity for the α 2 receptor, with an α 2 /α1 bind-
and South Africa. ing ratio of 1620, compared with ratios of
• Oral transmucosal administration highly 260, 220, and 160 for detomidine, clonidine,
effective in the cat. and xylazine, respectively.54 Currently, it
• Considered by some to be the best opioid is uncommon practice to administer large
investigated in the cat.49 doses of an α 2-agonist as a single agent, but
138 Chronic Pain in Small Animal Medicine

it is commonly accepted that low doses are kinase, and hence, the phosphorylation of
very useful when used as adjuncts in a bal- target regulatory proteins.57 In addition α2-
anced analgesic protocol. adrenoreceptor activation of G-protein-gated
Bulbospinal noradrenergic pathways can potassium channels results in membrane
regulate dorsal horn nociceptive processing hyperpolarization, causing a decrease in the
by the release of norepinephrine and the sub- firing rate of excitable cells in the CNS.58
sequent activation of α2-adrenergic receptors. Presynaptic α2-adrenoreceptors secrete
Epidural delivery of α2-agonists can produce norepinephrine, which binds with postsyn-
potent analgesia in humans and animals.55 aptic adrenoreceptors to stimulate target cell
Although the receptor is distinct, spinal response governing autonomic functions.
action of an α 2-agonist is mediated by a Medetomidine produces rapid sedation by
mechanism similar to that of spinal opioids: selectively binding to α2-adrenoreceptors in the
(1) α 2 binding is presynaptic on C fibers and neuron, inhibiting release of norepinephrine
postsynaptic on dorsal horn neurons, (2) α 2 necessary for neurotransmission (Figure 4.6).
receptors can depress the release of C-fiber Dense populations of α 2-adrenoreceptors
transmitters, and (3) β2-agonists can hyper- are concentrated in the mammalian spi-
polarize dorsal horn neurons through a Gi- nal cord dorsal horn, both presynaptically
coupled potassium channel (Figure 4.5). and postsynaptically, on non-noradrener-
α 2-Mediated analgesia (in neuropathic gic nociceptive neurons. On presynaptic
pain) involves spinal muscarinic and choliner- α 2-adrenoreceptors, when G 0 proteins are
gic receptor activation with nitric oxide (NO) activated, a decrease in calcium influx is
mechanisms, supporting that α2 receptors may mediated, leading to decreased release of
be primarily located on spinal cholinergic inter- neurotransmitters and/or neuropeptides,
neurons.56 Spinal α2 receptors, in conjunction including glutamate, vasoactive intestinal
with periaqueductal gray opioid receptors, peptide, CGRP, sP, and neurotensin. At
mediate the analgesic actions of NO. Sedative postsynaptic α 2-adrenoreceptors, Gi pro-
effects are presumed to be mediated at the tein–coupled potassium channels produce
level of the brainstem. It is generally accepted neuronal hyperpolarization that dampens
that effects of spinal α2-adrenoreceptor ago- ascending nociceptive transmission, thereby
nists are not naloxone reversible and show no producing postsynaptically mediated spinal
cross-tolerance to opioids. analgesia. The sedative-hypnotic effects are
One mechanism of α2-agonist action is apparently mediated by activation of supra-
the inhibition of adenylate cyclase. Decreased spinal α 2-adrenoreceptors located in the
availability of intracellular cAMP attenuates brainstem, where there is a relatively high
the stimulation of cAMP-dependent protein density of α 2-agonist binding sites.

FIGURE 4.5 Summary of opiate and α2 receptor action.

 Chapter 4 Pharmacologics (Drug Classes) 139

FIGURE 4.6 The release of norepinephrine is blocked by the administration of an α2-agonist.

Potential features of α2 agonists include • Decreased respiratory rate, but with pH,
the following (see Table 4.5): PaO2 , and PaCO2 maintained within nor-
mal limits.
• Sedation, muscle relaxation, and anxiolysis. • Both cats and dogs may vomit; cats (90%)
• Short-duration hypertension accompanied > dogs (20%).
by a compensatory baroreceptor-mediated
reflex bradycardia.

TABLE 4.5 The following data were taken from an educational demonstration in a live dog,
demonstrating the physiological responses to the α2-agonists (medetomidine), anticholinergic
(atropine), and reversal agent (atipamezole)
Heart Respiration
rate O2 sat rate
Parameters (Beats/ Mean BP Cardiac (%) Mucous PaO2 PaCO2 (Breaths/
[normal] min) (mmHg) output [95–100] membrane (mmHg) (mmHg) min)
[70–110] [60–100] (L/min) Color [Pink, [500–600] [40–55] [6–20]
[2.5–6] 1–3 s]

Baseline (1.1%
isoflurane)
91 76 2.95 98 Pink, fast 575 52 20
(10 μg/kg; IM)
medetomidine
admin
+ 5 min 49 96 1.33 93 Pale, slow 630 55 24
+ 15 min 50 90 1.36 95 Pinker, slow 563 54 18
(0.04 mg/kg, IV)
anticholinergic
admin
+ 3 min 77 125 1.45 100 Pink, faster 602 59 13
(50 μg/kg; IM)
atipamezole
admin
+ 1 min 86 147 1.56 99 Pink, fast X X 15
+ 5 min 89 96 2.3 98 Pink, fast 597 54 12

Source: By Dr. W.J. Tranquilli and Dr. K.A. Grimm, University of Illinois (data comes from a demonstration given to Pfizer Animal
Health veterinarians).
Note: Numbers in parenthesis are dog normal. Pink refers to color of mucous membranes, while 1–3 refers to capillary refill time in
seconds.
140 Chronic Pain in Small Animal Medicine

• Gastrointestinal atony with possible gas decrease by one-third to one-half of base-

accumulation. line value.
• Increased urinary output. • Should be avoided in animals with compro-
• Transient hypoinsulinemia and hyperglyce- mising cardiopulmonary disease.
mia have been reported in dogs.

MEDETOMIDINE/VATINOXAN
α2 MECHANISTIC SUMMARY
Veterinarians routinely utilize sedatives in
• Act at α 2-adrenergic receptor. their daily practice to ensure the safety and
• Hyperpolarize by increased potassium comfort of their patients and the hospital
conductance; block transmitter release by staff. α 2 -Agonists sometimes carry a con-
blocking calcium conductance. cern for cardiac function while the patient
• Act in the brain to produce sedation and is sedated. A new veterinary drug for seda-
depress arousal. tion and pain relief in dogs is now available.
• In the spinal cord, produce analgesia and This new drug (April 2022), an α 2 -agonist
depress sympathetic outflow. (medetomidine) and vatinoxan combina-
• In the spinal cord, act in the substantia gela- tion (Zenalpha; Vetcare Oy and Dechra)
tinosa to block C-fiber release and hyper- is indicated for use as a sedative/analgesic
polarize dorsal horn nociceptive neurons, in dogs to facilitate clinical examinations,
producing analgesia. clinical procedures, and minor surgical
• Effects on neuropathic pain may reflect mild procedures. The combination of the α 2 -
sympatholytic action. agonist (medetomidine) and vatinoxan
provides a unique balance of central and
peripheral activity that minimizes cardio-
vascular adverse effects, while maintain-
α2-AGONISTS AT A GLANCE ing the sedative and analgesic properties of
medetomidine. 60
• Not first-line analgesic agents, but excellent
analgesic adjuncts.
• At low doses, both sedation and analgesia
are dose dependent. MEMBRANE STABILIZERS
• Ceiling effect at higher dosages.
• Co-administration with anticholinergics is Neuropathic pain is often a result of many
controversial. underlying mechanisms, yet there may be a
• Inclusion in a premedication protocol mark- dominant mechanism that, when treated,
edly reduces the required dose of induction reduces pain to a tolerable level. For exam-
and maintenance anesthetic agents. ple, if it can be demonstrated that ecto-
• Up to 20% of dogs and 90% of cats will pic impulse generators, due to abnormal
vomit after administration. sodium channel activity, located in injured
• Increased urine output is reported in both or abnormally functioning primary affer-
dogs and cats. ent fibers, are generating increased traffic
• Transient hypoinsulinemia and hyperglyce- entering CNS pathways, treatment with
mia are reported in dogs. a sodium channel–blocking agent that
• α 2 -Agonists are sedative-analgesics, not reduces ectopic firing may dramatically
anesthetics. Therefore, under their influ- reduce pain. Mechanism-based pain man-
ence, the animal is still arousable and agement is an area of intense research. 61
may still bite in response to a noxious This includes reducing transmitter release
stimulus. in pronociceptive neurons by opioids or α 2δ
• Reflex bradycardia and bradyarrhythmias calcium channel–binding drugs, by inhibit-
are common. Heart rates may decrease by ing postsynaptic excitatory receptors such
50%. 59 as the NMDA or AMPA-kainate recep-
• Blood pressure may fall by one-quarter tors, by potentiating inhibitory transmitters
to one-third, and cardiac output may through reduced transmitter uptake or by
 Chapter 4 Pharmacologics (Drug Classes) 141

agonist administration, and by use-depen- MECHANISTIC SUMMARY

dent sodium channel blockers.
Trafficking, upregulation and downregu- OF INTRAVENOUS LIDOCAINE 4
lation, and even functional modulation of
sodium channels, are the primary players (SEE TABLE 4.6)
in neuropathic membrane remodeling and
• Intravenous lidocaine is not recommended
hyperexcitability, with potassium channels
for cats due to cardiovascular depression.
playing an important role. Many drugs that
• Lidocaine is a sodium channel blocker
block sodium channels are available for
(Figure 4.7).
clinical use. Local anesthetics are the most
• Sodium channels appear to be responsible
widely used: lidocaine and bupivacaine.
for spontaneous activity in nerve terminals
When applied at high concentrations to a
after local tissue and nerve injury.
nerve, impulse conduction and pain stop
• Intravenous sodium channel blockers at
when the impulse originates distal to the
concentrations that do not block enough
application site. This is effective for both
sodium channels to suppress conduction
nociceptive and neuropathic pain. Low con-
will block the ectopic generators.
centrations of lidocaine, two to three orders
of magnitude lower than those required to
TABLE 4.6 Intravenous lidocaine efficacy
block normal impulse propagation, selec- in humans. (See also Figure 4.7)
tively suppress subthreshold oscillations
and ectopic neuroma and DRG discharge, Clinical state Efficacy Reference
with similar CNS activity. Such sensitivity Postoperative
to sodium channel blockage is the basis for
Abdominal – opiate – 65
these drugs being given systemically with- sparing
out serious toxicity from failure of normal
neuronal conduction within the cardiovas- Cardiac – opiate – 66
cular and nervous systems. sparing
Systemic local anesthetics have long been Abdominal – 67
used for analgesia, particularly in humans hysterectomy
for neuropathic pain. The primary mode Cholecystectomy + 68
of action of intravenous lidocaine is a dose-
dependent blockade of spontaneous ectopic Cancer
activity in peripheral nerves and DRG cells.62 Bony metastases + 69
Importantly, these effects occur at plasma
concentrations that are lower than those Neuropathy – 70
required to produce a frank block of nerve + 71
conduction (5–10 μg/mL): for lidocaine,
effective concentrations may be on the order + 72
of 1–3 μg/mL. Neuropathic pain relief could Nerve injury
be explained, in part, by their actions on the
Nerve injury – VAS + 73
CNS, such as postsynaptic modification of
NMDA receptor activity.63 Nerve injury + 74
Long-term use of systemic (parenteral) – allodynia
local anesthetics (e.g., lidocaine) in humans Nerve injury – VAS + 75
is often precluded by tachyphylaxis and
dose-related toxic effects. Orally adminis- Nerve injury – VAS + 76
tered lidocaine-like antiarrhythmics, such as Stroke – stroke pain + 77
mexiletine, have been used as an alternative
with favorable results.64 The topical appli- Postherpetic + 78
neuropathy
cation of lidocaine (e.g., lidocaine patch) is + 79
reported to be effective for some forms of
Fibromyalgia + 80
nerve injury pain (e.g., postherpetic neural-
gia [PHN]), offering the advantage of fewer Diabetic neuropathy + 81
side effects because plasma concentrations
+ 82
are well below toxic levels.
142 Chronic Pain in Small Animal Medicine

than large fibers; they are blocked earlier

and to a greater degree, apparently related
to the shorter internodal distances of
smaller nerve fibers.
The functional blockade density and
duration of action of a local anesthetic for a
peripheral nerve block are dependent on both
the concentration of local anesthetic used
(sufficient to inhibit sodium channels) and
the use of a critical drug volume to achieve a
sustained critical exposure length. Raymond
et al.82 interpreted three nodes of Ranvier as
the minimal nerve length exposure necessary
to block effective nerve transmission (corre-
sponding to a nerve length of approximately
3.4 mm). Campoy et al.83 reported that in
the dog, volumes of 0.3 and 0.05 mL/kg
FIGURE 4.7 Lidocaine. Systemic sodium chan- produced sufficient distribution for perform-
nel blocking is provided (in humans) by plasma
ing brachial plexus and sciatic nerve blocks,
lidocaine (1–3 μg/mL), thereby providing anti-
hyperpathia by blocking ectopic activity from a
respectively.
neuroma/DRG. Topical local anesthetics for neuropathic
pain could depend on peripheral factors such
as ectopic discharges from sensitized cuta-
neous nerves bombarding the dorsal horn
• Low-dose intravenous sodium channel of the spinal cord. Damaged or regenerat-
blockers are antihyperalgesic and antial- ing sensitized fibers undergo changes in the
lodynic and may have little effect upon number and location of sodium channels,
high-intensity stimulus-induced acute noci- and ectopic impulses from injured peripheral
ceptor-mediated pain. nerves may be sensitive to lower concentra-
tions of local anesthetics than are required
A problem with systemic lidocaine is for blocking normal impulse conduction.84
its short duration of action and the need to A topical lidocaine patch (Lidoderm®: Endo
administer intravenously. This first issue Laboratories) holds promise for the treat-
is solved by anticonvulsants, whose mode ment of neuropathic pain conditions, as it
of action is sodium channel blockade (e.g., has shown benefit for several human neuro-
phenytoin, lamotrigine, carbamazepine, pathic pain states, including incisional neu-
oxcarbazepine, and zonisamide).81 TCAs ralgia, painful diabetic neuropathy, complex
circumvent the requirement for intravenous regional pain syndrome, and postamputa-
administration. tion stump pain.85

Local anesthetics at a glance

LOCAL ANESTHETICS • The amide link (lidocaine, bupivacaine) or
ester link (procaine, benzocaine) for the dif-
As previously stated, local anesthetics act ferent local anesthetics determines the drug
by blocking voltage-gated sodium channels disposition within the body.
(VGSCs), which are responsible for the tran- Metabolism of ester-linked local anes-
sient increase in the permeability of excit- thetics is primarily by nonspecific pseudo-
able membranes to sodium that is normally cholinesterase enzymatic hydrolysis in the
produced by depolarization of the mem- plasma. Amide local anesthetics are metab-
brane. This anesthetic effect elevates the olized primarily in the liver.
threshold and slows the rate of rise of the • Local anesthetics are weak bases, and the
action potential; at lower concentrations, it predominant form of the compound in solu-
slows conduction velocity. Aδ and C fibers tion at physiological pH is the ionized or
are more susceptible to local anesthetics cationic form.
 Chapter 4 Pharmacologics (Drug Classes) 143

• At clinical doses, vasodilation is present, Liposomes have been considered prom-

whereas at low concentrations, local anes-
thetics tend to cause vasoconstriction.
ising and versatile drug vesicles. Compared
with traditional drug delivery systems, lipo- 4
• Adding a vasoconstrictor to the local anes- somes exhibit better properties, including
thetic decreases local perfusion, delays the site targeting, sustained or controlled release,
rate of vascular absorption, and prolongs protection of drugs from degradation and
anesthetic action. Epinephrine (5 μg/mL clearance, superior therapeutic effects, and
or 1:200,000) is commonly used for such a lower toxic side effects. Given these merits,
response. several liposomal drug products have been
• There is presently no data to enlighten the successfully approved and used in clinics
concept of mixing local anesthetics, e.g., over the last couple of decades.
short onset and duration agent with a dif- Liposomes are self-assembled (phosphor)
ferent agent of long onset and duration. lipid-based drug vesicles that form a bilayer
• Harmful side effects are usually associated (unilamellar) and/or a concentric series of
with accidental intravenous administration multiple bilayers (multilamellar) enclosing a
of vascular absorption or large amounts of central aqueous compartment. The size of
anesthetic after aggressive regional admin- liposomes ranges from 30 nm to the microm-
istration. Always aspirate before injecting. eter scale, with the phospholipidbilayer being
Bupivacaine can cause cardiac dysrhyth- 4–5 nm thick (See Figure 4.8).
mias and ventricular fibrillation if injected As drug vehicles, liposomes exhibit out-
intravenously. standing properties, such as protecting the
• Clinical applications encapsulated substances from physiological
• Local infiltration – soaker catheters degradation,86 thereby, extending the half-
• Topical anesthesia life of the drug and controlling the release
• Intravenous administration NOT recom- of drug molecules87 with excellent biocom-
mended for cats patibility and safety. Furthermore, lipo-
• Epidural block somes can selectively deliver their payload
• Spinal (supra-arachnoid) block to the diseased site through passive and/or
• Peripheral nerve block active targeting, thus decreasing the systemic
• Intra-articular administration

BUPIVACAINE LIPOSOME
A longer-acting local anesthetic is now avail-
able for use in dogs. Bupivacaine liposome
injectable suspension is a sterile, nonpyro-
genic, white to off-white, preservative-free,
aqueous suspension of multivesicular lipid-
based particles containing bupivacaine.
Each milliliter of agent contains 13.3 mg
of bupivacaine. It is a local anesthetic in an FIGURE 4.8 This artificially constructed, spheri-
encapsulated liposomal formulation, devel- cal vesicle possesses a selectively permeable
oped with the goal of providing a longer wall that closely resembles the membrane of
duration of anesthesia compared with its a living cell. The membrane consists of a dual
non-liposomal counterpart, bupivacaine layer of phospholipids. Each phospholipid con-
hydrochloride. sists of a phosphate group head (blue) and a
A dose of 5.3 mg/kg (0.4 mL/kg) is fatty acid tail (orange). Liposomes can be used
administered by infiltration injection into the to carry drugs or genes to target cells. This is
particularly useful for highly toxic cancer drugs,
tissue layers at the time of incisional closure.
as it reduces unpleasant side effects. The multi-
A single dose administered during surgical colored spheres are depicting drug substances
closure may provide up to 72 hours of pain delivered through the liposome. (Adapted from
control for cranial cruciate ligament surgery J Pain Research. 8 June 2016, doi.org/10.2147/
in dogs. JPR.s89061.)
144 Chronic Pain in Small Animal Medicine

side effect, elevating the maximum tolerated

dose, and improving therapeutic benefits.88,89
Bupivacaine supplied as a liposome-
encapsulated injectable suspension (BLIS) is
approved for injecting into the incisional tis-
sue layers following cranial cruciate ligament
surgery in dogs. It is frequently used off-label
in both cats and dogs for tissue infiltration in
other surgeries, including amputations and FIGURE 4.9 Imipramine: one of the first tricyclic
mass removals, as well as tissue infiltration antidepressants.
for wound repairs. In such blocks, BLIS is
injected preceding closure of the wound, but
class, and only a few years after its intro-
not preemptively, as the liposome could be
duction in 1958, its analgesic properties
disrupted by the tissue or tissue debridement.
were identified (Table 4.7).91 For a number
Bupivacaine alone can be injected pre-
of years, TCAs were the mainstay for treat-
emptively and as BLIS at closure. BLIS is also
ment of neuropathic pain in humans (having
approved for peripheral nerve blocks for digit
been replaced by gabapentin and pregaba-
surgery in cats and is commonly used off-label
lin). And although treatment of neuropathic
for numerous other peripheral nerve blocks
pain with TCAs in humans is evidence-
(dental/oral, auriculopalpebral, great auricu-
based, it is not clear how these drugs actu-
lar, brachial plexus, Radial, Ulnar, Median and
ally relieve pain. Most research is based on
Musculocutaneouis nerve blocks [RUMM],
their ability to inhibit presynaptic reuptake
sciatic) in both cats and dogs. Herein, it can be
injected preemptively because the liposomes
are injected remote to the site of surgery and
TABLE 4.7 Tricyclic antidepressant
not in a location that would be disrupted by
exploration for human use over the
surgical incision or tissue debridement. decades92
Due to their relatively large size, the
liposomes release the bupivacaine locally Clinical Pharmacological
rather than diffusing throughout the tissue; development discoveries
accordingly, BLIS is unlikely to be effective 1958: Report of
for blocks that require migration of the local antidepressant effect
anesthetic to fairly distant tissues (testicu- 1960: First suggestion 1960–1980:
lar block, where the drug injected into the of analgesic effect Presynaptic reuptake
testicle must migrate to the spermatic cord) inhibition
or where the drug is ‘splashed’ or ‘lavaged’ (norepinephrine and
into a tissue rather than injected into the site, serotonin)
Postsynaptic receptor
where the liposomes can release the bupiva- blockage
caine locally (peritoneal lavage). (α-adrenergic,
Administration using a 25-gauge needle cholinergic,
or larger is advised, since smaller-bore nee- histaminergic)
dles can disrupt the liposomes, and vials
1970–1980: 1980: μ opioid receptor
should be ‘gently rolled’ rather than shaken Observations of interaction
for the same reason. Once drawn from the analgesic effect in
parent vial, drug within the syringe can be painful diabetic
kept at room temperature for up to 4 hours: neuropathy
be mindful that it contains no preservative.90 1980: First controlled 1988: NMDA
trial in painful diabetic antagonist–like effect
neuropathy
TRICYCLIC ANTIDEPRESSANTS 1984– : Numerous 1992: Calcium channel
controlled trials in blockade
For many years drugs with a character- neuropathic pain
istic tricyclic structure have been used to
1990– : Systematic 1998: Sodium channel
treat depression in humans (Figure 4.9).
reviews blockade
Imipramine was among the first drugs in its
 Chapter 4 Pharmacologics (Drug Classes) 145

of norepinephrine and serotonin, but these as those identified on sprouts from diseased
drugs also act as NMDA receptor antago-
nists and apparently block ion channels.
peripheral nerves.95 Antihistamines have
been shown to relieve pain, and TCAs may 4
play a role in analgesia through their anti-
histaminergic action. TCAs may actually
TCA MODE OF ACTION stabilize both diseased peripheral nerves and
hyperexcitable neurons of the CNS by block-
TCAs are characterized by their multiple ing sodium channels.96 Only a few studies
modes of action, with a particular ability to have shown calcium channel blockade with
inhibit reuptake of monoamines (serotonin tricyclics. Selective serotonin reuptake inhib-
and norepinephrine) from presynaptic termi- itors (SSRIs), lacking norepinephrine reup-
nals. Additionally, TCAs block several recep- take, having weaker ion channel blocking
tors (cholinergic, adrenergic, histaminergic) effects, and having no postsynaptic effects,
and ion channels, including sodium chan- are rendered less effective than the TCAs.
nels. The mechanism of TCA action might TCAs express many modes of action
best be identified as five drugs in one: sero- that could contribute to pain relief, and
tonin reuptake inhibitors, norepinephrine because of their multimodal mechanisms of
reuptake inhibitors, anticholinergic-antimus- action, their efficacy may be greater than
carinic drugs, α1-adrenergic antagonists, and other agents that demonstrate a more selec-
antihistamines. Norepinephrine is an inhibi- tive pharmacological effect. The number
tory transmitter that activates descending needed to treat (NNT) for TCAs is quite
inhibitory pathways and has been associated similar across different human neuropathic
with hyperalgesia in patients. pain conditions, with values of two to
Serotonin can activate the primary affer- three, meaning that every second or third
ent nerve fibers via 5-HT3 receptors. In patient with neuropathic pain treated with
addition, serotonin can cause mechanical a TCA will experience more than 50% pain
hyperalgesia, most likely by effects on the relief.97 Genetic polymorphism of different
5-HT1A receptor subtype. Opioids can be drug metabolizing enzymes likely explains
displaced from their binding sites with ini- the pharmacokinetic variability of these
tial administration of antidepressants. With drugs.
chronic administration, antidepressants TCAs were the first evidence-based neu-
can lead to modifications in opioid receptor ropathic pain treatments to be studied, and it
densities leading to increased endogenous is now understood that pain relief and relief
opioid levels. Additionally, antidepressant of depression are independent effects.98,99
medications can bind to the NMDA recep- Amitriptyline is best known as an inhibi-
tor complex, which reduces intracellular tor of catecholamine reuptake, although it
calcium accumulations acutely. Longer-term is also a strong local anesthetic as well,100
administration alters the receptor binding and is likely to relieve neuropathic pain by
of NMDA. Additionally, antidepressants suppressing ectopic discharge. The newer
can inhibit potassium, calcium, and sodium non-TCAs, such as SSRIs, antidepressants
channel activity. that alter both serotonergic and noradrener-
Opioid activity of TCAs may have the gic neurotransmission, and norepinephrine-
same effect as inhibition of norepinephrine selective antidepressants, have preferential
and serotonin reuptake – enhancing activity use in human medicine because of better
of neurons in the network comprising dif- tolerability; however, their efficacy for neu-
fuse noxious inhibitory controls, although ropathic pain relief is not yet as convincing
TCAs have low affinity for the μ opioid (Table 4.8).
receptor.93 Therefore, their opioid effect is TCAs (amitriptyline, imipramine):
likely minimal. Tricyclic-NMDA activity is
likely analgesic via its inhibition of neuronal • Block the reuptake of serotonin and norepi-
hyperexcitability.94 nephrine in the CNS. They also have anti-
α-Adrenergic receptor blockade in histamine effects.
peripheral neuropathy may be relieving pain • Are used for the treatment of chronic and
generated or maintained by noradrenergic neuropathic pain in humans at lower doses
stimulation of highly sensitive receptors such than required for depression.
146 Chronic Pain in Small Animal Medicine

TABLE 4.8 Antidepressants and mechanisms of action in producing analgesic effects91

Reuptake inhibition Receptor blockade
Opioid
α- H1- Muscarinic receptor Quinidine-
Serotonin Norepinephrine adrenergic histaminergic cholinergic interaction like effect
Classic TCAs

Imipramine + + + + + + +

Clomipramine + + + + + + +

Amitriptyline + + + + + + +

Desipramine − + + + + + +

Nortriptyline − + + + + + +

SSRIs

Paroxetine + − − − + ? −

Citalopram + − − − − ? −

Fluoxetine + − − − − + −

S-NRIs

Venlafaxine + + − − − ? −

Tetracyclines

Mianserin − + + + − + −

DULOXETINE recommend duloxetine as a first-line treat-

ment for major depressive disorder, given
Duloxetine is an antidepressant. In addition, the (then) high cost of duloxetine compared
duloxetine is used to help relieve nerve pain to inexpensive off-patent antidepressants
(peripheral neuropathy) in people with dia- and lack of increased efficacy.102 Duloxetine
betes or ongoing pain due to medical condi- appears less tolerable than some other anti-
tions such as arthritis, chronic back pain, or depressants.103 Generic duloxetine became
fibromyalgia (a condition that causes wide- available in 2013.
spread pain).
Duloxetine, sold under the brand
name Cymbalta (among others), is a medi- Fibromyalgia and Chronic Pain
cation used to treat major depressive A review of duloxetine found that it reduced
disorder, generalized anxiety disorder, fibro- pain and fatigue in human patients and
myalgia, neuropathic pain, and central sen- improved physical and mental performance
sitization. It is an SNRI administered orally. compared to placebo.104 The FDA approved
Duloxetine was approved for the treat- the drug for the treatment of fibromyalgia in
ment of major depression in 2004. While June 2008.
duloxetine has demonstrated improvement On November 4, 2010, the FDA approved
in depression-related symptoms compared duloxetine to treat chronic musculoskeletal
to placebo, comparisons of duloxetine to pain, including discomfort from OA and
other antidepressant medications have been chronic lower back pain.105–107
less successful. A 2012 Cochrane Review101
did not find greater efficacy of duloxetine Antidepressant summary
compared to SSRIs and newer antidepres-
sants. Additionally, the review found evi- • May be 5-HT selective or norepinephrine/5-
dence that duloxetine has increased side HT selective.
effects and reduced tolerability compared • Most reliable efficacy is noted with mixed
to other antidepressants. It thus did not inhibitors, but possibly norepinephrine alone.
 Chapter 4 Pharmacologics (Drug Classes) 147

• Hypothesized to augment tone in bulbospi- from recent data on antidepressants and

nal monoamine pathways and in ascending
pathways to the forebrain.
utilization of tramadol. There are at least
seven major subtypes of serotonin receptors, 4
• Some antidepressants also have NMDA and several of which have been identified in the
sodium channel blocking properties, which spinal cord.108 The serotonin transporter
may account for some side effects. (SERT) is best recognized as the site of action
of the SSRIs, which increases availability of
serotonin at the synaptic junction for recep-
SEROTONIN tor binding (Figure 4.10).
Although metabolism occurs rapidly,
The idea that combined blockade of sero- storage protects serotonin against metabo-
tonin, otherwise known as 5-HT, and nor- lism. It is synthesized and stored in presyn-
epinephrine uptake might be useful in the aptic neurons (serotonergic neurons, pineal
treatment of pain has gained recognition gland, and catecholaminergic neurons).

FIGURE 4.10 Serotonergic synapse and movement of 5-HT from synthesis, storage, release, and uptake
via SERT and metabolism.
148 Chronic Pain in Small Animal Medicine

Outside the CNS, serotonin synthesis is conduction.112 However, carbamazepine has

limited to enterochromaffin cells of the not been widely embraced in human medi-
gastrointestinal tract and platelets, where cine because of side effects, interaction with
90%–95% of the body’s serotonin is stored. other drugs metabolized in the liver, and
Platelets are unable to synthesize sero- erratic pain relief.
tonin, yet they avidly take up the amine Anticonvulsants are a category of medi-
from plasma, using the same transporter cations grouped together based only on
used by neurons.109 Although serotonin is their ability to suppress epileptic seizures.
a relatively weak platelet activator, in the Anticonvulsants, together with antiar-
presence of proaggregatory factors, such rhythmic drugs, can be looked at as sodium
as adenosine phosphate (ADP), epineph- channel or other channel neuronal activity
rine, and collagen, serotonin significantly regulators. Evidence firmly supports that
potentiates aggregation.110 Accordingly, anticonvulsants and local anesthetic drugs
any intervention that affects platelet sero- relieve neuropathic pain.113,114 Based on
tonin content or its release from dense NNT calculations, gabapentin is comparable
granules may theoretically have an impact with TCAs for neuropathic pain and is cur-
on hemostasis and thrombosis. In studies rently used more frequently than any anti-
performed in humans, all SSRIs have con- convulsant for human chronic pain.
sistently shown a drastic decrease in plate- Gabapentin was developed as an analog
let serotonin content after several weeks of the neurotransmitter GABA, but it has
of treatment, reaching levels around or since been shown not to interact with either
below 10% of the pretreatment serotonin GABA A or GABA B receptors (Figure 4.11).
levels.110 A similar effect has been shown Although not a sodium channel blocker,
with clomipramine.111 This potential for gabapentin depresses ectopic discharge by
gastrointestinal bleeding associated with suppression of calcium ion conductance. Its
the administration of antidepressants is mode of action is associated with binding to
particularly noteworthy in recognition of a highly specific [3H]gabapentin-binding site
the increased veterinary use of tramadol in the brain – the α 2-δ site – on voltage-gated
with NSAIDs. Sixty percent of the activity calcium channels (Figure 4.12).115
of tramadol is associated with the mono- Its mechanism of action is therefore
amine pathway. De Abajo et al.110 have doc- likely associated with modulation of certain
umented the synergistic effect of NSAIDs types of calcium ion currents. Gabapentin
together with SSRIs for causing upper gas- is unlike other antiepileptic drugs in that it
trointestinal bleeding in the human popula- does not affect voltage-dependent sodium
tion. See Table 4.8. channels.116

ANTICONVULSANTS
Even before peripheral and central sensiti-
zation had been defined in detail, the first
controlled clinical trials in humans with the
anticonvulsant carbamazepine established
its efficacy in relieving the pain of trigemi-
nal neuralgia and diabetic neuropathy. Only
carbamazepine, phenytoin, gabapentin, and
lamotrigine have been studied in random-
ized human clinical trials for relief of pain in
neuropathic pain disorders. Currently, only
carbamazepine and gabapentin have proved
effective in humans. FIGURE 4.11 Gabapentin [1-(aminomethyl) cyclo-
Carbamazepine blocks ionic conductance hexane acetic acid] was developed as a GABA
by suppressing spontaneous Aδ and C-fiber analog, but does not interact with the GABA
activity without affecting normal nerve receptor. It has anticonvulsant activity.
 Chapter 4 Pharmacologics (Drug Classes) 149

While pregabalin and gabapentin have

extremely similar mechanisms of action,
some studies suggest that the former (pre- 4
gabalin) exhibits an approximately six-fold
greater affinity for α 2δ subunit–contain-
ing VDCCs – than the latter (gabapen-
tin). Because pregabalin is understood to be
more bioavailable and potent in its VDCC
modulation than gabapentin, the recom-
mended human dosages of pregabalin to
treat medical conditions are lower than those
of gabapentin. Pregabalin is estimated to
FIGURE 4.12 Gabapentin is the most frequently
take effect within 40–120 minutes of admin-
used anticonvulsant for chronic pain in humans. istration, while gabapentin is estimated to
Both gabapentin and pregabalin bind at the α2-δ take effect within 30–60 minutes following
subunit of voltage-dependent calcium channels. administration.
Assuming pregabalin is more potent
than gabapentin (at the respective recom-
mended dosages to treat similar medical
PREGABALIN/GABAPENTIN conditions), perhaps it makes logical sense
that pregabalin is classified as a Schedule
Lyrica and gabapentin are usually consid- V substance in the United States, whereas
ered as first-line options to treat neuropathic gabapentin remains a standard prescription
pain. They both bind to voltage-gated cal- medication. Pregabalin has been reported as
cium channels in the CNS and, when bound, 2- to 4-fold and 3- to 10-fold more potent
result in decreased neurotransmitter release than gabapentin as an analgesic and anti-
in the CNS that leads to less neuropathic convulsant, respectively. In 2017, the United
pain. Pregabalin’s maximum absorption rate Kingdom opted to modify the legal classifi-
is nearly three times that of gabapentin in cation of pregabalin and gabapentin from
human patients. standard prescriptions to Class C controlled
Lyrica (pregabalin) and Neurontin substances. Typically, Lyrica is more expen-
(gabapentin) are both classified as “gaba- sive than gabapentin.
pentinoids” (i.e., α 2δ ligands). As gabapen- Gabapentin is commonly prescribed “off-
tinoids, Lyrica and Neurontin are chemical label” by veterinarians to treat seizures,
analogues of the inhibitory neurotransmit- pain, and anxiety in dogs and cats. Its mode
ter gamma-aminobutyric acid (GABA) that of action is thought to be inhibition of excit-
interact with α 2δ subunit-containing voltage- atory neurotransmitter release. It is often
dependent calcium channel (VDCC). used in combination with other analgesic
Neurontin was first approved for human medications such as NSAIDs or opioids. The
use by the FDA in 1993 for the treatment of common dosage is dog: 2–20 mg/kg BID and
epilepsy; subsequently in 2002 for the treat- cat: 2–10 mg/kg SID–BID.
ment of PHN; and again in 2011 (in a pro-
drug format) for the treatment of restless
leg syndrome (RLS). Lyrica is intended to NMDA ANTAGONISTS
be the successor to Neurontin and was first
approved by the FDA in 2004 for the treat- A single brief noxious stimulus results first
ment of epilepsy, diabetic neuropathic pain, in a pricking pain sensation by the afferent
and PHN. high-frequency, brief-latency, myelinated
The ‘official’ FDA-authorized medical Aδ fibers. A moment later, afferent long-
uses for pregabalin and gabapentin include latency unmyelinated C fibers convey a burn-
PHN and partial-onset seizures (as an ing, throbbing, aching pain. Both of these
adjunct); however, only pregabalin is FDA- impulses are received in sequence by the
authorized to treat diabetic neuropathic same second-order neuron. Repetition of the
pain, fibromyalgia, and neuropathic pain brief noxious stimulus at less than 3-second
associated with spinal cord injury. intervals will result in magnification of the
150 Chronic Pain in Small Animal Medicine

secondary burning component conveyed by Functional disruption of the α2-δ subunit

the C fibers: termed temporal summation or by gabapentin may result in an inhibition of
‘windup’. NMDA receptor antagonists block excitatory neurotransmitter release that leads
prolonged depolarization and temporal sum- to a decrease in mechanosensitivity during
mation of electrically stimulated C afferent mechanical manipulation of a joint,124 collab-
fibers without abolishing Aδ activation. orating in its peripheral effect.125 Gabapentin
The channel associated with the NMDA has been shown to modulate the effect of sP
receptor is blocked by normal resting physi- by inhibiting its facilitation mechanism in the
ological levels of magnesium, and no change rat,126 while Boileau et al. showed that a com-
in excitability of the neurons possessing pound chemically related to pregabalin and
NMDA receptors can occur until this is gabapentin (PD-0200347) reduced the pro-
removed. The magnesium block is removed duction of several catabolic factors, including
only by a shift in the membrane voltage matrix metalloproteinase (MMPs) and induc-
toward depolarization. Binding of glutamate ible nitric oxide (iNOS) in a canine anterior
to the receptor alone is insufficient to activate cruciate ligament sectioning model.127
the channel. Further, glycine is a required Apparently, anticonvulsants that act synap-
co-agonist with glutamate for activation of tically, such as barbiturates, are nonanalgesic,
the receptor: the release and binding of gly- while membrane-stabilizing anticonvulsants
cine and glutamate are needed together with are analgesic. Corticosteroids also have mem-
a non-NMDA-induced depolarization to brane-stabilizing properties, which may be a
remove the magnesium block. major mechanism of pain control when depot-
Gabapentin is an anticonvulsant, but also form corticosteroids are injected. Topical forms
a ‘classic’ NMDA antagonist in its mode of of the TCAs doxepin, gabapentin, lidocaine,128
action. Gabapentin was originally synthe- and bupivacaine, as well as ketamine, are now
sized to treat human spasticity; however, available for use in humans.
it has been found to be effective in chronic
pain and anxiety disorders. Gabapentin
has no effect on the nocifensive behaviors GABAPENTIN OVERVIEW
observed during the acute phase of the for-
malin test, but does block the development • Originally introduced as an antiepileptic
of the late phase, demonstrating a selective drug.
antihyperalgesic action.117,118 It is an effective • Apparently has no analgesic effect at GABA
antihyperalgesic agent in a knee joint model receptors.
of acute arthritis induced by administration • Well-suited for neuropathic pain.
of kaolin and carrageenan.119,120 Gabapentin • Gabapentin is highly bioavailable in dogs.
has demonstrated analgesic efficacy for • Gabapentin is metabolized by the liver and
human patients with peripheral diabetic neu- excreted almost exclusively by the kidneys.
ropathy (PDN) and PHN: NNT of 3.8 and Half-life is approximately 3–4 hours.
3.2, respectively. • As an NMDA antagonist, gabapentin does
Importantly, NMDA antagonists are not not alter nociceptive thresholds; therefore, it
only effective in preventing the development does not produce analgesia, but assists other
of pro-nociceptive changes, but may also drugs’ analgesic response (Figure 4.13).
reduce hyperalgesia, even when the changes • Appears effective only against hypersen-
have already developed.121 Some preclini- sitivity induced by tissue damage or neu-
cal studies report a synergistic interaction ropathy and may well be referred to as an
between opioids and NMDA antagonists. antihypersensitive agent.
This synergism is found in acute pain mod- • Gabapentin does not interact with any
els, in which NMDA antagonists are nor- known antiepileptic drug receptor sites.
mally rather inactive.122 • It does not exhibit affinity for common CNS
Gabapentin has also been observed to receptors, including adrenergic (α1, α 2 or β),
possess preemptive analgesic activity in a cholinergic (muscarinic or nicotinic), dopa-
rat surgical pain model.123 A single preemp- minergic (D1 or D2), histamine, serotonin (S1
tive administration dose dependently blocked or S2), or opiate (u, δ, or κ) receptors.129
the development of both static allodynia • No data on efficacy or safety in the dog or
and thermal hyperalgesia for over 48 hours. cat.
 Chapter 4 Pharmacologics (Drug Classes) 151

FIGURE 4.13 It is important to note that NMDA activation facilitates the nociceptive process to a state
of windup. Therefore, NMDA antagonists, such as gabapentin and ketamine, act as analgesic adjuncts
that address this facilitation, while etiology of the ‘baseline’ pain must be addressed with other agents.
(AMPA: alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, CGRP: calcitonin gene–related
peptide, GLU: glutamate, NK-1: neurokinin 1, sP: substance P.)

KETAMINE function.132 It preserves sympathetic reflexes

that help support blood pressure. In human
Ketamine was synthesized in 1963, deriving clinical studies, low-dose ketamine given
its name from being a ‘keto’ derivative of an before surgical incision in combination
amine. It has a chiral center in the cyclohexa- with opioids produced a 60% reduction
none ring, thereby existing as optical isomers in morphine use in postoperative patient-
(Figure 4.14). The S(+) isomer has a four- controlled analgesia.133 In a study of dogs
fold greater affinity for the NMDA receptor undergoing ovariohysterectomy, Slingsby
compared to the R(–) isomer, has twice the and Waterman-Pearson demonstrated
analgesic potency, and presents fewer psy- that ketamine was effective, but short
chomimetic effects.130 (S-ketamine is now acting.134
available commercially as Ketanest S ®.) At high doses, ketamine causes dissocia-
Ketamine binds to many sites in the CNS tive anesthesia, whereby subjects are awake
and peripheral nervous system (PNS), but dissociated from the environment.
including nicotinic, muscarinic, opioid, Dorsal horn windup is inhibited by low-
AMPA, kainite, and GABA A receptors.131 dose ketamine, whereas it is enhanced by
Ketamine also inhibits serotonin and dopa- low-dose morphine: differentiating the anal-
mine reuptake and downregulates volt- gesic role of NMDA blockade versus opiate
age-gated sodium and potassium channel agonism.135 Additionally, NMDA blockade
does not alter the tactile or thermal sensory
threshold.
An important field of ketamine appli-
cation is for neuropathic pain in humans.
Studies report a relief of both spontaneous
and evoked pain by prolonged treatment
with ketamine for neuropathic pain syn-
dromes of either peripheral or central ori-
gin.136 Some report effectiveness of ketamine
in neuropathic pain after chronic subcuta-
neous infusion137 or oral administration.138
FIGURE 4.14 Ketamine has a chiral center and Dysphoric and psychotomimetic effects are
thereby exists as an optical isomer. the major limiting problems with the clinical
152 Chronic Pain in Small Animal Medicine

use of ketamine (and dextromethorphan) in

the treatment of pain.
NMDA ANTAGONISTS
The analgesic action of low, subanes- AT A GLANCE
thetic doses of ketamine acts predominantly
from blockade of the NMDA receptor. In its Ketamine, tiletamine, amantadine, metha-
resting state, the NMDA receptor is inactive done, dextromethorphan, and gabapentin:
and does not participate in synaptic modu- • Ketamine acts both centrally and periph-
lation because its ion channel is plugged by erally at multiple receptor sites, includ-
magnesium. The magnesium plug is dis- ing NMDA, opioid, AMPA, kainate, and
lodged by postsynaptic depolarization or GABA A receptors.
when serine residues on the channel protein • Oral administration of ketamine produces
are phosphorylated following activation few adverse effects and may be more effec-
of calcium-dependent intracellular protein tive than subcutaneous administration.144
kinases. The NMDA receptor’s ion channel • Microdoses of ketamine have few, if any,
must be open, or ‘active’, before ketamine side effects, and its best use is with an anal-
can bind to or dissociate from its binding site gesic such as an opioid.
within the channel. Binding of ketamine to • Amantadine was originally developed as
phencyclidine sites within the ion channel an antiviral drug for use in humans and is
decreases the channel’s opening time and fre- available as an oral preparation. It is well
quency, thus reducing calcium ion influx and absorbed in the gastrointestinal tract and
dampening secondary intracellular signaling excreted relatively unchanged in urine.
cascades. • The pharmacology of amantadine in dogs
The NMDA receptor-channel complex and cats has not been well established.
is activated only by intense synaptic trans- • In humans, amantadine has been used for
mission across the second-order neuron neuropathic pain.
and not by routine physiological transmis- • Amantadine is used in veterinary patients
sion. Accordingly, meta-analyses of human for allodynia and opioid tolerance, allowing
clinical trials indicate that ketamine sup- lower opioid doses and complementing the
plementation of opioids for acute postop- opioid analgesia.
erative pain does not significantly improve • Amantadine is available in 100-mg capsules
analgesia; however, ketamine does benefit and 10-mg/mL elixir.
‘pathological’ pain as a ‘central sensitiza- • The feline toxic dose of amantadine is
tion modulator’ (antiallodynic, antihyper- 30 mg/kg.139
algesic, and opioid tolerance-reversing) in • Behavioral side effects from amantadine in
pain states of neuropathic or cancer pain dogs and cats begin at 15 mg/kg orally.140
(Table 4.9). • Methadone and dextromethorphan (the
active ingredient in many over-the-counter
cough syrups) are opioid derivatives. Both are
AMANTADINE weak, noncompetitive NMDA antagonists.
• Methadone also functions as a norepineph-
Amantadine is an orally available NMDA rine reuptake inhibitor.
antagonist, first recognized as an anti- • Methadone is commonly used for cancer
viral agent and later found to be useful pain in human patients because of its high
in the treatment of Parkinson’s disease. oral bioavailability, rapid onset, and time to
Administered intravenously, amantadine peak analgesic effect as well as the relatively
abolished or reduced pathological pain in long duration of activity.
humans with chronic neuropathic pain139 • In contrast to its pharmacokinetics in humans,
and surgical neuropathic pain in cancer methadone has a short elimination half-life,
patients.140 Oral amantadine reduced exper- rapid clearance, and low bioavailability in
imental sensitization and pain in human dogs,12 accounting for its infrequent use.
patients with chronic back pain.141 Lascelles • Erratic absorption, short elimination half-
et al.142,143 reported that the administration life, rapid clearance, and adverse effects
of amantadine might be a useful adjunct limit the usefulness of dextromethorphan
therapy for clinical management of osteo- for therapeutic purposes in dogs.145
arthritic and cancer pain in dogs refractory • Parenteral formulations of dextrometho-
to an NSAID. rphan are currently unavailable.
 Chapter 4 Pharmacologics (Drug Classes) 153

TABLE 4.9 A summary of evidence for ketamine analgesia in humans

Evidence obtained from a systematic review (or meta-analysis) of all the 4
Level 1 relevant randomized clinical trials
• Low-dose perioperative ketamine is opioid-sparing, reduces nausea and vomiting,
and has minimal side effects
• Ketamine added to opioid patient-controlled administration provides no additional
analgesic benefit
• Ketamine is most effective as a continuous low-dose infusion for acute pain
management
• Ketamine has ‘preventive’ but not ‘preemptive’ analgesic effects
• Ketamine is a safe and effective sedative/analgesic for painful procedures,
particularly in children

Level II Evidence obtained from at least one properly designed randomized clinical trial

• Ketamine is most effective as an ‘antihyperalgesic’, ‘antiallodynic’, or ‘tolerance-

protective’ treatment
• Ketamine is effective as a ‘rescue analgesic’ for acute pain unresponsive to
opioids
• Ketamine reduces acute wound hyperalgesia and allodynia
• Ketamine may reduce the incidence of chronic postsurgical pain following
laparotomy, thoracotomy, and mastectomy
• Ketamine reduces lower-limb ischemic rest pain, peripheral neuropathic pain, and
spinal cord injury pain
• Ketamine improves fibromyalgia symptoms, including tender point count and
aerobic endurance
• Intranasal ketamine reduces breakthrough pain of cancer-related and noncancer
origin
• Ketamine reduces migraine severity in both acute and prophylactic therapy
• Ketamine does not improve analgesia when used alone or in combination with
local anesthetic for peripheral nerve blocks, intra-articular injection, or wound
infiltration

Level III Evidence obtained from nonrandomized controlled trials

• Ketamine may be effective for refractory cancer pain in terminal-stage disease

• Ketamine may reduce severe chronic phantom limb pain

Level IV Evidence obtained from case series

• Ketamine improves analgesia in opioid-tolerant patients

• Intranasal ketamine may relieve migraine aura
• Ketamine may be effective in visceral pain based on human experimental models
and limited case reports
• At least 50% of patients fail to respond to oral ketamine and experience side
effects in the treatment of chronic neuropathic pain
• Long-term ketamine use may be associated with impairment of memory, attention,
and judgment

Source: Adapted from National Health and Medical Research Council. How to use the evidence: assessment and application of
scientific evidence. Ausinfo, Canberra, Australia, 2000, p. 8.
154 Chronic Pain in Small Animal Medicine

SUMMARY
Opioid analgesics have provided the most
consistent and effective analgesia for many
years and are still the best drugs available for
both acute and severe pain control in small
animals. It is frequently said that one cannot
implement ‘serious’ pain management with-
out the availability of opioids. Opioids are
the cornerstone of perioperative pain man-
agement, where they are commonly supple-
mented with other classes of drugs such as
α 2-agonists, NSAIDs, and local anesthet-
ics. The actual agents administered within
these classes of drugs are patient-dependent FIGURE 4.15 A multimodal drug scheme would be
and include selection criteria of the patient’s a logical approach to managing progressive neu-
ropathic pain. Logic resides in each drug’s inde-
physiological status, pain syndrome treated,
pendent efficacy and each drug’s different mode
concurrent drug administration, delivery form, of action/site of action.
duration of effect, potential for side effects,
drug familiarity of the prescriber, and cost.
Whereas opioids are the cornerstone for
approach to managing the progressive pain
‘severe’ and perioperative pain, NSAIDs are
state, wherein pain management utilizes a
the cornerstone for ‘lesser’ pain states treated
multimodal scheme, where drug classes are
longer-term. This is because of the NSAID
added rather than substituted. The doses are
characteristics as anti-inflammatories, anal-
empirical, and one could debate the order
gesics, and antipyretics. Further, adminis-
of implementation from bottom to top. The
tration is easier and side effects of NSAIDs
merit of this approach is the addition of
are fewer than with extended-use opioids.
agents from different drug classes, attempt-
Accordingly, the WHO suggests the manage-
ing to block as many of the ‘pain pathways’
ment of pain by the analgesic ladder.95
(transduction, transmission, modulation,
As veterinary medicine becomes more
and perception) as possible.
sophisticated in delivering pain therapy, drug
There exist a plethora of potential sites
profiles from human medicine are being con-
of analgesic action that may be exploited
sidered (and often implemented) for veteri-
with the development of agents directed
nary application. Consequently, a number of
toward both peripheral and spinal targets.
drugs administered in human medicine are
See Tables 4.10 and 4.11.
being used in veterinary medicine based on
an anthropomorphic approach and empirical
or anecdotal support. However, considering
that veterinary clinical trials with many of RADIOTHERAPEUTICS
these drugs (such as tramadol, amantadine,
and gabapentin) are currently nonexistent, Radiosynoviorthesis
the use of such drugs may have its place in
veterinary medicine, provided that (1) the
(Radiosynoviorthesis)
drug’s mode of action is understood, (2) the John M. Donecker, DVM, MS; Nigel R.
PK have been studied in the target species, Stevenson, BSc, PhD; Steven M. Fox MS,
and (3) physiology as well as pathophysiol- DVM, MBA, PhD; and Rob Menardi, DVM
ogy between man and the veterinary target
species are similar. Synovial inflammation is strongly impli-
Neuropathic pain can be thought of as cated in the pathogenesis of OA and other
the ‘maladaptive pain state’, potentially arthropathies. Synovitis is a common feature
resultant from any significant noxious insult. of symptomatic but preradiographic OA.
And it is much easier to identify in man than This indicates that chronic, early-stage joint
in nonverbal animals. Although not evi- inflammation occurs well before significant
dence-based, Figure 4.15 suggests a logical radiographic changes and drives progression
 Chapter 4 Pharmacologics (Drug Classes) 155

TABLE 4.10 Various drug classes, mechanisms of action, and effective applications
Drug class Mechanism Acute Tissue injury Nerve injury 4
Opioid (morphine) Opioid receptors on high-threshold X X X
C fibers
NMDA antagonist Blocks glutamate-spinal facilitation O X X
(ketamine)
NSAID Inhibits PG synthesis at injury site O X O
and spinal cord
IV lidocaine Blocks sodium channels O O X
Anticonvulsant Reduces spontaneously active O O X
(gabapentin) neurons
TCA (amitriptyline) Increases catecholamine levels O O X

TABLE 4.11 Summary of peripheral pain mechanisms and potential targets for new analgesics
Peripheral mechanism Peripheral target Type of drug
Nociceptor activation Sodium channels TTX-s channel blocker
Ectopic activity (neuroma, DRG) TTX-r channel blocker
Nociceptor sensitization Calcium channels N-channel blocker
L-channel blocker
Acid-sensitive ion channel Channel blocker
P 2 X 3 receptor Receptor antagonist
VR1 receptor Receptor agonist or antagonist
Opioid receptors μ, δ, and κ receptor agonists
Cannabinoid receptors CBI and CB2 agonists
Nicotinic receptors Receptor agonist
Adrenergic receptors α2-agonist
α1-antagonist
Prostanoid receptors EP antagonist
Prostanoid production COX I/II inhibitors
Serotonin receptors 5-HT1D agonist
5-HT2 antagonist
Kinin receptors B1 antagonist
B2 antagonists
Glutamate receptors NMDA antagonists
Nerve Growth Factor Trk A receptor antagonist
Cytokines IL-1β receptor antagonist
Interleukin-converting enzyme inhibitor
Protein kinase TNF-α receptor antagonist
Kinase isotype inhibitor

Abbreviations: TTX-r: tetrodotoxin-resistant ion channel, TTX-s: tetrodotoxin-sensitive ion channel, VR: vanilloid receptor.
156 Chronic Pain in Small Animal Medicine

toward cartilage loss, osteophyte forma- • Conversion electrons: low-energy electrons

tion, bone remodeling, and joint space nar- released from an atomic shell as a result of
rowing.146–148 The pathology of early-onset radioactive decay; resulting when gamma
synovitis and its role in OA have been well radiation emitted by the nucleus is trans-
characterized. Whereas normal synovium ferred to an electron; conversion electrons
is two or three cell layers thick and devoid are monoenergetic, in contrast to beta
of inflammatory cells, synovitis results in a particles.
number of profound changes in synovial tis- • Homogeneous 117mTin colloid (HTC): a
sue and the joint micro-environment. These novel preparation of the radionuclide 117mTin
include marked hyperplasia and permeabil- suspended in a colloid; HTC is well suited
ity of the synovial lining, significant overex- for intra-articular administration to treat
pression of proinflammatory mediators and synovial inflammation caused by traumatic
cytokines, infiltration of inflammatory cells, injury, OA, and other arthritides.
production of degradative enzymes, synovial • Radiocolloid: a radionuclide-labeled colloid
neovascularization, and increased serum suitable for intra-articular injection.
C-reactive protein – a biomarker of inflam- • Radionuclide: an unstable isotope of an
mation.149–151 The inflammatory response atom that emits radiation released from the
sensitizes peripheral neurons in synovial tis- atomic nucleus. Some radionuclides exist
sue, resulting in a pain response.152 naturally, but those with research and ther-
OA should not be thought of as a single apeutic applications are usually produced
entity, but as a sequence of events beginning artificially. A radioisotope.
with joint injury followed by synovitis and • Radiosynovectomy (RSV): refers to removal
progressing to degenerative joint disease of the synovium and its replacement with
(DJD) as the clinical endpoint.147 The dem- fibrotic tissue, for example, when joints
onstration that significant synovitis precedes are injected with beta-emitting radionu-
structural changes in the progression of clides with a wide tissue-penetration range.
OA indicates that early intervention target- Historically, RSV has been used inter-
ing preradiographic joint inflammation can changeably, though less accurately, as a syn-
delay or prevent chronic arthritic changes.148 onym for RSO.
Surgical and nonsurgical synovectomy • RSO: injection into the synovial space of
(synoviorthesis) have been used for reliev- a radioisotope to treat joint inflammation
ing synovitis in human, canine, and equine and mitigate chondromalacia when sys-
patients. Herein, the focus is on radiosynovi- temic or other traditional therapies have
orthesis (RSO) using a homogeneous colloid failed to produce a satisfactory response.
radiolabeled with 117mTin, a novel radionu- The goal of RSO is a reduction of syno-
clide that offers significant advantages over vitis characterized by pain and synovial
conventional radionuclides. hypertrophy.
• Synovectomy: destruction or surgical
removal of the membrane (synovium)
Definitions that lines an articular joint. Open surgi-
• Beta particle: a high-energy electron emit- cal, chemical, radiation, and arthroscopic
ted from the nucleus of a radioactive atom; synovectomies are all options for removing
beta particles typically have a wide tissue potentially damaging synovium from artic-
penetration range of 50–5,000 μm that ular joints.
diminishes over distance, making uniform • Synoviorthesis: a medical therapy using
dosing difficult and possibly necessitating intra-articular injection of a compound that
shielding during transport and handling. diminishes the degree of synovial hypertro-
• Colloid: a mixture of insoluble micro-par- phy, thereby mitigating pain and the devel-
ticles (particles between 0.1 and 100.0 μm opment of inflammation and arthritis. Can
in size) that remain distributed in solution be performed by chemical synoviorthesis or
without precipitating or settling to the bot- RSO, with the latter being preferred when a
tom; nontoxic colloids are used for binding suitable radionuclide is available.
radionuclides to prevent them from escap- • 117mTin (117m Sn): an artificially produced
ing the intra-articular space into systemic radionuclide of tin with medical applica-
distribution. tions for localized treatment and imaging.
 Chapter 4 Pharmacologics (Drug Classes) 157

117mTin has a half-life of 14 days. Two prin- Radiosynoviorthesis in

cipal forms of the energy that it emits are
(1) conversion electrons that have a short Clinical Practice 4
penetration range in tissue (~300 μm) and The term RSO was introduced in Europe in
(2) imageable gamma radiation, which the 1960s by Florian Delbarre to describe
enables monitoring of local distribution in therapeutically active irradiation of the syno-
tissue. 117mTin is metastable, indicated by the vial lining.153 Rheumatologists administered
‘m’ suffix, meaning that it is a radioisotope a colloid embedded with a radionuclide (i.e.,
with an energetic nucleus and a relatively a radiocolloid) of yttrium-90 (90Y) into the
long half-life and therefore distinct from articular space. Using this process, the col-
highly unstable radionuclides with shorter loidal particles are phagocytized by macro-
half-lives. phages in the synovial lining, after which they
emit therapeutically active irradiation of the
synovial tissue until the radionuclide decays
Radiosynoviorthesis for to its stable state. The number of inflamma-
tory cells causing synovitis is reduced, and
Intra-Articular Therapy inflamed tissue is replaced with a fibrotic
RSO has been successfully used in human synovial membrane, with a corresponding
medicine for more than 60 years in many alleviation of pain and improvement in func-
countries, particularly in Europe, where it tion.154,155 An early study of RSV using beta-
was first described and where its use conforms emitting samarium-153 (153Sm) in horses had
to guidelines published by the European mixed results, producing effective synovec-
Association of Nuclear Medicine.153–156 RSO tomy but with transient lameness and swell-
has been an accepted outpatient therapy for ing, as well as exposure of some nontargeted,
treatment of early-stage chronic synovitis in periarticular tissue.160
rheumatoid arthritis, psoriatic arthritis, and A key aspect of RSO is the choice of radio-
OA patients for decades.155,157 It has impor- nuclide. Three radionuclides are widely used
tant advantages versus surgical resection, in clinical practice to treat synovitis: 90Y, rhe-
the oldest ablative method. For example, as nium-186 (186Rh), and erbium-169 (169Er), all
a minimally invasive procedure, RSO lowers of which are artificially produced in a nuclear
bleeding risk in cases of hemophilic synovitis, reactor.154–156 In the case of RSO treatment, the
where it is routinely used.158,159 As a localized radionuclide emits radiation that penetrates
treatment, RSO avoids problems associated the innermost layer of the synovial membrane,
with systemic therapies such as toxicity where it produces energy of sufficient duration
resulting from chronic use of NSAIDs or and intensity to achieve apoptosis and abla-
immunosuppressive drugs. RSO also avoids tion of the inflamed cells. For this to occur,
tissue degradation that can occur from the radionuclide must have an adequate half-
overuse of intra-articular corticosteroids. life (t½), a selective tissue penetration range
In human medicine, it has a favorable cost- approximating the synovial thickness, and
benefit ratio, particularly when compared sufficient energy for therapeutic effect.
to surgery; a low rate of side effects; and As 90Y, 186Rh, and 169Er decay, they emit
application to virtually all articular joints, radiation in the form of beta particles with a
especially small, peripheral joints such as the relatively wide tissue penetration range.153–156
phalangeal joints.155 Current standards in While these radionuclides are therapeutically
human clinical practice generally take a con- useful and have been evaluated in large clini-
servative approach by recommending initial cal trials,154 their physical properties are not
treatment with front-line therapies, includ- necessarily ideal for RSO. For example, 90Y
ing systemic NSAIDs, glucocorticoids, and emits beta radiation that has a relatively wide
local joint therapies such as corticosteroid range of soft tissue penetration, which risks
and hyaluronic acid (HA) injections prior irradiation of adjacent nonsynovial tissue.
to RSO.154 However, in patients that either 186Re and 90Y have short half-lives (2.7 and
respond poorly or have adverse side effects 3.7 days, respectively), which create storage
following these traditional therapies, RSO is and logistical limitations and may not con-
a useful option that is now being considered sistently deliver sufficient irradiation at the
in veterinary medicine. synovial target site.159
158 Chronic Pain in Small Animal Medicine

TABLE 4.12 Comparison of radionuclides commonly used for radiosynoviorthesis

Maximum
Half- Maximum tissue Diagnostic
life energy penetration Therapeutic emission
Radionuclide (days) (keV) (mm) emission (keV) TGT joints (human)
Yttrium-90 2.7 2,280 11.0 Beta None Knee
Rhenium-186 3.7 1,070 4.4 Beta Gamma Shoulder, elbow, wrist,
(201) hip, ankle
Erbium-169 9.4 350 1.1 Beta None Metacarpophalangeal,
proximal
interphalangeal,
metatarsophalangeal
Tin-117m 13.6 152 0.3 Conversion Gamma Small joints
electrons (209)

Abbreviation: keV: kilo-electron volt.

Advantages of novel radionuclide 117mTin:
* 14-day half-life: long enough for therapeutic effect.
* Low-energy emissions: minimizes inadvertent tissue injury.
* Short, nondiminishing penetration in tissue: precise dosing, no effect on nontarget tissues.
* Emits abundant conversion electrons: versus high-energy beta emissions with wide range of soft tissue penetration.

Tin-117m: A Novel Radionuclide kilo-electron volts (keV), 117mTin can be

used diagnostically to detect the distribu-
117mTin is a unique radionuclide without the tion and duration of its presence in the tis-
disadvantages of high-energy beta-emitting sue of treated patients. This application is
radionuclides (Table 4.12 compares physical similar to that for technetium-99m (99mTc),
properties of 117mTin with other therapeutic a widely used systemic radionuclide with
radionuclides). As such, 117mTin is particu- gamma emissions of 140 keV that is used in
larly well suited for RSO, inclusive of dogs
and horses. Instead of high-energy beta par-
ticles with a wide tissue penetration range
(50–5,000 μm), tin–117m emits abundant
conversion electrons (Figure 4.16) in the
form of a low-energy particle with a short
penetration range of approximately 300 μm
in tissue.153–156 Tin-117m has a t½ of nearly
14 days, providing an ideal duration of
effect spanning several half-lives to achieve
therapeutic results and to enable short-term
stability during storage and handling. To
illustrate, there is >99% dose retention in
the joint of a dog (Figure 4.17) 3 days fol-
lowing intra-articular injection with HTC.161
No other radionuclide with the properties of
117mTin exists.162 In addition to conversion FIGURE 4.16 This diagram compares the radia-
electrons, 117mTin emits gamma radiation, tion dose range of conversion electrons emitted
by 117mTin (300 μm, green zone) with beta radia-
a zero-mass quantum of light and electro-
tion emitted by radionuclides such as 90-yttrium
magnetic radiation that results from nuclear and 169-erbium (50–5,000 μm, blue zone). The
decay of a radionuclide. Gamma radiation ultra-narrow, discrete radiation range of 117mTin
is nontherapeutic but readily detectable in enables more precise dosimetry and avoidance
tissue by imaging methods such as scintig- of adverse effects on adjacent tissues such as
raphy. By emitting gamma radiation at 159 can occur with beta-emitting radionuclides.
 Chapter 4 Pharmacologics (Drug Classes) 159

in human patients.153–165 Investigators noted

the value of the gamma emission component
of 117mTin, which provides an objective basis 4
for diagnostic monitoring, disease staging,
dosage estimates, and assessing response to
therapy.165,166

Radiosynoviorthesis in
Veterinary Medicine
Radiotherapy has had various applications in
companion animal medicine. For example,
the beta-emitter iodine-131 (131I) has been
used systemically to treat feline hyperthy-
roidism since the 1990s and is considered
the treatment of choice for that condition.166
Recognition is noted that each radionuclide
is unique, i.e., 117mTin differs in many ways
from 131I. (See Table 4.13.)
FIGURE 4.17 Scintigraphy of a homogeneous Palliative and curative radiation therapy
117mTin colloid (HTC)–injected canine elbow
is now commonly used at veterinary oncol-
shows high dose retention of the homogeneous ogy referral centers,167 and radionuclides
colloid with minimal uptake in the draining lymph
are also used for bone scanning in animals.
node 3 days after administration. Retention at
this time point was measured at >99% in synovial Not surprisingly, successful RSO in human
tissue, indicating a continuous therapeutic effect patients has created interest in using this
consistent with the 14-day half-life of 117mTin. method in companion animals and horses
(Image courtesy of Jimmy Lattimer, DVM.) as a treatment for synovitis. Experimental
RSO in horses has been attempted at univer-
sity centers both in Europe and the United
diagnostic procedures, including evaluation States.160,168,169 Investigators in those studies
of bone structure and function. used the beta-emitting radionuclides hol-
Due to its unique therapeutic and diagnostic mium-166 (166 Ho) or samarium-153 (153Sm).
(theranostic) properties as a conversion elec- However, high-energy emissions from either
tron and gamma emitter with an optimal t½, radionuclide resulted in some transient,
117mTin has attracted interest as a radiophar- periarticular soft tissue injury and minor
maceutical and also now as a medical device extra-articular joint leakage.160,168,169 In a
in the colloid form. Favorable results were small Australian study, 90Y was adminis-
reported in phase I and II clinical trials, where tered concurrently with methylprednisolone
117mTin was used to treat metastatic bone pain acetate to four horses with severe chronic

TABLE 4.13 Comparing 117mTin with 131I

Comparison Tin-
117m 131Iodine

Application RSO Feline hyperthyroidism

Administration Local device Systemic drug
Radionuclide distribution Intra-articular Systemic
Post-treatment isolation Not required Required
Therapeutic emission Conversion electrons Beta emitter
160 Chronic Pain in Small Animal Medicine

synovitis and hemarthrosis.170 Median A Homogeneous Colloid of 117mTin

return to normal joint use was 7 months, R-NAV, LLC, has developed a patented prep-
with two of the horses developing recurrent aration of 117mTin specifically for RSO and
hemarthrosis. other potential applications in veterinary and
In experimental studies with thu- human medicine. 117mTin is manufactured
lium-170 (170Th) and 90Y, healthy dogs using methods that produce yields sufficient
were used as models for comparing results to be scaled up for manufacturing thera-
of canine and human RSO.171–173 Results peutic dosages in commercial quantities.162
indicated that RSO in dogs is feasible and The 117mTin radionuclide is combined with
generally well tolerated. However, the a homogeneous colloid.162 The radionuclide
studies found that excessive dosages of particles are small enough to be phagocytized
beta-emitting radionuclides can reduce gly- by synovial macrophages, but large enough
cosaminoglycan synthesis in articular car- to avoid leakage outside the joint prior to
tilage and result in extra-articular leakage phagocytosis. In situ retention of the HTC in
of radiocolloid particles as late as 9 months laboratory animals has been measured out to
after intra-articular administration. Such five t½ (i.e., 70 days), a duration sufficient for
outcomes reflect the importance in clini- therapeutic efficacy. The HTC has demon-
cal applications of using well-characterized strated safety and efficacy following RSO of
radionuclides that emit radiation within experimental OA in rats and dogs and safety
well-defined parameters. Successful RSO in in normal canine elbow joints (Figure 4.18).
relatively small canine joints was notewor-
thy, given the commonplace occurrence of Clinically Important Features of 117mTin
canine elbow dysplasia and associated OA
– a small-joint pathology that would be dif- Several features of 117mTin make it well suited
ficult to treat surgically.174 for RSO and an improvement over other
therapeutic radionuclide:

A Safe and Effective RSO Radionuclide • Localized administration: intra-articular

dosing is suitable for outpatient use.
Based on widespread clinical and experi- • Non-beta emitter: avoids high-energy irra-
mental experience with beta-emitting diation of nonsynovial tissue, extra-articu-
radionuclides, a safe and effective radio- lar diffusion, or systemic distribution.
colloid suitable for RSO has the following
characteristics147,158:

• A limited, discrete emission penetration

depth that corresponds to the thickness of
the synovium (i.e., avoids irradiation too
shallow for clinical effect or that extends
beyond the synovial layer to affect nontar-
get tissue).
• An intermediate radionuclide t½ that is long
enough to provide a reasonable shelf life and
to produce a therapeutic effect, but short
enough to avoid excessive exposure.
• A homogeneous colloid that binds the radio-
nuclide so that it cannot escape beyond the
joint.
• Suitable colloid particle size for synovial
phagocytosis and in situ retention. FIGURE 4.18 Intra-articular injection of the radio-
nuclide 117mTin into the caudo-lateral aspect of
• Gamma emission for purposes of diagnostic
a canine elbow, positioned at 45-degree flexion,
imaging. between the lateral condyle of the humerus and
• Large production yields that allow scaling the triceps tendon. Following injection, the joint
up for cost-effective manufacturing. is put through a range of motion to disperse the
• A clinical profile that demonstrates a high radiocolloid throughout the synovial surface.
degree of efficacy and safety. (Photo courtesy of Cynthia Doerr, MD.)
 Chapter 4 Pharmacologics (Drug Classes) 161

• Emits low-energy conversion electrons: time of treatment. Early intervention tends

minimizes potential for synovial scarring
and eliminates collateral tissue damage.
to result in more consistent and durable
positive clinical outcomes. This is consis- 4
• Gamma radiation emitter: gamma energy tent with results seen in clinical trials, which
of 159 keV is suitable for diagnostic imaging showed better responses in cases of mild and
and is similar to the commonly used diag- moderate radiographic OA as compared to
nostic radionuclide 99mTc (140 keV). more severe disease.166,167 Early intervention
• Half-life of 14 days: enables sufficient tissue targeting joint inflammation prior to devel-
retention for therapeutic efficacy and a shelf opment of significant radiographic change
life of 5 weeks. may delay or prevent progression of arthritic
• Practical handling characteristics: ease of changes.
handling, hospital containment, and ship- 117mTin is administered as an intra-articu-

ping using standard radiological safety and lar injection, and necessarily requires that the
packaging practices. canine patient be sedated for the procedure.
There are several options for sedation avail-
Because non-beta-emitting HTC satis- able to the veterinary practitioner. The ideal
fies all of these criteria, it is considered to sedation protocol will provide appropriate
be uniquely suited for RSO treatment.162 depth of sedation and allow rapid recovery
Further evaluation in canine, feline, and for an outpatient procedure. Care should
equine models is expected to affirm its suit- be taken to dose appropriately to achieve a
ability for synovitis treatment combined deep plane of sedation, without which users
with diagnostic confirmation of therapeutic have observed a pain response upon inject-
response. ing 117mTin and possibly an increase in the
incidence of postinjection discomfort for
Field Experience with 117mTin 2–3 days. A popular sedation choice is an
α 2-adrenoreceptor agonist (medetomidine
in Veterinary Medicine or dexmedetomidine) in combination with
RSO is experiencing rapid growth as part of an opioid. A recently introduced combina-
a multimodal approach to the management tion of medetomidine and vatinoxan, an
of pain and OA in veterinary medicine. A α 2-adrenoreceptor antagonist (Zenalpha®,
commercial formulation of colloidal 117mTin Dechra Limited), may prove to be useful
is currently available as a veterinary medical due to its sedative and analgesic proper-
device and is marketed in the United States ties along with an agent to counteract the
under the brand name Synovetin OA®. At profound cardiopulmonary effects of the
the time of this writing, it has been adminis- α-adrenoreceptor agonist. Although not
tered as an outpatient procedure to over 700 approved for this use, alfaxolone can achieve
dogs across 60 veterinary treatment centers. short-term deep sedation. Some practitioners
Over a year of field experience has resulted in choose to induce general anesthesia with pro-
numerous learnings. pofol or alfaxolone for the 117mTin injection.
Many practitioners are finding RSO to
be a useful adjunctive therapy when incor-
porated into a multimodal approach to pain Safety for Dog Owners
management. It can be used in conjunction Regulations governing allowable radia-
with a wide variety of pharmacologic and tion exposure in the United States dictate a
therapeutic modalities without complication. maximum allowable dose to a member of the
It often allows for reduction or elimination public from a treated animal of 100 mrem
of systemic anti-inflammatory drugs, reduc- in a year.168 A study designed to quantify
ing the opportunity for systemic adverse the dose to pet owners after treatment with
events. The fact that the 117mTin colloid is 117mTin has demonstrated a margin of safety

compartmentalized within the joint ensures relative to the allowable dose.169 Pet own-
that it is unlikely, itself, to contribute to sys- ers were provided with personal dosimeters
temic adverse events. when their dogs were released to the home
The degree and durability of positive following treatment. They were instructed to
response appear to be inversely related to the wear the dosimeters in their homes and while
severity of existing radiographic OA at the interacting with their dog. After a period of
162 Chronic Pain in Small Animal Medicine

up to 30 days, the dosimeters were returned Despite their widespread use and obvious
to the investigators for analysis. The results benefit in many cases, NSAIDs are not always
demonstrated that the average dose to the sufficiently effective when used as monother-
owners was less than 10% of the annual apy.180 Additionally, there are safety and tol-
public dose limit, with the maximum as 25% erability concerns with their use in both dogs
of the limit. This clinical data validates the and cats.142,181–183 Furthermore, evidence for
safety of canine radiosynoviorthesis for dog efficacy of so-called ‘adjunctive analgesics’
owners. is extremely limited.142,184 OA-associated
pain is one of the most common reasons for
euthanasia in dogs.185,186
NERVE GROWTH FACTOR With advances in biotechnology, spe-
cific immunomodulatory therapies called
AND OSTEOARTHRITIS: ‘biological agents’ have been introduced for
the treatment of joint diseases, specifically,
AN OVERVIEW163 immune-mediated joint diseases.

Introduction
Chronic (maladaptive) pain is a disease unto MECHANISM-BASED
itself, a state in which the protective role of
pain transmission becomes deranged and path- THERAPY
ological. Despite their limited effectiveness for
Monoclonal antibodies (mAbs) are pro-
many chronic pain conditions and consider-
duced from single B-lymphocyte clones in
able side effect profile, opioids and NSAIDs
mice or through recombinant engineering.
continue to dominate clinical practice. It is
They are monovalent antibodies that spe-
largely believed that mechanism-based treat-
cifically bind to target molecules, including
ments, rather than disease- or diagnosis-based
cytokines, receptors, or actual cells.187 This
treatments, hold the key to the development
binding results in blocking activity of the
of new successful therapies. Shortcomings in
target. Antibody engineering technology
the pharmacologic management of pain are
has been developed to reduce immunogenic-
thought to be attributed to a failure to target
ity of respective mAbs.188 Included within
underlying mechanisms of chronic pain.
consideration of immunogenicity are route
OA is a slowly progressive DJD characterized of administration (IV vs. SQ), treatment
by whole-joint structural changes, includ- paradigm (continuous vs. intermittent), and
ing articular cartilage, synovium, subchon- concurrent immunosuppressive therapy. ln
dral bone, and periarticular components, clinical practice, these factors have proven to
which can lead to pain and loss of joint be relevant considerations in the therapeutic
function.171–175 use of mAbs.189,190
OA is a condition associated with clinical There are multiple mechanisms by which
signs in a large percentage of the population, mAbs produce their effect. These include
with an estimated minimum of 20%–30% of blockade of ligand-receptor interaction or sig-
dogs affected clinically and up to 40% of all naling pathways and altering cell populations
cats being affected clinically (90% of all cats (by engaging effector functions, including the
over 12 years of age). The disease is currently complement-dependent cytotoxicity, antibody-
incurable with negative consequences related dependent cellular cytotoxicity, and antibody
to pain, mobility impairment, and decreased dependent phagocytosis or apoptosis).191
quality of life, not to mention the grieving The activation and sensitization of
empathy of pet parents.174,176–178 peripheral nociceptors by inflammatory and
The pathological progression of OA, with hyperalgesic mediators such as cytokines are
joint capsule thickening and fibrosis, contribute recognized as one of the main peripheral
to the altered range of motion that compounds mechanisms responsible for joint pain.192
the musculoskeletal changes. Additionally, the Nerve growth factor (NGF) is one of the cyto-
ongoing nociceptive input into the CNS results kines that has received significant attention as
in somatosensory system changes and central a key regulator involved in both inflammatory
sensitization (windup).142,179 and neuropathic pain.193,194
 Chapter 4 Pharmacologics (Drug Classes) 163

Nerve growth factor (NGF) was the first receptor kinase or tyrosine receptor kinase.)
growth factor to be identified (in the 1950s).
In adults, the main role of NGF in the periph-
Trk receptors are a family of tyrosine kinases
that regulate synaptic strength and plastic- 4
ery shifts from trophic support (development) ity in the mammalian nervous system. Trk
of sensory and sympathetic neurons to modu- receptors affect neuronal survival and differ-
lation of nociceptive neuronal activity.195 entiation through several signaling cascades.
A noxious stimulus is any stimulus (e.g., When NGF binds to TrkA expressed on
chemical, thermal, or mechanical) that either the peripheral terminals of sensory nerve
damages or threatens to cause damage to fibers, the NGF/TrkA complex is internal-
normal tissue. NGF is produced and released ized. The NGF/TrkA complex is transported
by peripheral tissues following noxious stim- in a retrograde fashion to the cell body of
uli secondary to the production of inflam- sensory neurons, located in the DRG. This,
matory cytokines, such as IL-1 and tumor then, modulates and/or increases the expres-
necrosis factor alpha (TNF-α). NGF binds to sion of a variety of cell surface receptors
trkA receptors on multiple targets, with mul- and ion channels involved in nociception,
tiple modulating effects on pain signaling including the transient receptor potential
(Figure 4.19). (The abbreviation trk, often vanilloid 1 (TRPV-1), acid-sensing ion chan-
pronounced ‘track’, stands for tropomyosin nels (ASICs), bradykinin receptors, VGSCs,

4.19

FIGURE 4.19 When NGF binds to TrkA expressed on the peripheral terminals of sensory nerve fibers,
the NGF/TrkA complex is internalized. The NGF/TrkA complex is retrogradely transported to the cell
body of sensory neurons, located in the dorsal root ganglia (DRG). This modulates and/or increases the
expression of a variety of cell surface receptors and ion channels involved in nociception, including the
transient receptor potential vanilloid 1 (TRPV-1), acid-sensing ion channels (ASICs), bradykinin recep-
tors, voltage-gated sodium channels, voltage-gated calcium channels, and mechano-transducers. This
results in an increased excitability of primary afferent fibers (peripheral sensitization) through phenotypic
alterations. NGF/TrkA signaling also leads to transcriptional changes that result in the increased expres-
sion of pronociceptive neurotransmitters such as brain-derived neurotrophic factor (BDNF). Thus, NGF
induces functional, as well as phenotypic, alterations in the primary afferent fiber. In the periphery, NGF
also binds to TrkA located on mast cells and other immune cells and elicits the release of inflammatory
mediators such as histamine, serotonin, and NGF itself. Thus, NGF can trigger peripheral sensitization
and sensitizes adjacent inflammatory mediators. (From Vet Record [2018] doi: 10.1136/vr.104590 [Open
Access, no permission required].)
164 Chronic Pain in Small Animal Medicine

VGCCs, and mechano-transducers. This pivotal role in the pronociceptive processes,

results in an increased excitability of pri- an analgesic that blocks NGF/TrkA signal-
mary afferent fibers (peripheral sensitization) ing would likely enhance multimodal pain
through phenotypic alterations. management.
NGF/TrkA signaling also leads to Several reports196,197 suggest that NGF
transcriptional changes that result in the and TrkA expression in the CNS may con-
increased expression of pronociceptive neu- tribute to driving chronic pain, although this
rotransmitters such as brain-derived neuro- activity is less understood. How anti-NGF
trophic factor (BDNF). Thus, NGF induces therapies that are restricted to the periphery,
functional, as well as phenotypic, alterations such as mAbs, modulate centrally driven or
in the primary afferent fiber. maintained processes involved in chronic
In the periphery, NGF also binds to TrkA pain have yet to be defined.
located on mast cells and other immune cells, Neuropathic pain results from damage to
eliciting the release of inflammatory mediators the neurons of the somatosensory system, sec-
such as histamine, serotonin, and NGF itself. ondary to either direct injury or disease-related
NGF can trigger peripheral sensitization dysfunction, and results in the generation of
and sensitizes adjacent inflammatory media- ectopic discharges that occur independently
tors. In conditions where NGF is playing a of somatic stimuli (Figure 4.20).

4.20

FIGURE 4.20 Schematic diagram of the NGF mechanisms involved in the initiation and maintenance of
pain. (5-HT: 5-hydroxytryptamine, ASIC3: acid-sensing ion channel 3, BDNF: brain-derived neurotrophic
factor, BR2: bradykinin receptor 2, Cav: voltage-gated calcium channel, CGRP: calcitonin gene-related
peptide receptor, DRG: dorsal root ganglia, IL-1: interleukin I, K: delayed rectifier potassium chan-
nel, Nav: voltage-gated sodium channel, NGF: nerve growth factor, NK-1: neurokinin-I receptor, p75:
neutrophin receptor, SP: substance P, TNF-α: tumor necrosis factor alpha, trkA: tropomyosin receptor
kinase A, trkB: tropomyosin receptor B, TRVI: transient receptor potential cation channel subfamily V
member 1 receptor.) (Drawing courtesy of Caitlin Hottinger; From J Pain Research. 8 June 2016, doi.
org/10.2147/JPR.s89061 [Open Access, no permission required].)
 Chapter 4 Pharmacologics (Drug Classes) 165

All clinical studies have reported sig- contrast, the role played by NGF in the
nificant dose-dependent hyperalgesia at the
site of NGF injection. NGF administration
pathophysiology of neuropathic pain is
less clear. In spite of its high cost, relatively 4
has also shown the ability to induce nerve short-term follow-up periods in currently
sprouting of trkA-positive nociceptive as published trials, uncertain adverse effect
well as sympathetic nerve fibers, while NGF profile, and high cost, anti-NGF therapy
blockage by systemic injection of neutral- may find a role as a short-term treatment in
izing antibodies in models of neuropathic properly screened patients with refractory
pain appears to prevent allodynia and pain conditions.
hyperalgesia. Limitations in the knowledge of anti-
These NGF data are preliminary and NGF therapy remain elusive:
non-evidence-based; therefore, frequently
unavailable and/or speculative. Several • Currently, the longest follow-up time after
approaches have been developed to target anti-NGF mAb therapy in dogs and cats
the NGF pathway (Table 4.14) and its effect is 3 months. The mean trial duration for
on pain initiation and maintenance. The humans is 199 days.
majority of these efforts have centered on • The safety of concomitant use of NSAIDs
the NGF-trkA pathway and focus on three with anti-NGF mAb therapy has not been
methodological approaches: elucidated, nor have NSAID withdrawal
times prior to anti-NGF mAbs treatment.
• Sequestration of free NGF • Rapidly progressive OA and osteonecrosis
• Prevention of NGF binding and activation resulted in a 2010 moratorium on human
of trkA trials. Rapidly progressive OA is not a rec-
• Inhibition of trkA function ognized or described phenomenon in dogs
or cats. The risk of developing rapidly pro-
In nociceptive and inflammatory pain, gressive OA appeared to be significantly
NGF activity and its interaction with trkA greater when tanezumab was used in con-
have been well characterized as important junction with NSAIDs compared to tan-
mediators of pain initiation and mainte- ezumab monotherapy.
nance. In preclinical models of inflamma- • The efficacy of single injection NGF mAb
tory and visceral pain, NGF sequestration treatment appears to last at least 4–6 weeks,
and inhibition of trkA signaling have dem- with a magnitude of effect approximately
onstrated a consistent analgesic effect. In the same as with an NSAID.

TABLE 4.14 Mechanisms of action proposed for agents targeting the NGF pathway
Compound Mechanism of action Summary of evidence
MNAC13 • Monoclonal anti-trkA antibody • Analgesia in mouse models of inflammatory
and neuropathic pain
• Possible synergistic effect with opioids
• Mouse antibody with no equivalent humanized
antibody
ALE0540 • NGF inhibitor, prevents • Reduces pain behavior in animal models of
• NGF binding to both trkA and p75 neuropathic pain
• Deemed unsuitable for clinical trial due to lack
of specificity
K252a • Protein kinase inhibitor, inhibits • Reverses mechanical hypersensitivity in model
trkA, trkB, and trkC of acute necrotizing pancreatitis
• Deemed unsuitable for clinical trial due to lack
of specificity

Abbreviations: NGF: nerve growth factor, p75: neurotrophin receptor, trkA: tropomyosin receptor kinase A, trkB: tropomyosin receptor
kinase B, trkC: tropomyosin receptor kinase C.
166 Chronic Pain in Small Animal Medicine

IDEALIZED CRITERIA FOR • Reduced side effects

• Reduced tolerance/Dependency potential
NEW ANALGESIC THERAPY • Central opioid receptor analgesics
• Opioid-active partial mu agonist
IN CHRONIC PAIN • Morphine metabolite (M6G)
• μ-δ opioid analgesic
• Analgesic properties
• κ agonist analgesic
• Moderate-to-strong analgesic activity
• Controlled-release drug delivery systems
• Delayed onset of action is acceptable for
• Peripheral opioid receptor analgesics
treating chronic pain; fast onset of action
• Peripheral μ agonist
is required for treating acute or break-
• Peripheral κ agonist
through pain
• Anti-inflammatory analgesics
• No or low analgesic tolerance profile
• COX-2 inhibitors
• Not cross-tolerant to morphine
• COX-LOX inhibitors
• Side effect profile compatible with chronic use
• COX-NO–releasing compounds
• Nonsedating
• Disease-modifying compounds
• No or minimal respiratory depression
• Novel mechanism of action
• Minimal gastrointestinal, cardiovascu-
• Ion channel blocking drugs
lar, and renal effects
• Cannabinoid analgesics
• No or minimal physical drug dependence
• Muscarinic/Nicotinic/α 2-agonist drugs
• Minimal mood-altering activity
• Special-use products (e.g., unique effi-
• Not immunosuppressant
cacy for one disease condition or one
• Pharmaceutical considerations
species: e.g., OA in cats)
• Acceptable bioavailability for oral use pre-
ferred; alternatives include nasal, rectal,
oral transmucosal, transdermal, or inject-
able use
• Half-life and duration of action consistent HISTORICAL MARKET
with chronic use; once-per-day dosing
• No drug accumulation with chronic use DATA (U.S.)
• Nontoxic metabolite(s)
The 2008/2009 U.S. dog and cat pain man-
• Known and acceptable drug interactions;
agement project (C.F. Grass Consulting,
compatible use with opioids, NSAIDs
St. Louis MO, February 2009) data pro-
• Acceptable for use in senior populations
vides insight as to trends in the use of vari-
• Mechanism of action considerations
ous pain management drug classes. In the
• Nonopioid mechanisms of action preferred
United States a total of 26.7 million dogs
• Agonists at non-μ-opioid receptors may
were treated for pain in 2008 – down from
have advantages
27.5 million in 2007. A total of 6.1 million
• Indirect opioid agonists/peptide releas-
cats were treated for pain – down from 8.3
ers, opioid potentiators, and opioid toler-
million in 2007. By product class, NSAIDs
ance inhibitors may be useful
account for the vast majority of the pain
• Drugs with novel or ‘unknown’ mecha-
market, followed by opioids (Figure 4.21).
nisms of action are good
Of the total 2008 U.S. market value,
• Analgesics that also treat the emotive
44.6% was accounted for by the treatment
aspects of chronic pain, stress, or depres-
of OA, 24.1% for postoperative use, and
sion are useful
11.0% for nonsurgical soft tissue trauma
(Figure 4.22). Growth is observed in all
MAJOR THEMES IN types of managed pain (Table 4.15). More
than 94.3% of clinics use two or more pain
ANALGESIC PRODUCT products (Table 4.16).
DEVELOPMENT The 6-year growth curve for pain market
pharmaceuticals has been positive; however,
• Opioid combination products this trend was predicted to fall by approxi-
• Increased analgesic potency mately 10% due to a flattened economy
• Increased analgesic efficacy (Figure 4.23, Table 4.17).
 Chapter 4 Pharmacologics (Drug Classes) 167

4
TABLE 4.15 Growth in management of pain
Type of pain 2008 value Growth
Osteoarthritis $103,119,966 5.0%
Postoperative use $55,881,752 11.0%
Nonsurgical soft $25,461,610 23.2%
tissue trauma
Nonsurgical bone $15,123,896 31.2%
trauma
Nonarthritic $14,584,676 5.2%
orthopedic

FIGURE 4.21 Market by product class in 2008. Cancer pain $8,422,485 21.8%
Total sales $207.8 million.
All other types $8,826,407 28.6%

TABLE 4.16 Number of pain products used

in clinics in 2008
Number of pain % of clinics % of clinics
products used in 2008 in 2007
1 0.4 3.1
2 5.3 18.7
3 17.8 28.0
FIGURE 4.22 Market by type of pain treated in 4 25.0 19.5
2008.
5 20.1 13.2
6 9.1 7.8
7 9.7 9.7

FIGURE 4.23 Pain product sales trend 2004–2009p. (p: prediction in early 2009.)
168 Chronic Pain in Small Animal Medicine

TABLE 4.17 Pain products sales trend, 2004–2009p (dollars)

2004 2005 2006 2007 2008 2009p
Opioids 5,721,439 6,963,277 10,588,891 10,256,220 8,717,506 8,558,857
Corticosteroids 806,895 908,264 663,408 685,929 105,969 100,512
(for analgesia)
NSAIDs (for 124,998,342 145,021,959 161,351,595 175,986,872 195,774,224 185,040,699
analgesia)

Note: p: prediction in early 2009).

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CHAPTER

5
Nonsteroidal
Anti-Inflammatory Drugs
INTRODUCTION NSAIDs manifest their mode of action in the
arachidonic acid (AA) cascade (Figure 5.1).
Nonsteroidal anti-inflammatory drugs AA is a ubiquitous substrate derived from
(NSAIDs) are the fastest-growing class of drugs the continual degradation of cell membranes.
in both human and veterinary medicine. This Corticosteroids express their activity in the
reflects their broad use as anti-inflammatories, early stages of this course. AA is thereafter
analgesics, and antipyretics. As with antibiot- metabolized to various eicosanoids via the
ics, NSAIDs can be considered to have been cyclooxygenase (COX) pathway to prosta-
introduced in successive generations to date: glandins (PGs) or via the lipoxygenase (LOX)
pathway to leukotriene (LTs). Under the influ-
• First-generation, i.e., aspirin, phenylbuta- ence of local tissues, these end-product pros-
zone, meclofenamic acid tanoids can be proinflammatory and enhance
• Second-generation, i.e., carprofen, etodolac, disease processes and pain (Table 5.1).
meloxicam It is important to note that the function of
• Third-generation, i.e., tepoxalin, deracoxib, many prostanoids is tissue-dependent, e.g.,
firocoxib, mavacoxib, robenacoxib PGs may contribute to pain and inflamma-
tion in the arthritic joint, while they enhance
However, unlike the logic of ‘saving the normal homeostatic functions of vascular-
big-gun antibiotic’ for last, so as to avoid ization, as well as bicarbonate and mucous
microbial suprainfections, logic would dic- secretion, in the gastrointestinal tract.
tate using the optimal NSAID at the earliest At one time it was believed that block-
opportunity, so as to avoid the physiological ing the COX pathway led to a buildup of
complication of windup. the substrate AA, which would then lead to
Currently, several NSAIDs (aspirin, carpro- increased production of LTs.
fen, cinchophen, deracoxib, etodolac, firocoxib, This has been refuted by some,1 while sup-
flunixin, ketoprofen, mavacoxib, meloxicam, ported by others.2 Because corticosteroids
phenylbutazone, robenacoxib, tepoxalin, tolf- have their mode of action at a location higher
enamic acid, and vedaprofen) have approval in the arachidonic cascade than do NSAIDs,
for the control of canine perioperative and/ it is redundant to use them concurrently, and
or chronic pain in various countries. NSAIDs doing so markedly increases the severity of
approved for feline use are far more limited adverse reactions.3–5 Data from humans shows
(meloxicam, tolfenamic acid, ketoprofen, that the risk of NSAID-induced gastrointesti-
robenacoxib, carprofen, and aspirin in various nal complications is doubled when an NSAID
countries for short-term administration). is used concurrently with a corticosteroid.6

ARACHIDONIC ACID PATHWAY COX ISOZYMES

In most respects, NSAIDs can be characterized Approximately 20 years following discovery
as a class, although there are molecule-specific of the AA pathway as the mode of action for
characteristics among individual drugs. NSAIDs, it was discovered that the COX

174 DOI: 10.1201/9781003376422-7

 Chapter 5 Nonsteroidal Anti-Inflammatory Drugs 175

FIGURE 5.1 The AA pathway generates a variety of eicosanoids that influence various physiological
functions.

TABLE 5.1 Major prostanoids and their functions

Prostanoid Primarily found in Major biological action
TXA2 • Platelets • Platelet aggregation
• Monocytes • Vasoconstriction
• Bronchoconstriction
• Cellular proliferation
PGI2 (prostacyclin) • Vascular endothelium • Inhibition of inappropriate platelet
• Vascular subendothelium aggregation Vasodilatation
• Vascular permeability
• Bronchodilatation
• Inflammation
• Cholesterol efflux from arteries
PGE2 • Renal medulla • Vasodilatation
• Gastric lining • Inflammation
• Platelets • Fever
• Microvascular • Na+-K+ excretion/reabsorption
endothelium • Bronchodilatation
• Presynaptic adrenergic activity
• Cardioprotection
PGF2α • Brain • Vasoconstriction
• Uterus • Bronchoconstriction
• Uterine constriction
PGD2 • Mast cells • Sleep regulation
• Brain • Bronchoconstriction
• Temperature control
• Vasodilatation
176 Chronic Pain in Small Animal Medicine

FIGURE 5.3 The COX-1 receptor site differs from

the COX-2 receptor site by only a single amino
acid; however, the COX-2 site has a larger entry
FIGURE 5.2 COX-1–mediated PGs tend to be port and a characteristic side pocket. Small, tra-
more associated with constitutive physiological ditional NSAIDs fit into both sites, blocking both
functions, while COX-2–mediated PGs tend to COX-1– and COX-2–mediated PG production
be more associated with pain and inflammation. from AA, hence the term nonselective NSAID.

enzyme exists as at least two isoenzymes:

COX-1 and COX-2.7,8 These two distinct
COX isoforms have been identified as prod-
ucts of two separate genes.9 Early thinking
was that COX-1–mediated PGs were consti-
tutive physiologically and should be retained,
while COX-2–mediated PGs were pathologi-
cal and should be eliminated for the con-
trol of inflammation and pain (Figure 5.2).
COX-2–selective NSAIDs were designed for
this purpose: the selective suppression of
COX-2–mediated PGs (Figures 5.3–5.5). FIGURE 5.4 Coxib-class NSAIDs were designed
to be too large for the COX-1 receptor site (at
In contrast to COX-1, COX-2 is not
labeled dose); however, they fit hand-in-glove
widely expressed under normal physiological within the COX-2 receptor site. These drugs
conditions, but is upregulated in cells such spare COX-1–mediated PG production and block
as synoviocytes, fibroblasts, monocytes, COX-2–mediated PG production, i.e., they are
and macrophages under the influence of COX-1 sparing and COX-2 selective.

FIGURE 5.5 Overview of COX-1 and COX-2 nomenclature and clinical relevance.
 Chapter 5 Nonsteroidal Anti-Inflammatory Drugs 177

FIGURE 5.6 In humans, the two COX isoforms differ by a single amino acid; however, this single differ-
ence influences COX-2 inhibitor selectivity.

proinflammatory mediators. Both isoforms value. Therefore, a greater COX-1:COX-2

are membrane-bound glycoproteins found ratio suggests (theoretically) the more opti-
in the endoplasmic reticulum and, particu- mal performing NSAID. With this in mind,
larly COX-2, in the nuclear envelope of the pharmaceutical companies began designing
cell. The overall amino acid sequences of NSAIDs for which it takes a low concentra-
COX-1 and COX-2 are similar, the only tion to inhibit COX-2 but a high concentra-
difference in humans between the two iso- tion to inhibit COX-1. Many factors such
forms being in the active-site region that as species, incubation time, and enzyme
occurs at residue 523, where the isoleucine source can influence the data obtained from
residue in COX-1 is replaced by a valine enzyme preparations. Additionally, par-
residue in COX-2. This single difference has ticularly when measuring COX-2 potency,
been shown to have a marked effect on the the kinetics of inhibition are highly com-
overall size and shape of the binding site, plex and time dependent. Consequently,
apparently the basis for COX-2 inhibitor different values have been reported for the
selectivity (Figure 5.6). same drug. Although COX-1:COX-2 ratios
The IC 50 is defined as the concentration vary by investigators, relative ratio stand-
of a drug (NSAID) needed to inhibit the ings provide insight as to a drug’s expected
activity of the enzyme (COX) by 50%. In species-specific COX activity (Table 5.2).
keeping with the previous rationale, one Complicating this issue, some report ratios
would like to have a high concentration of of COX-2:COX-1 rather than the more con-
NSAID before causing 50% inhibition of ventional COX-1:COX-2.
COX-1 (‘good guy’) and a low concentra- It has been suggested that a COX-
tion of NSAID to reach the IC 50 for COX-2 1:COX-2 ratio of <1 would be considered
(‘bad guy’): COX-1 selective, a ratio >1 as COX-2
preferential, a ratio >100 as COX-2 selec-
IC50 of COX − 1( good ) HIGH tive, and a ratio >1,000 as COX-2 specific.
Selectivity nomenclature is used loosely,
IC50 of COX − 2 (bad ) LOW and such comparative ranking has not been
associated with clinical correlation. Hence,
The higher the numerator and lower almost all discussions of COX data pre-
the denominator, the higher the absolute sented by pharmaceutical manufacturers
178 Chronic Pain in Small Animal Medicine

include the disclaimer, ‘clinical relevance

TABLE 5.2 Canine COX-1:COX-2 ratios
of contemporary veterinary NSAIDs
undetermined’, because the data is sourced
reported by different investigators in vitro.
We now know that the ‘good-guy-COX-1/
Ratio of IC50 bad guy COX-2’ approach is naïve, recogniz-
Investigator Drug COX-1:COX-2 ing that COX-2 is needed constitutively for
Kay-Mungerford Meloxicam 12.2 reproduction, central nervous system (CNS)
et al.10 nociception, renal function, and gastrointes-
Carprofen 1.8 tinal lesion repair. In fact, the physiological
functions associated with COX activity over-
Ketoprofen 0.4 lap (Figure 5.7).
Brideau et al.11 Meloxicam 10 Accordingly, there is likely a limit as
to how COX-2 selective an NSAID can be
Carprofen 9
without causing problems, e.g. inhibiting
Ketoprofen 6.5 endogenous repair of a gastric lesion. This
Streppa et al.12 Meloxicam 2.7
limit is not known. More important than
how COX-2 selective an NSAID might be is
Carprofen 16.8 whether or not the NSAID is COX-1 spar-
Ketoprofen 0.2 ing, i.e., preserving homeostatic physiology.
Further, it is logical to avoid a COX-1–selec-
Aspirin 0.4 tive NSAID (ratio <1) perioperatively, so as
Li et al.13 Carprofen 5 not to enhance bleeding. The coxib-class
NSAIDs, with their high COX ratio and
Celecoxib 6.2
COX-1–sparing feature, have been shown to
Deracoxib 36.5 be associated with less risk for gastrointesti-
Firocoxib 155
nal complications in human studies.15

FIGURE 5.7 The clinical relevance of COX activity overlaps.14

 Chapter 5 Nonsteroidal Anti-Inflammatory Drugs 179

COXIB-CLASS NSAIDs products contribute to the pathogenesis of

Human coxib-class NSAIDs were designed

the inflammatory process in sepsis, includ-
ing COX-2, the inducible form of nitric oxide 5
to be safer for the gastrointestinal tract, synthase (NOS), and a variety of proinflam-
although any NSAID can be at risk for matory cytokines. Several of these mediators
adverse reactions (adverse drug event can, in turn, further activate this transcrip-
[ADE]). Analogous safety profiles have not tion factor, which creates a self-maintaining
been extensively investigated in the canine. inflammatory cycle that increases the sever-
Coxib-class NSAIDs were not designed to ity and the duration of the inflammatory
be safer for renal or hepatic function, and response, as well as regulates a negative-feed-
they have been associated with potential back control by inducing the transcription of
cardiovascular risks in humans. Fortunately, its own inhibitor.21 In addition to their mech-
companion animals are not at risk for anism of action on glucocorticoid receptors,
coxib-class NSAID cardiovascular prob- glucocorticoids also antagonize the activation
lems (atherosclerosis)16 as are humans, and of the NF-κB pathway.21
it may well be that the canine is an optimal The inhibitory effects on the NF-κB path-
target species for this class of drugs. The way are not shared by all NSAIDs (indo-
label precaution regarding potential sulfon- methacin and ketoprofen are inactive18);
amide hypersensitivity is likely theoretical. however, coxib-class NSAIDs appear effec-
Trepanier17reported that ‘sulfur drugs’ other tive. NF-κB activity of veterinary NSAIDs
than the antimicrobial sulfonamides do not has only recently been investigated. 22
produce a similar pathogenesis for the same
hypersensitivity.

NSAID SAFETY
NUCLEAR FACTOR κB The comparative safety of different NSAIDs
in dogs is difficult to determine. Such a query
The most commonly accepted theory account- compares the incidence of problems with one
ing for the inhibitory effects of NSAIDs on NSAID to that of a second NSAID. Incidence
the inflammatory response suggests inhibi- would then be a ratio consisting of the num-
tion of COX, thus preventing PG synthesis. ber of dogs with problems (numerator) over
Yet, some suggest that additional mechanisms the number of dogs treated with that drug at
are involved in the actions of these agents. a given point in time (denominator). Not all
Several studies have demonstrated unequivo- adverse drug events are reported, and not all
cally that NSAIDs such as sulindac, ibupro- reported events are directly causal; therefore
fen, and flurbiprofen cause anti-inflammatory the numerator is unknown. The denominator
and antiproliferative effects independently is also unknown, because it is impossible to
of COX activity and PG inhibition, and can determine the number of dogs on a drug at any
inhibit nuclear factor κB (NF-κB) activation given time. For these reasons, accurate com-
by decreasing serine/threonine κ beta (IKκβ) parative data is unobtainable. Accordingly,
kinase activity (IKK plays a role in the trans- most NSAID manufacturers can state with
location of NF-κB from the cytoplasm to the credibility, ‘no NSAID has been proved safer
nucleus).18 In 1994 Kopp and Ghosh reported than (fill in the blank)’. Nevertheless, all
that aspirin and salicylates block NF-κB.19 ADEs should be reported to the appropriate
NF-κB is a transcription factor that plays authority and drug manufacturer so that gen-
a critical role in the coordination of both eral trends can be tracked and documented.
innate and adaptive immune responses in sep- ADE reports at the U.S. Food and Drug
sis by regulating the gene expression of many Administration (FDA) Center for Veterinary
cellular mediators.20 Activation allows NF-κB Medicine provide some insights as to why
to translocate into the nucleus, where it regu- ADEs from NSAID use might be so high 23:
lates the expression of hundreds of genes that
are important in immune and inflammatory • Twenty-three percent of pet owners state
responses (Figure 5.8). Additionally, NF-κB that veterinarians never discuss adverse
stimulates the expression of enzymes whose effects of the medication.
180 Chronic Pain in Small Animal Medicine

FIGURE 5.8 NF-κB activity (pathway).

• Twenty-two percent of pet owners state they

are not given client information sheets about TABLE 5.3 Gastrointestinal adverse
the prescribed drugs, which are provided by events reported in clinical trials
pharmaceutical companies for the purpose Drug Vomiting Diarrhea
of pet owner education.
Carprofen 3.1% (3.8%) 3.1% (3.8%)
• Fourteen percent of prescribed NSAIDs are
dispensed in other than the original packag- Etodolac 4.3% (1.7%) 2.6% (1.7%)
ing, thereby denying pet owners drug infor-
Deracoxib 2.9% (3.8%) 2.9% (1.9%)
mation provided on the label.
• Only 4% of pet patients prescribed drugs Tepoxalin 2.0% (4.8%) 4.0% (0)
are given preadministration blood analyses. at 7 days at 7 days

19.6% at 28 days 21.5% at 28

As a class of drug, NSAIDs are most com- days
monly associated with adverse reactions to
the gastrointestinal tract (64%), renal system Meloxicam 25.5% (15.4%) 12.1% (7.4%)
(21%), and liver (14%). 23 There is no pub- Firocoxib 3.9% (6.6%) 0.8% (8.3%)
lished information relating to similar feline
ADEs. Gastrointestinal problems associated Note: Values represent mean of test article (placebo). Data
with NSAIDs can be as benign as regurgita- sourced from drug inserts. Caution should be used in
comparing adverse events among different drugs because of
tion or as serious as gastric ulceration and differences in study populations, data collection methods, and
perforation (Table 5.3). Vomiting has been reporting methods.
 Chapter 5 Nonsteroidal Anti-Inflammatory Drugs 181

identified as the most frequent clinical sign for this anatomical focus being at higher risk
associated with gastric perforation.3 Pet
owners should be informed that while taking
include that it is subject to recurrent bathing
by irritable bile reflux through the pylorus. 5
an NSAID, if their pet experiences vomiting, Apart from a few studies that have exam-
the drug should be stopped and the patient ined the effect of NSAIDs on gastric muco-
should promptly be examined. This is a con- sal production of prostanoids, 25–27 COX
servative approach since dogs are considered selectivity has largely been determined using
a ‘vomiting species’, and some NSAIDs are in vitro assays, and assumptions have been
associated with more vomiting than others. made about gastrointestinal effects based
on these in vitro data. Given the variability
in results from in vitro assays and the lack
of understanding of COX physiology in the
NSAID-ASSOCIATED canine proximal gastrointestinal tract, mak-
GASTROINTESTINAL ing assumptions about the clinical effects of
various NSAIDs based on in vitro data may
ULCERATION lead to erroneous conclusions.
Wooten et al. 28 reported an assessment
Gastric perforations are most frequently of the in vivo action of NSAIDs in the
found near the pyloric antrum of the stom- region of the gastrointestinal tract, which
ach and have a poor prognosis if not discov- appears to be at greatest risk for ulceration
ered early and treated aggressively. 3 in the dog. Purpose-bred mongrel dogs were
Risk factors identified with NSAID- given a COX-1–selective NSAID (aspirin at
associated gastric ulceration are most 10 mg/kg BID PO), a COX-2–preferential
commonly seen with inappropriate use: (1) over- NSAID (carprofen at 4.4 mg/kg SID PO),
dosing, (2) concurrent use of multiple NSAIDs, and a COX-2–selective NSAID (deracoxib at
and (3) concurrent use of NSAIDs with corti- 2 mg/kg SID PO) or placebo for 3 days, with a
costeroids.3 For nearly 50 years ‘steroid ulcer- 4-week washout period between treatments.
ation’ has been recognized with the sole use of Endoscopic mucosal biopsies were obtained
corticosteroids, attributed to a steroid-induced from the pyloric and duodenal mucosa and
gastric hypersecretion of acid together with a evaluated histologically, measuring COX-1
decreased rate of mucus secretion.24 and COX-2 protein expression with Western
Lascelles et al.3 observed that 23/29 gas- blotting and prostanoids via enzyme-linked
trointestinal perforations in an NSAID ret- immunosorbent assay (ELISA). This investi-
rospective review occurred in the area of the gation can be considered clinically relevant,
pyloric antrum (Figure 5.9). Possible reasons as it reflects the effect of a drug treatment
on the actual tissue levels of prostanoids, not
the drug effect on the total possible produc-
tion of prostanoids by a tissue, as has pre-
viously been inferred from in vitro–sourced
COX ratios.
PG levels were found to be significantly
higher in the pylorus than in the duodenum,
which may be explained by differences in
COX expression in the pylorus versus the
duodenum, where the need for protection
from refluxed bile is high. The ‘more tra-
ditional’ NSAIDs (aspirin and carprofen)
decreased the total concentration of PGs in
the gastric mucosa, while PG levels were not
altered by the coxib-class NSAID (deracoxib)
(Figure 5.10).
Thromboxane (TX) has been shown to
FIGURE 5.9 In a retrospective NSAID-associated be indicative of COX-1 activity in the gastro-
gastrointestinal perforation study, 23/29 perfora- intestinal tract of several species29; however,
tions were identified in the pyloric antrum. the linkage of TXB2 to COX-1 activity in the
182 Chronic Pain in Small Animal Medicine

FIGURE 5.10 Total PG and TXB2 pyloric tissue levels in an in vivo study of traditional vs. coxib-class
NSAID.28

canine gastrointestinal tract is speculated Findings from these studies demon-

but not confirmed. Carprofen administra- strate that different NSAIDs reduce pros-
tion also significantly reduced TXB2 concen- tanoid production to a different degree in
trations compared to deracoxib, suggesting the canine pylorus and duodenum, and this
that carprofen inhibits COX-1 in the gastric appears to be related to their COX selec-
mucosa, whereas deracoxib had no effect on tivity. This begs the question as to why
TXB2 (COX-1) concentrations (Figure 5.10). NSAIDs that appear to be highly selective
This is in keeping with the findings of for COX-2 have been shown to be appar-
Brainard et al., who reported that carprofen ently associated with perforating ulcers in
decreased clot strength and platelet aggrega- the pylorus and duodenum in the dog. To
tion (a COX-1–related phenomena), while date, the only study assessing the associa-
the coxib-class NSAID deracoxib actually tion between a selective COX-2 inhibitor
increased clot strength. Changes in plate- (deracoxib) and gastroduodenal perforation
let function, hemostasis, and prostaglandin revealed that in almost all cases (26/29)
expression after treatment with NSAIDs were of ulceration in dogs receiving the coxib-
seen. with various COX selectivities in dogs.29 class NSAID, an inappropriately high dose,
Other investigators have reported in vivo or concurrent administration with other
findings for commonly used NSAIDs. Sessions NSAIDs or corticosteroids, or rapid switch-
et al.25 reported that carprofen and deracoxib ing (<24 hours) from one NSAID to another
were both COX-1 sparing, while Punke et al.31 was identified. 3 This suggests that when
reported that firocoxib and meloxicam were gastrointestinal perforation occurs follow-
COX-1 sparing, while tepoxalin was not. ing administration of a selective COX-2
A novel finding of the Wooten study28 was inhibitor, other factors such as overdosing,
the intestinal mucosal presence of COX-2 in concurrent administration of drugs inhib-
the healthy research dogs. Heretofore, the iting prostanoid production, rapid change
presence of COX-2 was believed to be upreg- from one NSAID to another, or hitherto
ulated by disease. This finding might suggest unrecognized factors play a major role in
that COX-2 serves some unknown constitu- the production of ulceration. This is cor-
tive role in the intestinal mucosa. If this is roborated by documentation that 75–80%
true, the premise can be validated that an of all ADE reports with deracoxib use are
NSAID can be ‘too’ COX-2 selective. associated with inappropriate use. 32
 Chapter 5 Nonsteroidal Anti-Inflammatory Drugs 183

NSAIDs AND RENAL patient with compromised renal function is at

FUNCTION
risk with any NSAID administration, particu-
larly when underhydrated. 5
Through regulation of vascular tone, blood
flow, ion and water balance, and renin, PGs
are important for normal renal function.33
NSAIDs AND HEPATIC
In situations of decreased systemic blood FUNCTION
pressure or circulating blood volume, PGs
assist in regulating and maintaining renal Serious liver injury can occur from acetamin-
blood flow to maintain a mean arterial pres- ophen (paracetamol) overdose in humans and
sure ranging from 60 to 150 mmHg.34 Both dogs. (Technically, acetaminophen is not a
the COX-1 and the COX-2 isoforms are true NSAID since it is considered analgesic
expressed in the kidneys of dogs, rats, mon- but not anti-inflammatory.) Acetaminophen
keys, and humans, where they both play con- toxicity in cats presents primarily as methe-
stitutive roles (Figure 5.11). moglobinemia and Heinz body anemia, likely
Therefore, at recommended dosing, no from enhanced susceptibility of feline eryth-
one NSAID is safer than another on renal rocytes to oxidative injury.38
function in these species. NSAID drug com- Drug-induced hepatopathy (defined
plications of hypovolemia and hypotension as an elevation of liver enzyme values) is a
have led to acute renal failure and death in rare but potentially serious adverse conse-
both dogs and cats.37 Information regarding quence of several drug classes, including
COX-1 and COX-2 distribution or expression NSAIDs, volatile anesthetics, antibiotics,
under varying conditions of the feline kidney antihypertensives, and anticonvulsants. This
is unknown. Meloxicam is perhaps the most can occur with all NSAIDs. In comparison,
frequently administered NSAID in cats, and idiosyncratic hepatotoxicosis has become
repeated use (off-label) has been associated associated with the rare (estimated 0.02%
with acute renal failure in cats. The manu- incidence39) lethal liver toxicity of carprofen.
facturer cautions against such repeated use. All dogs with hepatotoxicosis have a hepa-
Blood urea nitrogen (BUN) and creatinine topathy; however, not all cases of hepatopa-
elevations occur relatively late in renal disease; thy are lethal. This hepatotoxicosis does not
therefore, screening urine for protein has been appear to be associated with dose or dura-
suggested for early disease detection. Any tion of administration, and no epidemiologi-
positive screening result should be followed by cal study has shown the hepatotoxicosis to
measurement of the urine protein:creatinine be breed related. A hypothesis for carprofen-
ratio for a more complete assessment. Any related hepatotoxicosis is that reactive acyl

FIGURE 5.11 Cyclooxygenase presence in the kidney.35,36

184 Chronic Pain in Small Animal Medicine

glucuronide metabolites are generated that

TABLE 5.4 Approximate plasma half-life of
can covalently bind and hepatize hepatocyte hepatic enzymes in the dog and cat
proteins, thereby promoting an immunologi-
cal response in the liver.40 – 42 Enzyme Dog Cat
It is good advice to characterize liver Alanine aminotransferase 40–61 3.5 hours
enzymes before and during NSAID admin- (ALT) hour
istration, especially when an NSAID is being
Aspartate aminotransferase 12 hours 1.5 hour
administered long-term. However, an increase (AST)
in liver enzymes is difficult to interpret, as any
chronic drug administration can cause an ele- Glutamate dehydrogenase 18 hours –
(GLDH)
vation, and liver enzymes are not a good mea-
sure of hepatic function. When liver enzymes Alkaline phosphatase (ALP)
are elevated and concern for liver function
Hepatobiliary isoenzyme 66 hours 6 hours
is present, liver function tests should be per-
formed. Mere elevation of liver enzymes may Corticosteroid isoenzyme 74 hours –
not be cause for discontinuing an NSAID. See Intestinal isoenzyme 6 min 2 min
Table 5.4 and Figures 5.12 and 5.13.

FIGURE 5.12 Subcellular location of hepatobiliary enzymes and relative magnitude and duration of
increase of plasma activities following acute, severe, diffuse injury to the liver.

FIGURE 5.13 Simplified algorithm for investigation of abnormal hepatic tests in an animal without severe
anemia. Concurrent extrahepatic diseases such as lymphocytic-plasmacytic enteritis, pancreatitis,
heart failure, and endocrinopathies can cause hepatic tests to be abnormal.
 Chapter 5 Nonsteroidal Anti-Inflammatory Drugs 185

ASPIRIN Topical irritation and physical damage to the

Aspirin presents unique risk factors to the

gastric mucosa barrier may result from a pH-
mediated effect of mucosal hydrophobicity 5
canine patient. Aspirin is both topically and from direct contact between aspirin and
and systemically toxic (even at low doses the gastric epithelium. In the highly acidic
of 5–10 mg/kg SID), chondrodestructive, gastric lumen, aspirin is mostly non-ionized
causes irreversible platelet acetylation, and is and lipid soluble. In this form, it can freely
associated with gastrointestinal bleeding of diffuse into mucosal cells where, at neutral
approximately 3 mL/day.43,44 pH, aspirin becomes ionized and water sol-
The American Medical Association uble. The water-soluble form cannot pen-
(AMA) reports that 16,500 people die each etrate lipid cell membranes and consequently
year associated with NSAID toxicity,45 becomes trapped in mucosal cells. The pres-
yet with an overrepresentation of aspirin; ence of intracellular aspirin causes increased
pet owners often consider aspirin benign membrane permeability, leading to an influx
because it is available over-the-counter, and of hydrogen ions from the gastric lumen or
the media suggest it is safe. Even low-dose an increased ‘back-diffusion’ of acid across
aspirin has consistently been associated with the gastric mucosal barrier. This increased
gastrointestinal petechiation and hemor- acid back-diffusion is crucial in initiating
rhage. Aspirin does not have an FDA license and perpetuating mucosal injury. The result
for use in the dog, and the plasma concentra- is edema, inflammation, hemorrhage, ero-
tions regarded as being therapeutic are rela- sions, and ulceration, as well as submucosal
tively close to the toxic levels.46 In theory, capillary damage.
since aspirin causes gastrointestinal lesions, Standard formulations of buffered aspi-
it would be inappropriate to sequentially rin have been shown not to provide sufficient
progress from aspirin to a strongly COX-2– buffering to neutralize gastric acid or to pre-
selective NSAID (which might restrict the vent mucosal injury. 51
COX-2 necessary for repair) without an ade- Enteric-coated aspirin causes less gastric
quate washout period following the aspirin. injury in humans compared with that from
It is also perilous to use aspirin together with administration of nonbuffered or buffered
another NSAID or corticosteroid. aspirin, but absorption is quite variable, 52,53
Development of gastric mucosal hemor- with coated tablets having been observed to
rhage, erosion, and ulceration associated pass in the feces. See Table 5.5 and Figures
with administration of NSAIDs is largely 5.14 and 5.15.
attributed to reduction of prostaglandin E
(PGE) synthesis in the gastric mucosa. PGs
play a key role in protection of the gastro- ANTIULCER AGENTS
intestinal mucosal barrier by (1) increas-
ing mucus and bicarbonate secretion, One goal of antiulcer treatment is to lower
(2) enhancing mucosal blood flow, (3) stimu- intragastric acidity so as to prevent fur-
lating epithelial cell growth, and (4) sup- ther destruction of the gastrointestinal tract
pressing acid secretion. mucosa. Cimetidine, a histamine (H2)-receptor
In addition, aspirin can cause direct cel- blocker, is commonly used. Cimetidine
lular toxicosis, independent of the inhibition requires dosing three to four times daily; how-
of PG synthesis. Aspirin may cause gastric ever, it is not effective in preventing NSAID-
mucosal injury via two mechanisms: (1) induced gastric ulceration. Omeprazole is a
direct damage to the gastric epithelial cell and substituted benzimidazole that acts by inhibit-
(2) indirect damage caused by its anti-prosta- ing the hydrogen-potassium ATPase (proton
glandin effects.46 The erosive effects of aspi- pump inhibitor) that is responsible for the
rin on the canine stomach have been known production of hydrogen ions in the parietal
since 1909, when Christoni and Lapressa cell. It is 5–10 times more potent than cimeti-
administered 150–200 mg of aspirin to dogs dine for inhibiting gastric acid secretion and
and noted gastric lesions.47 Interestingly, the has a long duration of action, requiring
discovery of aspirin’s ulcerogenic properties once-a-day administration. It may be use-
resulted in its use in the study of gastroduo- ful in decreasing gastric hyperacidity but has
denal ulcer disease in animal models.48,49 minimal effect on ulcer healing. Misoprostol
186 Chronic Pain in Small Animal Medicine

TABLE 5.5 Risk factors for NSAID-induced gastrointestinal complications (human)53

Risk factor Estimated increased risk
Established Prior clinical GI event (ulcer/complication) 2.4–4×

Advanced age (65+) 2–3.5×

Concomitant anticoagulation therapy 3×
Concurrent corticosteroid use 2×
High-dose NSAID or multiple NSAID use 2–4×
Major comorbidity (e.g., heart disease) Variable
Probable Long-term NSAID use
Coexisting Helicobacter. pylori infection
Dyspepsia caused by an NSAID

is a synthetic PGE1 analogue used to prevent

gastric ulceration. It decreases gastric acid
secretion, increases bicarbonate and mucus
secretion, increases epithelial cell turnover,
and increases mucosal blood flow. Both
cimetidine and misoprostol require dosing
three to four times daily, and adverse reac-
tions mimic those of gastritis and ulcer-
ations. See Table 5.6.

WASHOUT
FIGURE 5.14 Some human patients take high-
dose aspirin for their cardiac condition and a Washout between NSAIDs is poorly
‘third-generation’ NSAID for their musculoskel- researched; however, one survey report3
etal discomfort, thereby increasing their potential suggests that failure to implement a wash-
for gastric damage.55
out between different NSAIDs may put the
patient at risk for gastrointestinal pathology.
One must consider the reason for changing
NSAIDs when considering a washout period.
If the reason for change is efficacy in the
healthy dog, ‘washout’ is a lesser issue than
if the reason for change is intolerance. With
intolerance, a minimal washout time should
be no less than the time required to recover
from adverse clinical signs. Most agree that
washout following aspirin is a unique sce-
nario, due in part to the phenomenon of aspi-
rin-triggered lipoxin (ATL). 55 Five to seven
FIGURE 5.15 Potential for increased gastroin- days’ washout following aspirin is probably
testinal (GI) damage from the concurrent use adequate. One study has been conducted
of aspirin with another NSAID resides with the
where injectable carprofen was followed by
aspirin-triggered lipoxin (ATL) pathway. ATL is a
protective mechanism with aspirin consumption,
once-a-day dosing with deracoxib. 56 In this
which is blocked with the concurrent administra- study of a limited number of healthy dogs,
tion of another NSAID, giving rise to an alterna- no difference was noted in following inject-
tive pathway for arachidonic acid that actually able carprofen with either oral carprofen or
enhances the potential for aspirin toxicity.55 oral deracoxib. Pain relief during a washout
 Chapter 5 Nonsteroidal Anti-Inflammatory Drugs 187

TABLE 5.6 Pharmacological agents for NSAID gastrointestinal prophylaxis and treatment
Group Generic name Brand name Dose 5
Proton pump Omeprazole Prilosec Canine: 0.7 mg/kg, PO
inhibitors
(PPI) Lansoprazole Prevacid
Rabeprazole Aciphex
Pantoprazole Protonix
Esomeprazole Nexium
PG analog Misoprostol Cytotec Canine: 2–5 μg/kg, TID, PO
H2 blockers Cimetidine Tagamet Canine/Feline: 10 mg/kg, TID, PO, IV, IM
Feline: 3.5 mg/kg, bid, PO or 2.5 mg/kg, BID, IV
Ranitidine Zantac Canine: 2 mg/kg, TID, PO, IV
Famotidine Pepcid Canine/Feline: 0.5 mg/kg, SID, PO, IV, IM, SQ or
0.25 mg/kg, BID, PO, IV, IM, SQ
Nizatidine Axid Canine: 2.5–5 mg/kg, SID, PO
Mucosal sealant Sucralfate Carafate Canine: 0.5–1 g, TID–BID, PO
Feline: 0.25 g, TID–BID, PO

period can be obtained by the use of other of NSAIDs, but such a decision must be
classes of drugs, e.g. acetaminophen, trama- justified.) Second, a baseline status should
dol, amantadine, gabapentin, or opioids. be established for subsequent comparison,
should the patient show clinical signs sug-
gestive of drug intolerance. For the patient
ENHANCING RESPONSIBLE on a long-term NSAID protocol, the fre-
quency of laboratory profiling should be
NSAID USE determined by clinical signs and age. The
minimal effective dose should always be the
Every pet owner who is discharged with therapeutic objective, and routine examina-
medication, including NSAIDs, should have tion of the animal constitutes the practice of
the following questions addressed: good medicine. Since alanine aminotransfer-
ase (ALT) is more specific than serum alka-
• What is the medication supposed to do? line phosphatase (SAP) as a blood chemistry
• What is the proper dose and dosing for liver status, an elevation three to four
interval? times laboratory normal should prompt a
• What potential adverse response(s) are subsequent liver function test. Because the
possible? kidney expresses both COX isozymes con-
• What should I do if I observe an adverse stitutively, no one NSAID can be presumed
response? Both verbal and written instruc- safer than another for renal function, and
tions should be given. any patient that is hypotensive or insuf-
ficiently hydrated is at risk during NSAID
Preadministrative urinalysis and blood administration.
chemistries are well advised prior to dis- NSAIDs play a major role in a periop-
pensing NSAIDs for two primary reasons. erative protocol for healthy animals due to
First, the pet may be a poor candidate for their role as anti-inflammatories, analgesics,
any NSAID, i.e., it may be azotemic or have and antipyretics. NSAID inclusion helps pre-
decreased liver function. (These physiologi- vent CNS windup and provides synergism
cal compromises may not preclude the use with opioids. 56 Surgery cannot be performed
188 Chronic Pain in Small Animal Medicine

without resultant iatrogenic inflammation, the injectable product has a different phar-
and the best time to administer the anti- macokinetic profile than the oral product
inflammatory drug is preemptively, before due to its mixed-micelle formulation. Given
the surgery. It is imperative that surgical intramuscularly, the maximum concentra-
patients be sufficiently hydrated if NSAIDs tion (Cmax) of the injectable form (Cmax:
are used perioperatively. Under the influence 8.0 μg/mL at 1.5–8 hours) is half that of
of gaseous anesthesia, renal tissue may suffer the oral formulation (Cmax: 16.9 μg/mL at
from underperfusion, at which point PGs are 0.5–3 hours) and is reached later,60 sug-
recruited to assist with this perfusion, and if gesting that it be given several hours prior
the patient is under the influence of an anti- to surgery for maximal preemptive effect.
prostaglandin (NSAID), renal function may There are few objective pain assessment
be at risk. In human medicine, some suggest models for soft tissue from which to com-
that NSAIDs should not be withheld from pare NSAID efficacy.
adults with normal preoperative renal func- In contrast, force plate gait analysis in
tion because of concerns about postoperative an orthopedic model has become the stan-
renal impairment. 58 dard for ranking NSAID efficacy in canids
on an objective basis.60 Although several
NSAID manufacturers have made public
their studies comparing one or two prod-
NSAIDs AND BONE HEALING ucts, none have compared the large group
of NSAIDs most commonly used in clinical
Among their many uses, COX inhibitors
practice. Dr. Darryl Millis and colleagues at
(NSAIDs) are widely administered for mus-
the University of Tennessee reported such a
culoskeletal conditions, including post-
study,61 conducted independently of com-
surgical orthopedic analgesia. It has been
mercial support, using the force plate gait
hypothesized that these agents may modu-
analysis model, which is considered to be
late bone, ligament, or tendon healing by
the gold standard for objective assessment
inhibiting PG production. Results from ani-
(Figure 5.16).
mal models do suggest that NSAIDs and
Measuring ground reaction forces is
COX-2 inhibition may have a minimal effect
the most common way to objectively assess
on bone, tendon, and ligament healing, espe-
weightbearing in dogs. Using a force plate
cially at earlier stages, but bear no significant
platform, investigators can compare with
impact on the ultimate long-term outcome.
certainty the degree of lameness over a
In a review on the subject, 58 the authors pro-
period of time. In its simplest terms, force
posed that despite the contribution of PGs in
plate gait analysis measures ground reaction
the dynamic process of normal bone healing
forces that result when a dog places its limb
and pathophysiology, alternative mecha-
during a specific gait. The three orthogonal
nisms may maintain normal bone function in
ground reaction forces generated – vertical,
the absence of COX-2 activity. Direct com-
craniocaudal, and mediolateral – represent
parison studies suggest that adverse effects
the total forces transmitted through one limb
of selective COX-2 inhibitors on bone heal-
ing are lesser in magnitude than those of
nonselective NSAIDs. 58

EFFICACY
It is difficult to differentiate NSAID efficacy
in the perioperative setting, because most
clinicians administer NSAIDs as part of a
multimodal (balanced) analgesic protocol.
Perioperative analgesia from an NSAID
alone is rarely sufficient. Injectable carpro-
fen was designed for perioperative use, yet FIGURE 5.16 Comparative efficacy of contempo-
for labeled intramuscular administration; rary NSAIDs used in veterinary medicine.61
 Chapter 5 Nonsteroidal Anti-Inflammatory Drugs 189

FIGURE 5.17 Each gait generates a specific pattern of ground reaction forces. The first peak in vertical
forces (Z) of the m-shaped pattern of the walk represents the peak vertical forces associated with initial
paw strike. Y and X represent the craniocaudal and mediolateral forces, respectively. Breaking and
propulsion impulses are indicated by the shaded areas of the craniocaudal graphs.

to the ground (Figure 5.17). Typically, peak a given treatment regimen. Comparing the
force in the vertical axis is used to objectively relative amount of weight placed by the com-
measure limb function. When comparing promised limb on the force plate under dif-
NSAID efficacy, lame dogs (often with long- ferent NSAID regimens generates a relative
standing anterior cruciate ligament compro- rank of NSAID efficacy, or pain relief. See
mise) are walked over a force plate during Table 5.7.

TABLE 5.7 Comparison of NSAID efficacy studies used for U.S. FDA approval
Drug Primary assessment method Ground reaction force assessment
Carprofen • Subjective owner and veterinary assessment • No significant difference between
indicated improvement more likely in treated dogs placebo dogs and treated dogs
Etodolac • Ground reaction forces • Peak vertical force improved 0.4%,
2.3%, and 1.6% with placebo,
low-dose, and high-dose
treatments, respectively
• Vertical impulse improved 0.4%,
0.13%, and 0.22%, respectively
Deracoxib • Ground reaction forces • Peak vertical force improved 7.4%
with treatment vs. placebo
• Vertical impulse improved 4.9% with
treatment compared with placebo
Tepoxalin • Subjective changes compared with carprofen • Not measured
• No placebo comparison
• Subjective improvement similar to carprofen
Meloxicam • Subjective assessment of lameness, • Not measured
weightbearing, pain on palpation, and overall
improvement compared with placebo
• Significant improvement noted on day 14 of one
14-day study
• Significant improvement noted in the parameter
of overall assessment on day 7 by veterinary
assessors and on day 14 by owners in a second
study
Firocoxib • Subjective comparison to etodolac • Ground reaction forces were
• No comparison to placebo determined in a subset of patients
• Subjective efficacy comparable to etodolac • Results were comparable between
firocoxib and etodolac
190 Chronic Pain in Small Animal Medicine

Kinematic gait analysis, or motion administered in the morning or in the eve-

analysis, is used less frequently than force ning? Some argue that morning adminis-
platform analysis, but its use is increasing, tration is most logical, taking advantage of
mostly in research laboratories. Kinematic C max during that time of the day when the
evaluation measures changes in joint angles dog might be most active. Others suggest
with gait, the velocity and acceleration of the NSAID should be dosed so that C max is
changes in joint angles, and stride length, reached to ensure maximal rest for the ani-
as well as gait swing and stance times. mal, proposing that the animal performs
Kinematic evaluation is often combined best following a good night’s rest. There is no
with force platform gait analysis, providing consensus.
a powerful method of detecting abnormali-
ties and response to therapy.
Objective measurement of lameness With or Without Food
severity in cats is quite difficult, as cats
do not comply with force plate protocols. Many of the contemporary NSAIDs are
However, pressure mats have been used to labeled for use either with or without food.
reveal the distribution of pressures associ- Administration with food takes advantage
ated with paw contact,63 so that pressures of the increased production of gastric bicar-
on each digital pad and on the metacarpal bonate and associated buffering. Feeding
pad could be measured quantitatively fol- an NSAID together with food may enhance
lowing onychectomies. Use of the pressure acceptability in some dogs.
mat to evaluate lameness in cats will likely
see further development. The use of accel-
eration-based activity monitors may also NSAID Compatibility
allow for future objective measurement of with Other Agents
improved mobility following treatment for
osteoarthritic conditions in the cat.64 NSAIDs are highly protein bound and may
compete with binding of other highly pro-
tein-bound drugs, particularly in the hypo-
proteinemic animal, resulting in altered drug
ADMINISTRATION concentrations. Fortunately, the number of
other highly protein bound drugs is minimal.
Table 5.8 lists drugs and agents that may be
Time of Administration influenced by the concurrent administration
Time of administration is a common ques- of NSAIDs. Because pet owners tend to be
tion arising from NSAIDs labeled for dos- using more and more ‘natural’ products,
ing once daily: i.e., should the drug be some of which can potentially influence the

TABLE 5.8 NSAIDs: potential drug interactions64

May increase the toxicity May decrease the Toxicity may be
Drug of efficacy of increased by
Classical NSAIDs Warfarin, methotrexate, Furosemide, thiazide, Aminoglycosides,
(clinically significant valproic acid, midazolam, ACE inhibitors, furosemide, cyclosporine
COX-1 inhibition) furosemide, spironolactone, β-blockers (renal) glucocorticoids
sulfonylureas, heparin (gastrointestinal), heparin,
gingko, garlic, ginger,
ginseng (hemorrhage)
Coxibs and relatively Warfarin, methotrexate Furosemide, thiazides, Aminoglycosides,
COX-2–selective valproic acid, midazolam, ACE inhibitors, furosemide, cyclosporine
agents furosemide, spironolactone, β-blockers (renal), glucocorticoids
sulfonylureas (gastrointestinal)
Phenylbutazone, Warfarin, sulfonylureas Phenobarbital, alcohol,
acetaminophen rifampin, metoclopramide
 Chapter 5 Nonsteroidal Anti-Inflammatory Drugs 191

TABLE 5.9 Potential herb-drug interactions65

Herb Interacting drugs Results 5
St. John’s wort Cyclosporine, fexofenadine, • Decreased plasma drug concentrations
midazolam, digoxin, tacrolimus,
amitriptyline, warfarin, theophylline
Gingko Warfarin, heparin, NSAIDs • Bleeding
Omeprazole • Decreased plasma concentrations
Ginseng Warfarin, heparin, NSAIDs, opioids • Bleeding
• Falsely elevated serum digoxin levels
(laboratory test interaction with ginseng)
• Decreased analgesic effect (laboratory
test interaction with ginseng)
Garlic, chamomile, Warfarin, Heparin, NSAIDs • Bleeding
ginger

concurrent use of an NSAID (Table 5.9), it is in nine of nine dogs.71 Many oncologists are
advisable to ask owners for a complete list- now prescribing COX-2 inhibitors in con-
ing of everything they are giving their pet by junction with traditional modalities of sur-
mouth. gery, radiation therapy, and chemotherapy
for a variety of tumors.

NSAIDs and Cancer

Human studies have shown that patients
Cats and NSAIDs
receiving long-term NSAID therapy have There are approximately 69 million cats
a reduced risk of colorectal cancer. 66 Such in the United States72 and approximately
observations have led to research into the 10 million in the UK.73 Radiographically
role of NSAIDs as a preventative measure detectable degenerative joint disease (DJD)
against cancer development and as adjunc- is apparently detectable in as high as 90%
tive antineoplastic therapy. Published data of cats over 12 years of age.74 Efficacy of
also suggests that control of oncological NSAIDs for relief of chronic pain in the cat
pain can impact on the course of cancer is difficult to demonstrate but empirically
progression. 67 embraced. Probable reasons for the relative
PGs play a major role in cancer develop- void of evidence base for NSAIDs in cats
ment, including inhibition of immune sur- include:
veillance, promotion of angiogenesis, and
inhibition of apoptosis.68,69 High levels of • Assumption by pharmaceutical manufac-
PGs are found in tumors of many types that turers that the market for cat analgesics is
may exert effects in an autocrine or para- not financially rewarding.
crine fashion, and upregulation of COX-2 • Difficulty of identifying pain in cats, and
has been directly associated with tumor therefore indications for administration.
aggression.70 • Scarcity of information about NSAIDs in
In addition to decreasing PG production cats.
via inhibition of COX-2, NSAIDs also have • Potential risk of NSAID toxicity in cats.
COX-independent anticancer mechanisms, Salicylate toxicity in cats is well established.
including activation or inhibition of cellular
signaling pathways via upregulation or inhi- Cats present a unique susceptibility to
bition of oncogenes. Preliminary results of a NSAID toxicity because of slow clearance
study involving deracoxib, a COX-2–selec- and dose-dependent elimination. Cats have
tive inhibitor, as therapy for transitional cell a low capacity for hepatic glucuronidation
carcinoma have demonstrated stable disease of NSAIDs,75 which is the major mechanism
192 Chronic Pain in Small Animal Medicine

of metabolism and excretion for this class of • Provide pet owners with both oral and writ-
drug. ten instructions for responsible NSAID use.
Acetaminophen toxicity in cats results in • Conduct appropriate patient chemistry/
methemoglobinemia, liver failure, and death. urine profiling. Do not use in patients with
Cats are particularly susceptible to acet- reduced cardiac output or in patients with
aminophen toxicity due, in part, to defective overt renal disease.
conjugation of the drug and conversion to a • Conduct routine check-ups and chemistry
reactive electrolytic metabolite. profiles for patients on chronic NSAID regi-
Because of its delivery form as an elixir, mens. Do not fill NSAID prescriptions with-
meloxicam is sometimes used preferentially out conducting patient examinations.
in small dogs and cats. Only carprofen, • Caution pet owners regarding supplementa-
meloxicam, and robenacoxib are approved tion with over-the-counter NSAIDs.
for cats (country dependent). The manu- • Administer gastrointestinal protectants for
facturer of meloxicam has recommended at-risk patients on NSAIDs.
reducing the original approval dose from • Avoid NSAID administration in puppies
0.2 to 0.1 mg/kg because of some initial and pregnant animals.
gastrointestinal problems. This suggests • NSAIDs may decrease the action of angio-
particular attention be given to accurate tensin-converting enzyme (ACE) inhibitors
dosing of small dogs and cats. As with all and furosemide, a consideration for patients
NSAIDs in dogs or cats, gastric ulcerations being treated for cardiovascular disease.
have been observed. • Geriatric animals are more likely to be
treated with NSAIDs on a chronic schedule;
therefore, their ‘polypharmacy’ protocols
Looking to the Future and potentially compromised drug clear-
ance should be considered.
NSAIDs are the fastest-growing class • Provide sufficient hydration to surgery
of drugs in both human and veterinary patients administered NSAIDs.
medicine because of their relatively safe • Report ADEs to the product manufacturers.
resolution of a wide range of pathological
conditions. Based upon current understand-
ing of their mode of action, future NSAIDs
will likely not be developed to be ‘stronger
longer’, i.e., supremely COX-2 selective, SUMMARY
with a very long half-life. Instead, NSAID NSAIDs are a magnificent class of agents
development may well offer species- and/or that have changed the practice of both
disease-specific molecules, increased safety human and veterinary medicine. Their
profiles, and augmenting benefits such as utilization will likely continue for decades
nitric oxide (NO) inhibition. At present, to come as we learn more specific appli-
this class of drug offers immense benefits, cations and features of these molecules.
constrained most often only by issues of Additionally, NSAIDs are market leaders
safe, responsible use. for pharmaceutical companies, and public
awareness is a tenet in the overall market-
ing strategy for these agents. Consequently,
Improving Safety this class of drug is not only a fundamental
The following guidelines can be used to min- cornerstone of medical practice but also an
imize risk factors for NSAID ADEs: area of public scrutiny. As with all medica-
tions, adverse reactions from NSAIDs are
• Proper dosing. possible; however, the benefits far outweigh
• Administer the minimal effective dose. problems associated with their use. With
• Dispense in approved packaging together responsible use of NSAIDs, we must always
with owner information sheets. strive for the minimal effective dose, within
• Avoid concurrent use of multiple NSAIDs established dosing ranges, and assess the
and NSAIDs with corticosteroids. benefit:risk ratio for each individual patient.
• Refrain from use of aspirin. See Tables 5.10 and 5.11.
TABLE 5.10 U.S. FDA-approved NSAIDs with product details
Deramaxx® Rimadyl® Previcox® Metacam® EtoGesic® Zubrin®
Company Novartis Pfizer Merial Boehringer-Ingelheim Fort Dodge Schering-Plough
Active ingredient Deracoxib Carprofen Firocoxib Meloxicam Etodolac Tepoxalin
Formulation 25 mg, 75 mg, 100 mg Caplets/Chewable Chewable tablets Liquid suspension: to 150 mg, 300 mg Rapidly
scored chewable tablets: 25, 75, containing 57 or be squirted on food scored tablets disintegrating
tablets 100 mg scored 227 mg, Injectable: 5 mg/mL, tablets of 30, 50,
caplets or scored palatability 68% SC or IV 100, or 200 mg
chewable tablets
SC injectable: 50 mg
carprofen/mL
Dosage For the control of pain Oral and injectable: 5 mg/kg oral once 0.2 mg/kg injectable 10–15 mg/kg once 10 mg/kg orally or
and inflammation 4.4 mg/kg once daily daily once or oral once: daily 20 mg/kg on the
associated with or 2.2 mg/kg twice Tablets are scored, followed by Adjust dose until a initial day of
orthopedic surgery in daily and dosage 0.1 mg/kg oral satisfactory clinical treatment,
dogs: 3–4 mg/kg. Give For postoperative should be suspension daily response is obtained followed by a daily
prior to surgery for pain, administer calculated in Cats: 0.3 mg/kg reduced to minimum maintenance dose
postoperative pain 2 hours before the half-tablet presurgical one-time effective dose. of 10 mg/kg
For the control of pain procedure increments dose (contraindicated
and inflammation to follow in cats with
associated with OA in another NSAID or
dogs: 1–2 mg/kg daily meloxicam)
Indications For the control of pain For the relief of pain For the control of Control of pain and For the management Control of pain and
and inflammation and inflammation pain and inflammation of pain and inflammation
associated with associated with OA inflammation associated with OA in inflammation associated with
orthopedic surgery in in dogs and the associated with dogs associated with osteoarthritis in
dogs weighing control of OA in dogs Postoperative pain and osteoarthritis in dogs
<1.8 kg postoperative pain in inflammation dogs
For the control of pain soft tissue and associated with
and inflammation orthopedic surgeries orthopedic surgery,
associated with OA in dogs ovariohysterectomy,
and castration in cats
when administered
prior to surgery
Chapter 5 Nonsteroidal Anti-Inflammatory Drugs 193

(Continued)
5
TABLE 5.10 U.S. FDA-approved NSAIDs with product details (Continued)
194

Deramaxx® Rimadyl® Previcox® Metacam® EtoGesic® Zubrin®

Mechanism of A coxib-class drug that Inhibition of COX Inhibition of COX MOA not on label Inhibition of COX COX and LOX
action uniquely targets enzyme activity Oxicam-class NSAID activity inhibitor: ‘dual
COX-2 while sparing In vitro selective In vitro studies show Inhibits macrophage pathway inhibitor
COX-1 against COX-2 it to be highly chemotaxis of AA metabolism’
selective for COX-2
in canine blood
Maximum 2 hours Oral: Cmax of 16.9 μg/ Dogs: 2.5 hours 1.08–1.6 hour 2.3 ± 1.4 hours
concentration mL at 0.5–3 hours (Injection) and
(Tmax) Injectable: Cmax of 8.0 7.5 hours (oral)
μg/mL at 1.5–8 hours Cats: 1.5 hours
postinjection
Half-life 3 hours 8 hours in dog 7.8 hours Dogs: 24 hours 7.6–12 hours 2.0 ± 1.2 hours
Cats: 15 hours converts to the
Chronic Pain in Small Animal Medicine

After injection active metabolite

which has a long
half-life
Metabolism and Metabolism primarily Liver biotransformation: Primarily hepatic Not on label Primarily hepatic Primarily hepatic
excretion liver 70%–80% in feces metabolism and metabolism and with excretion
Excretion to feces is and 10%–20% in fecal excretion fecal excretion through feces
75%, urine excretion urine Enterohepatic 99%, minor urine
is 20% Some enterohepatic recirculation
circulation
Side effects within Vomiting, incisional Black or tarry stools, Vomiting, diarrhea, Vomiting, softstools, Weight loss, fecal Vomiting, diarrhea,
licensing studies lesions hypoalbuminemia, decreased appetite diarrhea, abnormalities, gastric lesions,
Serious adverse dermatological (use of this product inappetence, hypoproteinemia, decrease in total
reactions changes, increased at doses above the epiphora, small intestine protein, albumin
associated with liver enzyme levels, recommended autoimmune erosions and calcium,
this drug class idiosyncratic 5 mg/kg in puppies hemolytic anemia, death
can occur hepatotoxicosis less than 7 months thrombocytopenia,
without warning of age has been polyarthritis,
and in rare associated with pyoderma
situations result serious ADEs,
in death including death)
TABLE 5.10 U.S. FDA-approved NSAIDs with product details (Continued)
Deramaxx® Rimadyl® Previcox® Metacam® EtoGesic® Zubrin®
Packaging 30 count 14, 60, 150 count 10 and 30 count Oral: 1.5 mg/mL– 10, 7, 30, and 90 count Boxes containing 10
90 count 20 mL bottle of blister packs, 60 32 and 100 mL foil blisters each
injectable count bottles dropper bottles
Injection: 5 mg/mL in a
10 mL vial
Marketing status By prescription only By prescription only By prescription only By prescription only By prescription only By prescription only
Protein blinding >90% >99% >96% >99% >99% >98%
Bioavailability >90% >90% 38% Nearly 100% Nearly 100%
Concurrent use Concomitant use with Concomitant use with Concomitant use Concurrent use with Concomitant use with Concomitant use
statement any other anti- any other anti- with any other potentially other anti- with any other
inflammatory drugs, inflammatory drugs, anti-inflammatory nephrotoxic drugs inflammatory drugs, anti-inflammatory
such as other NSAIDs such as other drugs, such as should be carefully such as other drugs, such as
and corticosteroids, NSAIDs and other NSAIDs and approached NSAIDs and other NSAIDs and
should be avoided or corticosteroids, corticosteroids, Concomitant use with corticosteroids, corticosteroids,
closely monitored should be avoided or should be avoided other anti- should be avoided should be avoided
closely monitored or closely inflammatory drugs, or closely monitored or closely
monitored such as NSAIDs and monitored
corticosteroids,
should be avoided or
closely monitored
Pre-prescribing Thorough history and Thorough history and Thorough history Thorough history and Thorough history and Geriatric
advice physical exam physical exam and physical exam physical exam physical exam examination
Appropriate laboratory Appropriate laboratory Appropriate Appropriate laboratory Appropriate laboratory Appropriate
tests tests laboratory tests tests tests laboratory test
Miscellaneous In vitro: showed Not evaluated for In vitro: showed more Give with a meal to
more COX-2 intramuscular COX-2 inhibition enhance
inhibition than injection than COX-1 absorption
COX-1
Chapter 5 Nonsteroidal Anti-Inflammatory Drugs 195

5
 TABLE 5.11 NSAID pharmacokinetic parameters and dose recommendations for dogs and cats
Dog half-life Species Clearance
NSAID (hours) Dose/route Ref. Cat half-life (hours) Dose/Route Ref. difference? mechanisms
Acetaminophen 1.2 100 mg/kg PO 76 0.6 20 mg/kg PO 76 Cat > Dog Glucuronidation and
sulfation
1.2 200 mg/kg PO 76 2.4 60 mg/kg PO 76
4.8 120 mg/kg PO 76
Aspirin 7.5–12 25 mg/kg PO 77 22 20 mg/kg IV 78 Cat > Dog Glucuronidation and
glycination
37.6 IV? 79
Carprofen 5 25 mg PO 80 20 4 mg/kg IV 78 Cat > Dog Glucuronidation and
oxidation
8.6 25 mg bid PO 80 19 4 mg/kg SC, IV 81
196 Chronic Pain in Small Animal Medicine

7 days
7 25 mg SC 80
8.3 25 mg bid SC 7 days 80
Flunixin 3.7 1.1 mg/kg IV 82 1–1.5 1 mg/kg PO, IV 83 Cat > Dog Glucuronidation and
active transport
6.6 2 mg/kg PO 84
Ketoprofen 1.6 for 1 mg/kg PO racemic 85 1.5 for S-ketoprofen 2 mg/kg IV racemic 86 Cat = Dog Glucuronidation and
S-ketoprofen thioesterification
0.6 for R-ketoprofen 2 mg/kg IV racemic 86
0.9 for S-ketoprofen 1 mg/kg PO racemic 86
0.6 for R-ketoprofen 1 mg/kg PO racemic 86
0.5 for S-ketoprofen 1 mg/kg IV S-ketoprofen 87
0.5 for R-ketoprofen 1 mg/kg IV R-ketoprofen 87
Meloxicam 12 0.2 mg/kg PO 85 15 0.3 mg/kg SC Label Cat < Dog Oxidation
24 0.2 mg/kg PO, SC, IV 88
Piroxicam 40 0.3 mg/kg PO, IV 89 12 0.3 mg/kg PO, IV 90 Cat < Dog Oxidation

Note: Comparison of nonsteroidal anti-inflammatory drug elimination half-lives in cats and dogs and relationship with clearance mechanism.73 Correlation to base dosing intervals is undetermined.
 Chapter 5 Nonsteroidal Anti-Inflammatory Drugs 197

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5
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characteristics, in vitro enzymatic hydrolysis rates, cokinetic comparison of meloxicam and ketoprofen
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administration to dogs. J Pharm Sci 1968;57:828–831. Res Commun 2004;28:415–428.
79. Parton K, Balmer TV, Boyle J, et al. The pharmaco- 87. Lees P, Taylor PM, Landoni FM, et al. Ketoprofen
kinetics and effects of intravenously administered in the cat: pharmacodynamics and chiral pharma-
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1996;60:144–151. Ther 2003;26:259–263.
CHAPTER

6
Nutraceuticals
INTRODUCTION Education Act of 1994 (U.S.), the manu-
facturer is responsible for determining that
The world market for pet nutraceuticals was the supplement is safe and that any repre-
worth $960 million in 2004. About 60% sentations or claims made about it are ade-
of this was to dogs, a quarter to cats, and quately substantiated. Dietary supplements
10% to horses.1 Joint health products for do not need to be approved by the FDA
pets accounted for nearly half of the mar- before they are marketed and subsequently
ket, followed by vitamins, minerals, amino do not carry consumer confidence of FDA
acids, and antioxidants collectively con- endorsement.
stituting 20%. The widespread interest in Degenerative joint disease (DJD), or osteo-
nutraceuticals began in 1997 with publica- arthritis (OA), poses major therapeutic prob-
tion of the book entitled The Arthritis Cure lems in pets as well as humans. Treatment
by Dr. Jason Theodosakis. Three years with nonsteroidal anti-inflammatory drugs
later U.S. sales of nutraceuticals topped (NSAIDs) is designed to reduce pain and
$640 million. 2 inflammation, hallmarks of the disease. Yet
long-term use of NSAIDs, notably with com-
plications of inappropriate use,4 has been
associated with adverse effects, including
BACKGROUND gastrointestinal ulceration, hepatic toxicity,
renal failure, and, in some cases, negative
Nutraceuticals are natural, bioactive chemi- effects on chondrocytes and cartilage matrix
cal compounds that have health-promoting, formation.5 Such issues have led researchers
disease-preventing, or medicinal properties. to seek alternatives/adjuncts to NSAIDs for
They are prescribed drugs in a limited num- managing OA. Originally these compounds
ber of countries, but are primarily provided were considered to serve as building blocks
as dietary supplements delivered over the for cartilage and exogenous sources of carti-
counter. A supplement that can be adminis- lage matrix components. The long-standing
tered orally to promote good health and is rationale for using nutraceuticals is that pro-
not a drug is considered a nutraceutical. As vision of precursors of cartilage matrix in
functional foods, nutraceuticals are part of excess quantities may favor matrix synthesis
the daily diet as food and drink. Functional and repair of articular cartilage.
food is characterized (from traditional food) According to the North American Veteri-
‘if it is satisfactorily demonstrated to affect nary Nutraceutical Association (NAVNA),
beneficially one or more target functions in a nutraceutical is ‘a nondrug substance that
the body, beyond adequate nutritional effects is produced in a purified form and adminis-
in a way which is relevant to either the state tered orally to provide compounds required
of well-being and health or the reduction of for normal body structure and function
the risk of a disease’.3 with the intent of improving health and
Dietary supplements are regulated by well-being’. Further, the NAVNA defined a
the Food and Drug Administration (FDA) chondroprotective as an agent that intends
in a different manner from either over- to ‘stimulate cartilage matrix production
the-counter or prescription drugs. As laid by chondrocytes, inhibit matrix degrada-
out in the Dietary Supplement Health and tion, and potentially inhibit periarticular

200 DOI: 10.1201/9781003376422-8

 Chapter 6 Nutraceuticals 201

TABLE 6.1 Nutraceuticals used for OA UNDERSTANDING

Ascorbic acid Hyaluronic acid THE CONCEPTS 6
Avocado/Soybean Hydrolysate collagen
unsaponifiables OA involves cartilage loss from enzymatic
degradation of the extracellular matrix
Boswellia serrata Methylsulfonylmethane (Figure 6.1). This results in loss of proteo-
Bromelain Milk and hyperimmune milk glycans and the cleavage of type II collagen.6
(See Chapter 2 for further explanation.)
Cat’s claw Omega-3-PUFAs
Matrix metalloproteinases (MMPs) and
Chondroitin sulfate Phycocyanin aggrecanases play a major role among the
Cetyl myristoleate oil Ribes nigrum
degradative enzymes. MMPs are similar in
structure but differ somewhat in their pre-
Rosa canina ferred substrates. Collagenases (MMP-1, -8,
Curcumin S-adenosylmethionine and -13) cleave the intact triple helix of colla-
(SAMe) gen.7 Thereafter, the collagen fragments are
susceptible to further proteolysis by gelatin-
Chitosan Selenium
ases (MMP-2 and -9), enzymes that can also
Devil’s claw Strontium cleave aggrecan.8 Stromelysins (MMP-3,
Flavonoids Silicium
-10, and -11) are capable of degrading aggre-
can, denatured type II collagen, and small
Glucosamine Turmeric proteoglycans of the extracellular matrix.9
SO4/Acetyl/HCl Aggrecanases are principal mediators of
Green lip mussel Vitamin D aggrecan degradation, releasing core protein
and glycosaminoglycans (GAGs) constitu-
Ginger Vitamin E
ents of aggrecan into the synovial fluid.10
Willow A number of cytokines, most importantly
interleukin (IL)-1, are considered central to
the induction of degradative enzyme and
microvascular thrombosis’. The two most inflammatory mediator synthesis. Cytokines
popular nutraceuticals are glucosamine and appear to be first produced by cells of the
chondroitin sulfate. See Table 6.1. synovial membrane11 and later by activated

FIGURE 6.1 Although a disease of the total joint, OA characteristically involves the loss of cartilage.
This results from the degradation of aggrecan aggregates and cleavage of type II collagen (see also
pp. 70–101, Chapter 2).
202 Chronic Pain in Small Animal Medicine

chondrocytes.12 Generally, IL-1 is presumed to differences in molecular mass, degree of

to enhance cartilage degeneration and inhibit sulfation, and relative amounts of iduronate
efforts at repair. and glucuronate.17,18 Due to size (range from
To understand the supposition behind the 6 to 50 kDa), the form of chondroitin sul-
use of nutraceuticals, and particularly chondro- fate that is ultimately available after oral
protectives, several tenets must be understood. administration may be affected by intesti-
GAGs are long-chain polymers of disaccha- nal degradation and metabolism within the
rides. There are three major types in cartilage: liver.19 The gastric mucosa contains several
chondroitin sulfate-4 and -6, keratan sulfate, GAG-degrading enzymes, such as exoglyco-
and dermatin sulfate. Chondroitin is the sidases, sulfatases, and hyaluronidase-like
prevalent form in cartilage. GAGs are vital enzymes, capable of digesting chondroi-
in the hydration of cartilage, as they are the tin sulfate. This and the fact that charged
primary water-binding constituents within molecules with a molecular mass exceeding
the matrix. about 180 kDa are unlikely to be absorbed
without an active carrier system suggest the
parent chondroitin sulfate is unlikely to be
CHONDROITIN SULFATE absorbed intact. The monosaccharide build-
ing blocks of chondroitin sulfate (glucuronic
Chondroitin sulfate is one of two primary acid and N-acetylglucosamine) created by its
GAGs responsible for binding of water in digestive hydrolysis might be absorbed, yet
cartilage. The other primary GAG is keratan these hydrolysates likely show different bio-
sulfate. Loss of GAGs, particularly chon- logical and biochemical properties to those
droitin sulfate, occurs early in OA. This loss of the parent structure, for which beneficial
contributes to alterations in water binding in attributes have been proposed.
cartilage and subsequently to impaired car- Clearly, all chondroitin sulfate is not the
tilage mechanics and accelerated cartilage same. Chondroitin sulfate is expensive, and
breakdown. Chondroitin sulfate appears to it is possible that some suppliers may dilute
inhibit degradative enzymes, such as metal- chondroitin sulfate with compounds that
loproteinase, associated with OA. These deg- include sugars like maltose or other GAGs,
radative enzymes break down the cartilage such as dermatan sulfate, keratan sulfate,
and hyaluronan in synovial fluid. heparin, or HA, that can cause analytical
Chondroitin-4 has been derived primar- methods to overestimate contents. Therefore,
ily from mammalian tissues, whereas chon- despite language like ‘quality tested’ appear-
droitin-6 is derived primarily from aquatic ing on labels, there is no basis to compare
species, including shark cartilage. The pro- one product against another or to judge the
posed mechanisms of action for chondroi- quality of different products. ConsumerLab.
tin sulfate are somewhat similar to those of com reported in 2007 that 73% of ‘joint for-
glucosamine: stimulation of GAG synthesis mulas’ tested failed to meet their own label
and inhibition of degradative enzyme syn- claim for chondroitin content. 20 It is incum-
thesis, including MMPs.13 In contrast to bent on the consumer to be knowledgeable
glucosamine, chondroitin sulfate is shown about the product and the manufacturer.
to inhibit IL-1–induced type II collagen Consumers should buy from manufactur-
degeneration14 and improves synovial fluid ers that use United States Pharmacopeia
viscosity by increasing hyaluronic acid (HA) (USP)–grade materials. They should stay
concentration.15 away from products that are backed only by
The molecular weight of chondroitin sul- testimonials and not supported by scientific
fate directly influences its absorption after research. ‘We believe what’s happening with
oral administration, where higher gastroin- chondroitin is economic adulteration. Some
testinal permeability is achieved for low- manufacturers substitute with cheaper mate-
molecular-weight chondroitin sulfate.16 The rials that look like the more expensive, real
form and source of chondroitin sulfate also ingredients,’ says Dr. Tod Cooperman, presi-
apparently influence its pharmacokinetic dent of ConsumerLab.com, an independent
profile; in humans, chondroitin sulfate of testing group that tests and publishes data on
bovine origin is superior to chondroitin human and veterinary supplements for label-
sulfate obtained from shark cartilage due ing accuracy and product purity. 20
 Chapter 6 Nutraceuticals 203

In a placebo-controlled, double-blind
study in dogs with OA, owners and veteri-
narians were unable to distinguish between 6
dogs supplemented with chondroitin sulfate
or placebo after 12 weeks of follow-up. 21

GLUCOSAMINE
Glucosamine action in vitro includes a
reduction in proteoglycan degradation and
inhibition of the synthesis and activity of deg-
radative enzymes and inflammatory media-
tors, such as aggrecanases, MMPs, nitric
oxide (NO), and prostaglandin E2 (PGE 2), FIGURE 6.2 Articular cartilage fibrillation has been
with anabolic effects of GAG stimulation associated with loss of chondrocyte adhesion to
and proteoglycan production, including fibronectin in the extracellular matrix.
aggrecan, but no effect on type II collagen.13
Glucosamine also appears to inhibit Investigators of this observation suggest
NF-κB activity. 22 Glucosamine is a hex- that activation of protein kinase C, consid-
osamine sugar proposed to act as a pre- ered to be involved in the physiological phos-
cursor for the disaccharide units of GAG. phorylation of the integrin subunit, could
Nutritional glucosamine is suggested to pro- be one of the possible mechanisms through
vide the body with extra ‘building blocks’ which glucosamine sulfate restores fibrillated
for the creation of the cartilage matrix. Most cartilage chondrocyte adhesion to fibronec-
glucosamine in the body is in the form of tin, thus improving the repair process in
glucosamine-6-phosphate, 23 while glucos- osteoarthritic cartilage. 28 In trials assessing
amine is commercially available in three improvement in long-term symptomatic eval-
forms: glucosamine hydrochloride, glucos- uation of human knee OA, it was observed
amine sulfate, and N-acetyl-D-glucosamine. that glucosamine hydrochloride does not
Apparently, the form of glucosamine influ- induce symptomatic relief in knee OA to
ences its activity. Glucosamine hydrochlo- the same extent as glucosamine sulfate. 29,30
ride and glucosamine sulfate appear to This raises the question of the importance
inhibit equine cartilage degeneration more of sulfate and its contribution to the over-
consistently than N-acetyl-D-glucosamine in all effects of glucosamine. Glucosamine
vitro. 24 In addition, there is a suggestion that sulfate is highly hygroscopic and unstable.
GAG synthesis may be through promotion of Consequently, during manufacturing, vary-
incorporation of sulfur into cartilage. 25 ing amounts of potassium or sodium chlo-
Investigators have reported that in human ride are added to improve stability. Due to
patients, glucosamine sulfate increases the concerns over valid labeling, commercially
expression of cartilage aggrecan core pro- available capsules or tablets of glucosamine
tein and downregulates, in a dose-dependent sulfate were analyzed. The amount of free
manner, MMP-1 and -3 expression. 26 Such base varied from 41% to 108% of the milli-
transcriptional effects are supported by gram content stated on the label; the amount
reports that glucosamine sulfate increases of glucosamine varied from 59% to 138%
proteoglycan synthesis with no effect on its even when expressed as sulfate.31 Therefore,
physicochemical form, on type II collagen the results obtained with one single prepa-
production, or on cell proliferation in a model ration of glucosamine sulfate, even when
of human osteoarthritic chondrocytes.14 registered as a drug in Europe, cannot be
Osteoarthritic cartilage is characterized extrapolated to the vast majority of over-the-
by articular surface fibrillation, which has counter preparations sold without the appro-
been associated with a significant decrease priate quality controls.
in chondrocyte adhesion to extracellular Persiani et al.32 reported that glucosamine
matrix proteins and, more specifically, to is bioavailable both systemically and in the
fibronectin (Figure 6.2). 27 joint after oral administration of crystalline
204 Chronic Pain in Small Animal Medicine

glucosamine sulfate in human osteoar- Largo et al. 35 found that glucosamine sulfate
thritic patients. ‘The formulation used is the inhibits NF-κB activation and PGE 2 synthe-
original crystalline glucosamine sulphate sis induced by IL-1β in human chondrocytes,
1500 mg once-a-day soluble powder prepa- where NF-κB is considered a key regulator
ration which is a prescription drug in most of tissue inflammation, since it controls the
European and extra-European countries and transcription of a number of proinflamma-
differs from glucosamine formulations avail- tory genes that regulate the synthesis of cyto-
able in the United States and other countries. kines, chemokines, and adhesion molecules.
In fact, the U.S. Dietary Supplements Health NF-κB activity has been shown to be essen-
and Education Act of 1994 documented tial for MMP-1 and MMP-3 upregulation.36
the appearance of several poorly character- Glucosamine sulfate also inhibited the gene
ized dietary supplements containing either expression and protein synthesis of COX-2
inadequate active ingredient quantity, or induced by IL-1β, while no effect on COX-1
other glucosamine salts (e.g. hydrochloride), synthesis was seen.
derivatives (e.g. N-acetyl-glucosamine), or Kuroki et al. 37 have shown that within
dosage forms and regimens. This might also a canine articular cartilage and synovium
provide an explanation for the finding that explant co-culture system, glucosamine or
when other salts, formulations, and/or daily chondroitin sulfate alone retards increased
regimens have been used in clinical trials, the expression of proteinases and inflammatory
results have not been favorable. In particular, mediators associated with IL-1, while the
the recently completed National Institutes combination of glucosamine plus chondroi-
of Health (NIH)-sponsored Glucosamine/ tin sulfate primarily retarded detrimental
Chondroitin Arthritis Intervention Trial effects on matrix molecules.
(GAIT) trial in knee OA, indicated that the Some38 have questioned the potential for
symptomatic effect of glucosamine hydro- biological activity of glucosamine, pointing
chloride at the dose of 500 mg TID did not out that the bioavailability from a single or
differ significantly from placebo. This con- multiple dose of glucosamine hydrochloride
firmed the skepticism concerning the several is only 10–12% in dogs.39 It is questionable
confounders and problematic study design whether substantial amounts of glucosamine
of some trials, and the possible suboptimal reach the circulation following oral inges-
exposure of the patients to the active mol- tion,40 and it is proposed that glucosamine is
ecule that might also come from the adopted not essential for the biosynthesis of cartilage;
dose and dosing interval.’ glucosamine is only one of many substrates
It is interesting to note that the only clini- from which other metabolites are derived for
cally relevant results in the GAIT study were the synthesis of cartilage matrix.40
observed in the subgroup of more severe
patients when glucosamine hydrochloride
was combined with chondroitin sulfate, sup-
porting the hypothesis that increasing the GLUCOSAMINE AND
sulfate concentration may have therapeutic
effects.33
CHONDROITIN SULFATE
Some32 suggest it is unlikely that the clini- IN COMBINATION
cal effects of glucosamine sulfate are linked
to a mere stimulation of GAG synthesis, but Orally administered glucosamine hydrochlo-
support the theory that glucosamine sulfate ride and chondroitin sulfate in combination
inhibits IL-1–induced gene expression, pos- has become a popular nutraceutical offering.
sibly via the suppression of the cytokine In a multicenter, double-blind, placebo- and
intracellular signaling pathway and NF-κB celecoxib-controlled study (GAIT study) of
activation, thus reversing the proinflamma- 1,583 human patients with stifle joint OA
tory and joint-degenerating effects of IL-1. receiving 1500 mg glucosamine, 1200 mg
Crystalline glucosamine sulfate reportedly chondroitin sulfate, or both revealed that the
inhibits IL-1–stimulated gene expression supplementations did not reduce stifle joint
of COX-2, inducible nitric oxide synthase pain better than placebo.41 In a subgroup of
(iNOS), tumor necrosis factor alpha (TNF- that same study, patients with moderate-to-
a), IL-6, IL-1, MMP-3, and aggrecanase 2.34 severe pain, the response of the combination
 Chapter 6 Nutraceuticals 205

gained by in vitro research; studies in other

than target species; or data not gained with
objective, placebo-controlled, double-blinded 6
studies or any studies at all.43,44 The Arthritis
Foundation recommends that when a supple-
ment has been studied with good results, find
out which brand was used in the study, and
buy that product.45

FIGURE 6.3 Results from the GAIT study are not

conclusive; some suggest it shows the glucos- AVOCADO/SOYBEAN
amine and chondroitin sulfate combination is not
effective, while others interpret the data to sug-
UNSAPONIFIABLES
gest it is (rabbit or duck?).
Avocado/soybean unsaponifiables (ASu) has
become a nutraceutical compound of recent
glucosamine plus chondroitin sulfate was investigative interest. The unsaponifiable
significantly better. In this same subgroup, portions of avocado and soybean oils are
the positive control, celecoxib, showed no extracted via hydrolysis, and the extracts have
response. Worthy of note is that the study been shown to effectively treat several con-
was conducted under pharmaceutical rather nective tissue diseases.46 Synergism between
than dietary supplement regulations; there- the avocado and soya components, and their
fore, agents identical to the ones used may relative ratios, appear to be important.47 In
not be commercially available. Nevertheless, vitro studies show that ASu extracts reduce
‘analysis of the primary outcome measure proinflammatory mediators, including IL-6,
did not show that either supplement, alone IL-8, macrophage inflammatory protein-1β,
or in combination, was efficacious’.41 In con- nitric oxide (NO), and PGE2 by human artic-
trast, some nutraceutical manufacturers cite ular chondrocytes exposed to IL-1β.48
the GAIT study results as testimonial that It has been observed that osteoblasts
where an evidence-based efficacious drug isolated from subchondral OA bone demon-
(celecoxib) does not work, the glucosamine strate an altered phenotype from normal.49
and chondroitin sulfate combination does They produce increased amounts of alka-
(Figure 6.3)! line phosphatase, osteocalcin, transforming
Subsequent to the GAIT study, in an edi- growth factor (TGF)-P1, insulin-like growth
torial appearing in the New England Journal factor-1, and urokinase plasminogen acti-
of Medicine, Dr. Marc Hochberg states, ‘If vator. OA osteoblasts are also resistant to
patients choose to take dietary supplements parathyroid hormone stimulation, possibly
to control their symptoms, they should be contributing to abnormal bone remodeling
advised to take glucosamine sulfate rather and bone sclerosis in OA. 50
than glucosamine hydrochloride and, for OA is a total joint disease, which includes
those with severe pain, that taking chon- the involvement of subchondral bone.
droitin sulfate with glucosamine sulfate may Abnormal remodeling of the subchondral
have an additive effect’.42 bone plate exposed to excessive nonphysi-
Studies of in vivo or in vitro efficacy of ological mechanical loads makes it stiffer and
veterinary products are limited, and efficacy no longer effective as a shock absorber, thus
claims are frequently made from subjective increasing mechanical strain on overlying
assessments, which include owner testimoni- cartilage. It is proposed that intervention that
als or clinical trials lacking peer review. A reduces bone sclerosis might slow progressive
literature review suggests the bioavailability cartilage degradation. In addition, because
of these products in dogs after oral intake is microcracks, vascular channels, and neovascu-
limited and is insufficient to prevent or treat larization provide a link between subchondral
OA, whereas parenteral application (either bone and cartilage, IL-6, TGF-β, and perhaps
intramuscular or intra-articular) seems to other factors produced by osteoblasts may
approach the in vitro effect. Further, effi- contribute to the abnormal remodeling of
cacy data are confused by reference to data OA cartilage. 51
206 Chronic Pain in Small Animal Medicine

Since tidemark microcracks appear early studies for phycocyanin in the dog. The obser-
in OA cartilage, it is speculated that soluble vational study done by the manufacturer was
mediators produced by sclerotic subchondral based on owner observations of dogs on the
osteoblasts may modulate chondrocyte metab- ingredient PhyCox and not on the commercial
olism and contribute to cartilage degradation. product PhyCox-JS, and the study design was
Aligning this theory together with ASu pre- weak. Further, PhyCox-JS has not been thor-
vention of inhibitory effects of osteoarthritic oughly studied in use together with an NSAID.
subchondral osteoblasts on aggrecan and type
II collagen synthesis by chondrocytes, inves-
tigators propose that ASu may act via a new EICOSAPENTAENOIC ACID
mechanism of action at the subchondral bone
level in protecting cartilage.52 Among study Both arachidonic acid (AA) and EPA act
horses, ASu failed to ameliorate increasing as precursors for the synthesis of eico-
lameness, response to joint flexion, or syno- sanoids, important molecules functioning
vial effusion; however, GAG synthesis in the as hormones and mediators of inflamma-
articular cartilage was increased compared tion (Figure 6.4). The amounts and types of
with placebo-treated, OA-affected joints.53 eicosanoids synthesized are determined by
Investigators concluded that ASu extracts may the availability of the polysulfated fatty acid
have an anabolic effect directly on chondro- precursor and by the activities of the enzyme
cytes to increase GAG synthesis and, hence, system. The eicosanoids produced from AA,
help prevent articular cartilage damage by the principal precursor under most condi-
enhancing the articular cartilage matrix struc- tions, appear to be more proinflammatory
ture. In a canine study,54 ASu (4 mg/kg every than those formed from EPA (Figure 6.5).
3 days or daily) increased both TGF-β1 and Ingestion of oils containing omega-3
TGF-β2 levels in the stifle synovial fluid. TGF- fatty acids results in a decrease in mem-
β1 levels reached maximum values at the end brane levels of AA because the omega-3 fatty
of the second month and then decreased after acids replace AA in the substrate pool and
the third month, while TGF-P2 levels margin- reduce the capacity to synthesize inflamma-
ally increased during the first 2 months, fol- tory eicosanoids. Inflammatory eicosanoids
lowed by a marked increase at the end of the produced from AA are therefore depressed
third month. TGF-β is a stimulator of extra- when dogs consume foods with high levels
cellular matrix production, like collagen type of omega-3 fatty acids. In addition, EPA is
II and proteoglycan, in chondrocytes.55 thought to exert its therapeutic effect on OA
by reducing expression of genes encoding
for cartilage-degrading enzymes (aggreca-
PHYCOCYANIN nases) within the chondrocytes. 59 In vitro
studies revealed that by exposing normal
Phycocyanin, composed of two protein sub- canine cartilage to EPA before addition of
units with covalently bond phycobilins that the catabolic agent, oncostatin M, to initi-
are the light-capturing part of the blue pig- ate processes that mimic the cartilage dam-
ment in blue-green algae, is considered the age that occurs during the pathogenesis of
active agent in PhyCox®, commercialized as OA, cartilage degeneration was abrogated.60
PhyCox-JS® (Teva Animal Health, St. Joseph Food containing high concentrations of total
MO, USA). However, some data suggests that omega-3 fatty acids and EPA as well as a low
C-phycocyanin is a selective COX-2 inhibi- omega-6:omega-3 ratio appears to decrease
tor.56 Phycocyanin has been shown to have the severity of OA clinical signs as early as
antioxidant and anti-inflammatory proper- 21 days after initiation of implementation.
ties in vitro and in vivo (rodents).57,58 Other Flaxseed oil and fish oil are both rich in
ingredients in PhyCox-JS, which may contrib- omega-3 fatty acids. Fish oil is rich in EPA
ute to product efficacy, include glucosamine, and DHA, while flaxseed oil contains alpha-
flaxseed oil, turmeric, eicosapentaenoic acid linolenic acid (ALA). For ALA in flaxseed oil
(EPA), and docosahexaenoic acid (DHA). to have an anti-inflammatory effect, it must
PhyCox-JS is not a drug, but positioned as an be converted to EPA. Efficiency of ALA con-
animal nutraceutical of natural botanical ori- version to EPA is quite low (<10%), with most
gin (PhyCox). There are no pharmacokinetic ALA being used for energy. Accordingly, a
 Chapter 6 Nutraceuticals 207

FIGURE 6.4 EPA is the substrate for synthesis of many eicosanoids, which act as mediators of inflam-
mation. (HEPE: hydroxyeicosapentaenoic acid, HPETE: hydroperoxyeicosatetraenoic acid, HETE:
hydroxyeicosatetraenoic acid.)

FIGURE 6.5 Whereas AA-derived eicosanoids tend to be proinflammatory, EPA-derived eicosanoids tend
to be less inflammatory/suppress the inflammatory process. (PUFAs: polyunsaturated fatty acids.)
208 Chronic Pain in Small Animal Medicine

small amount of fish oil is more effective at of the synovial fluid lubrication and visco-
providing EPA and DHA than a large quan- elasticity.62 Perhaps HA therapy has disease-
tity of flaxseed oil containing ALA. modifying biological activity and an impact
on OA progression. Four potential mecha-
nisms have been proposed for the beneficial
HYALURONIC ACID clinical effects noted from HA therapy:

The proteoglycan aggrecan molecule of artic- • Restoration of elastic and viscous properties
ular cartilage is attached via a link protein to of the synovial fluid
HA. The entire complex is referred to as a pro- • Biosynthetic-chondroprotective effect of exog-
teoglycan or aggrecan aggregate (Figure 6.6). enous hyaluronans on cells (hyaluronans can
HA acts as an aggregating factor between the induce endogenous synthesis of HA by syno-
collagen, proteoglycan aggregate, and carti- vial cells, stimulate chondrocyte proliferation,
lage structural network as a whole. Synovial and inhibit cartilage degradation)59,63– 65
fluid contains high concentrations of HA, • Anti-inflammatory effects66,67
derived from type B synoviocytes embedded • Analgesic effect68,69
within the intimal lining of the joint capsule.
The viscoelastic properties of synovial fluid Pozo et al. reported that intra-articular HA
are determined by HA, and with the progres- reduced nerve impulse activity in nociceptive
sion of OA, HA concentrations decrease with afferent fibers in a cat model of acute arthritis.70
a resultant decrease in the viscoelastic prop-
erties of the synovial fluid. Intra-articular
injection of HA, called viscosupplementation, S-ADENOSYLMETHIONINE
has demonstrated significant improvement of
symptoms in patients with OA.61 S-adenosylmethionine (SAMe) is a nucleotide-
By definition, injectable HA (e.g. Legend®) like molecule synthesized from methionine and
is not a nutraceutical. However, it can be con- adenosine triphosphate (ATP) by all living cells.
sidered a chondroprotective agent, and there SAMe is particularly important to hepatocytes
are several commercially available forms of and plays a pivotal role in the biochemical
HA, differing by treatment regimens, total pathways of transmethylation, transulfuration,
dosing, and average molecular weights. and amino-propylation. A therapeutic appli-
Support for use of HA resides in the improve- cation of SAMe in joint disorders is derived
ment of OA symptoms with few side effects. It from pain reduction and improved joint func-
is unlikely that sustained beneficial effects of tion,71,72 based on potential antioxidant and
HA therapy result from temporary restoration anti-inflammatory activity.73 There are very

FIGURE 6.6 Hyaluronic acid is an integral part of the aggrecan aggregate, as well as synovial fluid.
 Chapter 6 Nutraceuticals 209

few studies reporting the effect of SAMe on not in small laboratory animals, in humans, in
articular chondrocytes or matrix. One study in
dogs reported an in vitro detrimental effect,74
bovines, or from in vitro studies. Dosage, dura-
tion, and route of the agent should be taken into 6
while one study in humans showed an in vitro account. Since most of these products are not
positive effect.75 Lippiello et al. have reported pharmaceuticals, neither purity nor content is
that the enzymatic inhibition of proteoglycan under control, although the package or infor-
synthesis by MMP-3 in vitro is reversed by the mational materials may suggest otherwise.
combination of glucosamine and SAMe, but Hyaline articular cartilage harvested from
not with either agent alone.76 joints of different animal species respond
quite differently to a variety of catabolic stim-
ulants that are commonly used by researchers
CURCUMINOIDS to establish in vitro models of cartilage degra-
dation that are believed to mimic mechanisms
Studies to support existing in vitro evidence of cartilage degradation in the pathogenesis
for nutraceutical alleviation of clinical signs for of DJDs. Innes et al.77 have pointed out that
OA are lacking. To date, green tea extract and exposure to IL-1α or -β, TNF-a, oncostatin
other Asian herbal remedies have not been eval- M, and retinoic acid can all cause significant
uated in companion animal models or in ani- increases in cartilage proteoglycan degrada-
mals with spontaneous disease. Curcuminoids, tion when bovine articular cartilage explant
types of phytonutrients extracted from tur- culture systems are used, but similar results
meric, have been found to exert some anti- are not seen with the canine. Species differ-
inflammatory effects in certain animal models ences may be due to species variability of
and in vitro assays. A curcuminoid extract in catabolic stimulants themselves, which may
dogs with OA was found to yield no treatment have different affinities for receptors and
effect using the objective assessment of force- other downstream regulators that manifest
plate analysis, although subjective assessment their metabolic effects on cartilage metabo-
by the observer was positive. lism. Differences in catabolic responses to
cytokines in dogs highlight the difficulty in
extrapolating results between species.
SUMMARY Perhaps the best advice for pet owners
is to spend their money where the science is
Clearly, credible evidence-based support for strong. Adding a nutraceutical will likely do
most nutraceuticals is meager. Arguably, the no harm, but evidence-based endorsement
success of nutraceuticals is being driven by is weak. Perhaps variability in testimonials
consumers’ desire to ‘do no harm’. And the role for various nutraceutical efficacies resides in
of nutraceuticals is shrouded with vagaries, genetic predisposition of as-yet-unidentified
innuendo, and misinformation. Preliminary subpopulations for their activity.
information guiding nutraceutical use should Figure 6.7 shows the molecular struc-
be considered with care. Results should be ture of some nutraceuticals and a chondro-
gathered in the target species (i.e., the dog) and protectant.

FIGURE 6.7 Molecular structure of different nutraceuticals and a chondroprotectant.

210 Chronic Pain in Small Animal Medicine

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 Chapter 6 Nutraceuticals 211

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rosis. Arthritis Rheum 1998;41:891–899. 66. Takahashi K, Hashimoto S, Kubo T, et al.
50. Hilal G, Massicotte F, Martel-Pelletier J, Hyaluronan suppressed nitric oxide production in
et al. Endogenous prostaglandin E2 and insulin- the meniscus and synovium of rabbit osteoarthritis
like growth factor 1 can modulate the levels of para- model. J Orthop Res 2001;19:500–503.
thyroid hormone receptor in human osteoarthritic 67. Yasui T, Akatsuka M, Tobetto K, et al. The effect of
osteoblasts. J Bone Miner Res 2001;16:713–721. hyaluronan on interleukin-1-alpha in induced pros-
51. Imhof H, Breitenseher M, Kainberger F, et al. taglandin E2 production in human osteoarthritic
Importance of subchondral bone to articular car- synovial cells. Agents Actions 1992;37:155–156.
tilage in health and disease. Top Magn Reson 68. DeVane CL. Substance P: a new era, a new role.
Imaging 1999;10:180–192. Pharmacotherapy 2001;21:1061–1069.
212 Chronic Pain in Small Animal Medicine

69. Moore AR, Willoughby DA. Hyaluronan as a drug 74. Steinmeyer J, Burton-Wurster N. Effects of three
delivery system for diclofenac: a hypothesis for antiarthritic drugs on fibronectin and keratin
mode of action. Int J Tissue React 1995;17:153–156. sulfate synthesis by cultured canine articular
70. Pozo MA, Balazs EA, Belmonte C. Reduction of cartilage chondrocytes. Am J Vet Res 1992;53:
sensory responses to passive movements of inflamed 2077–2083.
knee joints by hylan, a hyaluronan derivative. Exp 75. Harmand MF, Jana JV, Maloche E, et al. Effects
Brain Res 1997;116:3–9. of S-adenosylmethionine on human articular chon-
71. Soeken KL, Lee WL, Bausell RB, et al. Safety and drocyte differentiation. Am J Med 1987;83:48–54.
efficacy of S-adenosylmethionine (SAMe) for osteo- 76. Lippiello L, Prudhomme A. Advantageous use of
arthritis. J Fam Pract 2002;51:425–430. glucosamine combined with S-adenosylmethionine
72. Konig B. A long-term (two years) clinical trial with in veterinary medicine: preservation of articular
S-adenosinemethionine for the treatment of osteo- cartilage in joint disorders. Int J Appl Res Vet Med
arthritis. Am J Med 1987;83:78–80. 2005;3:6–12.
73. Center SA. S-adenosylmethionine (SAMe): an 77. Innes JF, Caterson B, Little CB, et al. Effect of
antioxidant and anti-inflammatory nutraceuti- omega-3 fatty acids on canine cartilage: using an in
cal. Proceedings of the 18th American College of vitro model to investigate therapeutic mechanisms.
Veterinary Internal Medicine Conference. Seattle, In: Proceedings of the 13th ESVOT Congress,
WA, 2000, p549–552. Munich, 7–10 September, 2006.
SECTION

3
 CHAPTER

7
Multimodal Management of Pain
INTRODUCTION the drugs in the combination can be antici-
pated to be less due to the lower dosing of
In addition to preemptive analgesia, multi- each respective drug. For nearly two decades
modal (or balanced) analgesia has changed the concept of ‘multimodal analgesia’ has
the way we treat pain.1 Multimodal analge- created important advances in the approach
sia denotes simultaneous administration of to providing analgesia in both acute4, 5 and
two or more analgesic drugs belonging to chronic pain in humans.6 Nociception results
different classes (Figure 7.1). (Multimodal in pain via multiple pathways, mechanisms,
can also denote different delivery methods and transmitter systems,7 and it is naïve to
and therapies.) consider that a single therapy would be as
Dosages of each drug can typically be effective as several different drugs acting on
reduced because various classes of drugs have multiple components of the nociceptive sys-
additive or synergistic analgesic effects when tem (Figure 7.2).
given together2 (e.g., opioid, α2-agonist, 3 non- Although there is no published evidence
steroidal anti-inflammatory drug [NSAID]). base that multimodal drug therapy is of ben-
As a result, adverse side effects from each of efit over monomodal therapy in veterinary

FIGURE 7.1 Multimodal analgesia denotes the simultaneous administration of different classes of drugs,
attempting to block the four physiological processes of transduction, transmission, modulation, and
perception.

DOI: 10.1201/9781003376422-10 215

216 Chronic Pain in Small Animal Medicine

FIGURE 7.2 Simplistic drawing of nociceptor transmission from the first- to second-order neuron. Most
analgesic drugs express their mode of action via a single pathway, transmitter, or receptor, and pain is
the result of a complex nociceptive network. Therefore, it is naïve to expect a single drug to block the
entire ‘network’. (ACH: acetylcholine, BNZ: benzodiazepines.) (Adapted from Tranquilli WJ, et al. Pain
Management for the Small Animal Practitioner. Teton New Media 2004, 2nd edition. With permission.)

patients suffering from chronic painful con- work by different modes of action and not
ditions such as osteoarthritis (OA), imple- compete for the same substrates or receptor
mentation seems implicit.8 Herein arises the sites) that block as many of the four physio-
question: ‘What drugs should go into the logical processes underlying pain as possible:
cocktail?’ Drugs comprising the cocktail transduction, transmission, modulation, and
should be from different classes (so they can perception (Table 7.1 and Figure 7.3).

TABLE 7.1 Pain recognition processes

Physiological
process Definition
Transduction Conversion of energy from a noxious stimulus (mechanical, thermal, or chemical)
into nerve impulses by sensory receptors (nociceptors)
Transmission Transference of neural signals from the site of transduction (periphery) to the CNS
(spinal cord and brain)
Modulation Alterations of ascending signals initially in the dorsal horn and continues
throughout the CNS
This includes descending inhibitory and facilitatory input from the brain that
influences (modulates) nociceptive transmission at the level of the spinal cord
Perception Receipt and cognitive appreciation of signals arriving at higher CNS structures
as pain
 Chapter 7 Multimodal Management of Pain 217

FIGURE 7.3 Drug classes listed are more effective than others in blocking each of the physiological pro-
cesses of transduction, transmission, modulation, and perception.

DRUG CLASSES FOR classes (Table 7.2). This combination is com-

monly used postoperatively and for address-
MULTIMODAL USE ing the World Health Organization’s cancer
pain ladder recommendation for mild-to-
A popular combination for multimodal use moderate and moderate-to-severe pain.
consists of drugs from the opioid and NSAID There are several opioid/NSAID combination

TABLE 7.2 Comparison of opioid and NSAID pharmacology

Opioids NSAIDs
Mechanism Predominantly central Predominantly peripheral
Availability Controlled substances Noncontrolled/Some available over the counter
Therapeutic ceiling No Yes
Tolerance Yes
Addiction Possible Not possible
Gastrointestinal side effects
Nausea and vomiting More frequent Less frequent
Constipation Frequent No
Gastric ulceration No Possible
Gastrointestinal bleeding No Possible
Respiratory side effects Depression Infrequent
Effects on pupil Yes No
Cognitive impairment Yes No
218 Chronic Pain in Small Animal Medicine

TABLE 7.3 Some NSAID-opioid commercial drug combinations available for human use
Combination Trade name Strength (mg)
Aspirin + Caffeine + Dihydrocodeine Synalgos 356.4 + 30 + 16

Aspirin + Caffeine + Propoxyphene Darvon compound-65 389 + 32.4 + 65

Aspirin + Carisoprodol + Codeine Soma compound w/codeine 325 + 200 +16

Aspirin + Codeine Empirin w/codeine #3 325 + 30

Empirin w/codeine #4 325 + 60

Aspirin + Hydrocodone LortabASA 500 + 5

Aspirin + Oxycodone Persodan-Demi 325 + 2.25

Percodan 325 + 4.5

Ibuprofen + Oxycodone Combunox 400 + 5

Ketoprofen + Hydrocodone Vicoprofen 200 + 7.5

Note: Acetaminophen is not included in this table because acetaminophen is not technically an NSAID: it has analgesic properties,
but not anti-inflammatory properties.

drugs commercially available for human use

(Table 7.3). Figure 7.4 shows a comparison
DELIVERY TECHNIQUES
of numbers needed to treat human patients, Local and regional administration techniques
comparing single-drug administrations to are re-emerging in popularity. Analgesic
combinations.9 infiltration at a nerve trunk or regional
Increased efficacy is obvious when administration via spinal injection provides
paracetamol is combined with various opi- regional analgesia. The principal benefit of
oids. Table 7.4 lists commonly used veteri- regional analgesia is reduced sedation and
nary protocols. other side effects compared with those seen
following parenteral administration of some
analgesic agents.

FIGURE 7.4 Numbers needed to treat demonstrates the increased efficacy when paracetamol is admin-
istered together with a different class of drug. (Paracetamol = Acetaminophen.)
TABLE 7.4 Various drugs commonly used in multimodal protocols
Drug Dose Species Route Duration Comments
Morphine 0.5–1.0 mg/kg Canine IM, SC, IV 3–4 hours Caution with IV administration: histamine
release – give slowly
0.05–0.1 mg/kg Feline IM, SC 3–4 hours
0.2 mg/kg: loading, IM Canine: IM then
0.1–0.5 mg/kg/hr continuous
Feline: rate infusion
0.05–0.1 mg/kg/hr (CRI) (IV)
0.1 mg/kg preservative-free Canine/Feline Epidural 12–24 hours
1–5 mg in 5–10 mL saline Canine Intra-articular
Meperidine 3–5 mg/kg Canine/Feline IM, SC 1–2 hours Do not give IV (histamine release)
Methadone 0.1–0.5 mg/kg Canine/Feline IM, SC, IV 2–4 hours NMDA antagonist activity
Oxymorphone 0.05–0.1 mg/kg Canine IM, IV, SC 3–4 hours Minimal histamine release
0.03–0.05 mg/kg Feline IM, SC 3–4 hours
Hydromorphone 0.1–0.2 mg/kg Canine/Feline IM, IV, SC 2–4 hours Minimal histamine release
Hyperthermia may be seen in cats
Fentanyl 5 μg/kg + 3–6 μg/kg/hr Canine IV Infusion

2–3 μg/kg + 2–3 μg/kg/hr Feline IV Infusion

Fentanyl patch 25 μg/hr Canine: 3–10 kg 1–3 days 24 hours to reach peak concentrations

50 μg/hr Canine: 10–20 kg 1–3 days

75 μg/hr Canine: 20–30 kg 1–3 days

100 μg/hr Canine: >30 kg 1–3 days

25–50 μg/hr Feline ≤6 days 6 hours to reach peak concentrations

(Continued)
Chapter 7 Multimodal Management of Pain 219

7
TABLE 7.4 Various drugs commonly used in multimodal protocols (Continued)
220

Drug Dose Species Route Duration Comments

Butorphanol 0.1–0.2 mg/kg Canine/Feline IM, IV, SC Dog: 1hours Low oral bioavailability
Cat: 2–4 hours
(10 mg/mL) 0.2–0.4 mg/kg IV, then Canine/Feline CRI
0.1–0.2 mg/kg/hr
Pentazocine 1–3 mg/kg Canine/Feline IM, IV, SC 2–4 hr
Nalbuphine 0.03–0.1 mg/kg Canine/Feline IM, IV, SC 2–4 hr
Buprenorphine 10–30 μg/kg Canine/Feline IM, IV, SC 4–10 hr 15–30 min onset
Excellent buccal mucosa absorption in cats and
dogs
Tramadol 2–10 mg/kg Canine PO 12–24 hours Nonscheduled
μ agonist activity
Chronic Pain in Small Animal Medicine

Serotonin and norepinephrine reuptake inhibitor

NMDA antagonist at lower doses, GABA
receptor inhibitor at high concentrations
5 mg/kg (suggested) Feline PO
Codeine 1–2 mg/kg Canine PO

α2-Agonist
Medetomidine/ 2–15 μg/kg Canine IM, IV 0.5–1.5 hours
Dexmedetomidine
5–20 μg/kg Feline IM, IV 0.5–1.5 hours Sedation, bradycardia, vomiting
1.0 mg/mL 1 μg/kg IV, then 1–2 μg/kg/hr Canine/Feline CRI

1–5 μg/kg Canine/Feline Epidural

2–5 μg/kg Canine/Feline Intra-articular

Xylazine 0.1–0.5 μg/kg Canine/Feline IM, IV 0.5–1.0 hours
TABLE 7.4 Various drugs commonly used in multimodal protocols (Continued)
Drug Dose Species Route Duration Comments
(Antagonist) 0.1 mg/kg IV Canine/Feline
yohimbine 0.3–0.5 mg/kg IM
(Antagonist) 0.05–0.2 mg/kg IV Canine/Feline 2–4 times the medetomidine dose
atipamezole
NMDA antagonist
Ketamine 0.5 mg/kg Canine/Feline CRI
IV then 0.1–0.5 mg/kg/hr
Amantadine 3–5 mg/kg Canine/Feline PO 24 hours Neuropathic pain
Dextromethorphan 0.5–2 mg/kg Canine PO, SQ, IV Not D-isomer of codeine
recommended Weak NMDA antagonist due to side effects10
Methadone 0.1–0.5 mg/kg Canine/Feline IM, SC 2–4 hours Opioid derivative
Tricyclic antidepressant
Amitriptyline 1.0 mg/kg Canine PO 12–24 hours Enhanced noradrenergic activity
0.5–1.0 mg/kg Feline PO 12–24 hours
Calcium channel modulator
Gabapentin 5–10 mg/kg Canine/Feline PO 12–24 hours VDCC inhibitor
Adjunct
Acepromazine 0.025–0.05 mg/kg Canine IM, SC, IV 8–12 hours 3 mg maximum total dose
Used to potentiate or prolong analgesic drug
effect
0.05–0.2 mg/kg Feline IM, SC 8–12 hours

(Continued)
Chapter 7 Multimodal Management of Pain 221

7
TABLE 7.4 Various drugs commonly used in multimodal protocols (Continued)
Drug Dose Species Route Duration Comments
Diazepam 0.1–0.2 mg/kg Canine/Feline IV 2–4 hours Used to potentiate or prolong analgesic drug
effect
0.25–1.0 mg/kg Canine/Feline PO 12–24 hours
Local anesthetics
Lidocaine (1%–2%) ≤6.0 mg/kg Canine Perineural 1–2 hours Onset: 10–15 min
Maximum dose: 12 mg/kg (canine)
6 mg/kg (feline)
≤3.0 mg/kg Feline Perineural 1–2 hours

2–4 mg/kg IV, then 25–80 μg/ Canine IV: CRI

kg/min
222 Chronic Pain in Small Animal Medicine

0.25–0.75 mg/kg slow IV, then Feline IV: CRI NOTE: efficacy and safety are not yet proven
10–40 μg/kg/min
Bupivacaine ≤2.0 mg/kg Canine Perineural 2–6 hours Onset: 20–30 min
(0.25%–0.5%) Maximum dose: 2 mg/kg (canine or feline)
≤1.0 mg/kg Feline Perineural 2–6 hours
Mepivacaine ≤6.0 mg/kg Canine Perineural 2–2.5 hours
(1%–2%)
≤3.0 mg/kg Feline Perineural 2–2.5 hours
 Chapter 7 Multimodal Management of Pain 223

Many traditional analgesic drugs, includ- delivery. Central nervous system (CNS) and
ing opioids and α 2-agonists, have a short
duration of action and the potential to pro-
cardiovascular disturbances are the most
common side effects. With excessive dos- 7
duce systemic side effects, including emesis, ing, the rate of depolarization of individual
respiratory depression, drowsiness, and cardiac cells is reduced, leading to prolonged
ileus. In contrast, local anesthetics are com- conduction of the cardiac impulse, arrhyth-
paratively safe. They are effective and rela- mias, or bradycardia and asystole.12 Rapid
tively inexpensive. Local anesthetics have the intravenous administration of local anes-
unique ability to produce complete blockade thetics can decrease vascular tone and myo-
of sensory nerve fibers and suppress the cardial contractility, resulting in the acute
development of secondary sensitization to onset of hypotension. CNS effects can range
pain. Therefore, local and regional anes- from mild to full-blown seizure activity. The
thetic/analgesic techniques are often used toxicity of most local anesthetics reflects
with opioids, α 2-agonists, N-methyl-D aspi- potency, and in dogs, the relative CNS toxic-
rate (NMDA) antagonists, and NSAIDs as ity of lidocaine, etidocaine, and bupivacaine
part of a multimodal strategy. is 1:3:5, respectively.13
Local anesthetics can be used in a vari-
ety of clinical settings to manage or preempt
LOCAL ANESTHETICS pain. Common uses include digital blocks
for feline onychectomy, dental blocks for
During the generation of an action poten- tooth extraction, local infiltration for cuta-
tial, voltage-gated sodium channels (VGSCs) neous procedures, intra-articular analgesia,
open and allow sodium ions to flow into the body cavity infusion before or after abdomi-
cell, which depolarizes the cell membrane. nal surgery, soaker catheters for wound anal-
Local anesthetics bind to a hydrophilic site gesia, and epidural deposition for abdominal
within the sodium channel on the cell mem- and/or hindlimb procedures. Most nerves
brane inner surface and block activation of can be blocked with 0.1–0.3 mL of 2% lido-
the channel, thereby preventing depolariza- caine or 0.5% bupivacaine solution using a
tion of the cell membrane. Small nerves and 25-gauge needle. Doses of local anesthetics,
myelinated fibers tend to be more responsive especially for cats and small dogs, should
to local anesthetics than are large nerves always be calculated carefully and are best
and unmyelinated fibers. Commonly, auto- administered with the animal under general
nomic fibers (small unmyelinated C fibers anesthesia or heavy sedation.
and myelinated B fibers) and pain fibers
(small unmyelinated C fibers and myelinated
Aδ fibers) are blocked before other sensory
Onychectomy
and motor fibers (differential block). Local Approximately 24% of owned cats in the
anesthetics are also more effective at sensory United States are declawed,14 and postop-
fibers because they have longer action poten- erative pain is a generally accepted conse-
tials and discharge at higher frequencies than quence.15 Effective analgesia can be provided
do other types of fibers (frequency-dependent by blocking the radial, ulnar, and median
blockade). In addition, some local anesthet- nerves (Figure 7.5), although one study16
ics, such as bupivacaine, can selectively block refutes this clinical observation. A combi-
sensory rather than motor function.11 nation of both lidocaine and bupivacaine
The practice of adding vasoconstrictors, (1.5 mg/kg of each) may provide both a
such as epinephrine, to local anesthetics so quicker onset and longer duration of analge-
as to reduce the rate of systemic absorption sic effect than when using either drug alone
and prolong the duration of action has fallen for blockade.
from favor with the availability of longer-
acting local anesthetics such as bupivacaine
and ropivacaine.
Dental
Adverse side effects of local anesthetics Sensory nerve fibers that innervate the bone,
are rare if appropriate dosage recommenda- teeth, and soft tissues of the oral cavity
tions are followed and are most commonly arborize from the maxillary or mandibu-
associated with inappropriate intravenous lar branches of the trigeminal nerve. Four
224 Chronic Pain in Small Animal Medicine

FIGURE 7.5 Onychectomy is an excellent example of where analgesia is markedly improved by preemp-
tive local anesthetic blockade. Three sites of local anesthetic deposition effectively block the distal
extremity. (Adapted from Tranquilli WJ, et al., Pain Management for the Small Animal Practitioner. Teton
NewMedia 2004, 2nd edition. With permission.)17

regional nerve blocks can be easily performed lesions, superficial lacerations, and as prein-
to provide analgesia for dental and oral sur- cisional blocks. A small subcutaneous bleb
gical procedures (Table 7.5 and Figure 7.6). (0.5–2.0 mL) is often sufficient for small
lesion removal in the dermis. Infiltrative
blocks for removal of subcutaneous masses
Dermal require a deeper area of desensitization, and
Local anesthetic infiltration is often imple- an inverted pyramidal area of infiltration
mented for removal of tumors or dermal works well (Figure 7.7).

TABLE 7.5 Dental nerve blocks with local anesthetic

Mandibular
Block Mental (inferior alveolar) Infraorbital Maxillary
Effect Anesthetizes all Affects the bone, teeth, Anesthetizes the Blocks the bone,
oral tissues rostral soft tissue, and tongue bone, soft tissue, teeth, soft tissue,
to the second on the ipsilateral side and dentition rostral and palatal tissue
premolar on the to but not including on the ipsilateral
ipsilateral side the upper fourth side
premolar
Location Mental foramen Lingual side of notch on Infraorbital foramen In the open mouth:
ventral to the caudal ventral mandible of the maxilla notch where the
rostral (mesial) cranial to the angular dorsal to the caudal zygomatic arch
root of the process, midpoint (distal) root of the meets the bone
second premolar between ventral and upper third surrounding the
dorsal borders of the premolar last maxillary
mandible molar
 Chapter 7 Multimodal Management of Pain 225

FIGURE 7.6 Local anesthetic blocks are highly effective in providing analgesia for oral cavity procedures.
Area blocked is rostral to the injection site. (A) Mental. (B) Mandibular. (C) Infraorbital. (D) Maxillary.

Body Cavities for pancreatitis20 and canine ovariohyster-

ectomy. 21 In the awake animal, pleural infu-
Intrapleural administration of bupivacaine sion of bupivacaine can be painful; therefore,
has been described to manage pain in dogs sodium bicarbonate is added. In either case,
undergoing intercostal or sternal thoracot- 0.02 mmol/kg (mEq/kg) of sodium bicar-
omy,18,19 as has peritoneal administration bonate is added to 0.2 mL/kg of 0.5%
bupivacaine solution, then saline is added
to produce a final volume of 10–20 mL for
administration via a thoracostomy tube or
abdominocentesis. There is evidence for a
reduction of postoperative pain after intra-
articular local anesthesia in human patients
undergoing arthroscopic knee surgery. 22 In
dogs, intra-articular bupivacaine provided
pain relief after stifle surgery better than
intra-articular morphine. 23

Other Local Anesthetic

Techniques
Constant rate infusion (CRI) of lidocaine is
also an effective method of delivering local
anesthetic (dog: 2-4 mg/kg IV bolus, then
25–80 mg/kg/min; cat: 0.25–0.75 mg/kg
slow IV, then 10–40 mg/kg/min; note: effi-
cacy and safety are not yet convincing).
Finally, lidocaine is available as a topical
patch product (Lidoderm®), 2% jelly, and in
a 10% spray formulation.
FIGURE 7.7 Local anesthetic, administered Specially designed catheters can be uti-
through three injection site arches, will ade- lized for longer-term (days) continuous infil-
quately infiltrate an area to be desensitized for
tration of local anesthetic, 24 particularly
procedures such as dermal mass removal. A
1:1 mixture of lidocaine and bupivacaine, not to
following procedures such as ear canal abla-
exceed 3.0 mg/kg of lidocaine and 2.0 mg/kg of tion (efficacious findings, 25 nonefficacious
bupivacaine, takes advantage of the more rapid findings26) and amputations and after large
onset of action of lidocaine together with the lon- soft tissue excision, such as fibrosarcoma
ger duration of effect from bupivacaine. removal in cats. 27 Commercial devices are
226 Chronic Pain in Small Animal Medicine

available (Pain Buster®) that include a local It has been suggested that epidurals are
anesthetic reservoir connected to a fenes- best utilized together with general anesthesia
trated catheter, or catheters can be con- as part of a balanced (multimodal) analge-
structed from red rubber or polyethylene sia protocol, and this probably plays a note-
tubing. Bupivacaine 0.25% is diluted to vol- worthy role in blocking CNS windup. The
ume and can be given as a bolus: 2 mg/kg technique is frequently used for perianal,
(cat: 1 mg/kg) first dose, then 1 mg/kg (cat: hindlimb, and abdominal surgery; however,
0.5 mg/kg) doses can be given thereafter at analgesia as far rostral as the thoracic limb
intervals >6 hours for 1–2 days. (using morphine) can be provided in a dose-
related manner. 29 Epidural morphine, with
or without long-lasting bupivacaine, has
EPIDURAL ADMINISTRATION been used to relieve pain associated with
pancreatitis and peritonitis. 29
In the 1970s it was discovered that epidural Urine retention and pruritus are reported
administration of opioids produced pro- as possible complications of this technique,
found analgesia in animals with minimal although occurrence is rare. The procedure is
systemic effects. 28 Since that time, interest contraindicated in animals with bleeding dis-
has increased in the epidural route for admin- orders because of the potential for hemorrhage
istration of analgesics, particularly in the into the epidural space with inadvertent punc-
delivery of opioids, where the motor paraly- ture of an epidural vessel. Due to the potential
sis of local anesthesia administration can be for blockade of regional sympathetic nerves,
avoided. The most frequently administered epidurals should not be performed on hypo-
drugs are the local anesthetics and opioids, volemic or hypotensive animals. Injection site
but α 2-agonists (xylazine and medetomidine) skin infection is also a contraindication.
and combinations of these drugs have also The procedure should be performed in a
been used (Table 7.6). sterile setting. The site for spinal needle inser-
Epidural drug administration and catheter tion is on the dorsal midline at the lumbosa-
placement for repeated administration have cral space (Figure 7.8). In the adult dog, the
several advantages: spinal cord ends at approximately the sixth
lumbar vertebra, rostral to the injection site.
• Requires lower drug doses than systemic The site for injection is just caudal to the sev-
injection, and therefore less risk for dose- enth dorsal spinous process, which can be
related side effects. easily identified because it is shorter than the
• Decreases perioperative injectable and others. Confirmation of correct needle place-
inhalant agent requirement. ment can be done by either the ‘hanging drop’
• Decreases procedural costs due to the long or ‘loss of resistance’ technique.30 Following
duration of action and decreased dose of correct needle placement, the drug(s) is
adjunctive drugs. injected slowly to ensure even distribution.

TABLE 7.6 Drug dose and action following epidural administration in dogs
Approximate Approximate
Drug Dose (dog) onset (minutes) duration (hours)
Lidocaine 2% 1 mL/3.4 kg (to T5) 10 1–1.5
1 mL/4.5 kg (to T13–L1)
Bupivacaine (0.25% or 0.5%) 1 mL/4.5 kg 20–30 4.5–6
Fentanyl 0.001 mg/kg 4–10 6
Oxymorphone 0.1 mg/kg 15 10
Morphine 0.1 mg/kg 23 20
Buprenorphine 0.003–0.005 mg/kg 30 12–18
(in saline solution)
 Chapter 7 Multimodal Management of Pain 227

little information about acupuncture was

available in the United States until after
President Richard Nixon’s visit to China in 7
1972. However, in 1826 Benjamin Franklin’s
grandson, a Philadelphia physician, pub-
lished that acupuncture was an effective
treatment for pain associated with rheuma-
tism and neuralgia among prisoners at the
Pennsylvania state penitentiary.33 It is a safe,
low-cost modality that is easy to adminis-
ter and has no side effects if performed by a
trained practitioner; it can be administered
stand-alone or as a complement to other
medical therapeutics. It is misleading to
FIGURE 7.8 Accurate spinal needle insertion refer to a single universal form of traditional
comes with practice; however, the skill is not Chinese acupuncture, as there are more than
particularly difficult, and patient analgesia is 80 different acupuncture styles in China
noteworthy.17 alone, in addition to many Japanese, Korean,
Vietnamese, European, and American styles.

OTHER DELIVERY ROUTES

Oral transmucosal (OTM) drug administra-
THEORY OF ACUPUNCTURE
tion is a relatively new delivery system used Traditional Chinese medicine places an
in humans, e.g., fentanyl lozenges. This same emphasis on function rather than struc-
route has been investigated by Robertson ture. Accordingly, in such practice it is more
et al.31 as it applies to the efficacy of important to understand the relationships
buprenorphine in cats. Because, in part, the between variables and the functional ‘whole’
Pka of buprenorphine (8.24) is similar to the of the patient than to identify the specifics
pH of the cat’s mouth (9.0), buprenorphine of a single pathology. Basic to the practice
is readily absorbed across the oral mucous of acupuncture is the yin-yang theory, where
membranes. Absorption by this route, rather yin and yang are interdependent but possess
than gastrointestinal, avoids hepatic first- similar characteristics (Figure 7.9). 34 They
pass elimination, because venous drainage can transform into each other and can con-
is systemic. As a result, the onset of anal- sume each other. In this regard, physiology
gesic action is as early as 30 minutes and and pathology are variations along a contin-
lasts up to 6 hours. This response in the cat uum of health and illness.
is similar to the intravenous administra- A common feature shared by all different
tion, as assessed by a validated nociception types of acupuncture is using needles to ini-
thermal model. OTM administration is easy tiate changes in the soft tissue. Needles and
and avoids multiple injections, making it an needle-induced changes are believed to acti-
excellent delivery form for both in-hospital vate the built-in survival mechanisms that
and take-home use. Apparently, buprenor- normalize physiological homeostasis and
phine is odorless and tasteless, as cats do promote self-healing. Herein, acupuncture
not resist OTM administration and do not
hypersalivate in response.

ACUPUNCTURE
Acupuncture falls under the categorization
of complementary and alternative medicine
as part of traditional Chinese medicine and
is utilized in humans in at least 78 countries FIGURE 7.9 The graphic that has come to repre-
worldwide. 32 From an historical perspective, sent the Yin-Yang theory.
228 Chronic Pain in Small Animal Medicine

can be defined as a physiological therapy pathways known as acupuncture channels,

coordinated by the brain, which responds or meridians, helping to maintain normal
to the stimulation of manual or electri- activities. Traditional Chinese medicine
cal needling of peripheral sensory nerves.35 suggests that a balanced flow of qi through-
Acupuncture can be effective for both out the system is required for good health,
peripheral soft tissue pain and internal dis- and acupuncture stimulation can correct
orders, but in the case of peripheral soft tis- imbalances.
sue pain, the result appears more predictable Since the mid-1990s, stimulation of acu-
because of the local needle reaction. puncture points has been believed to cause
biochemical changes that can affect the
body’s natural healing. The primary mech-
anisms involved in these changes include
HYPOTHESIS OF enhanced conduction of bioelectromagnetic
ACUPUNCTURE MECHANISMS signals, activation of opioid systems, and
activation of autonomic and CNSs, causing
The leading hypotheses include the effects the release of various neurotransmitters and
of local stimulation, neuronal gating, the neurohormones. 36 Approximately 30 years
release of endogenous opiates, and the pla- ago it was discovered that acupuncture
cebo effect. It is further proposed that the analgesia could be reversed by naloxone,
CNS is essential for the processing of these a pure antagonist to all known opioids. 37
effects via its modulation of the autonomic Acupuncture can change concentrations
nervous system, the neuroimmune system, of serotonin and biogenic amines, includ-
and hormonal regulation. Clinical obser- ing opioid peptides, met-enkephalin, leu-
vation suggests that acupuncture needling enkephalin, β-endorphin, and dynorphin.
achieves at least four therapeutic goals: Acupuncture can also be explained, in
part, by Melzack and Wall’s gate theory.
• Release of physical and emotional stress. When large unmyelinated Aδ and Aβ fibers
• Activation and control of immune and anti- are stimulated by acupuncture, impulses
inflammatory mechanisms. from small unmyelinated C fibers, transmit-
• Acceleration of tissue healing. ting ascending nociceptive information, are
• Pain relief secondary to endorphin and sero- blocked by a gate of inhibitory interneurons.
tonin release. The strongest evidence for acupuncture effi-
cacy in human cancer has been in the areas
Keeping in mind that acupuncture ther- of nausea, vomiting, and pain control.38,39
apy is considered to activate built-in survival Acupuncture is the placement of fine nee-
mechanisms, i.e., self-healing potential, it dles at defined locations in the body that are
is effective for those symptoms that can be rich in neurovascular or muscular structures
completely or partially healed by the body. in order to stimulate an endogenous response
Additionally, each individual has a different directed at analgesia, healing, and immune
self-healing capacity influenced by genetic modulation. Acupressure is the application
makeup, medical history, lifestyle, and age, of pressure to the same specific point loca-
all of which may be dynamically changing. tions for similar indications.40

Mode of Action
EASTERN PERSPECTIVES Neuroanatomical Approach
MEET WESTERN Due to the complexity of constructing and
interpreting placebo-controlled trials in acu-
PERSPECTIVES puncture, the practice of acupuncture rests
heavily on physiological data showing mea-
Ancient Chinese thought holds that qi is a surable changes in endogenous analgesic
fundamental and vital substance of the uni- mechanisms. There is considerable evidence
verse, with all phenomena being produced of measurable physiological effects, for exam-
by its changes. It is considered a vital sub- ple, enkephalins, endorphins, serotonin, nor-
stance of the body, flowing along organized epinephrine, purines, glutamate, neurokinin,
 Chapter 7 Multimodal Management of Pain 229

cannabinoid, ion channel modifiers, modifi- Special Considerations

cation of transcription, and through addi-
tional modification of associated cell
Acupuncture is a complex intervention and
requires additional training. However, the
7
types such as interneurons, microglia, and supplies are accessible, and acupuncture
astrocytes. is seldom regulated in the same fashion as
A body of work has developed showing pain-controlling pharmaceuticals.
the effects of acupuncture as neuromodula- Sterile, single-use needles are essential.
tion. From this evidence a logical and rational Advanced training in acupuncture is avail-
approach to treatment can be made, utilizing able in many regions throughout the world.
point locations that are based upon known Acupuncture can be integrated into veteri-
neuroanatomy and effects measured through nary pain treatments with an understand-
functional MRI (fMRI), chemical changes, ing of muscle function, nerve function, and
and microscopic deformation of soft tissue anatomy. Several human studies have shown
structures.41 While these points often occur the efficacy of acupressure, a modality that
in the same locations as the meridian points, is not limited to individuals trained in the
the rationale for their use is often different placement of needles. Acupuncture is a valu-
when approaching acupuncture from an evi- able adjunct, when used properly, to phar-
dence-based perspective and has been shown maceutical treatments and is meant to be
to be more effective and repeatable between used in a multimodal regimen rather than as
practitioners.42 a stand-alone therapy in most instances.

Metaphysical Approach
Acupuncture can be based on a metaphysi-
cal framework that involves moving invis-
SUMMARY
ible energy, called chi or qi. This approach The term multimodal has come to denote
has added to the clinical expertise of acu- the co-utilization of different delivery modes
puncture treatment for pain, but cannot be as well as a variety of different drug-class
corroborated by research, as chi is, by defini- agents. The objective of this is to provide the
tion, immeasurable. patient with a minimal effective dose of each
agent and therefore render optimal pain relief
Indications with the minimal risk for adverse response.
Somatic pain, including spinal conditions,
postsurgical conditions, trauma, wounds,
and chronic pain such as OA.43 REFERENCES
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combination during isoflurane administration in
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4. Skinner HB. Multimodal acute pain management.
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7. Muir WW, Woolf CJ. Mechanisms of pain and 24. Barber FA, Herbert MA. The effectiveness of an
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10. Kukanich B, Papich MG. Plasma profile and phar- for postoperative analgesia in dogs undergo-
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11. Skarda RT, Tranquilli WJ. Local anesthetics. In: Correlation between perioperative factors and suc-
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 CHAPTER

8
Multimodal Management
of Canine Osteoarthritis
INTRODUCTION processes associated with pain recognition
(i.e., transduction, transmission, modula-
For many years, pain was managed by admin- tion, and perception).
istration of a single pharmacological agent
(if it was managed at all), and often only
when the animal ‘proved’ to the clinician that
it was suffering. Within the past 10–15 years SYNERGISM: A
advancements in the understanding of pain
physiology, introduction of more efficacious
PERIOPERATIVE
and safe drugs, and the maturation of ethics BACKGROUND
toward animals have considerably improved
the management of pain that veterinary A study illustrating the concept of syner-
patients need and deserve. gism was reported by Grimm and others in
Following the lead in human medicine, 2000 (Table 8.1).1 Whereas the time to posi-
veterinarians have come to appreciate that tive response in a tail clamping model was
the network of pain processing involves an 1.5 hours and 2.4 hours for butorphanol
incredibly large number of transmitters and (0.2 mg/kg) and medetomidine (5 Ug/kg),
receptors, all with different mechanisms, respectively, the duration of response time for
dynamics, and modes of action. From this the combination was 5.6 hours rather than
appreciation comes the conclusion that it
is naïve to expect analgesia with a single
agent, working by a single mode of action.
Multimodal analgesia was initially under- TABLE 8.1 Results of a study by Grimm
stood as the administration of a combi- et al.1 which show that adding an opioid to
an α2-agonist results in a clinical response
nation of different drugs from different
that is greater than additive; the result is
pharmacological classes such that they act synergistic
by different, noncompeting modes of action.
However, the concept has further expanded Time until positive
to include different methods of delivery, e.g. Treatment group response (hours)
oral, systemic, transdermal, transbuccal, Saline control 0.0 ± 0.0
and epidural as well as nonpharmacological
Butorphanol 1.50 ± 1.50
modalities such as acupuncture and physi- (0.2 mg/kg IM)
cal rehabilitation. Central to the concept is
that drug combinations will be synergistic Medetomidine 2.36 ± 0.49
(5.0 μg/kg IM) (∑ = 3.86) (expectation if
(or at least additive), requiring a reduced
effects were additive)
amount of each individual drug, and there-
fore less potential for adverse response to Butorphanol 5.58 ± 2.28
medication. Selection of drugs within the (0.2 mg/kg IM) +
‘cocktail’ would be optimal if they collec- Medetomidine
(5.0 μg/kg IM)
tively blocked all four of the physiological

DOI: 10.1201/9781003376422-11 231

232 Chronic Pain in Small Animal Medicine

3.9 hours – the sum of each agent taken indi-

vidually. Synergism is a consistent response
when administering an opioid and an α2-
agonist together, making this combination an
excellent premedication for surgery.
Further, addition of a nonsteroidal anti-
inflammatory drug (NSAID) will guard
against inflammatory windup and sensitize μ
receptors to exogenous opioid effects. 2 From
these observations comes a recommendation
of the optimal surgical premedication proto-
col to include an opioid, an α 2-agonist, and a
COX-1–sparing NSAID.
Perioperative multimodal analgesia is
widely practiced today in veterinary medicine;
however, monotherapy continues to be a com-
mon practice for managing the chronic pain of
osteoarthritis (OA). NSAIDs are the founda-
tion for treating OA and are likely to be so for
some years to come. Many clinicians manage FIGURE 8.1 The quality of evidence pyramid delin-
the elusive pain of OA simply by sequencing eates the origin of confidence a clinician would
different NSAIDs until satisfactory patient have in a given treatment protocol.
results are found or unacceptable adverse reac-
tions are experienced. However, optimal clini-
cal results are more frequently obtained by MULTIMODAL OA
implementing a multimodal protocol for OA.
TREATMENT PROTOCOL
Nonmedical Management
QUALITY OF EVIDENCE (Figure 8.2)
Although contemporary experience precedes Diet
published literature, there is a growing evi-
dence base for the multimodal management Impellizeri et al.4 showed that in overweight
of OA. This evidence is a collation of clinical dogs with hindlimb lameness secondary to
expertise, client/patient preferences, available hip OA, weight reduction alone may result in a
resources, and research evidence, positioned substantial improvement in clinical lameness.
on the quality of evidence pyramid (Figure 8.1).
Quality of evidence is an important con-
sideration when making a therapeutic deci-
sion and can be graded from 1 to 4. Grades 1
and 2 compose the highest level of evidence,
consisting of systematic reviews (meta-analy-
ses) and well-designed, properly randomized,
controlled, patient-centered clinical trials.
Grade 3 notes a moderate level of evidence,
consisting of well-designed, nonrandomized
clinical trials, epidemiological studies (cohort,
case-control), models of disease, and dramatic
results in uncontrolled studies. Grade 4 is the
lowest level of evidence encompassing expert
opinions, descriptive studies, studies in non-
target species, pathophysiological findings,
and in vitro studies. Very few reports have FIGURE 8.2 The nonmedical management of OA
been made reviewing the quality of evidence is composed of weight control/exercise, an EPA-
of treatments for OA in dogs.3 rich diet, and physical rehabilitation.
 Chapter 8 Multimodal Management of Canine Osteoarthritis 233

FIGURE 8.3 The ‘functional unit’ of articular cartilage is the aggrecan aggregate, wherein a loss of struc-
ture results in a loss of function.7 (A) Cross-section of normal cartilage. (B) Proteoglycans (from chon-
drocytes), water, and collagen that comprise cartilage. (C) Aggrecan aggregate. (D) Chondroitin sulfate
GAG. (Adapted from Johnson SA. The Veterinary Clinics of North America Small Animal Practice 1997.)

Further, from the Labrador Retriever Life- like an activated macrophage, with upregu-
long Nestlé Purina Study, Kealy and others5,6 lation of interleukin (IL)-1, IL-6, and IL-8
showed that the prevalence and severity of gene expression. Also upregulated in arthritic
OA in several joints were less in dogs with chondrocytes are prostaglandin E2 (PGE2),
long-term reduced food intake, compared tumor necrosis factor alpha (TNF-α), nitric
with control dogs, and that food intake is an oxide (NO), and matrix metalloproteinases
environmental factor that may have a pro- (MMP)-2, -3, -9, and -13. These enzymes,
found effect on the development of OA in MMPs, and aggrecanases destroy collagen
dogs. Dogs on a restricted diet showed a sig- and proteoglycans faster than new ones can
nificant reduction in progression of OA hip be produced, transitioning the cartilage from
scores and lived longer. an anabolic state to a catabolic state.
Obviously, the content of the diet is criti- Imbalance of TIMPs and MMPs contrib-
cal. The adage ‘you are what you eat’ has been utes to the pathological breakdown of carti-
given support relative to OA from research lage (Figure 8.4).
conducted on eicosapentaenoic acid (EPA)–
rich diets by pet food manufacturers.
Aggrecan is the major proteoglycan (by
mass) of articular cartilage, consisting of
the proteoglycan monomer that aggregates
with hyaluronan. Many aggrecan monomers
attach to a hyaluronic acid chain to form an
aggrecan aggregate. Aggrecan aggregates,
type II collagen fibrils, water, and chondro-
cytes comprise the cartilage matrix wherein
structure reflects function (Figure 8.3). When
structure is altered, so too is function.
A disruption in the normal relationship of
collagen and proteoglycans in the articular
cartilage matrix is one of the first events in FIGURE 8.4 Normally, TIMPs counteract the
the development of OA. Compared with nor- destruction of MMPs, but in the arthritic state
mal cartilage, OA-affected cartilage behaves TIMPs cannot keep up and catabolism prevails.
234 Chronic Pain in Small Animal Medicine

omega-3 fatty acid EPA replaces AA in cell

membranes, the inflammatory cascade is
decreased. Further, dog chondrocytes selec-
tively store EPA (and no other omega-3 fatty
acid) in the chondrocyte membrane, which
turns off signal messenger RNA (mRNA)
that prompts production of degradative
aggrecanase. See Figure 8.6.
Clinical trial results from feeding EPA-
rich diets have demonstrated increased
serum EPA concentrations, improved clini-
cal performance as assessed by both the
veterinarian and the pet owner, improved
weightbearing as measured by force plate
gait analysis, and the potential for NSAID
dose reduction.9

Physical Rehabilitation
Physical rehabilitation is a term that defines
FIGURE 8.5 Eicosanoid production from AA or EPA.8 a broad spectrum of methods from the
most advanced techniques used in complex
Dietary fatty acids can help to correct orthopedic surgery recoveries to the simple
this imbalance by modulating the production techniques that can be taught to pet owners
of inflammatory mediators. PGE 2 , which for use at home with their pets. The goal is
increases in inflammatory conditions such as to restore, maintain, and promote optimal
OA, stimulates pain receptors and promotes function, optimal fitness, wellness, and qual-
additional inflammation. On the other hand, ity of life as they relate to movement disor-
PGE3 and LTB5, the eicosanoid products of ders and health.
EPA, have markedly less biological activity The chronic OA patient is often reluc-
than those derived from arachidonic acid tant to exercise. This reluctance may be
(AA) and are considered anti-inflammatory due to the patient’s unwillingness or inabil-
(Figure 8.5). The end result is that when the ity. Unwillingness is frequently due to pain,

FIGURE 8.6 Derivation of eicosanoids from omega-6 and omega-3 fatty acids.
 Chapter 8 Multimodal Management of Canine Osteoarthritis 235

which can be managed pharmacologically. evidence of the disease.10 Similarly, it is esti-

However, the inability is often a consequence
of decreased muscle mass and decreased
mated that one in five adult dogs is arthritic,
and pharmaceutical industry marketing sur- 8
joint range of motion, both the sequelae of veys suggest the ‘average clinic (one-man
OA. Physical rehabilitation focuses on the practice)’ sees approximately 45 new canine
patient’s inability to exercise, providing a OA cases per month.11
resultant ‘freedom of movement’ and serves NSAIDs will likely remain the foundation
as a palliation of the disease progression. for treating canine OA based on their anti-
Frequently, physical rehabilitation together inflammatory, analgesic, and antipyretic prop-
with weight control in earlier stages of erties. However, like all drugs, every NSAID
OA can be as effective as pharmacological has the potential for a patient-dependent intol-
intervention. Techniques of physical reha- erance. Further, NSAID adverse responses
bilitation easily implemented by pet owners are overrepresented by excessive dosing.12,13
include leash walking, sit-to-stand exercises, As OA patients age and possibly experi-
steps, inclines, dancing and wheelbarrowing ence renal and/or hepatic compromise, it is
exercises, treadmill activity, and cavaletti imperative that their maintenance NSAID
rails. administration be at the minimal effective
Weight control/exercise, an EPA-rich dose. A multimodal OA treatment protocol
diet, and physical rehabilitation comprise the is anchored on this tenet of minimal effec-
nonmedical component of a multimodal OA tive dose.
treatment regimen (Figure 8.2). NSAIDs relieve the clinical signs of pain.
This is achieved by suppression of prosta-
glandins (PGs), primarily PGE 2 , produced
MEDICAL MANAGEMENT from the substrate AA within the prostanoid
cascade (Figure 8.8). PGE 2 plays a number
(FIGURE 8.7) of roles in osteoarthritis, including (1) low-
ering the threshold of nociceptor activation,
Nonsteroidal Anti-Inflammatory (2) promoting synovitis in the joint lining,
(3) enhancing the formation of degradative
Drugs metalloproteinases, and (4) depressing car-
OA is one of the most prevalent and debili- tilage matrix synthesis by chondrocytes. In
tating chronic diseases in mammals. Thirty contrast, PGs also play a positive metabolic
percent of women and 17% of men aged 60 role such as enhancing platelet aggregation
and over have clinical OA, and over 70% of (to prevent excessive bleeding), maintaining
those aged 65 and older show radiographic integrity of the gastrointestinal tract, and
facilitating renal function. Eicosanoid activ-
ity is tissue dependent. Therefore, maintain-
ing an optimal balance of PG production
in various tissues and organ systems, while
inhibiting pain, is the ‘NSAID challenge’.
Coxib-class NSAIDs were developed
in an attempt to suppress COX-2–medi-
ated PGs while sparing COX-1–mediated
PGs, thereby decreasing the relative risk for
gastrointestinal hemorrhage and lesions.
Although analogous data in dogs is lacking,
nonselective (traditional) NSAIDs increase
the relative risk of gastrointestinal bleeding
in humans by a factor of 4.7. This might be
best illustrated by an observational cohort
study14 in elderly human patients. Relative
to intake of no NSAIDs and no coxibs, tra-
FIGURE 8.7 The medical management of OA is ditional NSAIDs have an adjusted ratio for
achieved with NSAIDs, chondroprotectants, and increased short-term risk of upper gastroin-
analgesic adjuncts. testinal hemorrhage of 4. This was reduced
236 Chronic Pain in Small Animal Medicine

FIGURE 8.8 Multiple eicosanoids are derived from the AA cascade, which serve various physiological
functions. Corticosteroids and NSAIDs block this cascade at points identified in the graphic.

to 3 by the combination of such nonselective impossible to determine because all ADEs

NSAIDs with the PG analog misoprostol. are not reported and all ADEs are not
However, the rates were significantly lower directly causal. The denominator is impossi-
for the COX-2 inhibitors, with 1.9 for rofe- ble to determine because there is no means of
coxib and 1.0 for celecoxib, the latter being knowing how many dogs are on a given drug
identical to the control group. Overall, dogs at any point in time. Therefore, accurate
may actually be a better (safer usage) tar- quotients cannot be derived or compared in
get species for the coxib-class NSAIDs than a responsible manner. Nevertheless, the FDA
humans since they tend to have similar (or tracks ‘global trends’ of ADEs in the interests
greater) gastrointestinal issues but do not of clinicians and patient well-being.
have the cardiovascular risk factors, namely At present, there is no evidence-based
atherosclerosis.15 guidance to address the contemporary ques-
The most common complications docu- tion of a ‘washout’ period when changing
mented with NSAID use in the dog are from one NSAID to a different NSAID.
associated with overdosing and the concur- Empirically, it seems appropriate to fol-
rent use with other NSAIDs and corticoste- low aspirin with a conservative washout of
roids.16,17 Adverse drug events (ADEs) are approximately 7 days. In one study18 con-
most frequently seen in the gastrointestinal ducted with a limited number of healthy
tract followed by renal and hepatic systems. dogs at Colorado State University, there was
U.S. Food and Drug Administration (FDA) no significant difference in clinical or clini-
licensing gives the clinician an assurance of copathological data between dogs that were
safety when individual NSAIDs are adminis- given an injectable NSAID followed by the
tered as labeled, together with consideration same molecule in tablet form from those
of the individual patient. Relative safety of dogs given the injectable NSAID followed by
one NSAID to another is an undeterminable a different coxib-class NSAID.
prevalence assessment. Prevalence implies
a quotient, with the numerator consisting
of the number of intolerant dogs over the
Nutraceuticals
denominator of how many dogs have been Next to NSAIDs, nutraceuticals are the fast-
administered the drug. The numerator is est-growing group of healthcare products in
 Chapter 8 Multimodal Management of Canine Osteoarthritis 237

TABLE 8.2 More than 30 nutraceuticals are potentially active in OA

Avocado/Soybean 8
Ascorbic acid unsaponifiables Boswellia serrata Bromelain
Cat’s claw Chondroitin sulfate Cetyl myristoleate oil Collagen hydrolysate
Curcumin Chitosan Devil’s claw Flavonoids
Glucosamine Green lipid mussel Ginger Hyaluronic acid
SO4/Acetyl/HCl
Hydolysate collagen Methylsulfonylmethane Milk and hyperimmune milk Omega-3 polyunsaturated
fatty acids
Phycocyanin Ribes nigrum Rosa canina Selenium
Strontium Silicium Turmeric Vitamin D
Vitamin E Willow

both human and animal health (see Nutrition Business Journal. Estimated sales
Chapter 6). Yet many do not understand of human-use glucosamine and chondroitin
the definition and constraints of a nutra- sulfate in 2004 approached $730 million.
ceutical. A nutraceutical is defined as a It would appear that popularity of these
food additive that is given orally. As such, supplements in the human sector is driving
nutraceuticals are not under regulation by veterinary use. The world market for pet
the FDA. In contrast, chondroprotectives nutraceuticals was worth $960 million in
are FDA-regulated. Together, chondropro- 2004. About 60% of this was given to dogs,
tectants and nutraceuticals are considered a quarter to cats, and 10% to horses. 22
disease-modifying osteoarthritic agents A meta-analysis of studies evaluating the
(DMOAAs), whereas nutraceuticals are efficacy of these supplements for OA 23 sug-
not considered disease-modifying osteo- gested potential benefit from these agents, but
arthritic drugs (DMOADs). More than 30 as is often the case with nutraceuticals, ques-
nutraceutical products have been listed tions were raised about the scientific quality
as potentially active in OA (Table 8.2).19 of the studies. Therefore, the Glucosamine/
Avocado/soybean unsaponifiables (ASu) is chondroitin Arthritis Intervention Trial
a recent entry to the nutraceutical pool. It (GAIT), a 24-week, randomized, double-
is suggested that this compound may pro- blind, placebo- and celecoxib-controlled,
mote OA cartilage repair by acting on sub- multicenter, $14 million trial was sponsored
chondral bone osteoblasts. ASu has been by the National Institutes of Health (NIH)
observed to prevent the inhibitory effect of to evaluate rigorously the efficacy and safety
subchondral osteoblasts on aggrecan syn- of glucosamine, chondroitin sulfate, and the
thesis while having no significant effect on two in combination in the treatment of pain
MMP, tissue inhibitor of metalloprotein- due to human OA of the knee. The primary
ase 1 (TIMP-1), COX-2, or inducible nitric outcome measure of the GAIT study was a
oxide (iNOS) expression. 20 20% decrease in knee pain. Analysis of the
About 21 million Americans have OA. 21 primary outcome measure did not show that
NSAIDs are the foundation for treating OA; either supplement, alone or in combination,
however, ongoing controversy over conven- was efficacious. 24 Prior to the GAIT study,
tional medications has created fertile soil for some investigations had suggested efficacy
the growth of alternative arthritis remedies, of these supplements. Discrepancies may be
particularly glucosamine and chondroitin. explained, in part, by the rigors of the GAIT
First popularized by the 1997 bestseller The study imposed by the NIH and the use of
Arthritis Cure by Dr. Jason Theodosakis, only pharmaceutical-grade supplements.
these supplements racked up combined sales Many nutraceuticals are least-cost formu-
of $640 million in 2000, according to the lations, and quality assurance is lacking to
238 Chronic Pain in Small Animal Medicine

nonexistent. 25,26 As a matter of record, in of OA cartilage by allowing proliferated cells

2005 alone, the FDA rejected 12 research to migrate to damaged areas.
model claims related to products reducing Focusing on the role of IL-1 as an initiat-
the risk of OA, joint degeneration, cartilage ing cytokine associated with induction of deg-
deterioration, and OA-related joint pain, ten- radative enzyme and inflammatory mediator
derness, and swelling. 27 synthesis in OA, Neil et al.31 have summa-
The rationale for using nutraceuticals rized reports on the impact of glucosamine/
is that provision of precursors of cartilage chondroitin sulfate on IL-1 (Table 8.3).
matrix in excess quantities may favor matrix Pharmacokinetic studies in dogs reveals
synthesis and repair of articular cartilage. that glucosamine hydrochloride is only
Glucosamine is an amino monosaccharide 10–12% bioavailable from single or multiple
(2-amino-2-deoxy-a-D-glucose) that, once doses. 51 At the current recommended intake,
modified as N-acetylglucosamine, is pro- it is extremely unlikely that relevant con-
posed to act as a precursor of the disaccharide centrations of glucosamine reach the joint52
units of glycosaminoglycans (GAGs) such as or that substantial amounts of glucosamine
hyaluronan and keratan sulfate. Chondroitin get into the circulation following oral inges-
sulfate is a GAG consisting of alternating tion. 53 Glucosamine is expected to be metab-
disaccharide subunits of glucuronic acid and olized rapidly by the liver or incorporated
sulfated N-acetylgalactosamine. Substitution into glycoproteins. Glucosamine is not ordi-
can occur at the C4 and C6 positions of the narily available in the circulation as a source
N-acetylgalactosamine ring to form chon- of cartilage matrix substrate; cartilage uses
droitin-4-sulfate and chondroitin-6-sulfate. glucose for that purpose.
Chondroitin sulfate is a normal constituent Charged molecules exceeding approxi-
of cartilage, with the ratio of 4:6 decreasing mately 180 daltons are likely not to pass the
with age. To date, there is no evidence that gastrointestinal mucosa and be absorbed
nutraceuticals modulate the natural course unless assisted by a carrier-mediated trans-
of OA. Their inclusion in foods is based port system; therefore, it is unlikely that
on theoretical considerations. ‘Therefore, chondroitin sulfate would be absorbed
although the use of nutraceuticals to treat intact via the gastrointestinal tract. The
OA is a reality, the efficiency of these com- gastric mucosa contains a number of GAG-
pounds to prevent or slow down OA disease degrading enzymes, such as exoglycosi-
remains a myth’.19 dases, sulfatases, and hyaluronidase-like
The literature contains some support for enzymes, which should degrade chondroitin
the use of glucosamine sulfate in humans. It sulfate.
has been observed that glucosamine hydro- Controversy remains over mechanisms by
chloride does not induce symptomatic relief in which nutraceuticals may lead to modulation
knee OA to the same extent as glucosamine of disease symptoms and cartilage degrada-
sulfate.28 Noteworthy is that glucosamine sul- tion in OA and which product is preferred
fate is very hygroscopic and unstable, which is for treatment. Perhaps our scientific com-
why varying amounts of potassium or sodium munity lacks the expertise to identify how
chloride are added during manufacturing. these products might work. Nevertheless, as
Dodge et al.29 reported that glucosamine sul- a class of agents, nutraceuticals fall short in
fate not only increased the expression of the evidence-based efficacy, lack dose titration
aggrecan core protein but also downregu- studies to validate appropriate doses, and
lated, in a dose-dependent manner, MMP-1 have shown inconsistencies in product qual-
and -3 expression. Some investigators30 have ity assurance. Good intentions in the few
suggested that the metabolic contribution have been clouded by many! A sound recom-
to OA cartilage from glucosamine sulfate is mendation for consumers is ‘buyer beware’.
associated with activation of protein kinase One might argue that the most responsible
C, considered to be involved in the physiologi- advice for recommending a nutraceutical is
cal phosphorylation of the integrin subunit. as an adjunct to a ‘science-based’ medici-
Herein, the glucosamine sulfate restores fib- nal, in that the nutraceutical may or may
rillated cartilage chondrocytes’ adhesion to not help. Recommending that the pet owner
fibronectin, thus improving the repair process spend money on a nutraceutical as the first
 Chapter 8 Multimodal Management of Canine Osteoarthritis 239

TABLE 8.3 Influence of IL-1 on articular cartilage matrix components, inflammatory

mediators, and degradative enzymes 8
Mediator/Matrix IL-1 effect on chondrocyte Chondroitin sulfate
molecule biosynthesis Glucosamine effect effect
References 32–37 (+) inhibits, or (−) fails to (+) inhibits, or (−) fails
inhibit effects induced to inhibit effects
by IL-1 induced by IL-1
COX-2/PGE2 Stimulates synthesis + References 38, 39 +/− References 44,
47, 48
iNOS/NO Stimulates synthesis + References 38, 40 +/− References 47, 49
MMPs Induces synthesis, activity, + References 38, 40, 41 + Reference 48
and secretion
Aggrecanases/ Increased synthesis and + References 42, 43
Aggrecan activity
PGs/GAGs Decreased synthesis, + Reference 44 + References 44,
increased degradation 48, 50
Type II collagen Inhibits synthesis − References 44, 45 + Reference 44
Transcription factors Stimulates increased mRNA + References 39, 46
(NF-κB, activator expression and activity
protein 1)

Note: Columns 3 and 4 note the + or – complementary effect from glucosamine and chondroitin sulfate.

line of treatment lacks convincing scientific and hyaluronidases, which degrade collagen,
underpinning. proteoglycans, and hyaluronic acid.56,57 It
is also reported to inhibit PGE synthesis. 58
Chondroprotectants: PSGAG has shown a specific potentiating
effect on hyaluronic acid synthesis by syno-
Polysulfated Glycosaminoglycan vial membrane cells in vitro. 59
Adequan®, a polysulfated glycosaminogly- Within 2 hours of administration,
can (PSGAG), is available as a chondropro- Adequan Canine® enters cartilage, where
tectant, as is the hyaluronic acid product it reduces proteoglycan degradation,
Legend. The products Chondroprotec and inhibits synthesis and activity of degrada-
IChON® are neither a nutraceutical nor a tive enzymes, stimulates GAG synthesis,
chondroprotectant. Both are licensed as topi- and increases hyaluronan concentrations.
cal wound devices, rather than drugs. Clinical data from Millis et al. (unpub-
Adequan Canine® is a PSGAG character- lished, 2005) demonstrated that comfort-
ized as a DMOAD which has met the rigors able angle of extension and lameness scores
of FDA registration. Experiments conducted were both improved following adminis-
in vitro have shown PSGAG to inhibit cer- tration of Adequan Canine® at both 4 and
tain catabolic enzymes which have increased 8 weeks following anterior cruciate liga-
activity in inflamed joints and to enhance ment transection, while the concentration
the activity of some anabolic enzymes.54 of neutral metalloproteinase was reduced
PSGAG has been shown to significantly relative to controls. In an era where evidence-
inhibit serine proteinases, which play a role based treatment is being emphasized, in this
in the IL-1–mediated degradation of carti- instance, the separation between patient
lage proteoglycans and collagen. 55 PSGAG response to FDA-approved drugs and unli-
has further been reported to inhibit some censed agents is gratifyingly widening.
catabolic enzymes such as elastase, stromely- Adequan Canine® is most appropri-
sin, metalloproteinases, cathepsin G and B1, ately administered in the early stages of OA
240 Chronic Pain in Small Animal Medicine

FIGURE 8.9 The strategy of early PSGAG treatment is to delay the point in time when ‘aggressive’ treat-
ment is required to keep the patient comfortable.

(Figure 8.9), since once hyaline cartilage is

lost, it is lost forever! The strategy in admin-
istering this chondroprotective is to delay
the time during progression of OA that
medically aggressive treatment is required
(Figures 8.10 and 8.11).
Summary of Adequan Canine® activity:

• Reduction in proteoglycan degradation

• Inhibition of synthesis and activity of
• Aggrecanases
• MMPs
• NO
• PGE 2 FIGURE 8.11 As degradative enzymes are released
• Stimulates GAG synthesis from arthritic cartilage (right), they change the com-
• Increases hyaluronan concentrations position of joint fluid. Synoviocytes of the joint lin-
ing, sensing these inflammatory mediators, act as
macrophages and release even more inflammatory
agents into the joint. As weightbearing loads and
unloads the cartilage, it acts as a sponge, absorb-
ing and releasing these inflammatory agents within
the joint. Hence, the worse it gets, the worse it gets!
PSGAG acts to dampen this catabolic activity.

ADJUNCTS
OA is both a chronic disease and an acute dis-
ease, with intermittent flare-ups that may ren-
der an NSAID ineffective as a sole analgesic
because of ‘breakthrough pain’ (Figure 8.12).
Further, chronic pain is not just a prolonged
version of acute pain. As pain signals are
FIGURE 8.10 Chondrocytes within the cartilage
matrix (far left) generate all components of the
repeatedly generated, neural pathways undergo
matrix. In the OA disease state, they also pro- physiochemical changes that make them hyper-
duce enzymes which degrade matrix aggrecan sensitive to the pain signals and resistant to
(pink structure). The PSGAG Adequan Canine® antinociceptive input. In a very real sense, the
helps to protect cartilage against the catabolic signals can become embedded in the spinal
activity of these degradative enzymes. cord, like a painful memory (Figure 8.13).
 Chapter 8 Multimodal Management of Canine Osteoarthritis 241

The main neurotransmitter used by noci-

ceptors synapsing with the dorsal horn of
the spinal cord is glutamate, a molecule that 8
can bind to a number of different receptors.
Discovering the role of the N-methyl-D-
aspartate (NMDA) receptor in chronic pain
has given rise to the (empirical) implementa-
tion of NMDA antagonists, such as aman-
tadine, which is occasionally administered
FIGURE 8.12 OA is both an acute and a chronic together with voltage-gated ion channel mod-
disease, with pain that can break through first to ulator gabapentinoids as adjuncts in a multi-
second (World Health Organization [WHO]) lad-
modal OA protocol (also finding efficacy in
der analgesics.

8.13
Pain

Time (response duration)

Brain and higher centers

Spinal dorsal horn Responds to:
Responds to: Exagerated electrical activity
Exagerated electrical activity 1. Lack of information
1. Axonally transported factors By:
2. DRGs, chemical and electrical CNS lesion • Turning up the gain (i.e. decrease
alterartions or disease in descending inhibition)
3. Neuronal loss
By:
• Glutamate windup
• Cytokine expression Central
• Glial activation amplification Microglia
• Synaptic rewiring
• Spinal disinhibition
Dorsal root ganglion Neuroimmune
Responds to: interactions in
Exagerated electrical activity the periphery
1. Lack of neurotrophins Peripheral and the CNS
2. Electrical signals from the amplification
injury site
3. Transported signals from the
injury site
By:
• Increased cytokine expression
PNS lesion or disease
• Altered neuropeptide expression
• Sympathetic sprouting
Peripheral tissue
Site of the nerve injury Responds to:
Responds to: Exagerated electrical activity
Exagerated electrical activity 1. De-innervation
1. Mechanical chemical trauma 2. Inactivity
2. Vascular disruption 3. Loss of nutrients
3. Distal demyelination By:
By: • NGF expression
• Local inflammatory response • Collateral sprouting
• Macrophage recruitment • Hyper-reinnervation
• Neuronal excitability • Neurotransmitter transport
• Ectopic electrical activity
• Neuroma formation

FIGURE 8.13 Neuropathic pain. Maladaptive (chronic) pain typically involves nervous system lesions or
disease, a marked neuroimmune response, and lasts an extended period of time – far beyond the heal-
ing process. Given enough input from the peripheral nervous system (PNS), the central nervous system
(CNS) changes, e.g., the CNS is dynamic (plastic). This is caused by ‘aggravation’ of CNS cell types,
principal to which is the microglia (a CNS macrophage).
242 Chronic Pain in Small Animal Medicine

8.14

Acute pain Chronic pain

Glutamate
Nociceptor Closed K+
channel Substance P
terminal

Guanylsynthase

AMPA
Ca++ K+
NMDA

PKC
K+ NO
Mg++ Na+ Na+
Ca++
Mg++ Production and release
Production and release Nitric oxide
of neurotransmitters
of neurotransmitters synthase
C-fos gene
expression

Wind-up

FIGURE 8.14 N-methyl-D-aspartate (NMDA) receptor activity plays a major role in differentiating acute
from chronic pain. When activated, the NMDA receptor site allows massive intracellular influx of Ca++,
which initiates the state of ‘wind-up’. (AMPA: alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic
acid, PKC, protein kinase C.)

other chronic pain diseases). When activated, involved in perception and transmission of
the NMDA receptor site allows a massive noxious stimuli provide multiple sites for
intracellular influx of Ca+ and subsequent potential new analgesic drug development
neuronal release of neurogenic transmitters (Figures 8.15 and 8.16).
(Figure 8.14). The receptors and pathways
8.15 Primary
afferent neuron Dorsal horn neuron

CGRP

CGRP
Nociception sP NK-1 Spinothalamic tract Hyperalgesia Wind-up
AMPA

Glu Activate

NMDA Facilitation

Hyper-
sensitivity

Opioid Inhibition

FIGURE 8.15 N-methyl-D-aspartate (NMDA) facilitation amplifies the nociceptive signals to a state of
hyperalgesia. Administration of an ‘adjunct’, such as an NMDA antagonist, blocks the NMDA-facilitated
nociceptive signaling, suppressing the nociceptive signal back to a state of ‘normalgesia’. (AMPA:
alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, CGRP: calcitonin gene related peptide,
Glu: glutamate, NK-1: neurokinin-1, sP: substance P.)
 Chapter 8 Multimodal Management of Canine Osteoarthritis 243

8.16

FIGURE 8.16 The moving target of pain management. Well-characterized receptors in the periphery are
activated by noxious stimuli, acute inflammation, and tissue injury, sending afferent information to the dor-
sal horn of the spinal cord where synaptic transmission to ascending pathways is subject to modulation
by descending pathways, local neuronal circuits, and a variety of neurochemicals. Each of these recep-
tors/modulators is a potential site for new analgesic drug development. (A2: adenosine A2 receptor, ASIC:
acid-sensing channels, ATP: adenosine triphosphate, B1/2: bradykinin receptors 1, 2, EAAs: excitatory
amino acids, EP: prostaglandin E receptor, H1: histamine H1 receptor, 5-HT: 5-hydroxytryptamine (sero-
tonin), IGluR: ionotropic glutamate receptor, IL: interleukin, IL-1R: interleukin 1 receptor, M2: muscarinic
M2 receptor, mGluR: metabotropic glutamate receptor, NO: nitric oxide, P2X3: purinergic receptor X3,
PAF: platelet-activating factor, ROS: reactive oxygen species, TrKA: tyrosine receptor kinase A.)

Implementing both the medical (Figure 8.7)

and nonmedical (Figure 8.2) management
principles to the canine osteoarthritic patient
provides the optimal benefits to the patient
(Figure 8.17). The evidence base for each
component of the multimodal management
approach is substantial, (see Table 8.4) and
impacts on the tenet of determining the min-
imal effective dose to maximize the safety of
therapy. See Figure 8.18.
Following adoption of the multimodal
scheme, the question at hand is sequenc-
ing the different modalities. Herein,
there appears to be two different sugges-
tions. Some suggest starting the patient
on nonpharmacologic modalities, such
as nutraceuticals, weight loss, and diet
modifications (dotted line), and thereafter FIGURE 8.17 Multimodal management of OA.
244 Chronic Pain in Small Animal Medicine

integrating the pharmacologic agents.

TABLE 8.4 Evidence rank of various
therapeutic approaches to OA
However, this approach is challenged by
two well-founded arguments. First, it
Selected references is well recognized that most of the non-
Modality establishing evidence base pharmacologic modalities take 3–4 weeks
NSAID 63–66 before a clinical response is observed, and
pet owners want to see a response sooner
Chondroprotectant 67–70
than that. Second, it is in the patients’ best
Adjuncts 71–74 interest to provide analgesia as soon as
Weight control/ 5, 8, 10, 75–77 possible. Anything less could be argued as
Exercise inhumane – not providing immediate relief
to the patient, which it needs and deserves.
EPA-rich diet 78–83
Accordingly, the solid line path would
Physical 84–87 appear the most ethical.
rehabilitation

FIGURE 8.18 Proposed algorithm for implementing a multimodal plan for nonsurgical management of the
OA patient. (Adopted from Lascelles, 2008.)
 Chapter 8 Multimodal Management of Canine Osteoarthritis 245

CANNABINOIDS and impending products, the implications

In human medicine, OA diagnoses have tri-

for their use, potential side effects, the regu-
latory issues, and the scientific literature. 8
pled since 2000 due to an aging population, It is essential for veterinary practitioners
increasing levels of obesity, and greater phy- to understand that the cannabis plant does
sician recognition of its prevalence.88 Animal not consist of a single therapeutic agent,
OA is following the same trend. Irrespective but a heterogeneous blend of a multitude
of the precipitating cause, the pathology of of compounds. Beyond its biological tax-
joint destruction in arthritis is driven by an onomy, Cannabis spp. are divided into two
overlapping profile of pathologic inflam- subtypes based on the plant’s intended use
matory cytokines including TNF-α, IL-1β, and legal classification. The first of these two
IL-6, IL-17, and IL-21.89–91 Because pain is recognized subtypes are known as ‘indus-
the predominant symptom of OA, it is also trial hemp’, ‘hemp’, or ‘low-THC (delta9-tet-
the primary target of intervention. Not only rahydrocannabinol) cannabis’. The current
is the treatment of chronic OA pain in pets legal landscape allows products that have
an ethical and humane issue but also spon- been formulated from the hemp subtype
taneous models, particularly domesticated to be easily obtained by animal caregivers
canine models, are appropriate for assess- through over-the-counter purchases, such as
ing OA pain treatments because they closely from retail outlets and online marketplaces.
mimic the pathophysiology and pathogenesis The second subtype is commonly described
of human OA pain.92 Recent reviews com- as ‘high-THC cannabis’ or ‘marijuana’. It
paring the efficacy of pharmacotherapies for should be noted that the term marijuana is
reducing OA pain conclude opioids are most a description of cannabis when used as a
effective, though abuse potential limits their recreational product. From a scientific and
utility, signaling a need for additional treat- medical perspective, the use of the term high-
ments with novel and complementary mech- THC cannabis is preferred.
anisms of action.93–96 Humans and animals are born with
The ubiquitous endocannabinoid system an ECS, which helps the body maintain
(ECS) plays a role in many physiological and homeostasis. Broadly speaking, the ECS is the
pathophysiological processes. Consistent mechanism through which the nervous sys-
with this, cannabis and its constituents tem and immune system (inflammatory reac-
are increasingly being recognized as bona tions) communicate and balance each other.
fide pharmacologic agents with significant The ECS has two key components: neu-
therapeutic potential. Case-in-point, can- rotransmitters and receptors.
nabidiol (CBD), the major non-THC con- Neurotransmitters are chemical sub-
stituent of cannabis, can exert numerous stances created by cells to transmit a mes-
biological effects through several different sage. These messenger molecules bind to the
receptors and signaling pathways, including second key element of the ECS, the CB1 and
anti-inflammatory effects in both acute and CB2 receptors. In 1987 a new G protein–
chronic conditions.97–105 It has been widely coupled receptor (GPCR) was discovered
reported that CBD possesses significant anti- and named CB1, followed two years later by
inflammatory properties in a variety of dif- a second GPCR, named CB2.
ferent experimental systems.106 The CB2 cannabinoid receptor is mostly
Clinical trials elucidating the benefits and found in immunity-related cells, and it is
safety of phytocannabinoids in companion largely involved in regulating the immune
animals are surfacing at academic institu- system and inflammatory conditions.
tions after years of research apprehension Although under normal ‘homeostatic’ con-
due to the controversial status of canna- ditions the CB2 receptors have a very low
bis. Public and commercial interest in this presence in neurons, in ‘nonhomeostatic’
emerging therapy for animals has resulted in situations such as inflammation, neuro-
a number of studies and clinical trials being degenerative diseases such as Alzheimer’s,
published or nearing publication.88,107 To Parkinson’s, and amyotrophic lateral sclero-
safely and effectively implement cannabinoid sis (ALS), as well as in cancers such as glio-
products, a veterinarian must examine the mas, its presence in the brain is dramatically
ECS, the many cannabinoids, the available increased in astrocytes as well as microglial
246 Chronic Pain in Small Animal Medicine

and cerebral microvascular endothelial cells. Examples of cannabinoids and their

Recent published work has provided evi- functions110:
dence that this receptor may also have a role
in modulating addictive disorders.108 Both • CBD exerts diverse pharmacological effects,
the CB1 and CB2 receptors play important such as improving sleep and reducing stress,
roles in many processes, including neuronal anxiety, and inflammation. In addition, it
plasticity, pain, anxiety, neuroinflammation, serves as an analgesic, an anti-inflammatory
immune function, metabolic regulation, agent, a potent antioxidant, an antiemetic, an
reward, craving, and bone growth.109 One of anticonvulsant, and a cardioprotective agent.
the functions of cannabinoid receptors in the • Cannabigerol (CBG) exerts analgesic, inflam-
immune system is modulation of cytokine matory, antibacterial, and muscle relaxation
release. effects, and it has benefits in inflammatory
Endogenous molecules, which occur nat- bowel disease and Crohn’s disease.
urally in the body, and phytocannabinoids • Some of the more recent research trends
or cannabinoids, which are found in hemp concern the role of the ECS in the gastro-
plants, can bind to either CB1 or CB2 recep- intestinal tract,98–100 leading to applica-
tors to regulate the ECS. The ECS requires tions for phytocannabinoids in managing
regulation to combat environmental and chronic disorders like inflammatory bowel
internal stressors, and this is where canna- disease. Cannabinoid receptors are funda-
binoids play an essential role. The ECS plays mentally involved in all aspects of intesti-
a part in sleep, emotion and mood, appetite, nal physiology, such as motility, secretion,
memory, digestion, immune function, repro- and epithelial barrier function. The ECS
duction, and fertility. has a strong impact on the pathophysi-
Cannabinoids refer to any naturally ology of the gastrointestinal tract and is
occurring, biologically active chemical con- believed to maintain homeostasis in the
stituent of the flowers, leaves, and stalks of gut by controlling hypercontractility and
cannabis plants. The cannabinoids found promoting regeneration after injury.
in plants, called phytocannabinoids, mimic • Cannabichromene (CBC) aids in neurogenesis
endogenous neurotransmitters to exert their and neuroplasticity to improve brain health.
effects on the ECS. • Cannabinol (CBN) has been used as an
While CBD is best known, it is one of 120 appetite stimulant and analgesic, for
identified cannabinoids,110 each with unique immune support, and as a sleep aid.
properties and effects within the ECS. This • Cannabielsoin (CBE) has not been studied
fact opens a world of targeted cannabinoid fully. CBE appears to lower blood pres-
applications for animal and human use. The sure and improve capillary strength. It has
number and actions of individual cannabi- potential use with neuropathies.
noids underscore the importance of being • Cannabicyclol (CBL) is derived from CBC
certain about which cannabis product is and has not been sufficiently studied.
selected and for what purpose. All hemp/can-
nabis products are not the same. The plants
yield different concentrations of the various TABLE 8.5 Comparative therapeutic
cannabinoids based on the breeding and effects of THC and CBD
selection of cannabis varieties, growth con-
ditions, harvesting practices, and extraction Therapeutic effects THC CBD1
processes. Most broad- and full-spectrum Psychoactive Yes No
CBD products are formulated by process-
Pain modulation Yes Yes
ing the hemp such that the cannabinoid
content is whatever cannabinoids happened Antiseizure Maybe Yes
to be in the harvested plants. The resulting Antitumor Yes Yes
varied concentration of cannabinoids is one
explanation for the inconsistent responses Helps with Yes Maybe
among animals. Other bioactive compounds nausea/Appetite
in cannabis plants can influence bioactivity, Anti-anxiety No Yes
and the method of administration affects a
Anti-inflammatory Yes Yes
body’s response.
 Chapter 8 Multimodal Management of Canine Osteoarthritis 247

Legally speaking, cannabis plants that gastrointestinal tract via cytochrome P450
naturally produce greater than 0.3% THC
are labeled ‘marijuana’ and are considered
(CYP) isoenzymes (as are many antiseizure
medications [ASMs]), some interaction or 8
illegal drugs under federal law. Plants produc- inhibition of metabolism is anticipated.120,121
ing less than 0.3% THC are considered hemp, Dose-related somnolence and sedation are
and the Farm Bill classified them as legal. commonly reported side effects of CBD
administration.121,122
Garcia et al.123 has reported on the safety
Safety and Efficacy of and effectiveness of a small, controlled,
Treating Refractory Epileptic 14-dog cohort of epileptic dogs treated with
placebo or CBD/CBDA-rich hemp extract
Seizures in Dogs treatment at 2 mg/kg orally every 12 hours
The use of CBD in childhood refractory for each 12-week arm of their cross-over
seizures has become a common therapeu- study. Results demonstrated:
tic approach for specific seizure disorders
in human medicine. From this experience, (1) Aside from a mild increase in alkaline phos-
there is an interest in using CBD, cannabid- phatase, there were no alterations observed
iolic acid (CBDA), or cannabinoid-rich hemp on routine bloodwork at 2, 6, and 12 weeks
products in the treatment of idiopathic epi- during either arm of the study.
lepsy in dogs. (2) Epileptic seizure frequency decreased across
Antiepileptic findings show that the the population from a mean of 8.0 ± 4.8
effects of cannabinoids are separate from during placebo treatment to 5.0 ± 3.6 with
the psychotropic and excitatory effects of CBD/CBDA-rich hemp extract (P = 0.02).
19-tetrahydrocannabidiol (THC) and that (3) Epileptic seizure event days over the
CBD exhibits a lack of central nervous 12 weeks of CBD/CBDA-rich hemp treat-
system excitation.111,112 No one mecha- ment was 4.1 ± 3.4, which was significantly
nism appears to be solely responsible for different than during the 12 weeks of pla-
the antiepileptic action of CBD.113 CBD cebo treatment (5.8 ± 3.1; P = 0.02). The
alone does not solely contribute to the anti- number of dogs with a 50% reduction in
epileptic properties seen in the use of such epileptic activity while on treatment were
preparations.114 The presence of minor can- 6/14, whereas 0/14 had reductions of 50%
nabinoids alongside CBDA augmenting or greater while on the placebo (P = 0.02)
potency provides conceptual evidence of the (4) Adverse events were minimal but included
‘entourage effect’ (synergism).114 somnolence (3/14) and transient increases
The pharmacokinetics, safety, and effi- in ataxia (4/14) during CBD/CBDA-rich
cacy of a blend of a CBD/CBDA-rich hemp hemp extract treatment; this was not sig-
extract in osteoarthritic dogs at 2 mg/kg in an nificantly different from placebo.
oil base provided orally every 12 hours have
been reported.115 Previous work describes
CBD and CBD/CBDA-rich hemp extract
administration being safe at doses between
POTPOURRI
2 and 10 mg/kg body weight provided as an
orally administered oil.116,117 Other studies
Diagnostics
have found mild adverse events associated Each year, the practicing clinician has more
with the administration of CBD to dogs; resources available to her or him than ever
these gastrointestinal signs were attributed before. Such resources include diagnostic
to the medium-chain triglyceride oil base of algorithms, electronic libraries, educational
the product rather than the cannabinoids.118 webinars, diagnostic hardware, etc. One
McGrath et al. found a significant 33% such offering is PainTrace®. This device is a
reduction in epileptic seizure days (seizure wearable monitor proposed to quantify both
days being defined as one or more events dur- acute and chronic pain. Real-time pain lev-
ing the day to account for cluster seizures) els are acquired using skin-mounted sensors
in dogs administered CBD compared to that process a direct ‘pain biosignal’ gener-
baseline reported seizure events.119 Because ated by the nervous system (term ‘biosig-
CBD is metabolized in the liver and the nal’ undefined). This device is an attempt to
248 Chronic Pain in Small Animal Medicine

objectively quantify pain, recognizing that 2. Williams JT. The painless synergism of aspirin and
opium. Nature 1997;390:557–558.
‘in humans’ pain is what the patient says it is, 3. Aragon CL, Hofmeister EH, Budsberg SC.
while in animals, pain is what the observer Systematic review of clinical trials of treatments
says it is’. Said differently, we will likely never for osteoarthritis in dogs. J Am Vet Med Assoc
be able to objectively quantify pain, because 2007;230:514–521.
4. Impellizeri JA, Tetrick MA, Muir P. Effect of
by definition ‘pain’ is the cognitive process- weight reduction on clinical signs of lameness in
ing of nociception, and likely such cognitive dogs with hip osteoarthritis. J Am Vet Med Assoc
processing is as variable as is the weather. 2000;216(7):1089–1091.
5. Kealy RD, Lawler DF, Ballam JM, et al. Five-year
longitudinal study on limited food consumption and
Checklists: Differential development of osteoarthritis in coxofemoral joints
of dogs. J Am Vet Med Assoc 1997;210(2):222–225.
Diagnoses 6. Kealy RD, Lawler DF, Ballam JM, et al. Evaluation
of the effect of limited food consumption on radio-
Arguably, few embrace checklists more than graphic evidence of osteoarthritis in dogs. J Am Vet
airplane pilots (based upon this author’s Med Assoc 2000;217(11):1678–1680.
7. Johnston SA. Osteoarthritis. Joint anatomy, physi-
experience as a combat pilot). No matter ology, and pathobiology. Vet Clin North Am Small
the frequency of performing repetitive tasks Anim Pract 1997;27(4):699–723.
from memory, distractions from various 8. Hayek MG, Lepine AJ, Martinez SA, et al. Articular
sources open the door for inaccuracies and Cartilage and Joint Health. Proceedings from a
Symposium on March 7, 2000 at the Veterinary
flawed sequela. Checklists minimize spuri- Orthopedic Society 27th Annual Conference, Val d’
ous results. Isere, France.
Diagnostic algorithms are to the clinician 9. Clinician’s update, Supplement to NAVC Clinician’s
Brief ®. April 2005.
much what checklists are to the pilot, and we 10. Solomon L. Clinical features of osteoarthritis. In:
are all trained in the discipline of entertain- Kelley WN, Ruddy S, Harris EDJ, Sledge C (eds)
ing differential diagnoses (DDXs) to reach Textbook of Rheumatology, Vol 2. WB Saunders,
Philadelphia, 1997, p1383–1408.
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there obvious value in discarding distrac- 12. Lascelles BDX, Blikslager AT, Fox SM, et al.
tors, but there is value in learning why DDXs Gastrointestinal tract perforations in dogs treated
with a selective cyclooxygenase-2 inhibitor: 29 cases
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experiences and insights from colleagues, 13. 3-Year Deramaxx Update. Novartis Animal Health
USA, Inc. 2007: DER 060058A 35618.
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having such a resource at your disposal elec- Observational study of upper gastrointestinal haem-
tronically! A number of Finnish veterinari- orrhage in elderly patients given selective cyclo-oxy-
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anti-inflammatory drugs. BMJ 2002;325:624.
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diagnostic algorithm from which input clini- pathologic findings in dogs with atherosclero-
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Such an exercise can be as valuable to the with Deramaxx (deracoxib) since its US launch.
‘seasoned’ clinician as it is for the ‘novice’ Advisor for the Practicing Veterinarian. 2004 (DER
030103A).
clinician. Do you ever find yourself saying, 17. Lascelles BDX, McFarland JM. Guidelines for
‘I have 25 years’ experience with XXX, safe and effective use of non-steroidal anti-inflam-
when, in reality, you have an experience with matory drugs in dogs. Technical Bulletin, Pfizer
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animals. In Gupta R, Srivastava A, Lall, R. (eds) rich hemp extract in the treatment of refrac-
Nutraceuticals in Veterinary Medicine. Springer, tory epileptic seizures in dogs. Front Vet Sci
Cham. 2019. DOI: 10.1007/978-3-030-04624-8_10 2022;9:939966.
CHAPTER

9
Chronic Pain in Selected
Physiological Systems
Ophthalmic, Aural, and Dental Ophthalmic Pain

OPHTHALMIC PAIN In 1993, Liu et al.7 compared propara-

caine and bupivacaine for onset time, corneal
Ocular pain can be severe, requiring prompt epithelial toxicity, and duration of action in
treatment from a welfare perspective as well rabbit eyes, finding that bupivacaine was less
as to prevent progression of the original dis- toxic to the corneal epithelium than propara-
ease. Ophthalmic pain in animals is often caine 0.5% and that increasing the pH of a
difficult to identify, but can be inferred from bupivacaine solution from 5.7 to 6.5 practi-
reports of humans with similar anomalies. cally doubled the duration of action.
Keratitis, iritis, and glaucoma result in a dull In 1999, Sun et al.8 compared bupi-
deep pain that has an inflammatory compo- vacaine, lidocaine, procaine, and benzo-
nent. Corneal foreign bodies and erosions caine. Onset time for all drugs was within
produce superficial pain, which is acute and 1 minute. Bupivacaine and lidocaine had a
sharp. longer anesthetic effect than procaine or
The cornea has the highest concentra- benzocaine, and the durations of action for
tion of free nerve endings in the body and lidocaine and bupivacaine in pH-adjusted
is therefore particularly sensitive to pain- solutions were significantly longer than
ful stimuli.1–3 Any ocular surgery, trauma, those of non-pH-adjusted solutions. These
or infection of the corneal epithelium may data support results from other studies7,9,10
cause severe and persistent pain that is diffi- documenting that the addition of sodium
cult to manage. Further, human studies have bicarbonate to solutions of local anes-
shown that only a limited amount of local thetic to raise the pH closer to the agent’s
anesthetic can be used without causing local pKa could reduce the latency, increase the
toxicity and severe damage to the cornea.4 intensity, and prolong the duration of neu-
The literature suggests that the ideal ral blockade without compromising toxic-
topical anesthetic agent for cataract surgery ity. For relief of corneal pain, topical local
should meet the following criteria: (1) no sys- anesthetics can be effective; however, they
temic toxicity and minimal corneal toxicity, should not be used beyond the perioperative
(2) no eye irritation, (3) prompt onset, and period because they may inhibit corneal re-
(4) adequate duration of action. 5 Several top- epithelialization, interfere with lacrimation,
ical agents, such as cocaine, tetracaine, and and produce corneal swelling and increased
proparacaine have been used in the past for corneal epithelial permeability.11 Regarding
anterior segment surgery; however, cocaine preemptive analgesia for intraocular surgery
and proparacaine have associated corneal in dogs, preliminary studies suggest that sys-
toxicity,6 and tetracaine does not produce temic lidocaine is effective with few adverse
sufficient anesthesia or adequate duration of side effects.12 Retrobulbar administration of
action. 5 That said, most cataract surgery is local anesthetics is commonly used for ocu-
done under general anesthesia. lar procedures in human medicine.

252 DOI: 10.1201/9781003376422-12

 Chapter 9 Chronic Pain in Selected Physiological Systems 253

Because glucocorticoids inhibit the vas- hypertensive effect of corticosteroids has been
cular and cellular responses characteristic
of early inflammation and also suppress the
documented in beagles19 with primary open-
angle glaucoma and in normal cats. 9
persistent, nonresolving changes of chronic All surgical diseases have an inflamma-
inflammation, they are commonly used for tory component. Further, atropine-resistant
ophthalmic conditions. In the latter stages miosis, rise in intraocular pressure, disrup-
of inflammation, glucocorticoids suppress tion of the blood-aqueous barrier, vasodilata-
formation of fibroblasts and their collagen- tion associated with vascular permeability in
forming activity as well as neovasculariza- the conjunctiva and iris, and possibly corneal
tion. Accordingly, topical glucocorticoids neovascularization are inflammatory effects
are effective for treating nonulcerative kera- caused by ocular prostaglandins (PGs). 20
titis by suppressing or preventing neovascu- Accordingly, nonsteroidal anti-inflammatory
lar ingrowth and scar tissue formation and drugs (NSAIDs) can be quite efficacious in
thereby preserve the structure and transpar- minimizing the detrimental effects of the
ency of the cornea.13 Topical glucocorticoid inflammatory response, including pain.
preparations are available as solutions, sus- Topical formulations of NSAIDs for
pensions, or ointments. Phosphate deriva- ophthalmic use became commercially avail-
tives provide a clear solution in contrast to able worldwide by the early 1990s. They are
acetate and alcohol derivatives, which are less often considered a safer alternative to topi-
water soluble and are in suspensions. Due to cal corticosteroids, avoiding the potential
the lipid-rich composition of the corneal epi- undesirable side effects associated with topi-
thelium, lipophilic acetate and alcohol corti- cal steroids, such as elevations in intraocular
costeroid preparations penetrate the cornea pressure and progression of cataracts (both
better than the polar preparations such as of which are less common in veterinary med-
sodium salts of the steroid phosphate.14 icine than in human medicine), increased
Absorption of glucocorticoid suspensions risk of infection, and worsening of stro-
is slow and may maintain therapeutic levels mal melting by activation of matrix metal-
for 2–3 weeks in humans, while a substantial loproteinases (MMPs). Topically applied
amount of active glucocorticoid may remain NSAIDs are commonly used in the manage-
up to 13 months in subconjunctival depots.15 ment and prevention of noninfectious ocular
Although not assessed in animals, intravitreal inflammation following cataract surgery.
administration of triamcinolone acetonide Additionally, they are used in the manage-
has been suggested for humans as a possible ment of pain following refractive surgery and
treatment for diabetic macular edema, pro- in the treatment of allergic conjunctivitis.
liferative diabetic retinopathy, chronic pre- Topical NSAIDs were first shown to be more
phthisical ocular hypotony, chronic uveitis, effective in intraocular penetration than sys-
and exudative retinal detachment. Vitreous temic formulations by Sawa and Masuda 21
concentrations from clinical injections can be and Miyake, 22 who also demonstrated the
present for up to 1.5 years after the applica- effects of topical NSAIDs on the prevention
tion.16 Systemic administration of glucocor- of intraoperative miosis and cystoid macu-
ticoids may either be combined with topical lar edema. They were first used in cataract
or subconjunctival therapy for treatment of surgery for the prevention of intraoperative
severe or refractory anterior uveitis or used miosis, 23 and later shown to be effective in
alone for the control of chorioretinitis, optic controlling the pain following refractive sur-
neuritis, or noninfectious orbital inflamma- gery, 24 with potential in the prevention and
tion.17 Topical glucocorticoids are considered treatment of cystoid macular edema. 25
contraindicated in the presence of corneal Topical NSAIDs are classified into six
ulceration because of delayed epithelial heal- groups based on their chemical composition:
ing rates, stromal keratocyte proliferation,
and collagen deposition. Further, debate over • Indoles
the use of glucocorticoids for the management • Phenylacetic acids
of ocular infections is unresolved. Steroid- • Phenylalkanoic acids
induced cataract has been produced experi- • Salicylates
mentally in cats by topical administration of • Fenamates
dexamethasone or prednisolone,18 and the • Pyrazolones
254 Chronic Pain in Small Animal Medicine

Salicylates, fenamates, and pyrazolones is more effective than the others in stabilizing
are considered too toxic to be used in the the blood-aqueous barrier in canine eyes.28 In
eye. 26 See Table 9.1. the dog, topical 0.1% indomethacin solution
In contrast to postoperative inflamma- was as effective as topical 1% indomethacin
tion, many forms of uveitis require prolonged suspension in preventing the increase in per-
corticosteroid therapy to control the inflam- meability of the blood-aqueous barrier and
mation and discomfort, but with the risk of the miotic response induced by aqueous para-
local toxicity. In some cases NSAIDs are a centesis.29 Further, it is reported in dogs that
potential alternative that provide safer treat- topical indomethacin readily penetrates the
ment.27 A comparative study of topical 1.0% cornea and enters the aqueous humor to pre-
suspensions of flurbiprofen, diclofenac, tol- vent in situ PG synthesis and blood-aqueous
metin, and suprofen showed that diclofenac breakdown.30 In a study comparing effects

TABLE 9.1 Commercially available topical NSAIDs for control of human ophthalmic pain and
inflammation
Chemical
Drug name Manufacturer class Formulation Indications
Generic Brand
Flurbiprofen Ocufen® Allergan Phenylalkanoic 0.03% Inhibition of intraoperative
acid solution miosis
Suprofen Profenal® Alcon Phenylalkanoic 1.0% solution Inhibition of intraoperative
acid miosis
Ketorolac Acular® Allergan Phenylalkanoic 0.5% solution Seasonal allergic
acid conjunctivitis,
postoperative
inflammation following
cataract surgery
Acular LS® Allergan Phenylalkanoic 0.4% solution Reduction of ocular pain
acid and burning/stinging
following corneal
refractive surgery
Diclofenac Voltaren® Novartis Phenylacetic 0.1% solution Postoperative
acid inflammation following
cataract surgery,
reduction of pain and
photophobia following
refractive surgery
Nepafenac Nevanac® Alcon Phenylacetic 0.1% Pain and inflammation
acid suspension associated with cataract
surgery
Bromfenac Xibrom® Bausch & Lomb Phenylacetic 0.9% solution Postoperative inflammation
acid and pain following
cataract surgery
Indomethacin Indocin® Various Indole 0.1% solution Prevention of the
inflammation linked with
cataract surgery and
anterior segment of the
eye, inhibition of
preoperative miosis and
treatment of pain related
to refractive surgery
Indocollyre® 0.5% solution
Indomelol® 1%
suspension
 Chapter 9 Chronic Pain in Selected Physiological Systems 255

of orally administered tepoxalin, carprofen, show signs of pain for weeks or months during
and meloxicam for controlling aqueocentesis-
induced anterior uveitis in dogs, as determined
the slow healing process.
Under such circumstances, topically 9
by measurement of aqueous prostaglandin E2 administered corneal anesthetic agents are
(PGE2) concentrations, Gilmour et al. con- inappropriate because of both short duration
cluded that tepoxalin was more effective than and toxicosis of the corneal epithelium with
carprofen or meloxicam for controlling the associated delay in healing. NSAIDs admin-
production of PGE2 in dogs with experimen- istered topically have offered some analgesic
tally induced uveitis.31 effects in humans with corneal ulcers36,37 and
Although rare, systemic adverse reac- may offer benefit in dogs, but can be associated
tions to topically applied NSAIDs have with delayed would healing and corneal melt-
been reported. The systemic absorption of ing. Stiles et al.34 have reported that the topical
topically applied ophthalmic preparations is use of 1% morphine sulfate solution in dogs
considered minimal; however, it is prudent with corneal ulcers provided analgesia for a
to consider the potential for systemic effects. subjective assessment of at least 4 hours with-
Severe adverse events associated with topical out interference with wound healing. These
NSAIDs appear to require potentiation in results are consistent with those observed in
the form of high total doses, ocular comor- the human patient and literature.38
bidities, or other risk factors such as previ- Glaucoma is one of the most frequent blind-
ous cataract or ocular surgeries, diabetes, or ing diseases in dogs, characterized by high
ocular vascular or cardiovascular disease.32 intraocular pressure (>25–30 mmHg in dogs;
As with systemic NSAID administration, >31 mmHg in cats) that causes characteristic
adverse reactions to topically administered degenerative changes in the optic nerve and ret-
NSAIDs in humans are not infrequently ina, with subsequent loss of vision. Glaucoma
associated with inappropriate use.33 results from the degeneration of retinal gan-
Pain associated with corneal ulceration in glion cells and their axons. Glaucomatous con-
animals or humans may not always be specifi- ditions characterized by degenerative retinal
cally treated,34 focusing instead on rapid cover- ganglion cell death in the absence of elevated
ing of nerve endings by advancing epithelium, intraocular pressure have not been recognized
thereby sparing the axons from noxious stimuli. in the dog. The dog has the highest frequency
And although uncomplicated corneal ulcers in of primary glaucomas of all animals, with the
dogs may heal in a few days, the dog is likely to narrow- or closed-angle type being the most
experience considerable pain during that time. common,39 and the contralateral eye usually
Dogs being treated for indolent or nonhealing develops glaucoma in affected dogs within a
corneal ulcers often require multiple episodes few months. Figure 9.1 illustrates tonometers
of debridement or surgical intervention35 and used to measure intraocular pressure.

FIGURE 9.1 (A) Tonovet®, a handheld magnetic rebound tonometer for measuring intraocular pressure,
(B) the more traditional Schiötz indentation tonometer, and (C) the tonopen applanation tonometer.
256 Chronic Pain in Small Animal Medicine

While glaucoma in human patients is usu- cat can cause discomfort to the patient and
ally not associated with clinical signs of ocular may result in aggressive behavior toward the
pain and discomfort, glaucoma in veterinary examiner. The ear canal is an invagination
patients is usually recognized when aggres- of epidermis forming a hollow skin tube in
sive clinical signs of the disease are present. the inside of the head that begins at the ear-
Nevertheless, most veterinary textbooks drum (Figure 9.2). Primary causes of ear dis-
address treatment for controlling intraocular ease are skin diseases that also have an effect
pressures associated with glaucoma, but few on the skin lining the ear canal. Cutaneous
address the associated pain. In some cases, enu- diseases such as atopy, food hypersensitiv-
cleation or evisceration may be the only way to ity, parasites, foreign bodies, hypothyroidism,
relieve the animal’s pain. If ocular pain is exac- and seborrheic disease frequently result in ear
erbated by exposure to bright light, relief may disease. Often complicating the condition is
be achieved by reducing ambient illumination. long-standing overtreatment of ears with ear
Glaucoma can be conceptualized as cleaners, drugs that irritate the epithelium, and
an optic neuropathy associated with char- cotton-tipped applicators. It has been theo-
acteristic structural damage to the optic rized that chronic inflammation, more com-
nerve and associated visual dysfunction.40 mon in the dog than in the cat, may initiate
Hypothesizing that part of the pain in human progression of otic lesions from hyperplasia
patients with painful, blind, glaucomatous to dysplasia, and perhaps even to neoplasia.44
eyes might be explained by optic neuropathy Perpetuating factors that prevent the ear canal
and optic nerve structural damage causing from effectively healing include infections with
neuropathic pain, Kavalieratos and Dimou41 bacteria and yeasts, improper treatment of the
have published a case report of significant pain ear, overtreatment of the ear with ear cleaners
relief with the administration of gabapentin. and medications, and otitis media. The exam-
Acupuncture is an area of emerging inter- iner should conduct an otoscopic examination
est and application in veterinary medicine. of the ear canals for the following:
There are few prospective controlled studies
on the use of acupuncture for ophthalmic pain • Parasites
in people or animals. Nevertheless, there are • Patency or stenosis
favorable reports when used in people. Nepp • Ulcerations
et al.42 reported favorable responses from • Exudates
acupuncture based upon visual analog score • Foreign bodies
(VAS) for a variety of painful ophthalmic • Color changes
conditions, including glaucoma, ophthalmic • Proliferative changes
migraine, blepharospasm, and dry eyes. There • Tumors
are also clinical reports of pain relief from • Excessive hair or waxy accumulation
keratoconjunctivitis sicca (KCS) in human
patients after acupuncture treatment.43 Cytological assessment should accom-
pany every infected ear examination. When
signs of vestibular dysfunction are present,
Aural Pain peripheral versus central vestibular disease
Ear disease is a common ailment of dogs. should be identified by performing a cranial
Approximately 15%–20% of all canine nerve examination. In many cases, proper
patients and approximately 6%–7% of all diagnosis and treatment of the underlying
feline patients have some kind of ear disease, pathology resolve the disease. However,
from mild erythema to severe otitis media.44 in some animals with severe infection and
In dogs, secondary otitis media occurs in disease, it can be impossible to medicate
approximately 16% of acute otitis externa because of their pain, apprehension, and,
cases and as many as 50%–80% of chronic often, resulting aggression. In these cases, it
otitis externa cases.45 Most patients with may be better to recommend surgical inter-
chronic otitis externa that has been present vention to prevent further suffering and to
for 45–60 days will have a coexisting otitis optimize client resources. With the salvage
media, and often an otitis interna. Chronic procedure of canine total ear canal ablation,
ear disease is often painful. Wolfe et al.46 have reported the favorable use
Manipulation of the pinna or otoscopic of local lidocaine delivery as compared to
examination of the painful ear of a dog or intravenous morphine.
 Chapter 9 Chronic Pain in Selected Physiological Systems 257

FIGURE 9.2 Anatomy of the canine ear and related otitis externa clinical observations. (Photographs
courtesy of Dr. Keith Hnilica; Otoscopy courtesy of Dr. Diane Lewis.)

Dental Pain to additional destruction of local tissues.

Inflammation along the periodontal space
An estimated 85% of dogs and 75% of cats can progress to periodontitis, characterized
over 3 years of age display some form of peri- by active destruction of the periodontal liga-
odontal disease.47 Gingivitis (inflammation of ment and alveolar bone with pocket forma-
the gingiva) results from the accumulation of tion, recession, or both. Periodontal disease
plaque. Bacteria present in plaque induce tis- can also progress to endodontic disease if
sue destruction via production of cytotoxins alveolar bone loss advances to the root apex
and degradative enzymes, with the resulting or lateral canal. Untreated, this may result in
endogenous inflammatory response leading chronic rhinitis and ophthalmic pathology.
258 Chronic Pain in Small Animal Medicine

FIGURE 9.3 Periodontal disease can lead to pain, anorexia, and systemic disease. (A) Bacterial plaque.
(B) Alveolar bone erosion. (C) Severe conditions can manifest as fistula with exudative purulent tracts.
1: Bacterial plaque. 2: Alveolar bone erosion. 3: Suborbital fistula. (Photographs courtesy of Brett
Beckman, DVM, FAVD, DAVDC, DAAPM.)

Pain associated with periodontal disease is 4. Moreira LB, Kasetsuwan N, Sanchez D,

et al. Toxicity of topical anesthetic agents to
often identified with the patient’s reluctance human keratocytes in vivo. J Cataract Refract Surg
to eat (Figure 9.3). 1999;25:975–980.
Evidence from animal experiments and 5. Williamson CH. Topical anesthesia using lidocaine.
clinical trials documents that selective and In: Fine IH, Fichman RA, Grabow HB (eds) Clear-
Corneal Cataract Surgery and Topical Anesthesia.
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sible for the stabilization of periodontal 6. Maurice DM, Singh T. The absence of corneal
conditions by reducing the rate of alveolar toxicity with low-level topical anesthesia. Am J
Ophthalmol 1985;99:691–696.
bone resorption.48 It may well be that those 7. Liu JC, Steinemann TL, McDonald MB, et al.
‘senior’ dogs on long-term NSAID treatment Topical bupivacaine and proparacaine: a compari-
for musculoskeletal disorders are also receiv- son of toxicity, onset of action, and duration of
ing prophylactic periodontal treatment. action. Cornea 1993;12:228–232.
8. Sun R, Hamilton RC, Gimbel HV. Comparison
One should remember that analgesics are the of 4 topical anesthetic agents for effect and cor-
second-best means of managing pain; the neal toxicity in rabbits. J Cataract Refract Surg
best means is to diagnose the cause and treat 1999;25:1232–1236.
9. DiFazio CA, Carron H, Grosslight KR,
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1986;65:760–764.
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 Case Reports
CASE REPORT1 Initial treatment consisted of immediate
forelimb amputation. Premedication consisted
Signalment: 16-year-old controlled diabetic of a combination of morphine and atropine.
castrated male cat. The owner reported Anesthesia was induced with a combination
that the cat was no longer jumping on to of intravenous midazolam followed by pro-
the kitchen counter and was eating less. pofol and initially maintained with isoflurane
Physical examination was normal, although in oxygen. Fentanyl was administered follow-
an orthopedic examination revealed pain on ing induction, and intravenous ketamine was
palpation of either coxofemoral joint and administered as an infusion throughout sur-
decreased range of motion in both coxofem- gery. Postoperatively, the patient was main-
oral joints. tained for 24 hours in an intensive care ward
Radiographs of the hips demonstrated and administered continuous infusions of fen-
bilateral coxofemoral joint osteoarthritis tanyl and ketamine until discharge on day 2.
(OA) with pronounced secondary changes. Home convalescence included a 3-day
Blood/Chemistry profiles revealed packed treatment of oral morphine and daily NSAID
cell volume (PCV) 39%; total protein (TP) administration.
65 g/L (6.5 g/dL); blood urea nitrogen (BUN) One month postoperatively, the patient
13.2 mmol/L (37 mg/dL), creatinine 247.5 appeared painful, and as the NSAID was
umol/L (2.8 mg/dL); and blood glucose continued, oral morphine was again pre-
22.03 mmol/L (397 mg/dL). scribed (twice daily), which the owners
Previous management included (1) oral increased to three times daily. Although the
ketoprofen, which was discontinued due to owners began dosing the morphine as they
vomiting and renal compromise; (2) oral felt necessary, the more frequent dosing
butorphanol, discontinued due to idiosyn- resulted in unacceptable sedation.
cratic dermal self-trauma; and (3) transmuco- All medications were stopped, and the
sal buprenorphine, which was discontinued patient was re-examined. Physical examination
after 3 days’ dosing because of lethargy and at this stage revealed pronounced vocalization
inappetence. when various parts of her body were palpated,
This senior-aged cat could have been especially the area of surgery. Allodynia from
given amantadine, tramadol, and/or a chon- neuropathic pain was diagnosed based on the
droprotective. However, the cat responded to patient’s painful response to nonpainful stimu-
acupuncture at 4- to 6-week intervals, with a lation. Injury of the peripheral nervous system
return of appetite and increased activity. Not (PNS) or central nervous system (CNS), resul-
all cats respond as well to acupuncture; how- tant from transection of nerves at the time of
ever, in this case sole management of clinical amputation, was speculated as the etiology of
signs by acupuncture spared any potential the neuropathic pain.
organ challenge by therapeutic drugs. The patient was administered amanta-
dine for 5 days and morphine for 2 days. Two
days following discontinuation of the aman-
CASE REPORT2 tadine, the patient was comfortable. At that
time she was administered oral morphine for
Signalment: 5-year-old spayed female 5 days, amantadine for 7 days, and gabapen-
Siberian husky. Presented for right forelimb tin for 10 days. The patient has maintained a
lameness. Physical examination revealed pain-free status since this round of therapy.
an otherwise healthy patient. Palpation Speculation holds that this patient’s pain
of the right humerus revealed soreness. might have been much worse and more dif-
Radiographs showed a lesion confirmed by ficult to treat had her acute pain not been
biopsy to be osteosarcoma. treated so aggressively.

260
 Case Reports 261

CASE REPORT2 at presentation. The owners reported their

dog was ‘happier’ but had difficulty getting
Signalment: 13-year-old female Labrador comfortable at night. She was still resistant
retriever with a 10-year history of hindlimb to joint manipulation. At this point acupunc-
stiffness, variably medicated with polysul- ture therapy was offered, but declined, and
fated glycosaminoglycan (PSGAG) (Adequan) amantadine (3 mg/kg orally once daily) was
injections, glucosamine, chondroitin sulfate, added to the patient’s treatment regimen.
manganese (Cosequin), and aspirin. She was After another 4 weeks, re-examination
being leash-walked 10 minutes per day and showed less lameness, but a persistent pain on
had free roam in the yard, but was growl- joint manipulation. Tramadol (4 mg/kg twice
ing at the owner when being helped into the daily) was added to the treatment regimen.
automobile. Two weeks thereafter the owner reported
Gait analysis revealed 7/10 lameness in considerable improvement, and an ortho-
both hindlimbs and 3/10 lameness in both pedic examination confirmed the owner’s
forelimbs. The left-sided limbs appeared impression.
worse than the right. Orthopedic examina- The patient continues the multimodal
tion showed a decreased range of motion in regimen, showing relapses when compo-
both elbows and some pain upon manipu- nents of the regimen are removed, although
lation. The left stifle produced crepitus dosages of each agent are continually being
on movement, with considerable pain on decreased. Painful flare-ups, usually associ-
manipulation. Painful, aggressive response ated with rigorous exercising, are effectively
was elicited with manipulation of both coxo- managed with small doses of acetaminophen
femoral joints, and crepitus was noted in the (5 mg/kg twice daily for 2–4 days). Although
right coxofemoral joint. Paralumbar muscles a disease-modifying osteoarthritic drugs
were noted to be tense, hard, and painful. (DMOAD) and an eicosapentaenoic acid
There were no neurological abnormalities. (EPA)–rich diet were not integrated into the
A complete blood cell count was normal. management regimen of this particular case,
Alkaline phosphatase was 405 IU/L (normal: they could easily be added in an attempt to
12–150 IU/L), and alanine aminotransferase further lower current drug dosages.
was 274 IU/L (normal: 5–105 IU/L). Both
preprandial and postprandial bile acid values
were normal. Initial management included REFERENCES
(1) a weight loss plan designed to lose
7.2 kg (16 lb) over the following 3 months; 1. Lascelles BDX, Robertson SA, Gaynor JS. Can
(2) physiotherapy of increasing controlled chronic pain in cats be managed? Yes! In: Managing
Pain in Cats, Dogs, Small Mammals and Birds.
lead exercise from 10 minutes once daily to Proceedings of a symposium held at the North
20 minutes three times daily over a 6-week American Veterinary Conference and the American
period; and (3) discontinue the aspirin, but Animal Hospital Association Annual Meeting,
2003.
continue the nutraceutical and begin a dif- 2. Hardie EM, Lascelles BDX, Gaynor JS. Managing
ferent nonsteroidal anti-inflammatory drug chronic pain in dogs: the next level. In: Managing
(NSAID) regimen. A revisit was scheduled Pain in Cats, Dogs, Small Mammals and Birds.
for 2 weeks so as to assess clinical progress Proceedings of a symposium held at the North
American Veterinary Conference and the American
and liver function. After 2 weeks, the patient Animal Hospital Association Annual Meeting,
was still lame, but less than previously noted 2003.
 Index
Note: Bold page numbers refer to tables and italic page numbers refer to figures.

peripheral sensory receptors, cascade, 82–83

A 3–4 eicosanoids, 174, 175
AA, see Arachidonic acid Afferent sensory neurons, 108–109 pathway, 82, 174
Aα fibers, 90 Aggrecan, 74, 75 Arginine vasopressin, 129
Aβ fibers, 14, 43, 89, 91–92, 228 Aggrecan aggregates, 75, 75–76, 77 ARS, see Acute radiation score
ACE, see Angiotensin-converting Aging cartilage, 79 Articular receptor systems, 90
enzyme Agonist (opioid), 127, 129, 129, 135 ASICs, see Acid-sensing ion channels
Acepromazine, 221 Agonist-antagonis (opioid), 129, 129 Aspartate aminotransferase
Acetaminophen (paracetamol), 119, ALA, see Alphalinolenic acid (AST), 184
120, 183, 190, 192, Alanine aminotransferase Aspirin, 118, 119, 185, 196
196, 218 (ALT), 184 Aspirin-triggered lipoxin (ATL), 186
Acid-sensing ion channels (ASICs), Algogenic substances, 56–57 ASu, see Avocado/soybean
58, 110, 163 Alkaline phosphatase (ALP), 184 unsaponifiables
Action potential, 4, 5, 6, 9, 11, 12, Allodynia, 53, 92, 92 Atipamezole, 221
12, 17, 19, 23, 24, 37, Alphalinolenic acid (ALA), 206 ATL, see Aspirin-triggered lipoxin
46, 92, 142, 223 α 2 agonists, 138, 220 Aural pain, 256, 257
Acupressure, 228 bulbospinal noradrenergic Avocado/soybean unsaponifiables
Acupuncture, 227 pathways, 138 (ASu), 205–206
channels or meridians, 228 at a glance, 140 Axonal protein flow, 16, 16
Eastern vs. Western perspectives inhibition of adenylate
indications, 229
metaphysical approach, 229
cyclase, 138
mechanistic summary, 140
B
mode of action, 228–229 medetomidine, 137 Barbiturates, 150
neuroanatomical approach, nitric oxide, 138 ‘Bell ringer’ model of pain, 9
228–229 potential features of, 139, 140 Beta particle, 156
side effects, 229 presynaptic α 2-adrenoreceptors, Biological agents, 162
special considerations, 229 138, 138 Biomarkers, 83–84
mechanisms, hypothesis of, 228 release of norepinephrine, BIPED, see Burden of disease,
theory of, 227–228 138, 139 Investigative, Prognostic,
Yin-Yang theory, 227, 227 xylazine, 137 Efficacy of intervention,
Acute pain, 29, 57; see also Pain AMA, see American Medical and Diagnostic
physiology Association Bleomycin, 107
pathological pain, 29 Amantadine, 118, 119, 152, 221 Blood urea nitrogen (BUN), 183
physiological pain, 28, 29 American Medical Association Blotting, 181
tactile allodynia, 40–41 (AMA), 185 Bone cancer model, 108, 108
Acute radiation score (ARS), 112 Amitriptyline, 118, 119, 146, 221 Breakthrough pain, 240
ADE, see Adverse drug event AMP, see Adenosine Bromfenac, 254
Aδ fibers, 90–91 monophosphate BUN, see Blood urea nitrogen
Adenosine, 13, 14, 29, 63, 91, 111, Analgesia Bupivacaine, 143, 143–144, 222, 226
128, 148, 208, 243 for cancer pain, 117, 118–120 Buprenorphine, 119, 129, 137,
Adenosine diphosphate (ADP), multimodal, 215, 215 220, 226
14, 148 product development, 166 Burden of disease, Investigative,
Adenosine monophosphate (AMP), Anatomically based cancer pain, 104 Prognostic, Efficacy
14, 148 Angiogenesis, 58, 84, 88, 109, 191 of intervention, and
Adequan Canine ®, 239–240, 261 Angiotensin-converting enzyme Diagnostic (BIPED),
Adjunctive analgesics, 162 (ACE), 192 84, 84
Adjuncts, 20, 21, 118–120, 149, Antagonist (opioid), 129, 129, 133 Butorphanol, 118, 119, 137, 220, 231
151, 152, 221, 240–245 Anthracycline antibiotics, 107
ADP, see Adenosine diphosphate
Adverse drug event (ADE), 179, 236
Antiarrhythmics, 38
Anticonvulsants, 38, 148–149, 155
C
Afferent receptors, 3–8 Antiulcer agents, 185–186 Calcitonin gene–related peptide
differentiated functions, 4 Apoptosis, 58, 81, 110, 112–113 (CGRP), 6, 89, 128
mediators of pain, 8 Arachidonic acid (AA), 81, 206 Calcium channels, 13

262
 Index 263

CAMP, see Cyclic AMP NSAIDs, 232, 235–236 Schwann cell

Cancer pain nutraceuticals, 236–239 (oligodendrocytes), 15
afferent sensory neurons, multimodal treatment protocol, stimulus-response curve, 21, 21
108–109 231–235, 243 windup, 19–22
analgesia for, 117, 118–120 nonmedical management, 232 Central sensitization, 110
anatomically based, 104 diet, 231–234 at dorsal horn, 92–93
animal cancer pain, prevalence physical rehabilitation, C-fos gene expression, 20–21, 33,
of, 105–107, 106, 107 234–235 45, 109
assessment in animals, 107–108 nonsurgical management, 244 CGRP, see Calcitonin gene–related
bone cancer model, 108 nutraceuticals, 236–239 peptide
central sensitization, 110 prevalence of, 70 Chemotherapeutic neuropathies, 112
chemotherapeutic neuropathies, quality of evidence, 231–232, 232 Chemotherapy, 111–112
112 refractory epileptic seizures in Chemotherapy-induced peripheral
chemotherapy, 111–112 dogs, 247 neuropathy (CIPN), 112
classifications for, 102, 102–104 synergism, 231, 231–232 Chi, 229
dissolution of hydrogel, 114, 114 therapeutic approaches, 244 Cholecystokinin (CCK), 127
end-of-life considerations, 121 Canine osteoarthritis staging tool Chondrocytes, 81
etiological classification, 57 (COAST), 95–96 Chondroitin sulfate, 118, 202–203
growth factors from tumor Cannabichromene (CBC), 246 Chondromalacia, 80–81
cells, 110 Cannabicyclol (CBL), 246 Chondron, 75
lactide and glycolide, 114, 114 Cannabidiol (CBD), 245–246, 246 Chondroprotectants, 239–240; see
mechanism-based treatment, 105 Cannabidiolic acid (CBDA), 247 also Chondroitin sulfate;
moving target of, 110–111 Cannabielsoin (CBE), 246 Glucosamine
neuropathic cancer pain, 104 Cannabigerol (CBG), 246 Chronic pain, 57
nociceptor excitation, 109 Cannabinoids, 245–247 acute nociceptive pain
nutritional management, 117 Cannabinol (CBN), 246 (physiological pain),
pain-generating mediators, 103 Capsaicin, 6 40, 40
paraneoplastic neuropathy, Carprofen, 118, 119, 180, 189, 196 defined, 40
103, 103 Cartesian model, 9, 9 hyperalgesia, 41
PLGA-g-PEG polymer, 114, 114 Cats idealized criteria for new
prevalence of cancer in animals, acetaminophen in, 130 analgesic therapy in, 166
105, 105 analgesics for cancer pain, 117, inflammatory pain, 40, 40–41
psychogenic pain, 103 119–120 integration of physical
radiation therapy, 113–117 case report, 260 dimensions, 41, 41
schemes for classifying, hepatic enzymes in, 184 maladaptive, 38
102–104 and NSAIDs, 191–192 neuropathic pain, 40, 41
severity-based, 104 pain assessment in, 58, 59–60, 60 questions related to, 56–57
spinal cord neoplasms, 103, 103 CBC, see Cannabichromene recognition and assessment of,
sympathetically dependent, 104 CBD, see Cannabidiol 61–64
taxonomy, 102 CBDA, see Cannabidiolic acid behavioral changes, 61
tissue and nerve injury, 113, 113 CBE, see Cannabielsoin in dogs, 63
triblock thermogel polymer, CBG, see Cannabigerol owner observations, 63
115, 115 CBL, see Cannabicyclol in selected physiological
tumor-induced local acidosis, CBN, see Cannabinol systems, 252–258
109–110 CBPI, see Canine Brief Pain Inventory ophthalmic pain, 252–258
tumors compressing nerve CCK, see Cholecystokinin tactile allodynia, 38–41
fiber, 103 CCLT, see Cranial cruciate ligament CIPN, see Chemotherapy-induced
visceral, 111, 111 transection peripheral neuropathy
WHO cancer pain ladder, Central nervous system (CNS) Citalopram, 146
104–105 afferent signal suppression, 19 Classifying pain, advantage of, see
Canine Brief Pain Inventory AMPA receptors, 20 Pain classification
(CBPI), 64 anesthetic-induced Clinical metrology instruments
Canine ear, 257 unconsciousness, 21 (CMIs), 63
Canine osteoarthritis and cardiovascular Clomipramine, 146
adjuncts, 240–245 disturbances, 223 CMIs, see Clinical metrology
cannabinoids, 245–247 dynamic, 19–22 instruments
checklists, differential neuronal isoform of NOS CMPS, see Composite measure pain
diagnoses, 248 (nNOS), 20 scales
chondroprotectants, 239–240 neuronal pools, 89 CNS, see Central nervous system
diagnostics, 247–248 NMDA antagonists, 20, COAST, see Canine osteoarthritis
medical management, 235 20–21 staging tool
chondroprotectants, pain-induced distress, 21 Codeine, 118, 137, 220
239–240 preemptive analgesia, 22, 22 Colloid, 156
264 Index

Composite measure pain scales DJD, see Degenerative joint disease Elbow dysplasia, 95
(CMPS), 107 DMOAAs, see Disease-modifying Elbow incongruity, 95
Constant rate infusion (CRI), 225 osteoarthritic agents ELISA, see Enzyme-linked
Convergence, 91 DMOADs, see Disease-modifying immunosorbent assay
Convergence projection theory, 30 osteoarthritic drugs Enantiomer, 132, 134–135, 137
Conversion electrons, 156 Docetaxel, 107 End-of-life considerations, 121
Corticosteroids, 168 Dogs Endbulb, 26–27
COX, see Cyclooxygenase pathway acute radiation score, 112 Endocannabinoid system (ECS), 245
COX isozymes, 174–178 analgesics for cancer pain, 117, CB2 cannabinoid receptor,
Coxib-class NSAIDs, 179, 182, 118–119 245–246
182, 190 case report, 260, 261 neurotransmitters, 245
Cranial cruciate ligament deficiency cranial cruciate ligament Endothelin, 58
(CrCLD), 70 deficiency, 70 Enthesophytes, 78
Cranial cruciate ligament epidural administration, 226 Enzyme-linked immunosorbent
transection (CCLT), 94 hepatic enzymes in, 184 assay (ELISA), 181
CrCLD, see Cranial cruciate with OA, 70 EPA, see Eicosapentaenoic acid
ligament deficiency pain assessment in, 58, 59–60, 60 Ephaptic cross-talk, 27
Creatinine, 183 pharmacokinetic studies in, 238 Epidural administration, 226,
Curcuminoids, 209 refractory epileptic seizures in, 226, 227
Cyclic AMP (cAMP), 14 247 Epitope, 103
Cyclooxygenase (COX) pathway, treating refractory epileptic Etiological classification, 57
174, 177, 183 seizures in, 247 Etodolac, 118, 119, 180, 189
clinical relevance of, 178, 178 Dorsal root ganglion (DRG) Etoposide, 107
COX-1, 176, 176, 177, 178, axonal cell bodies, 16 Evidence-based, 3, 61, 111, 145,
182, 183 neurons, 7 154, 205, 209, 229,
COX-2, 57, 73, 109, 176, 177, segmental, 14 236, 238
178, 182, 183 DRG, see Dorsal root ganglion Excitability, 8, 11, 17, 24, 28, 38,
CYP, see Cytochrome P450 Drug classes for multimodal use, 45, 46, 48–49, 56, 92,
isoenzymes 217, 217–218 136, 164
Cytarabine, 107 Drug Enforcement Agency Excitation, 6, 19, 24, 26, 27, 38, 49,
Cytochrome P450 (CYP) (DEA), 130 52, 109, 247
isoenzymes, 247 Drug-induced hepatopathy, 183
Cytokines, 23–24, 25–26, 29, 46,
52, 54, 72–73, 80–84, 86
Drugs used in multimodal
protocols, 219–222
F
Duloxetine, 146–147 FDA, see Food and Drug

D Dynamic trafficking
acute pain, 28–29
Administration
Fentanyl, 118, 120, 129, 137,
DAMPs, see Danger-associated ectopic discharge in dorsal 219, 226
molecular patterns roots, 27 patches, 130, 130, 219
Danger-associated molecular ephaptic cross-talk, 27 Fibrillation, 79, 81
patterns (DAMPs), 86 excitation and excitability, 28 Firocoxib, 118, 180, 189
DEA, see Drug Enforcement incisional pain, 30 Fish oil, 206, 208
Agency inflammatory pain, 29–30 Flaxseed oil, 206
Degenerative joint disease (DJD), injured afferent neurons, 27, Flunixin, 196
71–72, 94, 156, 200; see 27–28 Flunixin meglumine, 120
also Osteoarthritis intrinsic kinetic properties, 28 Fluoxetine, 146
Delivery techniques, 218, 223 membrane remodeling, 27 Flurbiprofen, 254
Delta (δ) receptors (OP1), 127 neuronal excitation, 28 fMRI, see Functional magnetic
Dental pain, 257–258 types of neuromas, 26 resonance imaging
Deracoxib, 118, 180, 189 vesicle exocytosis, 27 Food and Drug Administration
Descending modulatory system, 16 visceral pain, 30–31 (FDA), 113, 131,
Desipramine, 146 Dysesthesia (spontaneous pain), 53 193–196, 200, 236
Dexmedetomidine, 220 Force plate platform, 188
Dextromethorphan, 221
Diabetic neuropathy, 43
E Functional magnetic resonance
imaging (fMRI), 31
Diazepam, 222 Eburnation, 81
Diclofenac, 254
Differential diagnoses (DDXs), 248
ECS, see Endocannabinoid system
Ectopic discharge, 27, 142, 145,
G
Disease-modifying osteoarthritic 148, 164 GABA, see Gamma aminobutyric
agents (DMOAAs), 237 Efferent, 11, 18, 31 acid
Disease-modifying osteoarthritic Eicosanoids, 174, 175 Gabapentin, 118, 120, 148, 148,
drugs (DMOADs), Eicosapentaenoic acid (EPA), 206, 149, 150–151, 221
237, 261 207, 208, 233, 234, 261 GAGs, see Glycosaminoglycans
 Index 265

GAIT, see Glucosamine/chondroitin High-voltage activated (HVA), 13 classification of articular

Arthritis Intervention Historical market data (U.S.), 166, receptor systems, 89, 90
Trial study 167, 167, 168 sensory receptors, 89–90
Gamma aminobutyric acid (GABA), Homogeneous 117mTin colloid Joint capsule dynamics, 81–82
19, 24, 26, 27, 45, (HTC), 156 Joint components
49–50, 55, 148–149 HRQoL, see Health-related quality aggrecan, 74, 75
Gate theory, 9–11 of life aggrecan aggregates, 75,
GCMPS, see Glasgow Composite HVA, see High-voltage activated 75–76, 77
Measure of Pain Scale, Hyaluronic acid (HA), 81, 202, cartilage, 74
Short Form 208, 208 chondrocytes, 74–75
GDNF, see Glial-derived Hydromorphone, 129, 137, 219 collagen type II, 75–76
neurotrophic factor 5-Hydroxytryptamine (5-HT), 16 enthesophytes, 78
Gender and visceral pain, 31–32 Hyperalgesia, 9, 10, 41 GAGs, 76
Glasgow Composite Measure of primary, 9 hyaluronan, 76
Pain Scale, Short Form secondary, 9 mechanical instability, 78
(GCMPS), 112 Hyperpolarization-activated cyclic osteophytes, 77, 77–78
Glasgow Pain Scale, 58 nucleotide-gated (HCN) periosteum of bone, 78, 78
Glaucoma, 255–256 channel, 12 and physiology, 74–79
Glial cells Hypoalgesia, 10 proteoglycans, 76, 76
astrocytes, 23–25, 24, 25 subchondral bone, 77
Fractalkine, 25
GABA/glycinergic inhibition, 26
I synovial fluid, 79
zones of collagen orientation, 75
microglia, 23 IASP, see International Association Joint structure interactions, 73–74
oligodendrocytes, 23 for the Study of Pain JSSAP (Japanese) Canine Chronic
strategies targeting glial IBS, see Irritable bowel syndrome Pain Index, 64
activity, 25, 25–26 IC, see Interstitial cystitis
tripartite synapse, concept
of, 24
IC50 (half-maximal inhibitory
concentration), 177
K
Glial-derived neurotrophic factor Idiosyncratic, 183 Kappa (κ) receptors (OP2), 127
(GDNF), 58, 110 IL-1, 238, 239 Ketamine, 151, 151–152, 153, 221
Glucosamine, 118, 203–204 Imipramine, 144, 144, 146 Ketoprofen, 120, 196
and chondroitin sulfate in Incisional pain, 30 Ketorolac, 254
combination, 204–205 Indomethacin, 254 Kinematic gait analysis (motion
Glucosamine/chondroitin Arthritis ‘Industrial hemp,’ 245 analysis), 190
Intervention Trial Inflammation, 73
(GAIT) study, 205,
205, 237
Inflammatory mediators, 80–81, 91
Inflammatory pain, 29, 29–30
L
Glutamate, 7–8, 17, 19–20, 24, 45, Injury Lidocaine, 118, 120, 155, 222, 226
49, 51–52, 56, 94, mechanical stimuli of cutaneous constant rate infusion of, 225
138, 150 injury, 16–17 intravenous, 141, 141–142, 142
Glutamate dehydrogenase post-tissue injury, see Post- Ligand, 162
(GLDH), 184 tissue injury pain states Liverpool Osteoarthritis in Dogs
Glycosaminoglycans (GAGs), tissue and nerve, 113, 113 (‘LOAD’) CMI, 64
201–202, 204, 206, 238 International Association for the Local anesthetics, 142–143
Growth factors, 43 Study of Pain (IASP), body cavities, 225
from tumor cells, 110 41, 102 dental, 223–224, 224, 225
GUVQuest (owner-based, chronic Interstitial cystitis (IC), 34, 35 dermal, 224, 225
pain questionnaire), 64 Intra-articular opioid delivery, 132 onychectomy, 223, 224
Intra-articular structure other local anesthetic

H degradation, 82–88
arachidonic acid cascade, 82–83
techniques, 225–226
Long-ranging afferents, 47
H 2 blockers, 187 macrophages regulate Low-voltage activated (LVA), 13
HA, see Hyaluronic acid the progression of LVA, see Low-voltage activated
HCN, see Hyperpolarization- osteoarthritis, 84–88
activated cyclic
nucleotide-gated channel
potential biomarkers, 83–84
Irritable bowel syndrome (IBS), 34
M
HCPI, see Helsinki Chronic Pain mAbs, see Monoclonal antibodies
Index
Health-related quality of life
J Matrix metalloproteinases (MMPs),
74, 80, 81, 201, 233, 233
(HRQoL), 61, 63, 107 Joint afferents Mechanism-based treatment, 105,
Helsinki Chronic Pain Index Aβ and Aδ fibers, 90–91 162–165
(HCPI), 64 chemosensitivity of Aδ and Mechanoreceptors, 89
Hepatobiliary enzymes, 184 C fibers, 89, 91 Medetomidine, 137, 220, 231
266 Index

Medetomidine/vatinoxan, 140 pharmacological treatment of, and opioid commercial drug

Meloxicam, 118, 120, 180, 189, 196 44, 45 combinations, 218
Membrane remodeling, 27, 141 Neurotransmitters pharmacology, 217
Membrane stabilizers, 140–141 depolarization, 7, 7 potential herb-drug
Memory of pain, 42 and modulators, 7, 7 interactions, 191, 191
Meperidine, 129, 136, 219 receptor for binding, 7–8 and renal function, 183
Mepivacaine, 222 NGF, see Nerve growth factor risk factors for, 186
Meta-analysis, 132, 237 Nitric oxide (NO), 138 safety, 179–181
Methadone, 137, 219, 221 Nitric oxide synthase (NOS), 13 systemic adverse reactions, 255
Methotrexate, 107 endothelial NOS (eNOS), 13 ‘third-generation,’ 186
MFPS, see Multifactorial pain inducible NOS (iNOS), 13 washout, 186–187
scales neuronal NOS (nNOS), 13 weak analgesics, 132
Mianserin, 146 NMDA receptor, 19–22, 49 North American Veterinary
Mitoxantrone, 107 NNT, see Number needed to treat Nutraceutical Association
MMPs, see Matrix NO, see Nitric oxide (NAVNA), 200
metalloproteinases Nociception, 9 Nortriptyline, 146
Modulation, 6, 10, 25, 40, 135, first-order neurons, 14 NOS, see Nitric oxide synthase
141, 148–149, 152, 163, modulation by CNS, 10 NRS, see Numerical rating scale
216, 228, 238, 246 nitric oxide (NO), role of, 13 NSAIDs, see Nonsteroidal anti-
Monoclonal antibodies (mAbs), 162 Nociceptive pain, 28, 56; see also inflammatory drugs
MOR-NRI, 134 Acute pain Number needed to treat (NNT),
Morphine, 118, 119, 120, 129, 130, Nociceptive-specific neurons, 88 43–44, 44
219, 226 Nociceptors, 15, 88–89, 108 Numerical rating scale (NRS),
Moving target of cancer pain, activity of, 11 58, 107
110–111 excitation, 109 Nutraceuticals, 236–239
117mTin (117mSn), 156–157 and fiber types, 5 avocado/soybean
Mu (μ) receptors (OP3), 127 inflammatory mediators, 5 unsaponifiables,
Mucosal sealant, 187 signaling, therapeutic targets, 57 205–206
Multifactorial pain scales sympathetically maintained background, 200–201
(MFPS), 107 pain, 11 chondroitin sulfate, 202–203
Multimodal analgesia, 105, 215, Nodes of Ranvier, 15 curcuminoids, 209
215, 226, 231–232 Nonsteroidal anti-inflammatory eicosapentaenoic acid, 206–208
Muscle fatigue and spasm, 93–94 drugs (NSAIDs), 168, glucosamine, 203–204
Myelin, 15 235–236 glucosamine and chondroitin
administration, 190–192 sulfate in combination,

N and cancer, 191

and cats, 191–192
204–205
hyaluronic acid, 208
N-methyl-D aspirate (NMDA) compatibility with other in OA, 201, 236–239, 237
antagonists, 150, agents, 190–191 phycocyanin, 206
155, 223 future, 191–192 S-adenosylmethionine,
activation, 151 improving safety, 192 208–209
analgesic drug development, with or without food, 190 Nutritional management, 117
242, 242 time of administration, 190
in chronic pain, 241
at a glance, 152
antiulcer agents, 185–186
arachidonic acid pathway, 174
O
moving target of pain aspirin, 185 OA, see Osteoarthritis
management, 243 associated gastrointestinal Onychectomy, 223, 224
receptor activity, 242, 242 ulceration, 181–182 Ophthalmic pain
Nalbuphine, 220 and bone healing, 188 Opioids, 127, 168
Nepafenac, 254 chemical composition, 253–254 classification, 129, 129
Nerve fiber, 15 control of human ophthalmic enhanced pain, 129–130
Nerve growth factor (NGF), 110, pain and inflammation, at a glance, 136–137
162–165, 163, 164, 165 254, 254 overview, 136
Neurogenic inflammation, 37, 37, COX isozymes, 174–178 patch delivery, 130–131
91–92, 92 coxib-class, 179 receptor activation, 127–128
Neurogenic pain, 41 drugs and agents, 190, 190 supraspinal activity of, 128
Neurohumoral transmission, 12, 12 efficacy, 188, 188–190, 189, 189 Oral transmucosal (OTM) drug
Neuroma model, 43 enhancing use, 187–188 administration, 131, 227
Neuropathic cancer pain, 104 gastrointestinal problems, 180, Orally administered opioids, 130
Neuropathic pain, 38, 38, 39, 180, 181, 187 Osteoarthritic pain
41–42, 42, 241; see also and hepatic function, 183–184 aging cartilage, 79
Chronic pain herb-drug interactions, 191 central sensitization at dorsal
models of, 43–44 nuclear factor κB, 179, 180 horn, 92–93
 Index 267

COAST, see Canine Owner, see Pet owners nociceptor signaling:

osteoarthritis staging tool Oxymorphone, 129, 137, 219, 226 therapeutic targets, 57
convergence may amplify pain assessment, 58–64
afferent nociception, 91
definition, 71–72
P phenotypic to neuropathic pain,
43–44
degradative cycle, 72 Paclitaxel (Taxol), 107, 112 plasticity encoding, 8–9
DJD, see Degenerative joint Pain and suffering, difference PNS and DRG, 14–16
disease between, 56 Schwann cells, contribution of,
etiology, 72, 72–73 Pain assessment 43–44
inflammation, 73 in cats and dogs, 58, 59–60, 60 sensory neuron dynamics, 58
inflammatory mediators, of chronic pain, 61–64 tactile allodynia, 37–42
80–81, 91 client-specific outcome measures tracking elements in post–tissue
intra-articular structure scheme, 60, 60 injury pain, 44–57
degradation, 82–88 evidence-based confidence, visceral hypersensitization,
joint afferents, 89–91 61, 63 34–35
joint capsule dynamics, 81–82 health-related quality of life, 60 visceral pain, 35–37
joint components and mechanism-based classification, visceral stimuli, 32–34
physiology, 74–79 60–61, 61 voltage-gated ion channels,
joint structure interactions, physiological parameters, 58 11–14
73–74 summary of pain states, 61, 62 Pain recognition processes, 216, 216
MMP and TIMP imbalance, 81 veterinary practice, 58 Pain transmission
morphological changes, 79–80 Pain classifications brain and spinal cord, 17,
neurogenic inflammation, anatomically based cancer 17–18, 18
91–92 pain, 104 CNS plasticity, 19
nociceptors, 88–89 etiological classification, descending modulatory
osteoarthritis and joint 103–104 system, 16
instability, 94–95 neuropathic cancer pain, 104 dorsal horn acts as ‘gear box’
role of muscle fatigue and severity-based cancer pain, 104 in, 16–19
spasm, 93–94 sympathetically dependent dorsal horn neurons, 18,
source of pain, 74 cancer pain, 104 18–19
surgical intervention, 95 Pain management, 3 functional laminar
synovitis, 81 acupuncture, 227 organization, 17
vicious catabolic/anabolic delivery techniques, 218, 223 interneurons, 19
cycle, 72 drug classes for multimodal use, mechanical stimuli of cutaneous
Osteoarthritis (OA) 217–222 injury, 16–17
canine ‘groove’ model, 94 Eastern vs. Western memory and emotion, 16
catabolic process of, 83, 83 perspectives, 228–229 projection neurons, 19
evidence rank of therapeutic epidural administration, propriospinal neurons, 19
approaches, 244 226–227 secondary hyperalgesia, 16–17
and joint instability, 94–95 hypothesis of acupuncture WDR (wide dynamic range)
macrophages, 84–88, 85 mechanisms, 228 cells, 18
activated and polarized local anesthetics, 223–226 Painful diabetic neuropathy
macrophages, 87 mode of action, 228–229 (PDN), 43
cycle of inflammation, 84 other delivery routes, 227 PainTrace ®, 247
inflammatory ‘vicious’ pain pathway infers three- Pamidronate, 119
cycle, 84, 85 neuron chain, 3, 4 Paracetamol, see Acetaminophen
M1/M2 macrophages, physiology and neurobiology, 3 Paroxetine, 146
86–87, 87 theory of acupuncture, 227–228 Partial agonist, 129, 136
neutrophil-macrophage Pain pathway, 3, 4, 23, 154 Pathological pain, 29
activation, 86, 86 Pain physiology PEG (polyethylene glycol),
paracrine effects, 88 acid-sensing ion channels, 58 degradation of, 116–117
plastic cells, 86–87 activity of nociceptors, 11 Pentazocine, 220
NSAID therapy in, 81 afferent receptors, 3–8 Perception, 7, 9, 16, 19, 31, 32, 36,
nutraceuticals used for, 201, 201 CNS, dynamic, 19–22 40, 48, 95, 135, 216
pain, see Osteoarthritic pain cyclooxygenase, 57 Periodontal disease, 258, 258
‘total joint disease,’ 78, 78 dynamic trafficking, 26–31 Peripheral nervous system (PNS),
Osteoarthritis Biomarkers Network endothelin, 58 14–16
Consortium, 83 gate theory, 9–11 Pet owners, 121, 161, 179–181, 185,
Osteoblasts, 205–206 gender and visceral pain, 31–32 190, 192, 209, 234–235
Osteoclasts, 58, 110 glial cells, 23–26 PGs, see Prostaglandins
Osteophytes, 71, 73, 77–78, 95 growth factors, contribution of, Pharmacologics (drug classes)
Osteotomy, 94 43–44 α 2 agonists, 137–140
Otitis externa, 256, 257 neurogenic inflammation, 37 amantadine, 152
268 Index

analgesic product intrinsic interneurons, 50 drug classes, mechanism of

development, 166 ‘long-ranging afferents,’ 47, 48 action, and effective
anticonvulsants, 148–149 nerve conduction, 46 application, 155
bupivacaine liposome, 143–144 nerve injury and mechanism-based therapy,
cholecystokinin and opioids, 127 inflammation, 45 162–165
duloxetine, 146–147 neuromas, 53, 54 nerve growth factor and
gabapentin overview, 150–151 neuropeptide levels in spinal osteoarthritis, 162
historical market data (U.S.), cord, 45 peripheral pain mechanisms and
166–168 NMDA receptor, 49 new analgesics, 155
intra-articular opioid nociceptive processing, 52–53, 53 radiosynoviorthesis, 154–158
delivery, 132 p38MAP kinase, 49 in clinical practice, 157–158
intravenous lidocaine, 141–142 process of ‘neuroinflammation,’ comparison of
ketamine, 151–152, 153 51–52 radionuclides, 158
local anesthetics, 142–143 release of neurotransmitters, 45 for intra-articular therapy,
medetomidine/vatinoxan, 140 released PGs, 49 157
membrane stabilizers, 140–141 sodium channels, 53–54 in veterinary medicine,
new analgesic therapy in spinal chloride transporters on 159–160
chronic pain, 166 allodynia, 56, 56 Tin-117m, novel radionuclide,
NMDA antagonists, 150, 152 spinal cord and DRG, 53–55, 54 158–162
opioids, 127–131, 136–137 spinal facilitation, 48, 48, 50, 50 Referred pain, 30, 33, 35–36, 93
orally administered opioids, 130 tactile allodynia, 53 Regional classification of pain, 57
pregabalin/gabapentin, 149 terminal neuronal Rehabilitation, physical, 88, 231,
radiotherapeutics, 154–162 depolarization, 46, 47 234–235
serotonin, 147–148 tissue injury–evoked afferent Reversal of GABA/glycinergic
tapentadol, 134–136 activity, 46 inhibition, 26
TCA mode of action, 145–146 TNF-α binding protein, 54 RSO (radiosynoviorthesis), 156
tramadol, 132–134 tracking elements involved in, RSV, see Radiosynovectomy
tricyclic antidepressants, 44–57
144–145
zorbium, 131
transient high-intensity
stimuli, 45
S
Phenotype, 42–43, 45, 55, 58, 86, WDR (wide dynamic range) S-adenosylmethionine (SAMe),
88, 109–111, 205 neuron, 47, 47, 48 208–209
Phenylbutazone, 190 Prednisolone, 119, 120 S-NRIs (serotonin-noradrenalin
Phycocyanin, 206 Preemptive analgesia, 21–22, reuptake inhibitors), 146
Physical rehabilitation, 88, 231, 215, 252 Saline control, 231
234–235 Pregabalin/gabapentin, 149 SAMe, see S-adenosylmethionine
Physiological pain, 28, 29 Primary hyperalgesia, 9 Schwann cells, 15
Phytocannabinoids, 246 Prostaglandins (PGs), 253 contribution of, 43
Piroxicam, 119, 120, 196 Prostanoids, 174, 175 SDSs, see Simple descriptive scales
Plasticity encoding, 8–9 Proteoglycan, see Aggrecan Secondary hyperalgesia, 9
Platinum complexes, 107 aggregates Secondary somatic hyperalgesia, 33
PLGA-g-PEG polymer, 114 Proton pump inhibitors (PPIs), 187 Sensitization, 9, 21, 32, 37, 46, 88
PLGA-PEG-PLGA (PPP) hydrogels, P2X, 14, 46 Sensory neuron dynamics, 58
113–115, 117 Sensory receptors, 89, 89
PNS, see Peripheral nervous system
Poly(lactic-co-glycolic acid) (PLGA),
Q Serotonin, 147, 147–148
Severity-based cancer pain, 104
113, 115–116 Qi, 228, 229 Silent afferents, 32
Polyglycolide (PGA), 115, 116 QoL, see Quality of life Simple descriptive scales (SDSs),
Polylactide (PLA), 115, 116 Quality of life (QoL), 61, 63 58, 107
Polysulfated glycosaminoglycan SNL, see Spinal nerve ligation
(PSGAG), 239–240, 240
Postherpetic neuralgia (PHN), 43
R model
Sodium channels, 11, 15, 28, 140,
Post–tissue injury pain states Radiation therapy 142, 145, 147–148
activity in sensory afferents, 45 biocompatibility of PLGA- Somatic hyperalgesia, 31
astrocytes and microglia, 51, PEG-PLGA hydrogels, Spinal cord neuron
51–52, 52 113–115 hyperexcitability, 93
bulbospinal serotonergic degradation of PEG, 116–117 Spinal nerve ligation (SNL) model, 43
pathway, 50, 51 degradation of PLGA, 115–116 SSRIs, 146
damage to peripheral nerve, Radiocolloid, 156 Subchondral bone, 71–75, 77–78,
44–45 Radionuclide, 156 80–81, 205–206
dynorphin, 56 Radiosynovectomy (RSV), 156 Substance P (sP), 6, 89, 128
GABA/glycinergic terminals, 55 Radiotherapeutics Suprofen, 254
and inflammation, 52, 52 definitions, 156–157 Surgical intervention, 95
 Index 269

Sympathetic pain, 14 Tonovet ®, 255 convergence-projection theory,

Sympathetically dependent cancer Total hip arthroplasty, 95 30–31
pain, 104 Traditional Chinese medicine, 228 DRG neurons, 34, 34
Sympathetically maintained pain, 11 Tramadol, 119, 120, 132–133, 133, and emotion, 35
Synergism, 231, 231–232 134, 137, 220 fight or flight response, 30
Synovectomy, 156 Transcutaneous electrical nerve and gender, 31–32
Synovial fluid, 73–74, 76, 78–84, stimulation (TENS) in human studies, 32, 32
133, 201–202, 206, 208 therapy, 10 models, 31–32
Synovial intima, 73–74, 82 Transdermal buprenorphine poor localization of, 33–34
Synoviorthesis, 156 solution (TBS), 131 secondary somatic
Synovitis, 80, 80, 81 Transduction, 3, 27, 28, 45–46, hyperalgesia, 33
154, 216, 216, 217, 231 somatic hyperalgesia, 31

T Transient receptor potential

(TRP), 6
and somatic pain, differences
between, 36, 36
Tactile allodynia Transient receptor potential summary, 35–37
acute to chronic pain, 40–41 vanilloid (TRPV), 7 visceral afferent pathways, 34
Aβ afferents, 37–38 Transmission, 7, 8, 12, 154, 215, visceral sensitization
chronic pain, 38–40 216, 216, 217, 231 mechanisms, 36–37
neuropathic pain, 41–42 Transmucosal, 131 visceral-somatic convergence, 30
phenomenon of touch-evoked Tricyclic antidepressants (TCAs), Visceral stimuli, 32–34
pain (allodynia), 38 38, 133, 144, 144, release of sP and expression of
Tapentadol, 134–136 144–145 c-fos, 33
Taxonomy, 102 antidepressants and mechanisms secondary hypersensitivity, 33
TBS, see Transdermal of action, 146 ‘silent’ nociceptors, 32–33
buprenorphine solution for human use, 144, 144 Viscosupplementation, 208
TCA mode of action, 145–146 Imipramine, 144, 144 Visual analog scale (VAS), 58, 107,
TCAs, see Tricyclic antidepressants mode of action, 145 112, 256
Temporal classification, 57 Trigeminal neuralgia, 43 Voltage-dependent calcium channels
Temporal summation, see Windup TRP, see Transient receptor potential (VDCCs), 13, 149
TENS, see Transcutaneous TRPV1, see Vanilloid receptor VR1 Voltage-gated ion channels, 11–14
electrical nerve TRV, see Transient receptor Voltage-gated sodium channel
stimulation therapy potential vanilloid (VGSC), 11, 142, 223
Tepoxalin, 119, 180, 189 TTX, see Tetrodotoxin VRSs, see Verbal rating scales
Tetracyclines, 146 Tumor-induced local acidosis,
19-tetrahydrocannabidiol (THC),
245, 246
109–110
TX, see Thromboxane
W
THC cannabis, 245–246 Wallerian degeneration, 15, 15
Tetrodotoxin (TTX), 12
Texas VAS Instrument, 64
V Washout, 181, 186–187
WDR, see Wide dynamic range
THC, see 19-tetrahydrocannabidiol Vanilloid receptor VR1, 6 WHO, see World Health
Three-neuron chain, 3, 4 VAS, see Visual analog scale Organization
Thromboxane (TX), 181–182 Vascular endothelial growth factor Wide dynamic range (WDR),
Tidemark, 206 (VEGF), 80 18, 88
TIMPs, see Tissue inhibitors of VDCCs, see Voltage-dependent Windup, 19–22
metalloproteinase calcium channels World Health Organization (WHO)
Tin-117m, 158, 159 VEGF, see Vascular endothelial cancer pain ladder,
clinically important features, growth factor 104–105, 105
160–161 Venlafaxine, 146 opioid classification, 136, 136
conversion electrons, 158, 158 Verbal rating scales (VRSs), 58 Wound-healing macrophages, 86
field experience in veterinary Vesicle exocytosis, 27
medicine, 161
homogeneous colloid of, 160
VGSC, see Voltage-gated sodium
channel
X
radiosynoviorthesis in Vinca alkaloids, 107 Xylazine, 137, 220
veterinary medicine, Vincristine, 112
159–160
safe and effective RSO
Vincristine neuropathy, 43
Visceral cancer pain, 111, 111
Y
radionuclide, 160 Visceral hypersensitization, 34–35 Yin-Yang theory, 227, 227
safety for dog owners, 161–162 cross-organ convergence, Yohimbine, 221
Tissue inhibitors of 34–35, 35
metalloproteinase
(TIMPs), 81, 233, 233
interstitial cystitis, 34, 35
Visceral pain
Z
Tolfenamic acid, 120 agents in management of, 37 Zorbium, 131