Neurology

Opioids - Mechanism & Uses song

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Opioids - Mechanism & Uses

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Opioids act on Gi-coupled mu, kappa, and delta receptors, decreasing cAMP, hyperpolarizing neurons via increased K+ efflux, and inhibiting Ca2+ influx to reduce neurotransmitter release and pain signaling.
Mu receptor activation is responsible for analgesia, euphoria, respiratory depression, decreased GI motility, and miosis — the classic pentad of opioid toxicity includes pinpoint pupils, respiratory depression, and altered consciousness.
Morphine is the prototype opioid; it undergoes hepatic glucuronidation to morphine-6-glucuronide (active, more potent) and morphine-3-glucuronide (inactive), requiring dose reduction in renal failure to prevent toxic accumulation.
Fentanyl is 100x more potent than morphine, highly lipophilic, and available transdermally (patch), intrathecally, and IV — commonly used in procedural sedation and chronic cancer pain.
Meperidine (pethidine) is avoided in renal failure and MAOi users because its metabolite normeperidine causes seizures, and combined use with MAOis risks serotonin syndrome.
Methadone is used for opioid use disorder maintenance and chronic pain; it has a long, unpredictable half-life and blocks NMDA receptors in addition to mu receptor agonism, but prolongs the QTc interval.
Tramadol is a weak mu agonist that also inhibits serotonin and norepinephrine reuptake; it lowers the seizure threshold and is contraindicated with MAOis due to serotonin syndrome risk.
Naloxone is a competitive opioid antagonist used to reverse opioid toxicity; its short half-life (30–90 min) often requires repeat dosing or infusion, especially with long-acting opioids like methadone.
Constipation is the one opioid side effect that does not develop tolerance; peripheral mu receptor antagonists methylnaltrexone and naloxegol treat opioid-induced constipation without reversing central analgesia.
Codeine and hydrocodone are prodrugs requiring CYP2D6 conversion to active morphine and hydromorphone respectively — ultra-rapid metabolizers risk toxicity while poor metabolizers receive no analgesic benefit.