Fentanyl

At-a-glance clinical use

• Potent synthetic opioid used for intraoperative analgesia, blunting sympathetic responses, and as an adjunct in anaesthesia and sedation
  • Common settings: induction/maintenance of GA, TIVA adjunct, ICU analgesia/sedation, procedural sedation (with appropriate monitoring), neuraxial/epidural (specialist use)
• Typical IV bolus dosing (adult): 0.5–2 micrograms/kg for analgesia, 2–5 micrograms/kg for intubation response attenuation, higher doses (10–50 micrograms/kg) for cardiac anaesthesia/“high-dose opioid” techniques (context dependent)
  • Titrate to effect, reduce dose in elderly, frail, hypovolaemia, co-administered sedatives/volatile agents
• Onset/offset (IV): onset ~1–2 min, peak ~3–5 min, clinical duration after small bolus ~30–60 min (context sensitive with repeated dosing/infusion)
  • Offset after infusion depends on context-sensitive half-time (increases with duration due to redistribution and tissue uptake)
• Key adverse effects: respiratory depression, bradycardia, chest wall rigidity, nausea/vomiting, pruritus, urinary retention, ileus, tolerance and dependence with prolonged use
  • Histamine release is minimal compared with morphine (less hypotension/bronchospasm from histamine)

Immediate management pearls

• Respiratory depression/apnoea: airway support + ventilation, consider naloxone titration if clinically indicated (beware re-sedation due to shorter naloxone duration)
  • Naloxone typical IV titration: 20–40 micrograms increments every 1–2 min to adequate ventilation (avoid abrupt full reversal in opioid-tolerant patients)
• Chest wall rigidity (often with rapid/high-dose IV, especially with co-administered nitrous/volatile): treat with neuromuscular blockade and ventilation, consider naloxone if appropriate
  • Prevention: slower administration, avoid large rapid boluses, consider small dose muscle relaxant if high-dose technique
• Bradycardia: treat causes, anticholinergic (e.g., glycopyrrolate/atropine) if clinically significant, consider interaction with other vagotonic agents (propofol, remifentanil, beta-blockers)
  • Mechanism: increased vagal tone and reduced sympathetic tone

Classification and chemistry

• Synthetic phenylpiperidine opioid (same broad class as alfentanil, sufentanil, remifentanil)
• Highly lipid soluble, largely unionised at physiological pH (pKa ~8.4) but high lipophilicity drives rapid CNS effect
• Potency: ~100 times morphine (approximate, depends on endpoint and route)

Mechanism of action

• Predominantly μ-opioid receptor agonist (Gi/o-coupled): inhibits adenylate cyclase → ↓cAMP, presynaptic ↓Ca2+ influx, postsynaptic ↑K+ efflux → hyperpolarisation
  • Effects: analgesia (spinal/supraspinal), sedation, respiratory depression (brainstem), cough suppression, reduced GI motility
• Synergistic sedation/respiratory depression with benzodiazepines, propofol, volatile agents, gabapentinoids, alcohol

Pharmacokinetics (PK)

• Absorption/routes: IV (common), IM (less predictable), transdermal patches (chronic pain), buccal/intranasal preparations (breakthrough cancer pain, specialist prescribing)
• Distribution: rapid redistribution from brain to muscle/fat, large volume of distribution, high protein binding (mainly α1-acid glycoprotein)
  • Clinical implication: repeated boluses/infusions accumulate in peripheral compartments → prolonged offset
• Metabolism: hepatic CYP3A4 N-dealkylation to inactive metabolites (e.g., norfentanyl)
  • Drug interactions: CYP3A4 inhibitors (e.g., macrolides, azoles, protease inhibitors, grapefruit) can increase effect, inducers (e.g., carbamazepine, phenytoin, rifampicin) reduce effect
• Elimination: mainly renal excretion of metabolites, clearance reduced in severe hepatic impairment, renal failure has less effect than morphine (no active analgesic metabolites) but sensitivity may still increase
• Context-sensitive half-time: increases with infusion duration (slower offset than remifentanil, generally shorter than morphine for single bolus but can become prolonged with long infusions)

Pharmacodynamics (PD) and organ effects

• CNS: analgesia, sedation, euphoria/dysphoria, miosis (pinpoint pupils) unless severe hypoxia/hypercapnia
• Respiratory: dose-dependent respiratory depression, reduced ventilatory response to CO2 and hypoxia, can cause apnoea, may cause chest wall rigidity
  • Particularly hazardous with co-administered sedatives and in OSA, obesity hypoventilation, COPD, elderly
• Cardiovascular: generally haemodynamically stable, bradycardia common, minimal myocardial depression, minimal histamine release
  • High-dose opioid technique can reduce stress response and catecholamine surge (useful in cardiac surgery)
• GI/GU: nausea/vomiting, reduced gastric motility, constipation/ileus, biliary spasm (less prominent than morphine but possible), urinary retention
• Endocrine/immune: chronic opioids may suppress HPA axis and immune function, acute perioperative relevance usually limited

Indications and practical use

• Intraoperative analgesia and attenuation of laryngoscopy/intubation response, supplement to volatile/TIVA, analgesic component of balanced anaesthesia
• Adjunct in regional/neuraxial techniques (specialist practice): epidural/spinal opioids provide segmental analgesia but carry risk of delayed respiratory depression (less than morphine due to lipophilicity, still clinically important)
  • More rapid onset and shorter duration neuraxially than morphine, more rostral spread risk is lower than hydrophilic opioids but not zero
• ICU: analgesia/sedation adjunct, consider accumulation with prolonged infusion and organ dysfunction, daily sedation holds and analgesia-first strategies

Contraindications and cautions

• Absolute: hypersensitivity (rare), avoid transdermal initiation for acute pain/opioid-naïve patients
• Relative/caution: severe respiratory disease, OSA, raised intracranial pressure (CO2 retention), severe hepatic impairment, elderly/frail, concomitant CNS depressants
• Serotonin toxicity risk: fentanyl has serotonergic properties, caution with SSRIs/SNRIs/MAOIs and other serotonergic drugs (rare but important)
  • Features: agitation, hyperreflexia/clonus, autonomic instability, hyperthermia, management is supportive, stop serotonergic agents, consider cyproheptadine

Adverse effects and management

• Respiratory depression: support ventilation, titrated naloxone if needed, monitor for re-sedation
• Chest wall rigidity: ventilate, give neuromuscular blocker, consider naloxone, prevent with slow administration
• Bradycardia/hypotension: treat with anticholinergic/vasopressors as required, consider depth of anaesthesia and co-drugs
• PONV/pruritus: antiemetics, consider opioid-sparing multimodal analgesia, low-dose naloxone infusion sometimes used in specialist settings for pruritus (balance analgesia)

Comparisons (high-yield)

• Vs morphine: fentanyl is more potent, more lipid soluble, faster onset, shorter duration after single bolus, minimal histamine release, no active metabolites (better in renal failure than morphine)
• Vs alfentanil: fentanyl is more potent and longer acting, alfentanil has faster onset (lower pKa → more unionised at pH 7.4)
• Vs remifentanil: fentanyl has longer offset and accumulation with infusion, remifentanil is ester-metabolised by non-specific plasma/tissue esterases → very short context-sensitive half-time

Test yourself…