Opioid Analgesics
Opioids activate mu, kappa, and delta receptors to produce powerful analgesia. Understanding their pharmacology is essential for effective pain management while minimizing addiction and overdose risk.
## Opioid Receptor Pharmacology
Opioids exert their effects primarily through three G-protein coupled receptor types:
- **Mu (MOR)** -- Mediates analgesia, euphoria, respiratory depression, miosis, and constipation. The principal target of most clinical opioids.
- **Kappa (KOR)** -- Produces analgesia and dysphoria. Targeted by some mixed agonist-antagonists (butorphanol, nalbuphine).
- **Delta (DOR)** -- Modulates analgesia and mood. Less exploited therapeutically.
Activation inhibits adenylyl cyclase, opens potassium channels (hyperpolarization), and closes voltage-gated calcium channels (reduced neurotransmitter release), collectively dampening pain signaling.
## Classification
**Full agonists:** Morphine, hydromorphone, oxycodone, hydrocodone, fentanyl, methadone. Produce dose-dependent analgesia and respiratory depression with no ceiling effect.
**Partial agonist:** Buprenorphine -- binds mu receptors with high affinity but partial intrinsic activity, producing a ceiling effect on respiratory depression. Used for opioid use disorder (OUD) treatment and chronic pain (transdermal patches).
**Mixed agonist-antagonist:** Butorphanol, nalbuphine -- mu antagonist/kappa agonist. Useful but precipitate withdrawal in opioid-dependent patients.
**Weak opioids:** Codeine (prodrug, requires CYP2D6 to morphine), tramadol (also inhibits serotonin/norepinephrine reuptake).
## Clinical Uses
- **Acute pain** -- Post-surgical, trauma, acute MI. Short courses (<3-7 days) with multimodal analgesia.
- **Chronic cancer pain** -- WHO analgesic ladder; long-acting formulations for baseline pain with short-acting for breakthrough.
- **Opioid use disorder** -- Methadone and buprenorphine maintenance reduce mortality, overdose, and criminal activity.
- **Cough suppression** -- Codeine and dextromethorphan (non-opioid analgesic but acts at sigma receptors).
## Tolerance, Dependence, and Addiction
**Tolerance** develops to analgesia, euphoria, and sedation but NOT to constipation or miosis. Mechanisms include receptor desensitization and internalization.
**Physical dependence** manifests as withdrawal syndrome upon cessation: lacrimation, rhinorrhea, diarrhea, muscle cramps, anxiety. Unpleasant but not life-threatening (unlike alcohol/benzodiazepine withdrawal).
**Addiction** (opioid use disorder) involves compulsive use despite harm. Genetic, psychological, and social factors contribute beyond pharmacology alone.
## Overdose Management
Opioid overdose presents with the classic triad: respiratory depression, miosis, and decreased consciousness. Naloxone (Narcan) is a competitive mu-receptor antagonist that reverses overdose rapidly. Key points:
- IV/IM onset: 1-2 minutes. Intranasal: 3-5 minutes.
- Duration shorter than most opioids -- repeat dosing or infusion may be necessary.
- Can precipitate acute withdrawal in dependent individuals.
## Key Takeaways
- Prescribe the lowest effective dose for the shortest duration in acute pain.
- Tolerance does not develop to constipation -- always co-prescribe a bowel regimen.
- Buprenorphine and methadone are life-saving treatments for opioid use disorder, not "replacing one addiction with another."
- Naloxone should be co-prescribed with opioids for patients at overdose risk.