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amitriptyline

Adjunctive therapy

Brand: Elavil

Published 2026-02-15 · Last reviewed 2026-02-22 · 4 references

Content sourced from FDA labeling (DailyMed) and peer-reviewed literature.

Print sheet Review evidence

At a glance

Class: Adjunctive therapy·Typical dose: Major depressive disorder: start 25–50 mg at bedtime; increase by 25–50 mg every 3–7 days toward 100–150 mg/day in divided doses or as a single nightly dose. Maximum 300 mg/day under specialist supervision with ECG monitoring.·Half-life: Single-dose mean 21 h; Steady-state mean 24 h·TDM range: 80–250 ng/mL·LAI available: No

Class: Adjunctive therapy
Typical dose: Major depressive disorder: start 25–50 mg at bedtime; increase by 25–50 mg every 3–7 days toward 100–150 mg/day in divided doses or as a single nightly dose. Maximum 300 mg/day under specialist supervision with ECG monitoring.
Half-life: Single-dose mean 21 h; Steady-state mean 24 h
TDM range: 80–250 ng/mL
LAI available: No

Quick answers

What is amitriptyline?: Amitriptyline is an older tricyclic antidepressant. Today it is often used at low bedtime doses for neuropathic pain, migraine prevention, or sleep continuity, and at higher doses for depression when first-line options have not worked or were not tolerated.
What is Elavil?: Elavil is a brand name for amitriptyline.
What is Elavil (amitriptyline) used for?: Label indications include: Depression; off-label for neuropathic pain and migraine prophylaxis.
What drug class is Elavil (amitriptyline)?: Tricyclic Antidepressant.
What is the mechanism of action of Elavil (amitriptyline)?: Tertiary-amine tricyclic antidepressant that inhibits serotonin and norepinephrine reuptake while strongly antagonising histamine H1, muscarinic, and α1-adrenergic receptors; sodium-channel blockade contributes to analgesia.
What strengths does Elavil (amitriptyline) come in?: Oral tablets: 10 mg (scored), 25 mg, 50 mg, 75 mg, 100 mg, 150 mg.

General information

Amitriptyline is an older tricyclic antidepressant approved for major depressive disorder. In practice it is often used when first-line SSRIs/SNRIs have not worked or when insomnia, neuropathic pain, or migraine comorbidity makes a sedating agent desirable.

The drug’s strong anticholinergic and orthostatic profile often leads to slow titration, baseline cardiovascular review, and extra caution in older adults or patients with autonomic dysfunction.

Low nightly doses (10–50 mg) are common in ambulatory psychiatry for sleep continuity or analgesia, whereas higher doses (100–300 mg/day) are reserved for treatment-resistant depression under close monitoring.

Because overdoses are highly cardiotoxic, clinicians dispense limited quantities and ensure patients and caregivers understand secure storage.

Therapeutic drug monitoring of combined amitriptyline + nortriptyline trough concentrations (target 80–250 ng/mL) helps differentiate non-response from non-adherence or metabolic variability.

Guidelines emphasise co-prescribing a mood stabiliser when treating bipolar depression and avoiding abrupt discontinuation to prevent cholinergic rebound.

The compare tool and amitriptyline evidence feed can help align care plans with psychiatry, pain, and primary-care teams; the bipolar disorder hub summarizes adjunctive mood stabiliser strategies.

U.S. approvals

Major depressive disorder (1961)

Formulations & strengths

Oral tablets: 10 mg (scored), 25 mg, 50 mg, 75 mg, 100 mg, 150 mg.
Tablets may be split or crushed; pharmacies can compound 10 mg/mL oral solutions for patients with swallowing difficulty.
No extended-release, parenteral, or long-acting injectable formulations are available.

Generic availability

Multiple manufacturers supply low-cost generics throughout North America and Europe; bulk bottles are common in outpatient formularies.
Listed on the World Health Organization (WHO) Model List of Essential Medicines for neuropathic pain.

Amitriptyline remains a workhorse for off-label neuropathic pain and migraine prophylaxis despite declining first-line use for depression. Sedation and anticholinergic burden often limit adherence; comparing against secondary amine TCAs (nortriptyline, desipramine) or SNRIs helps tailor therapy to tolerability priorities.

View labelExact

Mechanism of action

Refer to the Glossary entry on Neurotransmitters for background on receptor systems involved in serious mental illness.

Inhibits presynaptic serotonin (SERT) and norepinephrine (NET) transport and modestly blocks dopamine reuptake, enhancing monoamine tone in mood and pain pathways.

Potent antagonism at histamine H1, muscarinic M1–M3, and adrenergic α1 receptors underpins sedative, anticholinergic, and orthostatic effects.

Sodium-channel blockade in peripheral nerves contributes to analgesic benefit for neuropathic pain.

Nortriptyline, the primary active metabolite, provides additional NET inhibition with comparatively less anticholinergic activity.

High affinity for SERT and NET with Ki values in the low nanomolar range.
Strong inverse agonist at histamine H1 leading to pronounced sedation and weight gain.
Broad muscarinic (M1–M5) antagonism explaining dry mouth, constipation, urinary retention, and blurred vision.
α1-adrenergic blockade producing orthostatic hypotension; weak dopamine transporter antagonism and sodium-channel blockade confer analgesia but raise arrhythmia risk in overdose.

Metabolism & pharmacokinetics

Oral bioavailability 30–60% owing to extensive first-pass metabolism; peak plasma concentrations occur 2–12 hours after ingestion.
Highly lipophilic (volume of distribution 10–20 L/kg) with >90% protein binding; readily crosses the blood–brain barrier and placenta.
Metabolised primarily by CYP2C19 and CYP2D6 to active nortriptyline; CYP3A4 and CYP1A2 mediate additional hydroxylation and demethylation pathways.
Parent half-life averages 10–28 hours; nortriptyline half-life 18–44 hours. Poor CYP2D6 metabolisers exhibit prolonged exposure and toxicity.
Steady-state typically achieved within 7–14 days; therapeutic drug monitoring targets combined amitriptyline + nortriptyline troughs of 80–250 ng/mL for antidepressant response, with toxicity risk rising above 300 ng/mL.
Elimination occurs mainly via urinary metabolites; <5% recovered unchanged in urine or faeces. Hepatic impairment slows clearance requiring lower doses.

Dosing & administration

Major depressive disorder: start 25–50 mg at bedtime; increase by 25–50 mg every 3–7 days toward 100–150 mg/day in divided doses or as a single nightly dose. Maximum 300 mg/day under specialist supervision with ECG monitoring.
Neuropathic pain, migraine prophylaxis, or sleep maintenance: initiate 10–25 mg nightly; titrate by 10–25 mg every 1–2 weeks up to 50–100 mg as tolerated, balancing analgesia with anticholinergic burden.
Older adults or frail patients: begin 5–10 mg nightly and titrate slowly; consider switching to nortriptyline or desipramine if cognition or anticholinergic burden becomes problematic.
Paediatric enuresis (off-label): 10 mg at bedtime for ages 6–10, 25 mg nightly for ages 11–16; taper after 1–3 months to avoid rebound symptoms.
Retitration after interruption ≥3 days requires restarting at 10–25 mg to mitigate orthostasis and arrhythmia risk.
Cross-taper from SSRIs: allow at least one-week washout (five weeks for fluoxetine) before reaching full TCA doses to avoid serotonin syndrome.
For bipolar depression or augmentation strategies, clinicians typically pair with a mood stabiliser (lithium, valproate, lamotrigine) and monitor for manic switch.

Adverse effects

FDA boxed warnings

Increased risk of suicidal thinking and behaviour in children, adolescents, and young adults during antidepressant initiation and dose changes; monitor closely.

Common side effects (≥10%)

Sedation: Prominent during initiation; shifting dosing to bedtime and gradual titration reduce daytime impairment, yet residual grogginess often persists.
Anticholinergic effects: Dry mouth, constipation, urinary retention, blurred vision, and anhidrosis are dose related; prophylactic bowel regimens and saliva substitutes are frequently required.
Weight gain & appetite increase: Average 2–4 kg gain over 6–12 months; monitoring BMI and discussing nutrition is common, and alternatives may be considered if metabolic syndrome develops.
Orthostatic hypotension & tachycardia: α1 blockade produces dizziness, syncope, and reflex tachycardia—heightened in older adults, dehydrated patients, or when combined with antihypertensives.
Cognitive slowing: Memory impairment, slowed processing, and fogginess limit daytime functioning; evaluate for anticholinergic delirium in the elderly.
Sexual dysfunction & sweating: Anorgasmia, erectile difficulties, and hyperhidrosis are common yet underreported; dose reduction or medication switches may be required.

Other notable effects

Cardiac conduction delays (PR/QRS/QT prolongation), arrhythmias, and sudden death in overdose; obtain baseline ECG for adults >40 years or those with cardiac disease.
Lower seizure threshold at doses >150 mg/day or in combination with bupropion, tramadol, or rapid titration.
Mania or hypomania induction in bipolar disorder without adequate mood stabilisation.
Hepatic transaminase elevations and rare cholestatic hepatitis—monitor if jaundice or pruritus develops.
Angle-closure glaucoma or urinary retention crises in susceptible patients.
Highly lethal overdose: 10–20 mg/kg may cause coma, arrhythmias, and death; emergency management includes sodium bicarbonate and cardiac monitoring.

Interactions

Contraindicated with monoamine oxidase inhibitors (MAOIs); allow 14-day washout to avoid serotonin syndrome and hypertensive crisis.
Potent CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion, quinidine) raise serum concentrations—consider 30–50% dose reduction and monitor for toxicity.
CYP2C19 inhibitors (fluvoxamine, omeprazole) and CYP3A4 inhibitors (macrolides, azole antifungals) increase exposure; adjust doses or monitor serum levels.
Enzyme inducers (carbamazepine, rifampin, phenytoin, St John’s wort, smoking) decrease concentrations and may lead to loss of efficacy.
Concomitant serotonergic agents (SSRIs, SNRIs, triptans, linezolid, tramadol) heighten serotonin syndrome risk; monitor for agitation, clonus, and autonomic instability.
Additive anticholinergic or CNS depressant effects with antihistamines, antipsychotics, opioids, alcohol, or benzodiazepines increase confusion, falls, and respiratory depression.
QT-prolonging agents (antiarrhythmics, macrolides, fluoroquinolones, antipsychotics) compound arrhythmia risk—consider ECG surveillance.

Other useful information

Patients and caregivers often benefit from practical guidance on orthostatic precautions, hydration, fibre intake, and rising slowly from sitting or lying positions.
Secure storage and limited quantities are common, especially for individuals with elevated suicide risk.
Taper plans are commonly used when discontinuing to prevent cholinergic rebound (flu-like symptoms, sleep disturbances, GI upset).
Monitor for manic switch or rapid cycling in patients with bipolar spectrum illness.
Obstructive sleep apnoea exacerbation can be considered in patients with baseline OSA or obesity.
Collaboration with primary care can support cardiovascular, metabolic, and fall-risk mitigation.

References

Related hubs:SMI toolkit·Support resources