Nortriptyline

Nortriptyline is a secondary-amine tricyclic antidepressant, the active metabolite of amitriptyline. It is used for depression and, off-label, neuropathic pain. It has fewer anticholinergic, sedative and hypotensive effects than amitriptyline, and a defined therapeutic concentration window.

Classification. Tricyclic antidepressant, secondary amine.

Mechanism. Preferentially inhibits noradrenaline reuptake, with weaker serotonin reuptake inhibition and moderate antihistamine and antimuscarinic effects. Sodium channel blockade underlies cardiac toxicity in overdose.

Pharmacokinetics. Well absorbed; extensive first-pass metabolism, mainly by CYP2D6 to 10-hydroxynortriptyline. Half-life about 18 to 44 hours. Levels vary several-fold between individuals, especially with CYP2D6 genotype. Therapeutic range about 50 to 150 ng/mL; levels over 150 ng/mL lose benefit and raise toxicity.

All regimens are oral with no loading dose.

Major depression, adults.

• Start 10 to 25 mg at night.
• Titration: increase by 25 mg every 3 to 7 days to 75 to 100 mg daily, given at night or in divided doses.
• Maximum 150 mg daily.
• Duration: at least 6 months after remission.

Older adults and adolescents with depression. 30 to 50 mg daily, as a single dose or divided.

Neuropathic pain (off-label). Start 10 mg at night; increase by 10 to 25 mg every 1 to 2 weeks to a usual 25 to 75 mg at night. Judge response after 4 to 6 weeks.

Dose adjustment by level. If response is poor at 100 mg daily, measure a trough level at least 1 week after the last dose change, 12 hours after the last dose, and adjust to the 50 to 150 ng/mL range.

Contraindications. Recent myocardial infarction, arrhythmias, heart block, mania, MAOI use now or within 14 days of stopping it, hypersensitivity. 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, delirium, hyponatraemia, mania. In overdose: coma, seizures, QRS over 100 ms and ventricular arrhythmia.

Common adverse effects. Dry mouth, constipation, dizziness, blurred vision, sweating, tremor, tachycardia, weight gain, sedation (less than with amitriptyline).

Interactions. CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion, terbinafine) and ritonavir can double levels. Rifampicin and carbamazepine lower levels. QT-prolonging drugs, anticholinergics and sedatives add to toxicity.

Common prescribing errors. Not checking levels after starting a CYP2D6 inhibitor; continuing at levels over the therapeutic window; large dispensed quantities in patients at risk of self-harm.

Special groups.

• Pregnancy: use only if benefit outweighs risk; neonatal withdrawal symptoms possible.
• Breastfeeding: low infant levels; acceptable with monitoring.
• Children: not advised for depression under 18 years.
• Older adults: a preferred tricyclic because of lower orthostasis; still start 10 mg.
• Kidney impairment: no adjustment; start low.
• Liver impairment: lower dose and level monitoring; avoid in severe disease.
• Regional: CYP2D6 ultrarapid phenotypes reported in some East African populations may produce low levels; measure a level if available.

Formulations. Capsules 10 mg, 25 mg, 50 mg and 75 mg; tablets and oral solution in some regions. Give at night in a single dose once the dose is settled.

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

Monitoring. Review within 1 to 2 weeks and after each dose change for suicidality. Repeat the ECG if the dose exceeds 100 mg daily or an interacting drug is added. Measure a trough level when response is poor, adherence is uncertain or a CYP2D6 inhibitor 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.

Stopping. Taper over at least 4 weeks.

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.