Opioid Analgesics

MOA Peripheral Effects Adverse Effects

Hypotension→ due to peripheral vasodilation, inhibition of Normeperidine @ high doseà seizures
-Produce analgesia primarily by activating receptors in the brain and
baroreceptor reflex and increase in histamine release Nausea and vomiting
spinal cord
Constipation→ universal (concomitant laxative use) Sedation
-Close voltage gated Ca2+ channels on presynaptic nervesà↓NT
Biliary colic→ contraction of biliary smooth muscle Itching
release (glutamate, ACh, NE, serotonin and substance P)
↓renal function→ ↓renal blood flow Constipation
-Open K+ channels on postsynaptic nerves→ inhibit of postsynaptic
Prolong labor by unknown mechanism on the uterus Urinary retention
neurons
Pruritus→ due to central effects and histamine release Hypotension
Spinal Analgesia: µ d and k receptors on spinal cord pain Stimulate ADH, PRL and somatotropin; inhibit LH Respiratory depression
transmission neurons & presynaptically on 1° afferents
-opioids inhibit release of excitatory NT (substance P and glutamate) CNS Effects Metabolism and Excretion
and the dorsal horn pain transmission neuron Converted to polar metabolites (mostly glucuronides)
-provide regional analgesia while minimizing unwanted resp -Morphine is conjugated to M3G (neuroexcitatory) or M6G(4-6x
depression, N&V, and sedation assoc. w/ supraspinal actions more potent)à do not cross BBBàno CNS effects
Analgesia→ reduce sensory and emotional components of
Supraspinal Analgesia: opioids inhibit inhibitory -Effects of Morphine or hydromorphone should be considered in pts
pain Euphoria→ floating sensation with ↓anxiety and
NTs(GABA)àactivate pain-inhibitory descending neurons to inhibit with renal impairment
distress
pain transmission neurons in the spinal cord -Heroine (diacetylmorphine)àrapidly hydrolyzed to
Sedation and drowsiness
Peripheral Analgesia: µ receptors on peripheral terminals of sensory monoacetylmorphineà morphine
Respiratory depression→ ↓central response to CO2
neuronsàanalgesia @ the knees for example -Remifentanil (ester)àrapidly hydrolyzed
Cough suppression→ ↓central cough center reflex
-Meperidine, normeperidine metabolites may accumulate in pts w/
Miosis→ excites PS→ pinpoint pupils are pathognomonic
-Opioids act concurrently at both spinal and supraspinal decreased renal fxn & pts on multiple high doses
following toxic dose (mediated by Morphine and most µ and
sitesàincrease overall analgesic efficacy -Fentanyl is metabolized by CYP3A4 (no active metabolites)
k agonists)
- Opioid agonist (morphine) can act on µ receptors and evoke a -Codeine, oxycodone, and hydrocodone metabolized by CYP2D6à
Truncal rigidity d/t action @ supraspinal level
release of endogenous opioids that act at d and k receptors production of metabolites with greater potency
Nausea & vomiting → activate brainstem trigger zone
(Codeineàmorphine)
- Glutamateàmain excitatory NT released from nociceptive nerve
terminals -Polar metabolites + glucuronides excreted in urine mainly
-Glucuronide conjugates can also be found in bile
Receptors: µ, δ, κ→ Gi Clinical Uses Contraindications
-Using a pure agonist(morphine) + weak partial agonist
-Majority act at the µ receptor and produce analgesia, euphoria, (Pentazocine)→diminish analgesia or induce a state of withdrawal
Analgesia→ moderate to severe pain
respiratory depression, and physiologic dependence -Head injuries(­ICP)→ CO2 retention causes cerebral vasodilation
Acute pulmonary edema→ Morphine will ↓anxiety, preload
-δ & κ are found primarily at the spinal level→ analgesia -Pregnancy→ fetal dependence
and afterload; if resp depression is an issueàFurosemide
-Impaired pulmonary function→ acute resp. failure
Cough→ dextromethorphan, codeine, levopropoxyphene
-Impaired hepatic function→ ↓metabolism of morphine
and noscapine
-Impaired renal function→ longer t½
Diarrhea→ Loperamide and Diphenoxylate
-Endocrine disease→ adrenal insufficiency(Addison’s) or
Anesthesia→ premedication and intraoperatively
hypothyroidism(myxedema) can have prolonged or exaggerated
Shivering → meperidine (activates α2 receptors)
response to opioids
-Concurrent use of Opioids and MAO-Is
-Mixed agonist-antagonist compounds w/ agonist selectivity for the Tolerance/Dependence/Addiction Drug Interactions
κ-receptor (Pentazocine, Butorphanol, and Nalbuphine)à“ceiling -Frequent use→ loss in effectiveness→ tolerance
effect”àlimits the amount of analgesia attainable with these drugs -Sedatives/hypnotics→ increase CNS depression (respiratory)
-Dependence→ physiologic withdrawal or abstinence
-psychotomimetic effects (psychosis, delirium, -Antipsychotics→ increase sedation, variable effects on resp.
syndrome
hallucinations, etc.)ànot reversible with naloxone depression and accentuate CV effects of anti-M & α-blockers
-Addiction→ euphoria, indifference to stimuli and sedation
-precipitate withdrawal in opioid tolerant ptsàfurther -MAO-I’s → life-threatening rxn especially with meperidine and
lead to compulsive use
limit clinical use tramadolàexcitement, muscle rigidity, hyperthermia,
-Physical dependence is common when used therapeutically,
unconsciousness
but addiction is not

Fernanda Ponce pg. 9

 Properties of Specific Opioids
Drug Name Class Description Metabolism Other
High affinity for µ receptor Conjugated to M3G (neuroexcitatory) Metabolites are polar and do not readily cross the BBB
Morphine
Standard for analgesia or M6G (4-6x more potent) Metabolite effects may be increased in renal impairment
Hydromorphone
Treat severe pain
Oxymorphone
Rapid hydrolysis to 6-
Heroin 6-monacetylmorphine (6-MAM) and heroine are more Pharmacological actions are due to 6-MAM and
MAM→morphine
(Diacetylmorphine) liposoluble than morphine and cross BBB morphine
Excreted in urine as free or conjugated
-µ receptor agonist; negative inotrope
Normeperidine t½=15-20 hours so it accumulates when
-Not recommended d/t high metabolite toxicity via Accumulation of normeperidine
given large doses @ short intervals
normeperidine→ tremor, twitching, pupil dilation, (excreted by both kidney and liver)
Meperidine t½= 3 hours
Meperidine Strong hyperactive reflexes & convulsions can occur in pts with decreased renal
Agonists -Blocks reuptake of serotoninà Serotonin syndrome→ or hepatic functionàseizures,
Significant antimuscarinic effectsàcontraindicated in pts
delirium, hyperthermia, HA, rigidity, coma, dysregulation of dysphoria, myoclonus
w/ tachycardia
BP, death [DO NOT combine with MAO-I’s]
µ receptor agonist; anesthetic adjuvant
Metabolized by CYP3A4 in the liver Transdermal patches provide sustained release
Fentanyl Rapid onset and shot duration (15-30min)
No active metabolites TXT of chronic pain & breakthrough pain in cancer pts
100x more potent than morphine
Equal potency to morphine but with less euphoria/sedation
No active metabolites Used to manage opioid withdrawal, heroin addiction,
and longer half-life
Methadone Abstinence syndrome (withdrawal) is and chronic pain
µ agonist, NMDA antagonist and serotonin/NE reuptake
Levorphanol prolonged but less severe than in
inhibitor
heroine Can cause QT prolongation, torsades and death
Levorphanol is even longer acting than methadone
Codeine Less efficacious than morphine Codeine analgesic effect is due to
Oxycodone Usually combined with aspirin, acetaminophen etc. Metabolites have greater potency
Mild to metabolism by CYP2D6 to morphine
Hydrocodone Codeine has low affinity for opioid receptors
Moderate
Increased risk of seizures
Agonists Weak µ agonist and NE/serotonin reuptake inhibitor
Tramadol May cause serotonin syndrome[DO NOT combine with
Useful for neuropathic pain
MAO-I’s, reuptake inhibitors or TCAs]
Pentazocine µ partial Developed to reduce addiction potential of opioids
agonist + κ
Butorphanol Potent analgesics in opioid naïve patients,
agonist Buprenorphineàmgmt. of opioid addiction (initially use alone, followed by maintenance therapy w/
but precipitate withdrawal in patients w/
κ agonist + µ Buprenorphine and Naloxone to minimize abuse potential)
Nalbuphine Mixed Agonist- physical dependency
antagonist
Antagonists
Used in mild to moderate pain, but are not routine due to ceiling effect
µ partial 1st three may cause psychotomimetic
Buprenorphine agonist + µ effects, but not buprenorphine
Do NOT give to pts taking pure agonist drugsàreduction of analgesia or precipitation of
antagonist
withdrawal
Naloxone Opioid TXT of acute opioid OD
Naltrexone Antagonist Maintenance drug for addicts in TXT programs Longer duration of action ¯craving for alcohol in chronic alcoholics
Most effective cough suppressors Receptors are different than those associated with
Codeine Lower dose than that required for
Antitussives Dextrometorphanàfree of addictive properties & produces opioid action
Dextrometorphan analgesic effects
less constipation than CodeineàOTC medication Caution in pts taking MAO-Is
Prescription opioid (Schedule V)
TXT diarrhea
Diphenoxylate Act on µ or d High doseàCNS effects
Commercial preps contain Atropine to discourage OD
Antimotility receptors Prolonged useàdependence
Agents No analgesic Nonprescription opioid
Loperamide effect Does NOT cross BBB TXT diarrhea
No potential for addiction

Fernanda Ponce pg. 10