Amitriptyline

Amitriptyline is a tertiary-amine tricyclic antidepressant used for depression, neuropathic pain, migraine prevention and, in some regions, nocturnal enuresis in children. At low doses it acts mainly through sedation and pain modulation; at antidepressant doses its anticholinergic, antihistaminic and cardiac effects limit use, and it is dangerous in overdose.

Classification. Tricyclic antidepressant, tertiary amine.

Mechanism. Inhibits serotonin and noradrenaline reuptake, with strong blockade of muscarinic M1, histamine H1 and alpha-1 adrenergic receptors, and sodium channel blockade that underlies both pain relief and cardiac toxicity.

Pharmacokinetics. Well absorbed, unaffected by food. Extensive first-pass metabolism; CYP2C19 demethylates it to nortriptyline (active) and CYP2D6 hydroxylates both. Half-life about 10 to 28 hours. Combined amitriptyline and nortriptyline concentration of about 100 to 300 ng/mL is the usual range when levels are measured.

All regimens are oral with no loading dose.

Major depression, adults (alternative after SSRIs or SNRIs).

• Start 25 mg at night (10 mg in older adults).
• Titration: increase by 25 mg every 3 to 7 days to 75 to 150 mg daily, given at night or in divided doses.
• Maximum 150 mg daily as an outpatient; up to 300 mg daily in hospital under specialist care.
• Duration: at least 6 months after remission.

Neuropathic pain (including painful diabetic neuropathy).

• Start 10 to 25 mg at night; increase by 10 to 25 mg every 1 to 2 weeks to a usual 25 to 75 mg at night. Specialist use may reach 150 mg daily.
• Judge pain response after 4 to 6 weeks at an adequate dose.

Migraine prevention. Start 10 to 25 mg at night; usual 25 to 75 mg at night. Review at 8 to 12 weeks.

Nocturnal enuresis in children over 6 years (licensed in some regions). Aged 7 to 10 years 10 to 20 mg at bedtime; aged 11 to 16 years 25 to 50 mg at bedtime. Treat for up to 3 months.

Contraindications. Recent myocardial infarction, arrhythmias, heart block, mania, severe liver disease, MAOI use now or within 14 days of stopping it, hypersensitivity. Use with caution in epilepsy, narrow-angle glaucoma, urinary retention and prostatic hypertrophy.

Serious adverse effects. Boxed-warning-level risk of suicidal thinking and behaviour in under 25 years. Arrhythmia, QT and QRS prolongation, postural hypotension, seizures, serotonin syndrome, urinary retention, paralytic ileus, delirium in older adults, hyponatraemia, mania. In overdose: coma, seizures, QRS over 100 ms and ventricular arrhythmia.

Common adverse effects. Dry mouth, sedation, constipation, blurred vision, weight gain, dizziness, sweating, tachycardia, sexual dysfunction.

Interactions. CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion, terbinafine) and ritonavir raise levels. Rifampicin and carbamazepine lower them. QT-prolonging drugs, other anticholinergics and sedatives add to toxicity. Tramadol adds seizure and serotonin syndrome risk. Alcohol adds sedation.

Common prescribing errors. Dispensing large quantities to patients at risk of self-harm; starting at 75 mg in older adults; missing recent myocardial infarction; combining with other serotonergic drugs.

Special groups.

• Pregnancy: use only if benefit outweighs risk; neonatal withdrawal and anticholinergic effects can occur with late exposure.
• Breastfeeding: low infant levels; acceptable with infant monitoring for sedation.
• Children: not advised for depression; used for enuresis from about 6 years in some regions.
• Older adults: avoid where possible; start 10 mg; risk of falls, confusion and retention.
• Kidney impairment: no adjustment; start low.
• Liver impairment: reduce dose and use with caution; avoid in severe disease.
• Regional: CYP2D6 ultrarapid phenotypes reported in some East African populations can lower levels; titrate to response and tolerance.

Formulations. Tablets 10 mg, 25 mg, 50 mg and 75 mg; oral solution in some regions. Give at night. No infusion form.

Baseline. ECG in patients over 40 years or with cardiac disease or QT risk, lying and standing blood pressure, mood history including past mania, suicide risk, sodium in older adults, intraocular pressure risk, bladder symptoms, medicines list.

Monitoring. Review within 1 to 2 weeks and after each dose change for suicidality and anticholinergic effects. Repeat the ECG if the dose exceeds 100 mg daily or an interacting drug is added. Check sodium 2 to 4 weeks after starting in high-risk patients; review the need for the drug if sodium falls under 130 mmol/L and stop it if under 125 mmol/L or if symptomatic. Weigh at each review.

Stopping. Taper over at least 4 weeks to avoid cholinergic rebound (nausea, sweating, insomnia, vivid dreams).

Referral and escalation. Refer to psychiatry for suicidal intent, psychosis, mania or failure of two adequate courses. Overdose, QRS over 100 ms, seizures or syncope needs emergency care.