OPIOID RECEPTORS

• ·MU (μ): analgesia, respiratory depression, euphoria, miosis, constipation, dependence. Targeted by most clinical opioids.
• ·KAPPA (κ): spinal analgesia, dysphoria, diuresis. Targeted by butorphanol, nalbuphine.
• ·DELTA (δ): mood + spinal analgesia. Limited clinical targeting.
• ·All are Gi-coupled → ↑K+ conductance + ↓Ca2+ entry → membrane hyperpolarization + reduced neurotransmitter release.
• ·Mu agonism produces both the analgesia AND the respiratory depression — receptor-mediated, not separable.

FENTANYL — workhorse

• ·Mu agonist, ~100× potency of morphine. Onset 1-2 min IV, peak 3-5 min, duration 30-60 min (single dose).
• ·Dose: bolus 1-3 mcg/kg for analgesia, 5-10 mcg/kg to blunt laryngoscopy in HTN/CAD.
• ·Infusion: 0.5-2 mcg/kg/hr maintenance, 0.025-0.05 mcg/kg/min for TIVA.
• ·Highly lipid-soluble → fast brain penetration + redistribution. Accumulates with long infusions (context-sensitive half-time rises).
• ·Pediatric IM: 1-2 mcg/kg if no IV.

REMIFENTANIL — uniquely short-acting

• ·Mu agonist, esterase-metabolized (organ-independent).
• ·FLAT context-sensitive half-time ~3 min regardless of infusion duration — unique among opioids.
• ·TIVA: 0.05-0.3 mcg/kg/min. Bolus 0.5-1 mcg/kg (caution: chest wall rigidity at high bolus).
• ·Use: cardiac surgery, neuro, ENT, any case needing rapid wake-up.
• ·Limitation: no residual analgesia — bridge with longer-acting opioid before stopping (acute hyperalgesia + tolerance possible after long infusions).

MORPHINE

• ·Reference opioid. Mu > kappa.
• ·Dose: 0.05-0.1 mg/kg IV (typical adult 2-5 mg q4h). Oral 30 mg.
• ·Onset 15-30 min IV, peak 60 min, duration 3-4 hr.
• ·Active metabolites: M6G (more potent than morphine, accumulates in renal failure → resp depression), M3G (neurotoxic — myoclonus).
• ·AVOID in ESRD. Caution histamine release (hypotension, bronchospasm — avoid in asthma + cardiac fragility).
• ·Intrathecal morphine 100-300 mcg for postop analgesia 18-24 hr; delayed resp depression peak 6-12 hr — monitor.

HYDROMORPHONE

• ·Mu agonist, ~5× potency of morphine. No active metabolites — safer than morphine in renal failure.
• ·Dose: 0.2-0.5 mg IV q3-4 hr. Oral 4-8 mg.
• ·Less histamine release than morphine.
• ·Workhorse for postop pain — less itching + nausea than morphine in many patients.

OXYCODONE + HYDROCODONE — oral

• ·OXYCODONE: oral mu agonist, ~1.5× potency of oral morphine. 5-10 mg q4-6h. Standard PO breakthrough.
• ·HYDROCODONE: oral mu agonist, ~equipotent with morphine. Usually combined with APAP (Norco, Vicodin) or ibuprofen — watch acetaminophen ceiling.
• ·Both CYP2D6 substrates — ultra-rapid metabolizers get more effect + risk; poor metabolizers get inadequate analgesia.

METHADONE — long half-life + NMDA activity

• ·Mu agonist + NMDA antagonist + serotonin reuptake inhibitor.
• ·Half-life 15-60 hr (variable) — accumulates over days. Steady state takes 5-7 days.
• ·Periop single dose 0.1-0.3 mg/kg at induction provides 24-48 hr analgesia.
• ·QT prolongation — ECG before chronic dosing; avoid concurrent QT-prolonging agents.
• ·Drug-drug interactions extensive (CYP3A4, CYP2B6) — methadone clearance affected by rifampin, ketoconazole, many others.
• ·Maintenance dosing only by certified providers (Schedule II + specific licensing).

BUPRENORPHINE — partial agonist

• ·Partial mu agonist + kappa antagonist. Ceiling effect on respiratory depression (safer in overdose).
• ·High mu affinity blocks effect of full agonists — significant periop implications.
• ·ASRA/ASAM 2021: continue periop in most cases + use higher-dose full-mu for breakthrough. Older 'hold 72 hr' approach falling out of favor.
• ·Formulations: sublingual (Suboxone — with naloxone, addiction Tx), transdermal (Butrans — chronic pain), buccal (Belbuca).

NALBUPHINE + BUTORPHANOL — agonist-antagonists

• ·Kappa agonist + mu antagonist (or partial). Ceiling on analgesia + resp depression.
• ·Nalbuphine 5-10 mg IV — opioid-induced pruritus reversal without losing analgesia from intrathecal morphine.
• ·Butorphanol 1-2 mg IV — labor analgesia, headache, some chronic pain.
• ·Will REVERSE mu agonism + precipitate withdrawal in opioid-dependent patients.

TRAMADOL + TAPENTADOL

• ·TRAMADOL: weak mu + SNRI. CYP2D6-activated (same ultra-rapid metabolizer concern as codeine). FDA contraindicated in children <12, post-tonsillectomy <18, breastfeeding. Lowers seizure threshold.
• ·TAPENTADOL: mu + NE reuptake inhibitor. Less serotonin effect than tramadol → less serotonin-syndrome risk.
• ·Both: less constipation than morphine. Both: still controlled substances + still cause respiratory depression.

EQUIANALGESIC TABLE (parenteral, ~equivalent to 10 mg IV morphine)

• ·Morphine 10 mg IV (reference)
• ·Hydromorphone 1.5-2 mg IV
• ·Fentanyl 100 mcg IV
• ·Oxycodone 10-15 mg PO
• ·Hydrocodone 10-15 mg PO
• ·Tramadol 100-150 mg PO
• ·Methadone (variable — START LOW, escalate slow due to accumulation)
• ·When ROTATING opioids: reduce calculated equianalgesic dose by 25-50% for incomplete cross-tolerance.

NALOXONE REVERSAL

• ·Mu antagonist. Bolus 0.04-0.1 mg IV (titrated — avoid abrupt full reversal in chronic users → withdrawal + pain crisis).
• ·Higher dose 0.4-2 mg IV/IM for full overdose (out-of-hospital, ED).
• ·Duration 30-60 min — SHORTER than most opioids → patients often re-sedate. Plan: infusion 4-8 mcg/kg/hr, observation 4-8 hr minimum, longer for long-acting opioids.
• ·Intranasal Narcan: 4 mg per spray — Good Samaritan rescue + community kits.
• ·Don't underdose in true overdose — death > withdrawal.

OPIOID-INDUCED HYPERALGESIA + TOLERANCE

• ·Long-term opioid use can paradoxically increase pain sensitivity (OIH) via NMDA-mediated central sensitization.
• ·Tolerance: same effect requires increasing dose; usually dose-dependent + reversible.
• ·OIH: dose escalation makes pain WORSE.
• ·Management: opioid rotation (especially to methadone — NMDA antagonism), ketamine adjunct, multimodal opioid-sparing, taper if possible.
• ·Acute periop pain in chronic opioid user: continue baseline + add multimodal + regional; do not try to detox during surgical episode.

SIDE EFFECTS + MITIGATION

• ·Respiratory depression: dose-dependent. Monitor RR + SpO₂ + capnography. Naloxone reversal.
• ·Constipation: tolerance does NOT develop. Prophylactic stool softener + stimulant laxative; methylnaltrexone for refractory.
• ·Nausea/vomiting: 30-50% incidence. Anti-emetics (ondansetron, scopolamine, droperidol, dex).
• ·Pruritus: histamine-mediated (morphine, codeine) or central mu effect. Nalbuphine 2.5-5 mg IV reverses pruritus from intrathecal morphine.
• ·Urinary retention: spinal/epidural morphine especially. May need straight cath.
• ·Sedation: dose-dependent; coadministered benzodiazepines compound.
• ·Sphincter of Oddi spasm (biliary): theoretical concern, clinical relevance modest. Some prefer meperidine in pancreatitis (avoided in modern practice for other reasons — normeperidine toxicity).

Suggested reading: Stoelting Pharmacology 6e Ch 3 · Miller's Anesthesia 9e Ch 23 · ASRA Multimodal Analgesia 2018 · FDA Codeine + Tramadol Pediatric Boxed Warning 2017