Fentanyl

Fentanyl is a synthetic phenylpiperidine mu-opioid agonist roughly 100 times as potent as morphine by weight. It has rapid onset and short duration after a single intravenous dose, which makes it the main intraoperative and procedural opioid, and a transdermal route for stable chronic pain in opioid-tolerant patients.

Class. Full mu-opioid agonist (synthetic).

Mechanism. Mu receptor agonism with high lipid solubility, giving rapid central nervous system entry. Brain-plasma equilibration takes about 6 minutes.

Pharmacokinetics. Intravenous onset 1 to 2 minutes, peak about 5 minutes, duration 30 to 60 minutes after small boluses. Redistribution ends the effect, so repeated doses or prolonged infusions saturate tissue stores and the context-sensitive half-time rises (from about 5 minutes after short infusions to 200 minutes or more after infusions over 8 hours). Terminal half-life 3 to 7 hours. Protein binding about 80 to 85%. Transdermal patches reach steady state at 12 to 24 hours, with a half-life of 17 hours after removal.

Metabolism. Hepatic, mainly CYP3A4, to inactive norfentanyl. Renal clearance of metabolites is not clinically significant.

Indications are intraoperative analgesia, adjunct to induction of anaesthesia, procedural analgesia, analgesia and sedation in intensive care, epidural and spinal adjunct, chronic cancer or severe pain in opioid-tolerant patients (patch), and breakthrough cancer pain (transmucosal products).

Anaesthesia and procedures (adults)

• Analgesia adjunct: 25 to 100 micrograms (0.5 to 1 microgram/kg) intravenously, repeated every 10 to 30 minutes as needed. Reduce in older or frail patients.
• Induction adjunct: 1 to 3 micrograms/kg before laryngoscopy or intubation to blunt the pressor response.
• Maintenance infusion: 0.5 to 5 micrograms/kg/hour.
• High-dose cardiac anaesthesia: 20 to 50 micrograms/kg, with ventilatory support.
• Spinal adjunct: 10 to 25 micrograms intrathecally with local anaesthetic. Epidural: 2 micrograms/mL mixed with bupivacaine 0.1% to 0.125% in infusion, or 50 to 100 micrograms bolus.

Intensive care. Infusion 25 to 200 micrograms/hour (0.7 to 10 micrograms/kg/hour), titrated to pain and sedation targets.

Transdermal (opioid-tolerant only)

• Opioid-tolerant means at least 60 mg oral morphine daily, 30 mg oral oxycodone daily or 8 mg oral hydromorphone daily (or an equivalent dose of another opioid) for 1 week or more.
• Patches 12, 25, 50, 75 and 100 micrograms/hour, replaced every 72 hours. A 12 micrograms/hour patch is roughly equivalent to 30 mg oral morphine daily (25 micrograms/hour to 60 mg).
• Do not increase the dose sooner than 3 days after the first patch, and after that no more often than every 6 days. Provide immediate-release opioid for breakthrough pain.
• Use only when opioid requirement is stable; not for acute pain, postoperative pain or opioid-naive patients.

Children. Intravenous 0.5 to 2 micrograms/kg for analgesia. Intranasal 1.5 micrograms/kg (maximum 100 micrograms each dose) for procedural pain, repeated once after 10 to 15 minutes if needed. Neonates: 1 to 4 micrograms/kg with ventilatory support.

Contraindications. Respiratory depression without ventilatory support; hypersensitivity; transdermal use in opioid-naive patients or for acute, intermittent or postoperative pain; monoamine oxidase inhibitor use within 14 days; severe untreated respiratory disease in unmonitored settings.

Boxed-warning-level risks. Life-threatening respiratory depression; accidental exposure to patches (especially children); addiction, abuse and misuse; CYP3A4 interactions; concurrent benzodiazepines or other central nervous system depressants; neonatal opioid withdrawal syndrome; heat exposure raising absorption from patches.

Adverse effects. Common: nausea, vomiting, constipation, sedation, pruritus, dizziness. Serious: respiratory depression, apnoea, bradycardia, hypotension, muscle rigidity (chest wall rigidity with rapid bolus), serotonin syndrome, delayed respiratory depression after epidural or intrathecal use.

Interactions. CYP3A4 inhibitors (ritonavir, clarithromycin, itraconazole, ketoconazole, diltiazem, verapamil) increase exposure markedly. CYP3A4 inducers (rifampicin, carbamazepine, phenytoin) reduce it; stopping an inducer can cause toxicity. Benzodiazepines and other depressants add sedation. Serotonergic drugs (SSRIs, linezolid, monoamine oxidase inhibitors) risk serotonin syndrome. Beta blockers add bradycardia.

Common prescribing errors. Prescribing a patch to an opioid-naive patient; assuming micrograms of different transmucosal products are interchangeable; confusing micrograms with milligrams; applying heat or fever without adjusting; failing to cover the first 12 to 24 hours after the first patch; unrecognised patch on the skin.

Special groups

• Pregnancy: used for epidural and spinal labour analgesia; neonatal respiratory depression if given near delivery; avoid prolonged use.
• Breastfeeding: single doses and labour epidural doses are acceptable.
• Older adults: reduce bolus doses by 30 to 50%; start at the lowest patch strength.
• Kidney impairment: no adjustment of dose for bolus use; useful when morphine accumulates.
• Liver impairment: reduce infusion rate and bolus size; prolonged clearance in severe disease.
• Regional: confirm availability and storage of controlled-drug stock, and the exact dose units on ampoules.

Formulations. Injection 50 micrograms/mL, transdermal patches (12 to 100 micrograms/hour), transmucosal lozenges, buccal tablets and sprays for breakthrough pain (doses are not interchangeable between products).

Administration. Give intravenous boluses over 1 to 2 minutes (slowly to avoid chest wall rigidity). Apply patches to clean, dry, non-hairy skin on the upper torso or arm, rotate sites, and fold used patches adhesive side in for disposal. Do not cut patches. Avoid external heat on the patch.

Baseline. Respiratory rate, oxygen saturation, sedation score, liver function, current opioid doses, interacting drugs, and for patches confirm opioid tolerance.

Monitoring. Respiratory rate, sedation and oxygen saturation continuously during and after parenteral doses, with capnography where available. For patches: pain control, sedation and respiratory rate for at least 24 to 48 hours after each initiation or increase, and after any change in interacting drugs or fever. Bowel function.

Therapeutic drug monitoring. Not used.

Dose reduction and stopping thresholds. Reduce the dose for respiratory rate under 10 breaths/minute, excessive sedation or hypotension. Remove a patch immediately for respiratory depression or severe sedation; effects continue for 17 hours or longer after removal.

Referral and escalation. Respiratory depression from a patch needs airway support, naloxone (repeated or by infusion because of the long effect), and observation for at least 24 hours after removal. Chest wall rigidity needs ventilatory support and, if refractory, naloxone or a neuromuscular blocker.