What is the comparison between nortriptyline and amitriptyline for migraine prevention in terms of efficacy and side effects?

Amitriptyline vs Nortriptyline for Migraine Prevention

Amitriptyline should be your first choice for migraine prevention, as it has consistent evidence supporting its efficacy, while nortriptyline lacks controlled trial evidence and should only be used when amitriptyline is not tolerated. 1

Evidence Base for Efficacy

Amitriptyline: Proven First-Line Agent

• Amitriptyline is the only tricyclic antidepressant with consistent support for efficacy in migraine prevention from controlled trials. 1
• The American Academy of Neurology recommends amitriptyline as a first-line preventive agent for episodic migraine, with demonstrated efficacy in reducing headache frequency by more than 50% in approximately 72% of patients. 2
• Effective dosing ranges from 30-150 mg/day in clinical trials. 1, 2

Nortriptyline: Insufficient Evidence

• There is no evidence from controlled trials supporting the use of nortriptyline for migraine prevention. 1
• Despite this lack of controlled trial evidence, nortriptyline is considered an alternative in patients who cannot tolerate amitriptyline due to its similar mechanism but potentially better tolerability profile. 3
• One small trial (14 patients) using low-dose nortriptyline (20 mg/day) showed no effectiveness, though this dose may have been subtherapeutic. 4

Side Effect Comparison

Amitriptyline Side Effects

• Common adverse events include drowsiness, weight gain, and anticholinergic symptoms (dry mouth, constipation). 1, 2
• These side effects are frequently reported but are generally well tolerated and seldom cause premature withdrawal from trials. 1
• Elderly patients should use amitriptyline with caution due to increased risk of anticholinergic effects. 2

Nortriptyline Side Effects

• Nortriptyline generally has a more favorable side effect profile compared to amitriptyline, with fewer anticholinergic effects and less sedation. 3
• In a recent head-to-head trial, nortriptyline (25 mg/day) caused 53 adverse drug reactions compared to 33 with venlafaxine, with xerostomia (dry mouth) being the most prevalent side effect. 5
• The side effect burden can still be substantial, though typically less than amitriptyline. 3

Clinical Decision Algorithm

When to Choose Amitriptyline

• Use amitriptyline as first-line for any patient requiring tricyclic antidepressant therapy for migraine prevention. 1, 2
• Particularly beneficial for patients with comorbid depression, sleep disturbances, or mixed migraine with tension-type headache features. 2, 6
• Superior to propranolol specifically for mixed migraine and tension-type headache. 1, 6

When to Choose Nortriptyline

• Reserve nortriptyline exclusively for patients who cannot tolerate amitriptyline's side effects, particularly excessive sedation, weight gain, or anticholinergic symptoms. 3
• Consider in elderly patients where anticholinergic burden is a concern, though evidence for efficacy remains lacking. 3

Dosing Strategy

Amitriptyline Dosing

• Start with 10-25 mg at bedtime and gradually titrate to 30-150 mg/day as tolerated. 2, 6
• Increase slowly over weeks to months to minimize side effects. 2
• Allow 2-3 months at therapeutic dose before declaring treatment failure—this is a critical pitfall to avoid. 2, 6

Nortriptyline Dosing (When Used)

• If using nortriptyline due to amitriptyline intolerance, typical dosing ranges from 25-100 mg/day, though specific evidence-based dosing for migraine is lacking. 3
• Apply the same 2-3 month trial period before assessing efficacy. 2, 6

Critical Clinical Pitfalls

• Do not discontinue amitriptyline prematurely—many clinicians stop treatment before the 2-3 month mark needed to assess true efficacy. 2
• Do not choose nortriptyline as first-line therapy based solely on its theoretically better side effect profile, as it lacks controlled trial evidence for migraine prevention. 1
• Educate patients to limit acute medication use to prevent medication overuse headache, which can worsen migraine frequency during preventive treatment. 2
• Avoid interfering medications like ergotamine during preventive treatment. 2

Alternative First-Line Options

If neither tricyclic is appropriate, consider:

• Propranolol 80-240 mg/day for pure migraine without tension-type features. 2, 6, 7
• Divalproex sodium or sodium valproate with strong evidence of efficacy. 2, 7
• Topiramate as a first-line option, particularly for obese patients or chronic migraine. 2, 7