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Use of cannabidiol (CBD) for the treatment of chronic pain

Article in Best practice & research. Clinical anaesthesiology · July 2020

DOI: 10.1016/j.bpa.2020.06.004

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Use of cannabidiol (CBD) for the treatment of chronic pain

Ivan Urits, MD, Kyle Gress, BS, Karina Charipova, BS, Kelly Habib, BS, David Lee,
BS, Christopher Lee, BS, Jai Won Jung, BS, Hisham Kassem, MD, Elyse Cornett,
PhD, Antonella Paladini, MD, PhD, Giustino Varrassi, MD, PhD, FIPP, Alan D. Kaye,
MD, PhD, Omar Viswanath, MD

PII: S1521-6896(20)30045-8
DOI: https://doi.org/10.1016/j.bpa.2020.06.004
Reference: YBEAN 1094

To appear in: Best Practice & Research Clinical Anaesthesiology

Received Date: 18 June 2020

Accepted Date: 25 June 2020

Please cite this article as: Urits I, Gress K, Charipova K, Habib K, Lee D, Lee C, Jung JW, Kassem
H, Cornett E, Paladini A, Varrassi G, Kaye AD, Viswanath O, Use of cannabidiol (CBD) for the
treatment of chronic pain, Best Practice & Research Clinical Anaesthesiology, https://doi.org/10.1016/
j.bpa.2020.06.004.

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© 2020 Published by Elsevier Ltd.

 Use of cannabidiol (CBD) for the treatment of chronic pain
Ivan Urits, MD 1; Kyle Gress, BS 2; Karina Charipova, BS 2; Kelly Habib, BS 3; David Lee, BS 3;
Christopher Lee, BS 4; Jai Won Jung, BS 2; Hisham Kassem, MD 5; Elyse Cornett, PhD 6; Antonella
Paladini, MD, PhD 7; Giustino Varrassi, MD, PhD, FIPP 8; Alan D. Kaye, MD, PhD 6; Omar Viswanath,
MD 3,4,6,9
1
Beth Israel Deaconess Medical Center, Department of Anesthesia, Critical Care, and Pain
Medicine, Harvard Medical School, Boston, MA
2
Georgetown University School of Medicine, Washington, DC
3
University of Arizona College of Medicine-Phoenix, Department of Anesthesiology,
Phoenix, AZ
4
Creighton University School of Medicine, Department of Anesthesiology, Omaha, NE
5
Mount Sinai Medical Center, Department of Anesthesiology, Miami Beach, FL
6
LSUHSC, Department of Anesthesiology, Shreveport, LA
7
Department MESVA, University of L'Aquila, L'Aquila, Italy
8
Paolo Procacci Foundation, Via Tacito 7, Roma, Italy
9
Valley Pain Consultants – Envision Physician Services, Phoenix, AZ

Corresponding Author: Ivan Urits

Beth Israel Deaconess Medical Center
Department of Anesthesia, Critical Care, and Pain Medicine
330 Brookline Ave
Boston, MA, 02215
Phone: (732)-501-7220
iurits@bidmc.harvard.edu

Article Type: Review

1
Abstract

Chronic pain can be recurrent or constant pain that lasts for longer than three months and can

result in disability, suffering, and a physical disturbance. Related to the complex nature of

chronic pain, treatments have a pharmacological and non-pharmacological approach. Due to the

opioid epidemic, alternative therapies have been introduced, and components of the cannabis

Sativa, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have gained recent interest as a

choice of treatment. The exact mechanism for cannabidiol is currently unknown, but unlike the

CBD's psychoactive counterpart, THC, the side effects of CBD itself have been shown to be

overall much more benign. The current pharmaceutical products for the treatment of chronic pain

are known as nabiximols, and they contain a ratio of THC combined with CBD, which has been

promising. This review focuses on the treatment efficacy of CBD, THC: CBD based treatments

for chronic pain and adverse events with each.

Key Words: Cannabidiol, Nabiximols, Chronic pain

2
Introduction

Chronic pain is defined as recurrent or constant pain that lasts or recurs for longer than

three months and can result in disability, suffering, and a physical disturbance (1,2). Chronic

pain affects 20% of the population, with musculoskeletal disorders being the most common

cause (2,3). The International Classification of Diseases (ICD) 11 has developed a systematic

classification of chronic pain into seven different categories: chronic primary pain, chronic

cancer-related pain, chronic postsurgical or posttraumatic pain, chronic neuropathic pain, chronic

secondary headache or orofacial pain, chronic secondary visceral pain, and chronic secondary

musculoskeletal pain (1). It is now more widely accepted that chronic pain is its own disease

entity and not just solely the result of an illness or an injury. Causes of chronic pain are

multifaceted, and providers must also consider the coexisting biopsychosocial factors such as a

patient's behavioral and emotional characteristics, socioeconomic factors, and quality of life (4).

Related to the complex nature of chronic pain, treatments can have a pharmacological

(nonsteroidal anti-inflammatory drugs and acetaminophen for nociceptive pain and tricyclic

compounds and serotonin-norepinephrine reuptake inhibitors for neuropathic or central

sensitization pain) or non-pharmacological (psychotherapy, cognitive behavioral therapy, and

exercise) approach (4). Over the last 25 years, there has been a concerning increase in treating

chronic pain that is not related to cancer pain with opioids as recommended by the World Health

Organization's (WHO) analgesic ladder (2,5). In 2018, the Center for Disease Control (CDC)

reported that opioids were involved in over 69.5% of all drug overdose deaths, with two out of

three opioid-related deaths related to synthetic opioids (6). Therefore, prescribing opioids for

3
chronic pain can be dangerous due to the physical dependence and risk for addiction and possible

overdose for chronic pain patients (7).

Related to the opioid epidemic and risks associated with prescribing opioids as a

treatment for chronic pain, alternative therapies have been introduced as a treatment option.

Specific components of the ancient plant Cannabis sativa have gained recent interest as a choice

of treatment for chronic pain due to the increasing public use as well as the recent legalization of

cannabis in many states in the USA (8). The two components of interest in the cannabis plant are

the psychoactive component Δ9-tetrahydrocannabinol (THC) and the non-psychoactive

component cannabidiol (CBD), which both act on the endocannabinoid system in the brain (2,9–

12). This review will focus on recent studies that investigate the treatment efficacy of CBD as

well as THC: CBD-based treatments for chronic pain and the adverse events associated with

each.

Etiology and Epidemiology of Chronic Pain

Pain can be divided into three physiologic categories: nociceptive, neuropathic, and

centralized pain/central sensitization (4). Beyond the biological causes, the etiology of chronic

pain should also include the psychosocial, physical, social, and psychological factors that lead to

the disabling features of the disease (13,14). Eight of the top 12 causes of disability globally are

low back and neck pain, migraine, arthritis, other musculoskeletal conditions, depression,

anxiety, and drug use disorder (15). The ICD-11 has divided chronic pain into chronic primary

pain (pain that cannot be better described by another chronic pain condition) and chronic

secondary pain (pain that may initially be a symptom of a separate disease). Examples of chronic

primary pain include widespread chronic pain, chronic primary visceral pain, and chronic

4
primary musculoskeletal pain, whereas examples of chronic secondary pain syndromes are

chronic cancer-related pain and chronic postsurgical pain (1).

According to recent reports from the CDC, an estimated 20.4% (50 million) of adults in

the United States have "high impact" chronic pain (pain that interferes with work or life most

days or every day) (16). In low-and middle-income countries, women, elderly patients, and

workers in low-income and low-education groups were more likely to experience chronic pain in

multiple areas of the body as well as have concurrent disabilities and mood disorders (15).

Furthermore, people with lower levels of education and from less wealthy neighborhoods are

more likely to experience chronic pain than those with higher levels of education and those who

live in wealthier neighborhoods (17).

When examining age, 62% of patients in the UK, over 75 reported chronic pain, which

reveals that chronic pain is more prevalent in the older population. (18). Yet, chronic pain is still

significant in young people, with numbers as high as 30% (18). In terms of chronic postsurgical

pain, the increased reliance on opioid prescribing after surgery has led to chronic pain in 10% of

patients as a result of opioid-induced hyperalgesia. Furthermore, chronic postsurgical pain is

more commonly associated with younger age (19,20). Related to the widespread and complicated

nature of chronic pain, effective interventions and treatments need to be examined.

Traditional Treatment Options for Chronic Pain

Related to the biopsychosocial cause of chronic pain, the current treatment options that

exist have a multifaceted approach of combining pharmacological, physical, and psychological

components. When examining the pharmacological options for chronic pain, physicians can

consult the WHO analgesic ladder that was initially developed for treating cancer pain but has

5
been applied to chronic non-cancer pain (21). Following the ladder, the first step recommends

non-opioid analgesics such as aspirin or NSAIDs (22). Not only does long-term NSAID use

increase the risk of gastric ulcers, but meta-analyses have also shown that they can increase the

risk of coronary heart disease (23–25). The second step of the ladder recommends weak opioids

for mild to moderate pain such as codeine, whereas the third step recommends strong opioids

such as morphine and oxycodone that are more potent but also contain more dangerous side

effects (22). Opioid therapy as a treatment for chronic pain has the potential to result in life-long

dependence and tolerance, where chronic opioid use is needed to maintain a new level of

homeostasis (26). Lastly, antidepressants (tricyclic antidepressants, serotonin, and

norepinephrine reuptake inhibitors) and antiepileptics (gabapentin and pregabalin) have been

used in chronic pain conditions that are neuropathic in nature (21). In terms of physical

treatments, interventional pain management tools such as nerve block injections, surgical

procedures to destroy peripheral nerves, intrathecal drug delivery systems of opioid medications,

and spinal cord stimulation have been used, although their efficacy has been called into question

as well as the invasive nature of the treatments (27–31). Lastly, evidenced-based therapies have

shown non-pharmacological and non-invasive treatments such as therapeutic exercise, cognitive

behavioral therapy, mindfulness, and physiotherapy/occupational therapy can be effective

treatments for chronic pain (22).

Advent of CBD

The Cannabis sativa plant contains at least 144 components known as cannabinoids, which

are drugs that act on the endocannabinoid system in the brain. The two cannabinoids of medical

interest are the psychoactive Δ9-tetrahydrocannabinol (THC) and the non-psychoactive

6
component cannabidiol (CBD) (32). Medical marijuana contains cannabis or cannabinoids that

have a THC concentration greater than 0.3% and should be administered through a medical

vaporizer device (33). On the other hand, CBD products that are extracted from hemp contain

less than 0.3% THC and can come in many forms, including oils, sprays, and food, among many

other options (33,34). Since these CBD products do not contain greater than 0.3% THC, they do

not require a prescription like typical medical marijuana, and the products in them are not

regulated and sometimes do not contain the same ingredients as marketed (34). Some cannabis

products that are currently available are Sativex, a drug that contains THC and CBD in a 1:1

ratio, and is used for the treatment of multiple sclerosis, and Epidiolex, an oral CBD solution

used for the treatment of seizures in two severe forms of childhood epilepsy (32,35). Two

synthetic cannabinoids for medical use, dronabinol, and nabilone mimic the structure of THC

and are approved for the treatment of weight loss in patients with AIDS and chemotherapy-

induced nausea (32).

Beyond the established drugs, CBD has many promising therapeutic and medical

applications other than its effect on chronic pain, which will be discussed in a separate section

below. Zuardi et al. conducted a double-blinded placebo-based study of the anxiolytic effect of

CBD using the Test of Public Speaking in a Real Situation (TPSRS) where 60 healthy male

subjects were asked to speak in front of a group made of the other participants while their blood

pressure and heart rate were recorded. Different doses of CBD (100, 300, 900 mg), the

benzodiazepine clonazepam (1 mg) and placebo were divided amongst the subjects in 5 groups.

The results showed that the 300 mg CBD dose produced the greatest anxiolytic effect. This

suggests that the dosing of CBD effectiveness follows a bell-shaped curve (36). MRI studies

have shown that CBD produces anxiolytic effects by modulating blood flow in the limbic and

7
paralimbic areas of the brain and has the potential to be effective in treating anxiety disorders

(37).

The antipsychotic effects of CBD have also been studied. CBD has been shown to

decrease the depersonalization symptoms in artificially induced psychosis by the drug N-methyl-

D-aspartate (NMDA) (38). McGuire et al. performed a double-blind trial on schizophrenia

patients where patients either received CBD (1000 mg) (N=43) or placebo (N=48) with their

current antipsychotic medications. Lower positive psychotic scores were shown in the CBD

treatment group, and those treated with CBD were more likely to have been rated as improved

between the two groups (39,40). Furthermore, CBD has been shown to be effective in treating

the psychotic symptoms in patients with Parkinson's disease as well, although this is a relatively

new area of study and needs further research (36). Although CBD is still a novel drug treatment,

preliminary studies on the effectiveness of CBD as an anxiolytic, anti-inflammatory, and

antipsychotic drug have shown promising results.

Mechanism of Action for CBD

The exact mechanism of action for cannabidiol (CBD) is still currently unknown. CBD is

a major phytocannabinoid component of the plant Cannabis sativa, and when isolated from

Cannabis sativa, CBD is found to have effects that deviate from the traditional uses of the

original plant form (41). The most well-known proposed mechanism for CBD is its non-

competitive antagonistic effect on type 1 cannabinoid receptors (CB1) and type 2 cannabinoid

receptors (CB2) (42). CB1 receptors have a strong presence in the central nervous system (CNS),

particularly in regions of the midbrain and spinal cord that are both responsible for pain

perception (42). In a study by Laprairie et al., CBD was proposed to be a negative allosteric

8
modulator (NAM) on CB1 receptor internalization, G protein-dependent signaling and

phosphorylation, and arrestin2 protein recruitment on heterogeneous cells that expressed CB1

receptors (43). While CB1 receptors were primarily distributed in the CNS, CB2 receptors are

more often associated with the immune system, and antagonistic effects on these receptors

demonstrate a role in the inhibition of the inflammatory response, particularly the suppression of

mast cell degranulation and neutrophil propagation, within the vicinity of pain centers (44). One

study involving hamster ovaries by Thomas et al. suggests that even low concentrations of CBD

are capable of interacting with both CB1 and CB2 receptors to elicit a therapeutic response when

given in combination with THC (45). However, in light of the fact that CBD independently has a

relatively low binding affinity for both CB1 and CB2 receptors, other mechanisms have been

proposed. One notable proposed mechanism is the role of CBD in G protein-coupled receptor

activity, specifically on G protein-coupled receptor 3 (GPR3) (45). GPR3 is expressed in the

brain and spinal cord and is involved in neuronal development, pain reception, and emotion

regulation (45). A study by Ruiz-Medina et al. discovered that downregulation of GPR3 led to a

heightened sensitivity to various forms of stimuli and neuropathic pain, thus suggesting one

possible mechanism for the role of CBD in neuropathic pain (45,46). Many other non-CB1 and

CB2 mechanisms have been proposed to explain the therapeutic effects of CBD, including its

agonistic effect on serotonin 5-HT1A receptors and upregulation of anandamide signaling for

psychiatric conditions, the agonistic effect on vanilloid TRPV1, μ and δ receptors for pain

regulation, and inhibition of TNF-α in inflammatory conditions (47–51). New mechanisms of

action continue to be proposed as a whole host of receptors capable of interacting with CBD are

discovered.

9
Pharmacokinetics and Pharmacodynamics

While THC is the main psychoactive component of cannabis, cannabidiol is the major

non-psychoactive component (52). Cannabidiol has been attributed to analgesic, anti-oxidative,

anti-inflammatory, anticonvulsant, and anxiolytic properties (53–56). Combined with recent

evidence of a good safety profile, cannabidiol makes a promising candidate for the future of

chronic pain management.

Cannabidiol's lack of psychoactivity is secondary to its minimal binding affinity to CB1

receptors. In the presence of THC, CBD can also function as a non-competitive, negative

allosteric modulator, the CB1 receptor, antagonizing THC's psychoactive effect, and

subsequently improving the tolerability of concomitant THC use (43,57–59). In the setting of

chronic pain, CBD's analgesic effects come from a THC-independent mechanism through

multiple non-cannabinoid receptors and ion channels (44,60).

CBD also functions as a suppressor of cell-mediated and humoral immunity (44,61).

While the mechanism of how CBD targets the inflammatory response is still unknown, it is

known that CBD decreases microglial and macrophage migration, which may play a role for the

treatment of inflammatory diseases, such as multiple sclerosis, cancer, diabetes, and neuropathic

pain (62–64).

CBD has multiple potential routes of administration. The most common, recreationally, is

smoked cannabis. For medicinal purposes, this inhaled route is considered detrimental as

smoking exposes patients to combustion byproducts and relies on self-titration that can lead to

higher rates of side effects (65,66). Vaporization is considered a safer alternative, offering

similar rapid onset and rapid peak effect within 10 minutes (67,68). But bioavailability is

approximately 31% and subject to variability based on inhalation techniques (67–69).

10
 Oral administration to is possible, but related to the low water solubility of CBD, there is

also large variability in its absorption. Unfortunately, the oral route is also associated with slower

onset of action, more psychoactive effects, and low bioavailability of approximately 6% (44,60).

Oral mucosal and sublingual delivery offer similar bioavailability of 6%, but there is less

variation in its absorption. Due to its high lipophilicity, CBD has a large volume of distribution

(approximately 32L/kg), and so transdermal patches are typically not considered to avoid large

amounts of drug accumulation within the skin (68,70).

CBD is mainly metabolized by the liver by CYP3A and CYP2C, similar to THC, and is

then subsequently excreted via the feces (69,71,72). Terminal half-life is between 18-32 hours

(72).

Efficacy of CBD for Treatment of Chronic Pain

In recent studies, CBD has demonstrated beneficial effects in the setting of chronic pain

(73). Many of the studies compare CBD with its psychoactive counterpart, THC, and have

yielded analgesic effects that have not fully been understood. As a non-psychoactive analgesic,

CBD will have its own niche within the current standard of treatment for chronic pain, but many

more studies will be needed to find its optimal use.

In the early 2000s, two trials assessed the safety and efficacy of sublingual CBD in

comparison to THC and a 1:1 mixture of THC: CBD (56,74). Wade et al. was a double-blinded,

randomized placebo-controlled crossover study assessing 24 patients with a known neurological

diagnosis. The enrolled patients were clinically stable but unresponsive to the current standards

of pain therapy. In this study, patients were observed across two-week treatment periods, with 20

of the patients completing the study. For the patients that did not continue, they cited

11
intoxication, vasovagal episode following the initial dose, sublingual burning, and marked

psychoactive response to THC (56).

Of the remaining 20 patients, there were 14 diagnoses of multiple sclerosis, four spinal

cord injuries, one brachial plexus lesion with associated neuropathy, and one phantom limb pain

following an amputation. Patients were assessed for pain, muscle spasms, spasticity, loss of

bladder control, and tremors. CBD alone resulted in statistically significant improvements in pain

compared to placebo. Improvements in muscle spasms, spasticity, and bladder control were also

observed with CBD compared to placebo; however, these did not reach statistical significance.

CBD: THC resulted in statistically significant improvements in muscle spasms and also non-

statistically significant improvements in pain and bladder control. In respect to orientation,

memory, and concentration, CBD and CBD: THC offered minimal blunting in comparison to the

THC extract. It is also interesting to note that doses that were used in the study were far less

compared to the maximum dose permitted, giving room for potentially better symptom

management (56).

Like Wade et al., Notcutt et al. established a similar set up with a double-blinded,

randomized placebo-controlled crossover study. Thirty-four patients with uncontrolled chronic

neuropathic pain were given CBD, THC, THC: CBD, and placebo in 1-week intervals following

an open-label two-week THC: CBD run-in period. Throughout the study, the patients' two main

symptoms were monitored and assessed via a visual analog scale (VAS). During the run-in

period, 16 of 34 patients had a greater than 50% decrease in VAS for either one of their two main

symptoms. Ten of which, reporting greater than 50% reduction in VAS for both symptoms (74).

During the crossover study, THC and THC: CBD fared better than placebo in terms of

addressing the main symptom (p<0.01 and p<0.05 respectively) and secondary symptom

12
(p<0.001 and p<0.054 respectively). Of the group that did not receive Cannabis-Based Medicinal

Extracts (CBME) rescue medications, 9 of 24 patients noted improvements of at least 50% in one

of their symptoms with THC and/or THC: CBD, whereas only three patients were able to

achieve a similar effect with CBD. While the effect of CBD was not equivalent to that of THC

and THC: CBD, it is difficult to assess the effect of each extract on pain specifically as VAS

scores are influenced by not just pain, but also sleep mood and environment. It is, however,

promising that all eight patients with residual pain following a failed spinal surgery noted some

improvement with CBD, potentially demonstrating an anti-inflammatory effect that can be

further studied (74).

When crossover trials were compared with the run-in THC: CBD, nine patients

responded that the crossover THC: CBD was equivocal or more effective, eight patients

responded that THC was equivocal or more effective, and four patients found that CBD was just

as effective. It should be noted, however, that CBD was not titrated much more than the dose

required for the original THC: CBD dose. Not only that, but CBD had a better outcome than the

placebo, which no patients found as effective when compared to the original THC: CBD run-in

(74).

Other benefits also included improved sleep quality (P<0.05 for CBD) and improved

mood as reflected by the General Health Questionnaire 28 and Beck Depression Inventory. The

mood, however, was measured at the beginning, end of the run-in period, and end of the study,

marking the benefit of the overall treatment with the various cannabis extracts. Interestingly

though, psychomotor and cognitive function were found to be equivocal in this study. On

detailed analysis, there were actually improved performances following treatment (74).

13
 During the initial titration, two of the first few patients involved in the study experienced

dysphoria and lightheadedness due to inappropriate dosing intervals. Symptoms resolved within

2 hours, and future events were mitigated with increased intervals from 15 minutes to 30

minutes. Other common side effects were mild in nature, including dry mouth, dizziness,

dysphoria, and euphoria. These side effects occurred less frequently with CBD compared to THC

and THC: CBD. Other less frequently occurring side effects included a vasovagal episode, which

the patient was still able to continue in the study without the THC period, and no episodes of

panic attacks were observed (74).

A prospective cohort study by Capano et al. followed 97 patients with a diagnosis of

chronic pain and stable opioid use for the past two years. Ninety-four patients were able to

tolerate, twice daily, hemp-derived CBD-rich soft gels, which contained 15.7mg CBD, 0.5mg

THC, 0.3mg cannabidivarin, 0.9mg cannabidiolic acid, and 0.8 mg cannabichromene, and >1%

botanical terpene blend. Of the three patients who did not continue with the CBD hemp extract, 2

had adverse effects of drowsiness, and one was concerned about cost following the study as CBD

is not covered by insurance. Other side effects noted during the study included one account of

each: "heart rac[ing]," which was addressed by combining twice-daily dosing into one single

dose, nausea, heartburn, and dry mouth, and nighttime anxiety and disturbed sleep. Otherwise,

CBD was well-tolerated without significant adverse events (75).

Across the eight week study, 50 of 94 patients (53.2%) were able to reduce their opioid

medications, with 2 of them being able to completely eliminate their need for opioids. It is

important to note that this number may also be underreported as many patients had noted

hesitancy in their reports due to fear of losing their opioid prescriptions. As CBD was not

covered by insurance and opioids were, if financial problems occurred, patients would be unable

14
to have adequate pain control. Six patients were also able to reduce or eliminate their need for

anxiety medications, and four patients were able to do the same for their sleep medication. In

contrast, the three patients who had declined CBD hemp extract did not appreciate any of these

positive outcomes (75).

Quality of life was also assessed as a secondary outcome through the Pain Disability

Index (PDI), 4-item Patient Health Questionnaire (PHQ-4), Pittsburgh Sleep Quality Index

(PSQI), and 3-item scale assessing Pain Intensity and Interference (PEG), and subjective, open-

ended questions. Open-ended questions revealed that 89 (94%) of hemp CBD users had an

improved quality of life. Among the other studies, significant improvements were noted in sleep

quality (p=0.03) and pain intensity (p=0.006), as reflected by PSQI and PEG, respectively.

Interestingly, when results of the PHQ4 were broken down by gender, a significant improvement

was noted in males in comparison to females at week 8. This effect, however, was not present at

baseline or at week 4 (75).

The efficacy and safety of CBD have also been preliminarily analyzed in the treatment of

chronic pain in patients with a history of renal transplant. Cunetti et al. assessed seven renal

transplant patients with chronic pain who had requested CBD for their analgesic treatments.

Patients were more than one year out of their kidney transplant and received careful monitoring

of creatinine, blood count, liver function, liver enzymes, and immunosuppressant levels. Six of

the seven patients noted improvement of their pain by two weeks into the study. Two noted

optimal pain control of their comorbid osteoarticular pain and neuropathic pain, while 4 noted

partial improvement and 1 noted no change. In the one patient that had no change with CBD

levels, closer inspection of the data revealed that the patient responded earlier in the studies. Pain

control was found to be better at low doses of CBD, and in fact, worsened with increasing doses

15
of CBD. The doses were not decreased until day 21 of the three-week study, so potentially

further extension of the study may have led to more positive outcomes (76).

Overall, CBD was well tolerated in renal transplant patients outside of mild adverse

effects such as nausea, dizziness, dry mouth, drowsiness, and intermittent heat episodes, most of

which were self-resolving similar to prior studies. One patient did, however, require a temporary

reduction in their dosing secondary to intractable nausea, but it is important to note that this

specific patient had a history of digestive intolerance to several other medications. Tacrolimus

levels were variable between patients; one patient experienced lower levels, while another

experienced elevated levels with worsening creatinine. These fluctuations in tacrolimus,

however, were easily controlled within a week of dose adjustments and were unable to be linked

to an interaction between CBD and calcineurin inhibitors. Cyclosporine levels in these patients

were stable and remained unchanged throughout the course of the study (76).

In the setting of fibromyalgia, Van de Donk et al. performed a double-blinded,

randomized, placebo-controlled crossover study between Bedrocan (22.4mg THC, <1mg CBD),

Bediol (13.4mg THC, 18.8mg CBD), and Bedrolite (18.4mg CBD, <1mg THC), and a cannabis

placebo. In contrast to previous studies, patients were given a single vapor inhalation, and pain

thresholds, spontaneous pain scores, and drug high were then assessed for 3 hours (53).

With respect to relief of spontaneous pain and electrical pain, no treatments had a better

effect compared to placebo. Bediol had the next best effect at decreasing spontaneous pain by

30%, although Bediol and Bedrocan's influence on spontaneous pain was correlated with the

magnitude of drug high (P<0.001 for both). Bedrocan and Bediol did, however, lead to an

increased pressure pain threshold (P=0.006 and P=<0.001 respectively), which Van de Donk et

al. concluded that CBD would be suitable for the nature of pain in fibromyalgia for patients in

16
future clinical studies. Adverse effects were well tolerated and included drug high, coughing,

sore throat, dizziness, and nausea. No serious adverse events were noted (53).

With recent studies, CBD has shown promise in the setting of chronic, neuropathic, and

possible inflammatory pain. Its potential use as an antispasmodic and analgesic that works across

various different diagnoses gives it multiple potential uses. Further large randomized, double-

blinded, placebo-controlled studies with CBD in the setting of fibromyalgia and chronic opioid

use for chronic pain, and also further studies of the potential interaction between CBD and serum

tacrolimus levels are ways that can accelerate the current understanding of CBD for chronic pain.

Efficacy of nabiximols for the treatment of chronic pain

Nabiximol (Sativex) is an oromucosal spray composed of a one to one ratio of CBD and

delta-9 tetrahydrocannabinol (THC). According to the International Association for the Study of

Pain (IASP), the definition of chronic pain is the persistence or recurrence of pain that has lasted

longer than three months (22). The IASP has further categorized chronic pain into primary and

secondary chronic pain syndromes. Chronic primary pain is a pain in the absence of evidence of

tissue damage and is not a symptom of an underlying condition, whereas chronic secondary pain

is secondary to an underlying condition such as trauma, diabetes, multiple sclerosis, or cancer

(77). One particular study that explored the application of nabiximol in chronic pain of various

classifications was a recent cohort study published in 2019 that identified 800 severe chronic

pain patients in the German Pain e-Registry that were being treated with the nabiximol (Sativex)

oromucosal spray. Three groups were formed based on the characterization of a patient's chronic

pain: nociceptive, neuropathic, or mixed. The primary outcome measured in this study was an

aggregated nine-factor symptom relief score (ASR-9) that consists of pain intensity index (PIX),

17
a modified version of the pain disability index (mPDI), sleep, Marburg Questionnaire on

Habitual Health Findings (MQHFF), physical and mental quality of life, depression, anxiety, and

stress. Over the course of twelve weeks, patients would record a response to each factor while

being treated with nabiximol. 15.4% of patients found at least a 50% improvement in all nine

factors, and 56% of patients found at least a 50% improvement in a minimum of five out of nine

factors. Patients with neuropathic pain found a statistically significant improvement in their

ASR-9 compared to their mixed and nociceptive chronic pain counterparts. Patients with

neuropathic pain also experienced the fewest number of adverse events, and only a single patient

with neuropathic pain discontinued nabiximol due to adverse events. The most commonly

reported adverse events were an increase in appetite and distortion of taste. No serious adverse

events were reported. Although the study had several limitations such as a lack of placebo group

or a broad characterization of a patient's chronic pain without an exact diagnosis, there was

demonstrated benefit and safety in the use of nabiximol for chronic pain management of various

classifications and improvement in multiple factors associated with ASR-9, with particular

emphasis on improvement in patients with neuropathic pain (78).

Many studies have examined the therapeutic role of nabiximol in neuropathic pain of

diverse etiologies. A randomized, double-blind study by Berman et al. aimed to understand the

effects of chronic neuropathic pain secondary to brachial plexus avulsion with the use of

nabiximol (Sativex) for patients who presented to a pain clinic. Forty-eight patients who

qualified with a threshold pain score of at least 4 out of an 11-point scale were placed in either a

placebo control group, an experimental group where patients would self-administer nabiximol in

the form of an oromucosal spray, or an experimental group who self-administered an oromucosal

spray that contained THC exclusively. The study demonstrated a statistically significant decrease

18
in the Short-Form McGill Questionnaire (SF-MPQ) Pain Rating Index, SF-MPQ Visual

Analogue Scale, and Pain Review Box Scale-11 when comparing the placebo group to those who

were treated with nabiximol oromucosal spray. Only the Pain Review Box Scale-11 had a

statistically significant improvement in those treated with the THC oromucosal spray compared

to the placebo. In addition, there was a statistically significant improvement in sleep quality and

reduced sleep disturbances in both treatment groups compared to placebo. Such encouraging

findings warranted further studies on the efficacy of nabiximol in improving the management of

chronic neuropathic pain, sleep quality, and reducing sleep disturbances secondary to

neuropathic pain (79). Another randomized, double-blind clinical trial by Nurmikko et al.

examined the efficacy of self-administered nabiximol (Sativex) oromucosal spray on top of a

patient's current analgesic regimen for primary chronic neuropathic pain and allodynia. Sixty-

three patients were randomized into a treatment group while 62 patients served as placebo over a

five-week period. The treatment group was found to have a considerable reduction in its primary

metric, pain intensity score on a normal numeric rating scale (NRS) from 0-10, compared to a

placebo group. In addition, there was a statistically significant decrease in reported sleep

disturbances, neuropathic pain scale composite score, pain disability index, and a patient's global

impression of change in the treatment group compared to placebo. These findings mirror the

results in the study by Berman et al. In addition, 74% and 63% of the placebo and treatment

group were on a pre-existing opioid regiment that was continued throughout the study,

respectively. Therefore, there is evidence to suggest that a multi-modal analgesic plan consisting

of a patient's current analgesic regimen concomitant with nabiximol oromucosal spray may

greatly benefit the patient in their management of chronic neuropathic pain (80). One study

published in 2014 by Hoggart et al. performed an open-label 38-week multicenter clinical trial

19
with the nabiximol (Sativex) oromucosal spray for patients diagnosed with neuropathic pain

secondary to an underlying diagnosis of diabetes mellitus or co-existence with allodynia for an

average of at least five years. These patients were recruited from two older parent studies

conducted from 2005-2006, which were 15-week long, multicenter, double-blind randomized

clinical trials that separately studied and explored the efficacy of the nabiximol in neuropathic

pain with allodynia and diabetic neuropathy (81,82).Though statistical significance was

demonstrated in the efficacy of nabiximol in pain severity NRS in these older studies, the study

concluded that further research should be conducted to measure the safety and tolerance of

nabiximol over an extended period of time (81,82). The objective of the study by Hoggart et al.

was to determine the efficacy and safety of nabiximol and observe if there would be developed

tolerance in the setting of long-term use. Two double-blind randomized clinical trials established

one group with 173 patients who were diagnosed with peripheral neuropathic pain with co-

occurring allodynia, and another group consisted of 230 patients who were diagnosed with

peripheral neuropathic pain secondary to diabetes mellitus. In the allodynia randomized control

group, 90 patients received nabiximol, while 104 patients were on placebo. In the diabetic

neuropathy randomized control group, 113 received nabiximol while 132 received a placebo.

84% of all patients were on a pre-existing analgesic regimen and were allowed to continue their

pain regimen, which included anticonvulsants, NSAIDs, opioids, and tricyclic antidepressants.

Similar to the study by Nurmikko et al., neuropathic pain severity on a 0 – 10 NRS was the

primary measure for efficacy of nabiximol and was recorded weekly. The results demonstrated

that for patients who were treated with nabiximol and diagnosed with neuropathic pain with

associated allodynia or secondary to diabetes mellitus, there was a notable decrease in NRS by

week 4 of treatment with a majority of patients reporting a statistically significant decrease of

20
30% or better in pain at the nine-month mark compared to their baseline NRS value. Other

secondary measures also demonstrated improvement compared to baseline, which includes a

subject global impression of change (SGIC), the sleep quality NRS, and neuropathic pain scale

(NPS). No indications for developed tolerance towards nabiximol was demonstrated in this

study, and no new observed adverse effects were seen with long-term use compared to prior

studies or compared to the two parents studied conducted in prior years. Therefore efficacy,

safety, and tolerance were well demonstrated with long-term use of nabiximol in the

management of chronic neuropathic pain, regardless of primary or secondary causes (82).

The nabiximol oromucosal spray has also shown promise in managing spasticity in

multiple sclerosis (MS). A prospective randomized, double-blind study by Markova et al.

compared the efficacy of self-administered nabiximol (Sativex) vs. first-line treatment for MS

spasticity in patients who had moderate to severe progressive MS refractory to first-line

treatment (approximately 48.2% of enrolled patients) or relapse-remitting MS (approximately

40.8% of enrolled patients). The primary measure of this study was an MS spasticity 0 – 10

NRS, where ≥ four on the NRS equated to moderate to severe disease. One hundred ninety total

patients were placed in an initial four-week trial of nabiximol in addition to their current

treatment for MS, which included oral baclofen, tizanidine, and/or dantrolene. Responders to

nabiximol were identified by having patients fill a Minimal Clinical Important Difference

(MCID) report where ≥20% improvement from baseline equated to a proper response to

nabiximol. After four weeks of treatment, all patients entered a one to four weeks washout period

where they continued their original MS regimen without nabiximol. One hundred six patients

were evenly randomized into a nabiximol treatment group and placebo control group for 12

weeks. By week 12, there was a statistically significant improvement in patients who

21
demonstrated at least a ≥30% improvement in MS spasticity NRS while using nabiximol

compared to placebo. Other metrics that were statistically significantly improved were: mean

pain NRS, modified Ashworth scale which is one way of measuring spasticity, and MS

Expanded Disability Status Scale (EDSS) which quantifies physical disability due to MS. Based

on this study, there is evidence to suggest a clinically significant role of nabiximol oromucosal

spray as add-on therapy in the management of chronic pain and disability due to spasticity in MS

refractory to traditional first-line medications (83).

Perhaps one of the most significant areas of interest for the role of nabiximol in chronic

pain management is in the context of cancer. A systematic review from 2005 - 2014 on the

prevalence of pain in cancer patients estimates that chronic pain is present in 39.3% of patients

after the resolution of their cancer, 55% of patients during their cancer therapy, and 66.4% in

those with terminal, advanced, or metastatic cancer (84). A pilot, randomized control trial by

Lynch et al., studied the efficacy of the nabiximol (Sativex) oromucosal spray in neuropathic

pain secondary to chemotherapy treatment with cisplatin, vincristine, or paclitaxel. Eighteen

patients were randomized into treatment, while 16 patients were randomized into a placebo

group, and both underwent a four-week treatment period. The primary measured outcome was a

pain intensity NRS from 0-10 with secondary measures that consisted of the Short Form-36

Health Survey (SF-36), which qualified a patient's health status, adverse effects, and quantitative

sensory testing (QST). Although five patients in this study reported a modest decrease in their

pain intensity NRS value from baseline, there was insufficient evidence to suggest a difference in

the pain intensity NRS, SF-36, and QST between the treatment and placebo group. However, no

notable medication-induced adverse effects were reported. This study, therefore, concluded that,

given the relatively safe use of nabiximol, larger studies should be conducted moving forward as

22
funding, power of the study given the small sample size, and duration of treatment were major

barriers (85). A larger double-blind, randomized control study published in 2018 by Licthman et

al. assessed the efficacy of nabiximol (Sativex) oromucosal spray in patients with an average

pain NRS between 4-8 on opioid therapy and diagnosed with advanced-stage cancer who

suffered from chronic pain refractory to opioid medication. The study by Lichtman et al. is a

phase three study based on two older studies, both of which showed promise but failed to

demonstrate statistical significance in the use of nabiximol to improve average pain NRS score

for patients with chronic pain due to advanced or terminal cancer (86,87). In this phase three

study, 199 patients were randomized into a treatment group with nabiximol, while 198 patients

were randomized into a placebo group. Both groups were started on a two-week period of a self-

dosing regimen of nabiximol and then remained on a fixed-dose for an additional three weeks. At

the conclusion of the study, there was no demonstrated statistically significant improvement in

average pain NRS score, the primary outcome of interest, compared to placebo. However, there

was a statistically significant improvement in sleep disruption NRS scores, which is consistent

with prior studies that also concluded the beneficial role of nabiximol in improving the quality of

sleep for patients with chronic pain. Although the primary outcome measured in this study failed

to show significant improvement compared to placebo, the potential benefit of nabiximol in

cancer-related pain cannot be ruled out. Additional studies are warranted to continue exploring

the role of nabiximol in managing cancer-related chronic pain and improving secondary

outcomes (88).

23
Safety

The overall safety and adverse events of CBD, as well as the potential drug-drug

interactions, need to be considered when prescribing CBD. Related to CBD's activity on the

CYP450 isoforms, drug-drug interactions are seen with drugs that act at CYP3A4 and CYP2C19,

most notably immunosuppressants, chemotherapy drugs, antiepileptics, antidepressants, and

antipsychotics (89). For example, the antiepileptic drug Sativex (4 sprays) was co-administered

with ketoconazole (400 mg), and the bioavailability of CBD increased by 89% due to the

CYP3A4 inhibition (90). Furthermore, CBD inhibits the uridine 5' diphospho-

glucuronosyltransferase (UGT) enzymes UGT1A9 and UGT2B7, resulting in decreased

excretion of drug substrates such as acetaminophen and ibuprofen and thus increased side effects

(91).

Beyond drug-drug interactions of CBD with other drugs, the clinical adverse effects of

CBD are also of interest. For the established antiepileptic drug Epidiolex, the most common

cause of discontinuation was hepatic injury and transaminase elevation. Patients also reported

milder side effects like sedation, fatigue, and lethargy (92). Lattanzi et al. performed a systematic

review and meta-analysis examining four trials involving 550 patients with Lennox-Gastaut

syndrome (LG) and Dravet syndrome (DS), two forms of childhood epilepsy syndromes, and the

effect of CBD on seizures frequency and adverse effects of the drug. The most commonly

reported adverse effects were somnolence, anorexia, diarrhea, and increased serum

aminotransferases (93). However, most of these adverse events were contributed to either the

dose of CBD, with greater adverse effects shown in higher doses, or drug-drug interactions with

other antiepileptic drugs patients were on such as valproate and clobazam (40).

24
 Unlike THC, which has well-studied adverse and psychogenic effects, the side effects of

CBD itself have been shown to be overall much more benign (94). In a single-dose crossover

trial in 38 healthy volunteers, oral CBD (300, 600, and 900 mg) was given, and participants were

asked to complete behavioral tasks that assessed their reactivity to negative stimuli. The results

showed that the CBD did not affect the heart rate or mean arterial pressure of the participants

except for the 900 mg dose of CBD, which showed a slight increase in heart rate (95). According

to the World Health Organization's Expert Committee on Drug Dependence report in 2018, the

adverse effects of CBD were mild symptoms such as fatigue, diarrhea, and anorexia (96).

Related to the lack of tolerance or physical dependence, the World Health Organization has

recommended that CBD not be labeled as a scheduled substance (96).

Recommended use

Related to the complex legal issues surrounding CBD as well as the novelty of

prescribing CBD as a treatment option, the guidelines for CBD use in a medical setting needs to

be explored further (97). Because of the United States' unclear regulations around CBD, many

CBD products manufactured in the United States may be falsely advertised with inaccurate

quantities of ingredients. Therefore, it is recommended that patients use CBD products made in

Europe due to their stringent requirements of a THC level of less than 0.2% in their CBD

products. (34). Physicians should use the Mayo Clinic's check-list for finding a high-quality

CBD product to recommend to patients: Does it meet the quality standards of the Current Good

Manufacturing Practice (CGMP) certification from the US and Food Drug Administration and is

it certified as organic by the US Department of Agriculture? Does the company have a reporting

program for adverse events? 3. Are the products laboratory tested to confirm a THC level <0.3%

25
and that it contains no pesticides or heavy metals? (34). Although CBD does not contain FDA

approval for medical use, patients still self-medicate with CBD related to the easy consumer

access to the product. Therefore, physicians should familiarize themselves with the available

products and guidelines in order to give the best recommendations to their patients.

Conclusion

Chronic pain can cause a serious physical disability for many patients that results in

chronic suffering. Causes of chronic pain are multifaceted, often involving physical, social, and

psychological entities. The recent and on-going opioid epidemic occurring in the United States

has ignited some concern overprescribing opioids as a treatment for chronic non-cancer pain.

The cannabis plant and its two components of medical interest, THC and CBD, have recently

been in the spotlight in the medical community related to their action on the endocannabinoid

system and anxiolytic effect. The current pharmaceutical products for the treatment of chronic

pain are known as nabiximols, and they contain a ratio of THC combined with CBD. While these

products have shown some promising results as a treatment for chronic pain, the efficacy of CBD

must be questioned since the product contains THC as well as CBD. Furthermore, the safety

profile of current CBD products, specifically non-pharmaceuticals, should be questioned due to

their false advertising and variable quantities of CBD in the product. Therefore, careful selection

of a CBD product should be made by physicians and patients to ensure patients are taking a high-

quality product. Despite these concerns, CBD is a promising area for the treatment of chronic

pain, and further studies need to be performed to evaluate the role of CBD in chronic pain

management.

26
Conflict of Interest

The authors have no conflicts of interest to disclose.

Funding Statement

No funding was received for the completion of this manuscript.

Practice Points

- Unlike THC which has well-studied adverse and psychogenic effects, the side effects of

CBD itself have been shown to be overall much more benign

- Nabiximols contain a ratio of THC combined with CBD

- While nabiximols have shown promise as a treatment for chronic pain, the efficacy of

CBD alone is uncertain

- Due to current regulation, over the counter CBD products manufactured in the United

States may be falsely advertised with inaccurate quantities of ingredients

- Due to CBD's activity on the CYP450 isoforms, drug-drug interactions are seen with

drugs that act at CYP3A4 and CYP2C19, most notably immunosuppressants

Research Agenda

- The efficacy and recommended doses of CBD for the treatment of chronic pain should be

further investigated

- Further research is needed on the physiology and mechanisms of the role of the

endocannabinoid system in the propagation of chronic pain

27
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