Opioids in Anaesthetic Practice

Introduction

1. Opioid Receptors (5 marks)

Receptor Classification

Signal Transduction

• Inhibition of adenylate cyclase → reduced intracellular cAMP
• Inhibition of voltage-dependent Ca2+ channels → reduced neurotransmitter release
• Activation of inwardly rectifying K+ channels → membrane hyperpolarisation
• Net effect: reduced neuronal excitability and inhibition of pain signal transmission

Endogenous Opioid Peptides

1. Preproenkephalin - gives rise to methionine- and leucine-enkephalin (delta > mu)
2. Preprodynorphin - gives rise to dynorphins (kappa-preferring)
3. Proopiomelanocortin (POMC) - gives rise to β-endorphin (mu-preferring), ACTH, and MSH

2. Individual Opioid Agents and Pharmacokinetics (8 marks)

Morphine

• Prototype mu-agonist, naturally occurring phenanthrene alkaloid
• Bioavailability: ~30% oral (extensive first-pass), ~100% IM/IV
• Protein binding: ~35%, partially to albumin
• Metabolism: Hepatic glucuronidation (primarily UGT2B7) to:
  • Morphine-6-glucuronide (M6G): Active full mu-agonist with analgesic and respiratory depressant properties - accumulates in renal failure, can cause loss of consciousness and severe respiratory depression in compromised renal function (Barash, p. 1548)
  • Morphine-3-glucuronide (M3G): Inactive at opioid receptors; accumulation implicated in opioid-induced hyperalgesia and neurological excitatory phenomena
• Half-life: ~2-4 hours; M6G has a longer half-life
• Special concern in renal failure: M6G accumulation prolongs respiratory depression; use with caution (Morgan & Mikhail, p. 1270)
• Histamine release: Due to direct mast cell degranulation - can cause flushing, hypotension, bronchospasm; less common with slow IV administration

Fentanyl

• Synthetic phenylpiperidine; ~100x more potent than morphine
• Highly lipophilic - rapid onset (1-2 min IV), rapid redistribution
• Protein binding: ~80-85% (α1-acid glycoprotein)
• Metabolism: CYP3A4 hepatic metabolism → inactive norfentanyl; high hepatic extraction ratio (~1.5 L/min approaching liver blood flow)
• Pharmacokinetics: Context-sensitive half-time increases significantly with prolonged infusion due to redistribution from peripheral compartments (fat, muscle)
• Doses in practice: Induction co-induction: 1-5 mcg/kg; infusion: 0.5-5 mcg/kg/hr; neuraxial use
• Reduces the MAC of volatile agents (e.g., 1.67 ng/mL plasma concentration reduces isoflurane MAC by ~50%), with a ceiling effect on MAC reduction - cannot be used as a sole anaesthetic (Miller's Anesthesia, p. 2718)

Remifentanil

• Ultra-short-acting synthetic opioid; unique ester side chain
• Metabolism: Plasma and tissue non-specific esterases (within erythrocytes) - NOT hepatic, NOT renal
• Context-sensitive half-time: ~2 minutes regardless of infusion duration - the most rapidly acting opioid available
• Clearance: 3-5 L/min, exceeding hepatic blood flow, confirming extrahepatic clearance
• Plasma level falls by 50% within ~40 seconds after stopping infusion
• Renal/hepatic failure: Pharmacokinetics unaffected
• Administered as continuous infusion (typically 0.05-0.5 mcg/kg/min TCI or weight-based)
• Concern: Profound analgesia intraoperatively followed by abrupt offset necessitates pre-emptive postoperative analgesia; associated with opioid-induced hyperalgesia at higher infusion rates (Barash, p. 1548)

Alfentanil

• Intermediate-acting phenylpiperidine
• Metabolism: CYP3A4 and CYP3A5 - polymorphic expression accounts for great interindividual variability in clearance
• Smaller volume of distribution than fentanyl → faster onset of effect site equilibration
• Used for short procedures, co-induction, and laryngoscopy attenuation

Sufentanil

• ~5-10x more potent than fentanyl
• High hepatic extraction ratio (clearance ~0.9 L/min)
• Greater mu-receptor selectivity
• Used in cardiac anaesthesia and high-dose opioid techniques; neuraxial use

Morphine Alternatives: Hydromorphone, Oxycodone, Codeine

• Hydromorphone: 5-7x more potent than morphine; active metabolite hydromorphone-3-glucuronide can cause neuroexcitation; shorter duration
• Codeine: Prodrug requiring CYP2D6 conversion to morphine; poor analgesic in slow metabolisers (~7-10% Caucasians); dangerous in ultra-rapid metabolisers (neonatal deaths reported)
• Tramadol: Dual mechanism - weak mu-agonist + serotonin-norepinephrine reuptake inhibition; lowers seizure threshold; risk of serotonin syndrome

Methadone

• Long-acting synthetic opioid; mu-agonist + NMDA receptor antagonism
• Bioavailability: 60-95% oral; high lipophilicity
• Metabolism: CYP2B6 (pharmacogenetically variable)
• Long and unpredictable duration of action; associated with QTc prolongation (torsades de pointes risk at doses >100mg/day)
• Useful perioperatively in opioid-dependent patients (Barash, p. 1548)

Buprenorphine

• Partial mu-agonist / kappa-antagonist - ceiling effect on respiratory depression
• Very high receptor affinity - difficult to reverse with naloxone (higher doses may be needed)
• Long duration of action (~24-72 hours)
• Used in opioid dependence (Suboxone when combined with naloxone) and chronic pain

Mixed Agonist-Antagonists (Pentazocine, Nalbuphine, Butorphanol)

• Kappa-agonists / mu-antagonists or partial agonists
• Ceiling effect on analgesia and respiratory depression
• May precipitate withdrawal in opioid-dependent patients
• Pentazocine: kappa activation causes dysphoria and psychotomimetic effects; increased cardiovascular work (unlike typical mu-agonists)

3. Pharmacological Effects by System (8 marks)

Central Nervous System

• Analgesia: Supraspinal (PAG, rostroventral medulla), spinal (dorsal horn substantia gelatinosa), and peripheral (inflammatory states - immune cell-mediated opioid peptide release)
• Sedation and altered consciousness: Opioids reduce consciousness through decreased cortical acetylcholine release (morphine injection to substantia innominata reduces prefrontal cortical acetylcholine). Not complete anaesthetics - MAC reduction is incomplete and demonstrates a ceiling effect
• Euphoria/dysphoria: Mu-activation → euphoria (mesolimbic pathway); kappa-activation → dysphoria
• Miosis: Stimulation of Edinger-Westphal nucleus (mu and kappa); does not habituate with tolerance; useful clinical sign of opioid effect
• Nausea and vomiting: Direct stimulation of the chemoreceptor trigger zone (area postrema); vestibular sensitisation contributes - exacerbated by ambulation
• Sleep disturbance: Opioids reduce deep (slow-wave) sleep, increase stage 2 sleep, inhibit REM sleep; associated with sleep-disordered breathing (central sleep apnea prevalence ~24% with chronic opioid therapy) (Miller's Anesthesia, p. 2719)

Respiratory System

• Respiratory depression: Primary concern; mediated via mu-receptors in the brainstem (pre-Botzinger complex and parabrachial nucleus)
  • Opioids blunt the ventilatory response to hypercapnia and hypoxia
  • Reduced respiratory rate is the dominant effect; tidal volume also decreased
  • The CO2 response curve shifts right (increased PaCO2 threshold) and becomes less steep
  • High-dose rapid injection (e.g., remifentanil bolus) can cause apnoea without time for CO2 compensation (Barash, p. 1567)
• Chest wall rigidity ("wooden chest syndrome"): High doses of potent synthetic opioids (fentanyl, remifentanil) cause thoracoabdominal muscle rigidity, impeding ventilation; managed with naloxone, succinylcholine, or neuromuscular blockade
• Upper airway effects: Opioids suppress brainstem neurons maintaining upper airway tone and depress arousal reflexes → increased obstructive apnoeas perioperatively
• Antitussive effect: Suppression of cough reflex at the medullary cough centre (codeine used clinically for this)

Cardiovascular System

• Generally minimal direct cardiac effects at clinical doses in normovolaemic patients
• Bradycardia: via central vagal stimulation (morphine, fentanyl)
• Histamine-mediated vasodilation and hypotension: Morphine (direct mast cell degranulation); minimal with fentanyl/remifentanil
• High-dose opioid anaesthesia (e.g., 50-100 mcg/kg fentanyl): haemodynamic stability maintained - basis for cardiac anaesthesia; however, still not sufficient as sole agent
• Methadone: QTc prolongation - risk of torsades de pointes

Gastrointestinal System

• Decreased GI motility: Opioids act on mu and delta receptors in the enteric nervous system and spinal cord → reduced peristalsis, delayed gastric emptying, decreased bowel sounds → opioid-induced constipation (does not habituate)
• Sphincter of Oddi spasm: Biliary colic can be worsened; morphine more than fentanyl
• Nausea/vomiting (see CNS above)
• Peripherally acting mu-receptor antagonists (methylnaltrexone, naloxegol): treat opioid-induced constipation without reversing central analgesia

Urinary System

• Increased urinary sphincter tone → urinary retention (especially with neuraxial opioids)
• Reduced detrusor muscle contraction

Endocrine / Immune Effects

• Suppression of hypothalamic-pituitary axis: reduced LH, FSH, testosterone, estrogen with chronic use
• Immunosuppressive effects (especially mu-receptor mediated): reduced NK cell activity, impaired lymphocyte function - concern in chronic users and cancer patients

4. Opioid Tolerance and Opioid-Induced Hyperalgesia (3 marks)

Tolerance

• Defined as the need for increasing doses to achieve the same analgesic effect
• Mechanisms: receptor internalisation and downregulation, G-protein uncoupling, upregulation of cAMP pathway (adenylyl cyclase superactivation as counterregulatory response)
• A118G polymorphism (most common SNP of the mu-opioid receptor gene) - asparagine to aspartate substitution at position 40 - associated with higher opioid requirements; meta-analysis of >4600 patients showed carriers had significantly higher analgesic requirements (Miller's Anesthesia, p. 2681-2682)

Opioid-Induced Hyperalgesia (OIH)

• Paradoxical increase in pain sensitivity with continued opioid use
• Distinct from tolerance - patients become more sensitive to nociceptive stimuli, not just less responsive to opioids
• Mechanisms: NMDA receptor sensitisation, spinal dynorphin upregulation, activation of descending pain facilitatory pathways
• Clinically seen with remifentanil infusions (especially >0.1 mcg/kg/min); may be attenuated with NMDA antagonists (ketamine, methadone) (Barash, p. 1536)

5. Opioid Antagonists and Reversal (3 marks)

Naloxone

• Pure competitive mu (and to lesser extent kappa, delta) antagonist
• Dose: 40-400 mcg IV (titrated); paediatric 10 mcg/kg
• Duration: 30-90 minutes - shorter than most opioids → re-narcotisation is a risk; may require repeat dosing or infusion
• Onset: ~1-2 minutes IV
• Caution: Precipitates acute withdrawal in opioid-dependent patients; may cause pulmonary oedema, hypertension, tachycardia, and cardiovascular collapse through sympathetic surge - use smallest effective dose to restore ventilation without fully reversing analgesia

Naltrexone

• Oral long-acting opioid antagonist; used in opioid dependence treatment and alcohol use disorder
• High receptor affinity; duration ~24 hours

Methylnaltrexone / Naloxegol / Alvimopan

• Peripherally restricted (do not cross the blood-brain barrier)
• Reverse peripheral opioid effects (constipation, urinary retention) without reversing central analgesia

6. Opioids in Special Situations (3 marks)

Renal Failure

• Morphine: Avoid or use with extreme caution - M6G accumulates and causes prolonged respiratory depression and loss of consciousness
• Meperidine (pethidine): Avoid - normeperidine accumulation causes seizures
• Fentanyl, alfentanil, sufentanil: Preferred; no significant active metabolite accumulation
• Remifentanil: Ideal; esterase metabolism unaffected by renal function (Morgan & Mikhail, p. 1270)

Hepatic Failure

• Morphine clearance reduced; accumulation likely
• Fentanyl and sufentanil: high hepatic extraction ratio - clearance may be reduced in severe liver disease
• Remifentanil: extrahepatic metabolism - unaffected by hepatic failure

Opioid-Dependent Patients and the Opioid Epidemic

• Patients on long-term opioids have significantly higher intraoperative requirements
• Pre-emptive multimodal analgesia with regional techniques, ketamine, NSAIDs, and gabapentinoids is essential
• Abrupt opioid cessation perioperatively risks acute withdrawal; continue or convert baseline doses
• Buprenorphine: partially agonises and blocks mu-receptors; if discontinued pre-operatively, patients lose tolerance protection; if continued, higher opioid doses needed intraoperatively

Obstetrics

• Morphine and pethidine cross the placenta → neonatal respiratory depression
• Fentanyl used intrathecally (typically 15-25 mcg) for spinal analgesia; neuraxial opioids preferred as they minimise systemic transfer
• Remifentanil patient-controlled analgesia used in labour as alternative to epidural

Summary Table: Comparative Pharmacokinetics of Anaesthetic Opioids

Conclusion

• Miller's Anesthesia, 10th Edition (Elsevier, 2023) - Chapters 22 & 35
• Barash, Cullen & Stoelting's Clinical Anesthesia, 9th Edition - Chapter 20
• Morgan & Mikhail's Clinical Anesthesiology, 7th Edition - Chapter 11
• Goodman & Gilman's Pharmacological Basis of Therapeutics - Chapter 23