amitriptyline

tricyclic antidepressant· Brands: Elavil, Tryptizol, Laroxyl, Saroten, EndepIMPO

Mechanism of action

Amitriptyline is a tertiary amine tricyclic antidepressant. It blocks presynaptic serotonin (SERT) and noradrenaline (NET) transporters, increasing monoamine availability in the synaptic cleft, and it also antagonises muscarinic acetylcholine, histamine H1 and alpha1 adrenergic receptors, which accounts for much of its side effect profile. Sodium channel blockade, potassium channel effects and weaker NMDA receptor and opioid-related actions are thought to contribute to its analgesic effect in neuropathic pain at doses below those used for depression. Its metabolite nortriptyline is a secondary amine with relatively greater noradrenergic selectivity, and both compounds contribute to clinical effect. Full antidepressant action usually takes several weeks, whereas analgesic benefit in neuropathic pain may appear sooner. Abrupt withdrawal can cause cholinergic rebound symptoms.

Pharmacokinetics

Amitriptyline is absorbed well from the gut and undergoes extensive first pass metabolism, giving an oral bioavailability of roughly one third to one half, varying between individuals. It is metabolised mainly by CYP2C19, CYP2D6, CYP3A4 and CYP1A2 to nortriptyline, an active metabolite with antidepressant activity, and then to hydroxy and glucuronide conjugates. Protein binding is high and the volume of distribution is large. Elimination half-life is about 10 to 28 hours for amitriptyline and 15 to 40 hours for nortriptyline, with steady state reached in roughly one to two weeks, slower in older people and in hepatic impairment. Excretion is largely renal as inactive metabolites, so renal impairment seldom requires dose change, but poor CYP2D6 metabolisers and enzyme inhibitors can produce high plasma levels. Plasma level monitoring, usually of nortriptyline, is available in some centres to assess adherence or toxicity.

Indications & dosing

Major depressive disorder

Start 25-50 mg at night, titrate to 100-150 mg daily. Lower doses in the elderly. Hospital inpatients may receive up to 300 mg daily under specialist supervision.

adult · PO: 25–150 mg once daily · Start 25-50 mg at night, titrate to 100-150 mg daily. Lower doses in the elderly. Hospital inpatients may receive up to 300 mg daily under specialist supervision.

Neuropathic pain (e.g. diabetic neuropathy, postherpetic neuralgia)off-label

Start 10 mg at night, increase by 10-25 mg weekly as tolerated. Analgesic effect is independent of antidepressant action and often occurs at lower doses.

adult · PO: 10–75 mg at night · Start 10 mg at night, increase by 10-25 mg weekly as tolerated. Analgesic effect is independent of antidepressant action and often occurs at lower doses.

Migraine prophylaxisoff-label

Start 10 mg at night, titrate to 25-75 mg. Review after 8-12 weeks. Withdraw gradually if effective.

adult · PO: 10–75 mg at night · Start 10 mg at night, titrate to 25-75 mg. Review after 8-12 weeks. Withdraw gradually if effective.

Nocturnal enuresis

Age 6-10 years: 10-20 mg; age 11 years and older: 25-50 mg. Use only after non-drug measures fail. Review after 3 months.

pediatric · PO: 10–50 mg at night · Age 6-10 years: 10-20 mg; age 11 years and older: 25-50 mg. Use only after non-drug measures fail. Review after 3 months.

Fibromyalgiaoff-label

Used for sleep and pain. Start 10 mg at night, titrate slowly. Evidence is modest; consider specialist input.

adult · PO: 10–50 mg at night · Used for sleep and pain. Start 10 mg at night, titrate slowly. Evidence is modest; consider specialist input.

Contraindications & precautions

Known hypersensitivity to amitriptyline or other tricyclic antidepressants · May cause allergic reactions including rash, urticaria, or anaphylaxis.
Concomitant use with monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping an MAOI · Risk of serotonin syndrome and hypertensive crisis.
Recent myocardial infarction or history of clinically significant ischaemic heart disease, arrhythmias, or heart block · Tricyclics can worsen cardiac conduction and precipitate arrhythmias.
Severe hepatic impairment · Risk of accumulation and toxicity; dose reduction may be needed in milder impairment.
Narrow-angle glaucoma · Anticholinergic effects may precipitate acute angle-closure glaucoma.
Acute porphyria · Tricyclic antidepressants are considered unsafe in porphyria.
Bipolar disorder, acute mania · May precipitate manic episodes or rapid cycling; use only with specialist advice and mood stabiliser cover.
Urinary retention or prostatic hypertrophy · Anticholinergic effects may worsen retention.
Taper gradually on withdrawal to avoid cholinergic rebound, rebound insomnia, agitation, and flu-like symptoms.
Monitor for suicidal ideation and behaviour, especially during initiation and dose changes, particularly in young adults.
Use with caution in the elderly: start at a low dose and titrate slowly because of increased risk of falls, confusion, anticholinergic effects, and cardiac events.
Avoid concomitant use with MAOIs and other serotonergic drugs; allow an appropriate washout period.
Check ECG at baseline and during dose escalation in patients with cardiac disease or risk factors for QT prolongation.
Advise patients to avoid alcohol and other CNS depressants because of additive sedation.

Adverse effects

Dry mouth, constipation, blurred vision, urinary hesitancy (anticholinergic effects)
Sedation and drowsiness
Orthostatic hypotension and tachycardia
Weight gain and increased appetite
Cardiac arrhythmias including QT prolongation, torsades de pointes, and heart blockserious
Seizuresserious
Hyponatraemia (SIADH)serious
Suicidal ideation and behaviourserious
Blood dyscrasias (e.g. agranulocytosis, leukopenia)serious
Mania or hypomaniaserious

Interactions

fluoxetinemajorAvoid the combination if possible. If co-prescription is deemed necessary, use extreme caution. Consider an alternative antidepressant that does not inhibit CYP2D6. If used, reduce the amitriptyline dose and monitor for signs of toxicity and serotonin syndrome. Monitor ECG, blood pressure and heart rate. Advise the patient to report any symptoms such as palpitations, syncope or serotonin syndrome features. Monitoring should continue for several weeks after stopping fluoxetine due to its long half-life.

Renal & hepatic adjustment

Hepatic impairment (mild): Reduce initial dose and titrate slowly. Monitor for sedation, anticholinergic effects and orthostatic hypotension.
Hepatic impairment (moderate): Use a lower initial dose and titrate cautiously. Consider an alternative if hepatic impairment is significant. Monitor closely.
Hepatic impairment (severe): Avoid: amitriptyline is contraindicated in severe hepatic impairment. (avoid)

Monitoring, pregnancy & toxicity

Suicidal ideation, mood and clinical response · At initiation, at each dose change, and regularly during the first weeks of treatment.
ECG (QRS duration, QTc) in patients with cardiac disease, elderly patients, or those on higher doses · Baseline and after significant dose increases or when clinically indicated.
Anticholinergic and CNS effects (dry mouth, constipation, urinary retention, blurred vision, confusion, sedation) · At each review, especially after starting or increasing the dose.
Orthostatic blood pressure and heart rate · Baseline and periodically, particularly in elderly patients or those on antihypertensives.
Serum sodium in elderly patients or those at risk of SIADH/hyponatraemia · Baseline and periodically during treatment.
Plasma amitriptyline plus nortriptyline levels if poor response, suspected toxicity or poor adherence · As clinically indicated; not routine.
Pregnancy: Use only when clearly indicated and if safer alternatives have been ineffective or are unsuitable. Avoid abrupt discontinuation. Use the lowest effective dose. Late pregnancy exposure may cause neonatal withdrawal or anticholinergic effects, so monitor the neonate. Seek specialist advice and follow regional or local formulary guidance.
Toxicity: Anticholinergic and CNS toxicity: dry mouth, blurred vision, mydriasis, tachycardia, urinary retention, ileus, sedation, confusion, hallucinations, agitation, drowsiness, coma and respiratory depression. · Support airway, breathing and circulation. Activated charcoal if within 1 to 2 hours and airway is protected. Use benzodiazepines for agitation or seizures. Avoid physostigmine.
Toxicity: Cardiac conduction delay and arrhythmia: QRS widening, QTc prolongation, ventricular arrhythmias, hypotension, bradycardia, heart block and cardiac arrest. · Continuous ECG monitoring. Give sodium bicarbonate for QRS greater than 100 ms or arrhythmia. Correct hypoxia, acidosis and electrolyte abnormalities. Avoid class IA and IC antiarrhythmics.
Toxicity: Seizures and coma. · Give IV benzodiazepines for seizures and provide supportive care. Consider sodium bicarbonate if acidosis or wide QRS is present. Monitor for rhabdomyolysis.
Toxicity: Severe hypotension. · Give IV fluids and use vasopressors if needed. Avoid agents that worsen cardiac conduction.

Antidotes & reversal

Sodium bicarbonate · QRS >100 ms or shock: 1-2 mmol/kg IV boluses, target arterial pH 7.50-7.55; avoid class 1a/1c antiarrhythmics.

Clinical notes

Licensed indications vary by country and formulary: depressive illness and, in many settings, neuropathic pain, migraine prophylaxis, chronic tension-type headache and some functional bowel or bladder syndromes, usually at much lower doses (for example 10 to 75 mg at night) than the 75 to 150 mg historically used for depression; use in paediatric nocturnal enuresis is regional and usually specialist. It is not a first-line antidepressant because of toxicity and anticholinergic burden. Use with caution or avoid in recent myocardial infarction, arrhythmia or heart block, uncontrolled glaucoma, urinary retention, prostatic hypertrophy, epilepsy, hyperthyroidism and severe hepatic impairment. Sedation and anticholinergic effects include dry mouth, constipation, blurred vision, urinary hesitancy, falls and confusion in older adults, and hyponatraemia can occur. Combining with MAOIs, SSRIs, tramadol, triptans or other serotonergic drugs risks serotonin syndrome, and CYP2D6 inhibitors raise plasma levels. Overdose is life threatening through arrhythmia, hypotension and seizures, so pack sizes are restricted in some countries. Abrupt cessation causes withdrawal symptoms. All doses quoted are teaching examples only.

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BNF; local formulary; manufacturer's summary of product characteristics (SmPC); specialist pain or psychotropic prescribing guidance.