Alfentanil

Alfentanil is a short-acting synthetic mu opioid agonist with a faster onset and shorter duration than fentanyl. About 90% is un-ionised at physiological pH, so it crosses into the brain very rapidly, which makes it useful for covering brief, intense stimuli such as intubation and short painful procedures. It is metabolised by CYP3A4, so interacting drugs and liver disease can prolong its effect greatly. It causes respiratory depression, bradycardia and muscle rigidity.

Class. Opioid analgesic (phenylpiperidine, mu receptor agonist).

Mechanism. Agonist at mu opioid receptors in the brain and spinal cord. It is about one fifth to one tenth as potent as fentanyl.

Pharmacokinetics. Intravenous onset 1 to 2 minutes; peak effect about 1.5 minutes; duration 10 to 15 minutes after a single bolus. Protein binding about 92%. Small volume of distribution (0.4 to 1 L/kg). Clearance 3 to 8 mL/kg/minute. Elimination half-life about 90 minutes, prolonged in liver disease, older adults, neonates and with CYP3A4 inhibitors. Hepatic metabolism by CYP3A4 to inactive metabolites, excreted in urine. Context-sensitive half-time rises with infusion duration but is shorter than that of fentanyl.

Indications are analgesia for short procedures, blunting the response to laryngoscopy and intubation, supplementation of general anaesthesia, and analgesia in ventilated intensive care patients.

Adults

• Short procedures in spontaneously breathing patients: 5 to 15 micrograms/kg intravenously, with monitoring and oxygen.
• Induction with assisted ventilation: 20 to 50 micrograms/kg intravenously, with a hypnotic and a muscle relaxant.
• Blunting the pressor response to intubation: 10 to 30 micrograms/kg intravenously 1 to 2 minutes before laryngoscopy.
• Maintenance: boluses of 5 to 15 micrograms/kg as needed, or infusion 0.5 to 1 microgram/kg/minute, reduced as the procedure ends.
• Stop the infusion 15 to 30 minutes before the planned end of surgery.
• Obesity: dose by ideal body weight.
• Older adults, debilitated patients and liver impairment: reduce doses by 30 to 50% and extend intervals.
• No fixed maximum dose; titrate to effect with airway support.

Children

• Induction and procedures: 10 to 20 micrograms/kg intravenously.
• Maintenance: boluses of 5 to 10 micrograms/kg or infusion 0.5 to 1 microgram/kg/minute.
• Neonates and young infants: reduced clearance; reduce doses by 50% and monitor.

Contraindications. Hypersensitivity to alfentanil or other opioids; acute respiratory depression or obstructive airway disease without airway control; use with strong CYP3A4 inhibitors unless doses are reduced and ventilation is available; unmonitored use.

Boxed-warning-level risks. Respiratory depression and apnoea (including delayed recurrence); chest wall rigidity with rapid injection; bradycardia and asystole; interaction with CYP3A4 inhibitors giving prolonged effect; risk with other central nervous system depressants.

Adverse effects. Common: nausea, vomiting, itching, bradycardia, hypotension, dizziness. Serious: apnoea, chest wall rigidity, laryngospasm, asystole, convulsions, delayed respiratory depression, serotonin syndrome with serotonergic drugs, tolerance and dependence with prolonged use.

Interactions. Erythromycin, clarithromycin, azole antifungals, ritonavir, diltiazem and verapamil inhibit CYP3A4 and can prolong respiratory depression for hours. Rifampicin and carbamazepine reduce the effect. Propofol, benzodiazepines, volatile agents and nitrous oxide reduce requirements and add hypotension. Beta blockers add bradycardia. Serotonergic drugs and monoamine oxidase inhibitors can cause serotonin syndrome.

Common prescribing errors. Giving a bolus too fast; forgetting that rigidity may need a neuromuscular blocker; using full doses in older adults or liver disease; combining with a CYP3A4 inhibitor; using in a spontaneously breathing patient without oxygen, monitoring and airway equipment; confusing alfentanil with fentanyl doses, since doses in micrograms/kg differ several-fold between the two drugs.

Special groups

• Pregnancy: crosses the placenta; neonatal respiratory depression with use at caesarean section before delivery.
• Breastfeeding: compatible after a single dose; watch the infant for drowsiness.
• Older adults: reduce doses and extend intervals.
• Kidney impairment: no adjustment; metabolites are inactive.
• Liver impairment: reduce doses and extend intervals because clearance falls in cirrhosis.
• Regional: confirm the concentration on the ampoule (500 micrograms/mL), because mistakes with 5 mg/10 mL and 1 mg/2 mL presentations are common; check the patient’s interacting medicines, since macrolides and azoles are widely used.

Formulations. Injection 500 micrograms/mL (1 mg in 2 mL and 5 mg in 10 mL ampoules).

Administration. Give boluses slowly over 30 to 60 seconds. For infusion dilute in 0.9% sodium chloride or 5% glucose (for example 5 mg in 50 mL gives 100 micrograms/mL) and use an infusion pump.

Baseline. Airway assessment, respiratory function, liver function, current CYP3A4 inhibitors, other sedatives and serotonergic drugs, age and weight.

Monitoring. Continuous electrocardiogram, oxygen saturation, capnography and blood pressure. Respiratory rate and sedation score in spontaneously breathing patients. Observe for at least 30 to 60 minutes after the last dose in case of delayed respiratory depression.

Therapeutic drug monitoring. Not used.

Dose reduction and stopping thresholds. Stop and support ventilation for respiratory rate under 10 breaths/minute, oxygen saturation under 94% on oxygen, or loss of responsiveness. Reduce doses for bradycardia under 50 beats/minute or hypotension. After more than 1 week of infusion, taper by 10 to 25% every few days to prevent withdrawal.

Referral and escalation. Apnoea needs airway support, ventilation and naloxone in 40 microgram increments intravenously every 2 minutes, repeated because naloxone may wear off before alfentanil if CYP3A4 inhibitors are present. Chest wall rigidity needs a neuromuscular blocker and ventilation. Bradycardia needs glycopyrronium 0.2 mg or atropine 0.5 to 1 mg intravenously. Prolonged effect after interacting drugs needs continued ventilation and monitoring.