Amitriptyline
Formerly Elavil
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Major depressive disorder | Adults | Monotherapy or adjunctive | FDA Approved |
Amitriptyline is a tertiary amine tricyclic antidepressant approved for the treatment of depression in adults. It was one of the earliest TCAs introduced (FDA approval 1961) and remains widely prescribed globally, particularly for off-label pain and headache indications at lower doses. Amitriptyline is on the WHO Model List of Essential Medicines for neuropathic pain. Due to its prominent anticholinergic, sedative, and cardiotoxic profile, it is now rarely used as a first-line antidepressant in most guidelines, being positioned as a second- or third-line option when SSRIs and SNRIs are inadequate.
Neuropathic pain (diabetic neuropathy, postherpetic neuralgia, chronic pain syndromes) — Evidence quality: High. Recommended as first-line by NeuPSIG, NICE, and AAN guidelines alongside SNRIs and gabapentinoids.
Migraine prophylaxis — Evidence quality: Moderate. AAN Level U; EHF meta-analysis supports efficacy; used as first- or second-line in multiple international headache guidelines.
Tension-type headache prophylaxis — Evidence quality: Moderate. Most widely studied agent for chronic tension-type headache.
Fibromyalgia — Evidence quality: Moderate. Low-dose amitriptyline (25–50 mg) improves pain, sleep, and fatigue scores.
Insomnia (associated with depression or pain) — Evidence quality: Low. H1 antagonism provides sedation; used when co-morbid pain or depression coexists.
Irritable bowel syndrome — Evidence quality: Moderate. ATLANTIS trial (2023) confirmed benefit in IBS refractory to first-line treatments.
Nocturnal enuresis (children ≥6 years) — Evidence quality: Moderate. Approved indication in UK/EU; used after non-drug and desmopressin failure.
Dosing
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Depression — outpatient initiation | 25–50 mg at bedtime | 75–150 mg/day | 150 mg/day | Increase by 25–50 mg every 3–7 days FDA PI initial: 75 mg/day divided or 50–100 mg at bedtime; can give as single bedtime dose or divided TID + bedtime |
| Depression — hospitalised / treatment-resistant | 100 mg/day | 150–200 mg/day | 300 mg/day | Higher doses require specialist supervision and ECG monitoring TDM recommended: target 80–250 ng/mL (amitriptyline + nortriptyline) |
| Neuropathic pain — initial management (off-label) | 10–25 mg at bedtime | 25–75 mg/day | 150 mg/day | Titrate by 10–25 mg every 1–2 weeks Analgesic effect at lower doses than antidepressant doses; use caution above 100 mg |
| Migraine / tension headache prophylaxis (off-label) | 10–25 mg at bedtime | 25–75 mg/day | 150 mg/day | Allow 4–6 weeks for full prophylactic effect Most evidence at doses up to 100 mg/day for migraine |
| Fibromyalgia (off-label) | 10–25 mg at bedtime | 25–50 mg/day | 75 mg/day | Low doses preferred; higher doses rarely improve efficacy but increase side effects Also improves sleep quality and fatigue |
| IBS — refractory to first-line therapy (off-label) | 10 mg at bedtime | 10–30 mg/day | 30 mg/day | Per ATLANTIS trial protocol; titrate based on response and tolerability Very low doses effective for visceral pain modulation |
Special Population Adjustments
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Elderly patients (≥65 years) | 10 mg at bedtime | 10 mg TID + 20 mg at bedtime (50 mg/day) | 75–100 mg/day | AGS Beers Criteria: avoid due to strong anticholinergic effects Consider nortriptyline or desipramine as safer TCA alternatives in elderly |
| Adolescents (≥12 years, depression) | 10 mg TID + 20 mg at bedtime | 50 mg/day | Individualised | Not recommended <12 years; close monitoring for suicidality required FDA PI dose; not first-line in paediatric depression |
| CYP2D6 poor metabolisers | Reduce by 50% | Guided by TDM | Guided by TDM | CPIC recommends alternative TCA or 50% dose reduction with TDM CYP2C19 ultrarapid metabolisers may have sub-therapeutic levels |
| Hepatic impairment | 10 mg at bedtime | Individualised | Individualised | Extensively hepatically metabolised; reduced clearance expected FDA PI advises caution; no specific dose guidance |
Combined amitriptyline plus nortriptyline trough concentrations of 80–250 ng/mL are associated with optimal antidepressant response. Levels above 300 ng/mL carry substantially increased toxicity risk including cardiac conduction abnormalities. Blood should be drawn 12–16 hours post-dose at steady state (approximately 7–14 days). TDM is recommended when the daily dose exceeds 100 mg, in non-responders, in the elderly, in known or suspected CYP2D6 or CYP2C19 polymorphism, and when CYP inhibitors are co-prescribed. A 10-fold interindividual variability in amitriptyline metabolism makes TDM especially valuable for this agent.
Pharmacology
Mechanism of Action
Amitriptyline is a tertiary amine tricyclic antidepressant that potently inhibits the reuptake of both serotonin and norepinephrine at presynaptic terminals, thereby increasing synaptic concentrations of these monoamines. Among the TCAs, amitriptyline has particularly strong binding affinity for histamine H1, muscarinic M1, and alpha-1 adrenergic receptors, which accounts for its prominent sedative, anticholinergic, and hypotensive effects respectively. Sodium channel blockade at higher concentrations contributes to both its analgesic properties in neuropathic pain and its cardiac toxicity in overdose. Chronic treatment produces downstream adaptive changes including beta-adrenergic receptor downregulation and desensitisation of presynaptic autoreceptors, which are thought to underlie the 2–4 week latency to antidepressant effect. Amitriptyline is N-demethylated to its principal active metabolite, nortriptyline, which is a more selective norepinephrine reuptake inhibitor and contributes meaningfully to the overall pharmacological action.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | 90–95% from GI tract; bioavailability ~50% due to extensive first-pass metabolism; Tmax 1–5 h (up to 8 h) | Well absorbed but significant hepatic first-pass effect; food does not meaningfully alter absorption |
| Distribution | Vd 12–18 L/kg; protein binding ~95–96%; distributes to brain, heart, liver | Very large tissue distribution; crosses placenta; excreted in breast milk at ~1:1 ratio to plasma; not removed by dialysis |
| Metabolism | Hepatic: CYP2C19 (N-demethylation → nortriptyline), CYP2D6 (hydroxylation), CYP3A4, CYP1A2; active metabolite nortriptyline and (E)-10-hydroxynortriptyline | Subject to CYP2D6 and CYP2C19 genetic polymorphism; 10-fold interindividual variability in metabolism; nortriptyline reaches higher AUC than parent drug |
| Elimination | t½ ~21 h (amitriptyline), ~23–31 h (nortriptyline); 12–80% excreted in urine within 48 h as metabolites; <5% unchanged | Steady state in 7–14 days; prolonged effect from active metabolite nortriptyline; highly lethal in overdose due to extensive tissue distribution and cardiac toxicity |
Side Effects
Amitriptyline has the highest anticholinergic and sedative burden among commonly used TCAs. The incidence figures below are drawn from clinical trial data, large observational studies, and the EMA SmPC, as the original FDA label predates modern frequency-reporting standards. Side effects are dose-related and are a major reason amitriptyline is now considered a second-line antidepressant.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Dry mouth (xerostomia) | ≥25% | Most common TCA side effect; persists throughout treatment; increases dental caries risk |
| Drowsiness / sedation | ≥20% | Most sedating TCA; H1 antagonism-driven; can be therapeutic when insomnia coexists |
| Dizziness | ≥20% | Alpha-1 adrenergic blockade; significant fall risk in elderly |
| Constipation | ≥20% | Anticholinergic-mediated; can progress to ileus in severe cases |
| Weight gain | ≥20% | Average 1.8 kg over early treatment; H1 antagonism and appetite stimulation |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Blurred vision | ~10–15% | Anticholinergic effect on accommodation; exclude narrow-angle glaucoma before prescribing |
| Liver test abnormalities | 10–12% | Usually mild, asymptomatic transaminase elevations; consistently elevated ALT in ~3% of patients |
| Tachycardia | 5–10% | Anticholinergic-mediated resting heart rate increase; dose-related |
| Urinary retention / hesitancy | ~8.7% | More pronounced in men and patients with prostatic hypertrophy |
| Orthostatic hypotension | 5–10% | More prominent than with secondary amine TCAs; measure standing BP during titration |
| Sexual dysfunction | ~6.9% | Mostly erectile dysfunction and low libido in males with depression; less apparent in pain patients |
| Tremor | 3–6% | Fine postural tremor; dose-related; may indicate supratherapeutic levels |
| Headache | 3–5% | Paradoxical in headache prophylaxis context; usually transient at initiation |
| Diaphoresis | 2–5% | Noradrenergic-mediated; can persist |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Suicidal ideation / behaviour | Uncommon | First 1–2 months or dose change | FDA Boxed Warning; close monitoring in those <25 years; consider discontinuation |
| Cardiac arrhythmia / QRS & QT prolongation | Rare at therapeutic doses; common in overdose | Any time; severe in overdose | Baseline and follow-up ECG; lethal cardiotoxicity in overdose; sodium bicarbonate for QRS >100 ms in poisoning |
| Seizures | Rare (~0.1–0.4%) | Dose-dependent; common in overdose | Use with caution in epilepsy; lowers seizure threshold; manage acutely with benzodiazepines |
| Serotonin syndrome | Rare | Hours to days after adding serotonergic agent | Discontinue all serotonergic agents immediately; cyproheptadine if severe; supportive care |
| Paralytic ileus | Very rare | Any time; risk highest in elderly or with co-anticholinergics | Surgical emergency; discontinue amitriptyline; review all anticholinergic medications |
| Hepatotoxicity | Rare (clinically apparent) | Weeks to months | Monitor LFTs if symptoms arise; discontinue if ALT >3× ULN with symptoms; grouped among TCAs with greater hepatic risk |
| Agranulocytosis / bone marrow suppression | Very rare | Weeks to months | CBC if unexplained fever or infection; discontinue if confirmed |
| Mania / hypomania induction | Uncommon | First 2–8 weeks | Screen for bipolar disorder before starting; discontinue and manage manic episode |
| Acute angle-closure glaucoma | Very rare | Any time | Urgent ophthalmology referral if eye pain, halos, or acute visual loss; screen before prescribing |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Excessive sedation / fatigue | 8–12% | Most common in outpatients on antidepressant doses; less problematic at low pain doses |
| Weight gain | 4–6% | Becomes a major issue after 3–6 months; average gain 1.8 kg |
| Anticholinergic effects | 4–6% | Dry mouth and constipation; worse in elderly and at higher doses |
| Dizziness / orthostasis | 2–4% | Alpha-1 blockade; limits tolerability in elderly |
Sedation is the most dose-limiting side effect of amitriptyline and occurs more frequently than with secondary amine TCAs such as nortriptyline or desipramine. Administering the entire daily dose at bedtime exploits the sedating effect therapeutically while minimising daytime impairment. If daytime sedation persists beyond 2–3 weeks, consider reducing the dose, switching to nortriptyline (its less sedating metabolite), or using a different drug class. Avoid combining amitriptyline with other CNS depressants, especially in patients at fall risk.
Drug Interactions
Amitriptyline is metabolised by multiple CYP enzymes (CYP2C19, CYP2D6, CYP3A4, CYP1A2), creating numerous pharmacokinetic interaction opportunities. Its pharmacology also produces interaction risks through anticholinergic, adrenergic, serotonergic, and sodium-channel blocking mechanisms. The 10-fold interindividual variability in metabolism amplifies the clinical impact of enzyme inhibitors and inducers.
Monitoring
-
ECG
Baseline; repeat if dose >100 mg/day, cardiac symptoms, or age >40
Routine Assess QRS, QTc, and PR interval. QRS >100 ms warrants caution; >120 ms requires discontinuation or cardiology input. Amitriptyline prolongs QT interval more than secondary amine TCAs. -
Plasma Drug Level
Steady state when dose >100 mg/day; repeat with dose changes
Routine Measure combined amitriptyline + nortriptyline trough (12–16 h post-dose). Target: 80–250 ng/mL. Levels >300 ng/mL carry high toxicity risk. Especially important given 10-fold interindividual metabolic variability. -
Blood Pressure
Each visit during titration; then periodically
Routine Orthostatic vital signs (lying and standing). Amitriptyline has greater orthostatic hypotension potential than nortriptyline. -
Psychiatric Status
Weekly for first 4 weeks; then every 2–4 weeks
Routine Assess for worsening depression, suicidality, agitation, and mania/hypomania. FDA mandates close monitoring especially in patients <25 years. -
Weight & Metabolic
Baseline, then every 3–6 months
Routine Record weight and BMI. Monitor fasting glucose in diabetic or pre-diabetic patients, as amitriptyline can alter blood sugar in both directions. -
Hepatic Function
If symptoms develop; consider baseline in liver disease
Trigger-based LFT abnormalities occur in 10–12% of patients but are usually mild. Clinically apparent hepatotoxicity is rare but amitriptyline is grouped among TCAs with greater hepatic risk. -
Intraocular Pressure
If eye symptoms develop
Trigger-based Screen for narrow-angle glaucoma before prescribing. Anticholinergic mydriasis can precipitate acute angle-closure.
Contraindications & Cautions
Absolute Contraindications
- Concurrent or recent MAOI use — at least 14 days must elapse between MAOI discontinuation and amitriptyline initiation, and vice versa.
- Acute recovery phase after myocardial infarction — markedly elevated arrhythmia and conduction disturbance risk.
- Known hypersensitivity to amitriptyline or related dibenzocycloheptadiene compounds.
Relative Contraindications (Specialist Input Recommended)
- Pre-existing cardiac conduction disease (bundle branch block, prolonged QTc, Brugada syndrome) — requires cardiology consultation.
- Uncontrolled narrow-angle glaucoma — anticholinergic effects may precipitate acute angle closure.
- Severe hepatic impairment — extensively metabolised; reduced clearance increases toxicity risk.
- CYP2D6 poor metaboliser status — CPIC recommends alternative or 50% dose reduction with TDM.
- Active suicidal ideation in patients <25 years — FDA Boxed Warning.
Use with Caution
- Elderly patients — AGS Beers Criteria lists amitriptyline as highly anticholinergic and potentially inappropriate; increased fall, delirium, and cognitive impairment risk.
- History of seizure disorder — lowers seizure threshold in a dose-dependent manner.
- Urinary retention / prostatic hypertrophy — anticholinergic effects worsen obstruction.
- Bipolar disorder — may precipitate manic switch; not approved for bipolar depression.
- Hyperthyroidism — enhanced cardiovascular effects of TCAs.
- Diabetes mellitus — both elevation and lowering of blood sugar levels have been reported.
- Patients undergoing surgery — discontinue several days before elective surgery when possible; inform anaesthetist.
- Patients with eating disorders (purging behaviour) — risk of dehydration and electrolyte disturbance compounding cardiac toxicity.
Antidepressants increase the risk of suicidal thinking and behaviour in children, adolescents, and young adults (18–24 years) with major depressive disorder and other psychiatric disorders. Amitriptyline is not approved for use in patients under 12 years of age. All patients started on therapy must be monitored closely for clinical worsening, suicidality, or unusual behavioural changes, particularly during the first months or at dose changes. Families and caregivers should be advised of the need for daily observation.
Patient Counselling
Purpose of Therapy
Amitriptyline is prescribed to help restore the balance of brain chemicals that regulate mood, or at lower doses, to modify the way nerves transmit pain signals. Full antidepressant benefit may take 2 to 4 weeks or longer. For pain and headache prevention, improvement may be gradual over 4 to 6 weeks. It is important to continue the medication as directed even if improvement is not immediately apparent.
How to Take
Amitriptyline tablets can be taken with or without food. The dose is most commonly taken once daily at bedtime because of its sedating properties. Swallow tablets whole with water. Do not stop amitriptyline abruptly, as this can cause withdrawal symptoms including nausea, headache, and irritability. Your doctor will advise a gradual taper over at least 2 to 4 weeks when stopping treatment.
Sources
- Sandoz Inc. Amitriptyline Hydrochloride Tablets USP — Full Prescribing Information. FDA; revised 2025. FDA Label (PDF) Current US prescribing reference for indications, dosing, contraindications, and boxed warning.
- Accord Healthcare Ltd. Amitriptyline 10 mg Film-Coated Tablets — Summary of Product Characteristics (SmPC). EMC; 2024. EMC SmPC European regulatory reference with detailed pharmacokinetic data including Vd, bioavailability, and Tmax values.
- Leucht C, Huhn M, Leucht S. Amitriptyline versus placebo for major depressive disorder. Cochrane Database Syst Rev. 2012;12:CD009138. DOI Cochrane review confirming amitriptyline’s efficacy over placebo in MDD with NNT of approximately 4.
- Ford AC, Wright-Hughes A, Alderson SL, et al. Amitriptyline at low-dose and titrated for irritable bowel syndrome as second-line treatment in primary care (ATLANTIS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023;402(10414):1773–1785. DOI Landmark UK primary care trial demonstrating low-dose amitriptyline (10–30 mg) improves IBS symptom scores vs placebo.
- Couch JR; Amitriptyline Versus Placebo Study Group. Amitriptyline in the prophylactic treatment of migraine and chronic daily headache. Headache. 2011;51(1):33–51. DOI Large placebo-controlled trial showing amitriptyline is superior to placebo for migraine and chronic daily headache prophylaxis at 8 weeks.
- Max MB, Lynch SA, Muir J, Shoaf SE, Smoller B, Dubner R. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med. 1992;326(19):1250–1256. DOI Classic RCT establishing TCAs as effective for diabetic neuropathic pain, with amitriptyline showing significant benefit over placebo.
- Hicks JK, Sangkuhl K, Swen JJ, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants: 2016 Update. Clin Pharmacol Ther. 2017;102(1):37–44. DOI CPIC guideline recommending dose adjustments for CYP2D6 and CYP2C19 polymorphisms affecting amitriptyline metabolism.
- Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14(2):162–173. DOI NeuPSIG systematic review recommending TCAs (including amitriptyline) as first-line for neuropathic pain.
- Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults. Neurology. 2012;78(17):1337–1345. DOI AAN/AHS guideline listing amitriptyline as a Level U agent for migraine prophylaxis in adults.
- American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder, Third Edition. Am J Psychiatry. 2010;167(Suppl):1–152. DOI APA guideline positioning TCAs as second-line agents for MDD after SSRI/SNRI failure.
- Thour A, Marwaha R. Amitriptyline. In: StatPearls. Treasure Island (FL): StatPearls Publishing; Updated July 18, 2023. NCBI Comprehensive clinical review covering mechanism, dosing, pharmacogenomics, adverse effects, and monitoring.
- Schulz P, Turner-Tamiyasu K, Smith G, Giacomini KM, Blaschke TF. Amitriptyline disposition in young and elderly normal men. Clin Pharmacol Ther. 1983;33(3):360–366. DOI PK study demonstrating age-related changes in amitriptyline clearance and volume of distribution.
- Venkatakrishnan K, von Moltke LL, Greenblatt DJ. Human drug metabolism and the cytochromes P450: application and relevance of in vitro models. J Clin Pharmacol. 2001;41(11):1149–1179. DOI Review detailing CYP2C19, CYP2D6, and CYP3A4 contributions to amitriptyline metabolism with clinical implications.