What is the proper usage and dosage of Amitriptyline (tricyclic antidepressant) for treating depression and chronic pain?

Amitriptyline for Depression and Chronic Pain

For chronic neuropathic pain, start amitriptyline at 25 mg at bedtime and titrate by 25 mg every 3-7 days as tolerated to a maximum of 150 mg/day, requiring 6-8 weeks with at least 2 weeks at maximum tolerated dose for an adequate trial. 1

Dosing for Neuropathic Pain (Primary Indication in Guidelines)

Amitriptyline is recommended as a first-line treatment for neuropathic pain despite limited high-quality evidence, based on decades of clinical experience. 1, 2

Starting and Titration Protocol

• Start at 25 mg at bedtime 1
• Increase by 25 mg every 3-7 days as tolerated 1
• Maximum dose: 150 mg/day 1
• Duration of adequate trial: 6-8 weeks, including at least 2 weeks at maximum tolerated dosage 1

Special Populations

• Geriatric patients: Use lower starting doses (10 mg three times daily with 20 mg at bedtime) and slower titration 1, 3
• Adolescent patients: Same conservative dosing as elderly (10 mg three times daily with 20 mg at bedtime) 3
• Not recommended for patients under 12 years of age 3

Therapeutic Monitoring

• If blood concentration of amitriptyline plus its active metabolite (nortriptyline) is <100 ng/mL, continue cautious titration 1
• For chronic pain with comorbid depression, responders require serum concentrations of at least 131.5 ng/mL of the active moiety (amitriptyline + nortriptyline) 4
• Plasma levels are generally higher in elderly patients due to decreased hepatic metabolism; monitor carefully 3

Dosing for Depression (FDA-Approved Indication)

Outpatients

• Initial: 75 mg/day in divided doses 3
• Alternative: 50-100 mg at bedtime, increased by 25-50 mg as necessary 3
• Maximum: 150 mg/day for outpatients 3

Hospitalized Patients

• Initial: 100 mg/day 3
• Titrate gradually to 200 mg/day if necessary 3
• Maximum: 300 mg/day for a small number of hospitalized patients 3

Maintenance Therapy

• Usual maintenance: 50-100 mg/day (some patients require only 40 mg/day) 3
• May be given as a single daily dose, preferably at bedtime 3
• Continue for 3 months or longer to prevent relapse 3
• Therapeutic effect may take up to 30 days to develop 3

Clinical Considerations and Mechanism

Amitriptyline works through multiple mechanisms: inhibition of serotonin and norepinephrine reuptake, and blockade of sodium channels required for neuronal impulse conduction. 1

Pain Relief Independent of Antidepressant Effect

• Analgesic efficacy occurs at doses below those required for antidepressant effects 2, 5
• Pain reduction is independent of mood changes in non-depressed patients 5
• Low-dose amitriptyline (25 mg) shows good analgesic and sleep regulatory effects 6

Evidence Quality and Real-World Use

• No first-tier or second-tier evidence exists for amitriptyline in neuropathic pain, only third-tier evidence 2
• Despite lack of high-quality trial evidence, decades of successful clinical use support its continued role 2
• Only a minority of patients achieve satisfactory pain relief, but failure with one antidepressant does not predict failure with all 2

Safety and Monitoring

Cardiac Precautions

• Obtain screening electrocardiogram for patients over 40 years 1
• Use with caution in ischemic cardiac disease or ventricular conduction abnormalities 1
• Limit doses to <100 mg/day when possible in cardiac patients 1
• Monitor for prolonged QTc interval 1

Common Adverse Effects

• Somnolence, dry mouth, blurred vision, constipation, weight gain 1
• Adverse events occur in 55% of patients on amitriptyline vs 36% on placebo (NNH 5.2) 2
• Slow titration (10-25 mg increments every 2 weeks) improves tolerability 1

Contraindications and Preclusions

• 46.7% of patients prescribed amitriptyline for painful neuropathic disorders have at least one preclusion for its use 7
• Preclusions are more common in women (48.3% vs 43.4% in men) and increase with age 7
• Despite preclusions, clinical judgment may support use given the low doses used for pain (average 33.6 mg starting, 42.1 mg maintenance) 7

Specific Pain Conditions

IBS (Second-Line Treatment)

• Start at 10 mg once daily at bedtime 1
• Titrate slowly to maximum of 30-50 mg once daily 1
• Requires careful explanation of rationale and counseling about side effects 1

Erythromelalgia (Third-Line Treatment)

• Systemic amitriptyline is a third-line option after aspirin and gabapentin/pregabalin 1
• Trial for 3-4 months 1
• Topical amitriptyline 1-2% compounded with 0.5% ketamine applied up to 3 times daily is effective in 75% of patients 1

Fibromyalgia

• Recommended despite limited evidence of effectiveness 8
• Use with caution as part of multimodal approach 8

Cyclic Vomiting Syndrome (Prophylaxis)

• Starting dose: 25 mg at bedtime 1
• Goal dose: 75-150 mg or 1-1.5 mg/kg at bedtime 1
• Slow titration (10-25 mg increments every 2 weeks) to goal dosage 1
• Dosed at night due to sedative effects 1