Pethidine

Pethidine is a synthetic phenylpiperidine mu-opioid agonist, about one tenth as potent as morphine. It is now rarely preferred because its neurotoxic metabolite accumulates, it has a short analgesic effect with a long metabolite half-life, and it has a dangerous interaction with monoamine oxidase inhibitors. Its remaining uses are obstetric analgesia in some settings and treatment of post-anaesthetic shivering.

Class. Full mu-opioid agonist (phenylpiperidine).

Mechanism. Mu receptor agonism. Weak anticholinergic and serotonin reuptake effects add to adverse effects.

Pharmacokinetics. Oral bioavailability about 50%. Intramuscular onset 10 to 15 minutes, duration 2 to 4 hours. Intravenous onset about 5 minutes. Half-life 3 to 5 hours. Hepatic metabolism (CYP2B6, CYP3A4, CYP2C19) to norpethidine, which is neuroexcitatory, has a half-life of 15 to 30 hours (longer in renal failure) and accumulates.

Indications are moderate to severe acute pain where morphine is unsuitable, labour analgesia in some settings, and post-anaesthetic shivering.

Adults

• Intramuscular or subcutaneous: 50 to 100 mg every 3 to 4 hours as needed. Older or frail adults 25 to 50 mg.
• Intravenous: 25 to 50 mg given slowly over at least 5 minutes, repeated every 4 hours.
• Post-anaesthetic shivering: 12.5 to 25 mg intravenously.
• Labour: 50 to 100 mg intramuscularly, repeated after 1 to 3 hours if needed. Maximum 400 mg in 24 hours in most practice (some labels allow 600 mg).
• Duration: maximum 48 hours of treatment because of norpethidine accumulation.
• Oral use is not preferred because of erratic effect and metabolite accumulation.

Children. Intramuscular 0.5 to 2 mg/kg every 3 to 4 hours; use only if no alternative is available.

Contraindications. Monoamine oxidase inhibitor use now or within 14 days (potentially fatal serotonin syndrome or hypertensive crisis); severe renal impairment; epilepsy or seizure history; raised intracranial pressure; respiratory depression; paralytic ileus; hypersensitivity; phaeochromocytoma.

Boxed-warning-level risks. Addiction, abuse and misuse; life-threatening respiratory depression; accidental exposure; neonatal opioid withdrawal syndrome; interactions with monoamine oxidase inhibitors, CYP3A4 and CYP2B6 modulators; concurrent benzodiazepines and other central nervous system depressants.

Adverse effects. Common: nausea, vomiting, dizziness, sedation, dry mouth, sweating, tachycardia. Serious: respiratory depression, norpethidine neurotoxicity (tremor, myoclonus, agitation, seizures), serotonin syndrome, hypotension, delirium.

Interactions. Monoamine oxidase inhibitors (including moclobemide, selegiline, linezolid) give severe, possibly fatal reactions. Serotonergic drugs (SSRIs, SNRIs, tricyclic antidepressants, tramadol, ondansetron) increase serotonin syndrome risk. Enzyme inducers (ritonavir, phenytoin, carbamazepine) increase norpethidine formation, and CYP3A4 inhibitors reduce it. Benzodiazepines and alcohol add sedation.

Common prescribing errors. Using for more than 48 hours; prescribing to a patient on an antidepressant or monoamine oxidase inhibitor; giving to a patient with kidney impairment; delivering repeated intravenous boluses too quickly.

Special groups

• Pregnancy: used in labour with neonatal respiratory depression risk; norpethidine persists in the neonate for days.
• Breastfeeding: avoid; norpethidine accumulates in the infant.
• Older adults: lower doses and shorter use.
• Kidney impairment: avoid; norpethidine accumulation and seizures.
• Liver impairment: reduce the dose; avoid in severe disease.
• Regional: availability is declining; morphine, fentanyl or a nonopioid regimen is preferable.

Formulations. Injection 50 mg/mL, tablets 50 mg in some markets.

Administration. Give intravenous doses diluted to 10 mg/mL in 0.9% sodium chloride, slowly over at least 5 minutes with titration. Give intramuscular injection into a large muscle.

Baseline. Antidepressant and monoamine oxidase inhibitor history, kidney function, seizure history, respiratory status and sedatives.

Monitoring. Pain, respiratory rate, sedation and mental state. Watch for tremor, twitching or agitation as signs of norpethidine toxicity. Check neonate for respiratory depression after labour use.

Therapeutic drug monitoring. Not used.

Dose reduction and stopping thresholds. Stop at 48 hours, or earlier for tremor, myoclonus, agitation, seizures or respiratory depression.

Referral and escalation. Seizures need a benzodiazepine; naloxone is not advised for norpethidine seizures because it can worsen them. Serotonin syndrome and respiratory depression need emergency care. Change to morphine or another alternative if opioid analgesia must continue.