What is the dosage and treatment protocol for amitriptyline (tricyclic antidepressant) for nerve pain, specifically diabetic neuropathy or postherpetic neuralgia?

Amitriptyline for Nerve Pain

Start amitriptyline at 10 mg at bedtime and titrate every 3-7 days up to 75 mg at bedtime as tolerated, but recognize that duloxetine or pregabalin are superior first-line choices with FDA approval for diabetic neuropathy and better safety profiles. 1, 2

Why Amitriptyline is NOT First-Line

While amitriptyline has an impressive NNT of 1.5-3.5 for neuropathic pain, this figure is likely inflated by small crossover trial designs 1, 3. More importantly:

• Only duloxetine and pregabalin have FDA and European Medicines Agency approval specifically for diabetic peripheral neuropathy 1, 2
• A 2012 Cochrane review found no top-tier unbiased evidence supporting amitriptyline's efficacy—only second-tier evidence exists 3
• Doses above 100 mg/day are associated with increased risk of sudden cardiac death 1
• Anticholinergic side effects (dry mouth, constipation, sedation, urinary retention) limit tolerability, particularly in elderly patients 1

Specific Dosing Protocol for Amitriptyline

Initial dose: 10 mg at bedtime, especially in elderly patients 1

Titration schedule: Increase by 10-25 mg every 3-7 days based on tolerability 1

Target dose: 25-75 mg at bedtime 1

Maximum dose: Do not exceed 100 mg/day due to cardiac risk 1

Time to effect: Pain reduction typically occurs within 3 weeks in responders 1

Critical Safety Considerations

Obtain baseline ECG before initiating therapy if the patient has any cardiovascular history 1. Absolute contraindications include:

• PR or QTc interval prolongation on ECG 1
• Recent myocardial infarction or unstable angina 1
• Cardiac conduction abnormalities 2, 4
• Narrow-angle glaucoma 4
• Severe orthostatic hypotension or high fall risk 4

When to Use Amitriptyline

Amitriptyline is appropriate as a second-line agent when 2, 4:

• Duloxetine is contraindicated (severe renal impairment, liver disease, glaucoma)
• Pregabalin causes intolerable weight gain or edema
• Cost is a major barrier (amitriptyline is inexpensive)
• Patient has failed duloxetine and pregabalin at adequate doses

Evidence for Specific Neuropathic Pain Conditions

Postherpetic neuralgia: Amitriptyline 25-150 mg daily showed 66% of patients achieved significant pain reduction within 3 weeks in RCTs 1

Diabetic neuropathy: Second-tier evidence shows benefit, but duloxetine (NNT 4.9-5.2) and pregabalin (NNT 4.04-5.99) have stronger evidence 1, 2, 3

Mixed neuropathic pain: Some evidence of effect, but only 38% of patients achieve adequate pain relief versus 16% with placebo 3

Practical Algorithm

1. First-line: Start duloxetine 60 mg daily OR pregabalin 150 mg/day (50 mg three times daily) 2, 4

2. If first-line fails after 4 weeks: Add the other first-line agent (duloxetine + pregabalin combination) rather than switching to amitriptyline 4

3. If both first-line agents fail or are contraindicated: Consider amitriptyline 10 mg at bedtime ONLY after ECG screening and cardiovascular risk assessment 1, 4

4. Titrate amitriptyline: Increase by 10-25 mg every 3-7 days to 75 mg at bedtime maximum 1

5. Reassess at 3 weeks: If no response, discontinue and consider gabapentin or combination therapy 1, 4

Common Pitfalls to Avoid

• Do not use amitriptyline as first-line when FDA-approved alternatives exist 1, 2
• Do not exceed 100 mg/day due to cardiac mortality risk 1
• Do not skip ECG screening in patients with any cardiac history 1
• Do not use in elderly patients with fall risk due to sedation and orthostatic hypotension 4
• Do not combine with other anticholinergic medications without careful monitoring 1

Alternative to Amitriptyline: Nortriptyline

If a tricyclic antidepressant is necessary, nortriptyline 10-25 mg at bedtime titrated to 25-100 mg is preferred over amitriptyline due to fewer anticholinergic side effects and similar efficacy 1. Nortriptyline has less sedation, less dry mouth, and less constipation while maintaining the favorable NNT of tricyclics 1.