Introduction
Amitriptyline is a tricyclic antidepressant (TCA) that has been in clinical use since the 1960s. Originally developed for the treatment of depression, it has since gained FDA approval for various other indications and remains widely prescribed despite the development of newer antidepressant classes. Amitriptyline is notable for its multifaceted pharmacological profile and continues to be an important therapeutic option in neurology, psychiatry, and pain management.
Mechanism of Action
Amitriptyline exerts its therapeutic effects primarily through inhibition of the reuptake of serotonin and norepinephrine in the central nervous system, thereby increasing the concentration of these neurotransmitters in the synaptic cleft. Additionally, it demonstrates significant antagonistic activity at muscarinic acetylcholine, histamine H₁, and alpha-1 adrenergic receptors, which contributes to both its therapeutic effects and side effect profile. The drug's analgesic properties in neuropathic pain conditions are thought to involve enhancement of descending inhibitory pain pathways in the central nervous system.
Indications
- FDA-approved:
- Major depressive disorder - Neuropathic pain associated with diabetic neuropathy - Migraine prophylaxis - Tension-type headache prophylaxis
- Off-label uses (with supporting evidence):
- Fibromyalgia - Postherpetic neuralgia - Irritable bowel syndrome - Nocturnal enuresis in children (>6 years) - Insomnia (particularly with comorbid depression)
Dosage and Administration
Depression:- Initial: 25-50 mg orally at bedtime
- Maintenance: 50-150 mg daily (maximum 300 mg/day in divided doses)
- Initial: 10-25 mg at bedtime
- Titration: Increase by 10-25 mg every 3-7 days
- Maintenance: 25-100 mg daily
- Geriatric: Start with 10 mg at bedtime, slow titration
- Hepatic impairment: Reduce dose by 50%
- Renal impairment: Use caution, consider reduced dosing
- Pediatrics: Not recommended under age 12 for depression
Pharmacokinetics
- Absorption: Well absorbed from GI tract, extensive first-pass metabolism
- Distribution: Volume of distribution: 5-10 L/kg, >90% protein bound
- Metabolism: Hepatic via CYP2D6, CYP2C19, and CYP3A4 to active metabolite nortriptyline
- Elimination: Half-life: 10-50 hours, renal excretion (mostly as metabolites)
- Steady-state: Achieved in 4-10 days
Contraindications
- Hypersensitivity to amitriptyline or other TCAs
- Acute recovery phase following myocardial infarction
- Concomitant use with MAOIs (allow 14-day washout period)
- Untreated narrow-angle glaucoma
- Severe liver impairment
- History of QT prolongation or arrhythmias
Warnings and Precautions
- Black Box Warning: Increased risk of suicidal thinking and behavior in children, adolescents, and young adults
- Cardiac conduction abnormalities (prolonged QT interval, heart block)
- Orthostatic hypotension
- Seizure threshold lowering
- Increased intraocular pressure
- Hyponatremia/SIADH
- Bone marrow suppression
- Hepatic impairment monitoring required
- Withdrawal symptoms upon abrupt discontinuation
Drug Interactions
- MAOIs: Risk of serotonin syndrome (absolute contraindication)
- SSRIs/SNRIs: Increased serotonergic effects
- CYP2D6 inhibitors: Increased amitriptyline levels (e.g., fluoxetine, paroxetine)
- Anticholinergics: Additive adverse effects
- CNS depressants: Enhanced sedation (alcohol, benzodiazepines, opioids)
- Antihypertensives: Reduced efficacy
- Sympathomimetics: Enhanced pressor effects
- Warfarin: Increased anticoagulant effect
Adverse Effects
Common (≥10%):- Sedation/drowsiness
- Dry mouth
- Constipation
- Blurred vision
- Weight gain
- Orthostatic hypotension
- QT prolongation and arrhythmias
- Seizures
- Neuroleptic malignant syndrome
- Serotonin syndrome
- Agranulocytosis
- Hepatitis
- Suicidal ideation
Monitoring Parameters
- Baseline:
- ECG (assess QTc interval) - Liver function tests - Renal function - Complete blood count - Blood pressure (standing and supine)
- Ongoing:
- Therapeutic drug monitoring (optimal range: 100-250 ng/mL) - ECG at dose escalation >100 mg/day - Mood assessment and suicide risk evaluation - Weight and metabolic parameters - Adverse effect assessment at each visit
Patient Education
- Take medication at bedtime to minimize daytime sedation
- Do not abruptly discontinue medication (taper over 2-4 weeks)
- Avoid alcohol and other CNS depressants
- Rise slowly from sitting/lying position to prevent dizziness
- Use sugar-free products for dry mouth relief
- Report any chest pain, palpitations, or unusual heart rhythms
- Notify provider if pregnancy is planned or suspected
- May impair ability to operate machinery or drive
- Therapeutic effects may take 2-4 weeks to manifest
- Keep medication safely stored away from children and pets
References
1. FDA Prescribing Information, Amitriptyline Hydrochloride Tablets 2. Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. Cambridge University Press; 2013. 3. Finnerup NB, et al. Pharmacotherapy for neuropathic pain in adults: systematic review and meta-analysis. Lancet Neurol. 2015;14(2):162-173. 4. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd ed. 2010. 5. Micromedex Solutions. Amitriptyline Drug Monograph. Truven Health Analytics. 6. Lexicomp Online. Amitriptyline Hydrochloride. Wolters Kluwer Health. 7. UpToDate. Amitriptyline: Drug Information. Wolters Kluwer. 8. British National Formulary. Amitriptyline Hydrochloride. 2023.