Amitriptyline

Indications

• FDA-approved for major depressive disorder in adults and adolescents; the label does not establish safety in children under 12 years of age.
• Off-label first-line oral agent for painful diabetic neuropathy, postherpetic neuralgia, and other peripheral neuropathic pain syndromes.
• Off-label migraine and tension-type headache prophylaxis, where low bedtime doses of 10-50 mg are usually effective within 2 to 4 weeks.
• Off-label for fibromyalgia and centralized pain, generally combined with exercise and cognitive behavioral therapy rather than used alone.
• Off-label for chronic insomnia and for functional gastrointestinal disorders such as irritable bowel syndrome, at doses far below the antidepressant range.

Mechanism of action

• Blocks presynaptic serotonin and norepinephrine reuptake transporters; the parent drug is more serotonergic and its metabolite nortriptyline more noradrenergic.
• Potent histamine H1 antagonism drives sedation, appetite stimulation, and weight gain, and underlies its usefulness at low bedtime doses for insomnia.
• Muscarinic M1 blockade produces dry mouth, constipation, urinary retention, blurred vision, tachycardia, and cognitive slowing in older adults.
• Alpha-1 adrenergic blockade causes orthostatic hypotension and falls, which is the main practical limit on titration in geriatric patients.
• Sodium channel blockade contributes to analgesia and also explains the QRS widening, arrhythmia, and seizures that dominate overdose presentations.

Pharmacokinetics

• Well absorbed orally with extensive first-pass metabolism; peak plasma concentrations occur roughly 4 hours after an oral dose and food has little effect.
• Elimination half-life is about 10 to 28 hours, permitting once-daily bedtime dosing, with steady state reached in approximately 4 to 5 days.
• Demethylated by CYP2C19 to nortriptyline, an active metabolite, then hydroxylated by CYP2D6; both enzymes carry clinically relevant genetic polymorphism.
• CYP2D6 poor metabolizers accumulate parent drug and hydroxy metabolites; CPIC advises a 50 percent dose reduction or selection of an alternative agent.
• Highly protein bound with a very large volume of distribution, so hemodialysis and forced diuresis do not remove meaningful amounts in overdose.

Dosing

• Start 25 mg PO at bedtime in healthy adults, or 10 mg in older or frail patients, then increase by 25 mg every 3 to 7 days as tolerated.
• Usual antidepressant target is 50-150 mg/day; outpatient maximum is 150 mg/day and closely supervised inpatient maximum is 300 mg/day.
• Neuropathic pain and headache prophylaxis usually respond to 10-75 mg at bedtime, well below the doses needed for antidepressant effect.
• Supplied in the United States only as oral tablets of 10, 25, 50, 75, 100, and 150 mg; give the daily dose at bedtime to exploit the sedation.
• No formal renal adjustment exists, but use lower doses and slower titration in hepatic impairment because oxidative clearance is reduced.
• Taper by roughly 25 mg every few days when stopping to avoid cholinergic rebound with nausea, malaise, insomnia, vivid dreams, and akathisia.

Adverse effects

• Anticholinergic effects are near universal, with dry mouth in over half of patients plus constipation, blurred vision, and urinary hesitancy.
• Sedation and weight gain are common and often dose limiting; orthostatic hypotension raises fall and fracture risk substantially in older adults.
• Dose-dependent slowing of cardiac conduction prolongs PR, QRS, and QT intervals and can provoke ventricular arrhythmia at supratherapeutic levels.
• Overdose is frequently lethal; ingestion above roughly 10 mg/kg produces QRS widening, seizures, coma, and refractory hypotension within hours.
• Lowers seizure threshold, can precipitate mania in bipolar disorder, and may trigger acute angle-closure glaucoma or complete urinary retention.
• Sexual dysfunction, diaphoresis, and fine tremor are frequent; agranulocytosis and cholestatic hepatitis are rare but described in the label.

Monitoring

• Obtain a baseline ECG in patients over 50 years, in anyone with known cardiac disease, and before titrating above 100 mg/day in any adult.
• Repeat the ECG after significant dose increases; a QRS above 100 ms or QTc above 500 ms should prompt dose reduction or discontinuation.
• Plasma levels are less well defined than for nortriptyline; a combined amitriptyline plus nortriptyline concentration of 100-250 ng/mL is commonly cited.
• Draw levels for suspected toxicity, nonresponse at an adequate dose, questionable adherence, or known CYP2D6 or CYP2C19 variant status.
• Track weight, orthostatic blood pressure, bowel and bladder function, and suicidality closely during the first several weeks of treatment.

Interactions

• Contraindicated with monoamine oxidase inhibitors and within 14 days of stopping one because of hypertensive crisis and serotonin syndrome risk.
• The label contraindicates concomitant cisapride because of additive QT prolongation and the resulting risk of torsades de pointes.
• CYP2D6 inhibitors including fluoxetine, paroxetine, bupropion, and duloxetine markedly raise tricyclic levels and warrant dose reduction plus level checks.
• Additive QT risk arises with methadone, ondansetron, and class IA or III antiarrhythmics; anticholinergic load compounds with antihistamines and oxybutynin.
• Alcohol and other sedatives amplify central nervous system depression, and the drug blunts the antihypertensive effect of clonidine and guanfacine.

Special populations

• Pregnancy data are broadly reassuring but limited; neonatal irritability, feeding difficulty, and transient withdrawal follow third-trimester exposure.
• Excreted into breast milk at low relative infant doses, though nortriptyline is generally preferred when a tricyclic is required during lactation.
• Safety in children under 12 years is not established, and adolescent use carries the class suicidality warning with mandatory close follow-up.
• The Beers Criteria list amitriptyline as potentially inappropriate at age 65 and older; if used at all, start at 10 mg and titrate very slowly.
• Reduce the dose in hepatic impairment; no renal adjustment is specified, though hydroxy metabolites accumulate in advanced kidney disease.

Clinical pearls

• Nortriptyline delivers most of the analgesia with far less anticholinergic and orthostatic burden.
• A one to two week supply can be fatal; dispense small quantities to patients at suicide risk.
• Analgesic dosing is separate from mood dosing: 10-75 mg at bedtime often controls pain.