6.6 Opioids & Analgesics
Opioids are potent analgesics acting on opioid receptors in the CNS and periphery. They remain the gold standard for severe acute pain but carry significant risks of tolerance, dependence, and overdose.
Opioid Receptors
μ (Mu) Receptor
Primary target for most analgesics
Effects: Analgesia, euphoria, respiratory depression, miosis, constipation
Gi/o-coupled → ↓ cAMP, ↓ Ca²⁺ influx, ↑ K⁺ efflux → neuronal hyperpolarization
κ (Kappa) Receptor
Analgesia, sedation, dysphoria
Spinal analgesia without respiratory depression
Example: Pentazocine (mixed agonist-antagonist)
δ (Delta) Receptor
Analgesia, possible role in mood/reward
Less clinically targeted
Endogenous Ligands
Endorphins: μ, δ agonists (stress-induced analgesia)
Enkephalins: δ > μ agonists
Dynorphins: κ agonists
Strong Opioid Agonists
Morphine
Prototype μ agonist, from opium poppy
IV/IM/PO: severe pain, MI, pulmonary edema (↓ preload)
Metabolism: glucuronidation → morphine-6-glucuronide (active, more potent)
Histamine release → itching, hypotension
Fentanyl
100x more potent than morphine
Rapid onset, short duration (lipophilic, rapid CNS penetration)
Uses: anesthesia, transdermal patches (chronic pain), IV for breakthrough pain
High abuse potential, major cause of overdose deaths
Methadone
Long half-life (24-36h)—once daily dosing
Also NMDA antagonist → may prevent tolerance
Opioid maintenance therapy (substitution for heroin), chronic pain
Risk: QT prolongation, unpredictable pharmacokinetics
Hydromorphone, Oxycodone, Hydrocodone
Semisynthetic opioids, commonly prescribed
Oxycodone: often combined with acetaminophen (Percocet) or alone (OxyContin)
Hydrocodone: combined with acetaminophen (Vicodin)
Moderate Opioid Agonists & Prodrugs
Codeine
Weak μ agonist, prodrug → morphine (via CYP2D6)
~10% metabolism to morphine (variable due to genetic polymorphism)
Uses: mild-moderate pain, cough suppression
Poor/ultra-rapid metabolizers → ineffective or toxic
Tramadol
Weak μ agonist + SNRI activity (dual mechanism)
Lower abuse potential than traditional opioids
Risk: Seizures (especially high dose or with SSRIs), serotonin syndrome
Mixed Agonist-Antagonists & Partial Agonists
Buprenorphine
Partial μ agonist, κ antagonist
High affinity, slow dissociation—long duration
Ceiling effect for respiratory depression (safer)
Uses: opioid maintenance therapy (Suboxone with naloxone), chronic pain
Nalbuphine, Butorphanol, Pentazocine
κ agonists, μ antagonists/partial agonists
Analgesia with less respiratory depression
Can precipitate withdrawal in opioid-dependent patients
Adverse Effects of Opioids
Respiratory Depression
↓ Responsiveness to CO₂ in medullary respiratory centers
Most dangerous effect, cause of overdose death
Exacerbated by benzodiazepines, alcohol
Constipation
μ receptors in GI → ↓ motility, ↑ tone
NO tolerance develops—manage prophylactically
Peripherally-acting antagonists: methylnaltrexone, naloxegol
Miosis
Pupillary constriction (Edinger-Westphal nucleus)
Pinpoint pupils = classic overdose sign
Nausea/Vomiting
Stimulation of chemoreceptor trigger zone (area postrema)
Vestibular sensitization
Tolerance develops with continued use
Tolerance, Dependence, & Addiction
Tolerance
↓ Response with repeated exposure—requires ↑ dose for same effect
Mechanisms: receptor downregulation, desensitization, cellular adaptation
Develops to analgesia, euphoria, respiratory depression; NOT to miosis or constipation
Physical Dependence
Adaptive state—withdrawal syndrome upon cessation or antagonist administration
Withdrawal symptoms: Anxiety, dysphoria, mydriasis, lacrimation, rhinorrhea, yawning, piloerection, muscle aches, diarrhea
Onset: 6-12h (short-acting), 24-48h (methadone)
Addiction (Opioid Use Disorder)
Compulsive drug-seeking despite harm—psychological dependence
Mesolimbic dopamine pathway → reward, reinforcement
Treatment: MAT (medication-assisted treatment) with methadone or buprenorphine + counseling
Opioid Antagonists
Naloxone (Narcan)
Competitive μ, κ, δ antagonist
Rapid reversal of opioid overdose (respiratory depression)
Short t½ (~1h)—may need repeat dosing if long-acting opioid
Precipitates withdrawal in dependent patients
Available as nasal spray, auto-injector for bystander use
Naltrexone
Long-acting oral or IM (monthly depot) antagonist
Relapse prevention in opioid use disorder (after detoxification)
Also approved for alcohol use disorder
Blocks effects of opioids—prevents euphoria