Lamotrigine for Migraine Prophylaxis
Lamotrigine is NOT recommended for general migraine prophylaxis, as it has failed to demonstrate efficacy in reducing migraine frequency or intensity in controlled trials. 1
Evidence Against Lamotrigine for Migraine Prevention
The most definitive evidence comes from a randomized, double-blind, placebo-controlled trial that directly tested lamotrigine (200 mg/day) versus placebo for migraine prophylaxis. 1 This study found:
- Attack rates actually improved more on placebo than on lamotrigine (baseline 4.4 attacks/month reduced to 3.0 on placebo vs. baseline 3.6 reduced to 3.2 on lamotrigine). 1
- The changes were not statistically significant, leading investigators to conclude lamotrigine is ineffective for migraine prophylaxis. 1
- Adverse events, particularly skin rashes, were more common with lamotrigine than placebo. 1
A head-to-head comparison trial showed topiramate 50 mg was superior to lamotrigine 50 mg, with responder rates of 63% vs 46% for frequency reduction (p=0.02) and 50% vs 41% for intensity reduction (p=0.01). 2
The One Exception: Migraine Aura Prevention
Lamotrigine IS the treatment of choice specifically for preventing disturbing or frequent migraine auras, though it does not reduce headache itself. 3
An open-label case series of 47 patients with severe migraine aura showed:
- 68% of patients responded (>50% reduction in aura frequency). 4
- Mean monthly aura frequency decreased from 4.2 to 0.7 episodes. 4
- Response was excellent (>75% reduction) in 70% of responders. 4
- Auras returned within 2 months when lamotrigine was stopped and ceased when reintroduced. 4
Specific Indications for Lamotrigine in Aura Prevention:
Consider lamotrigine specifically for patients with: 4
- Prolonged aura (lasting >60 minutes)
- Frequent typical aura with speech symptoms
- Basilar-type migraine
- Typical aura without headache
- Hemiplegic migraine
Current Guideline-Recommended Approach
The most recent 2025 American College of Physicians guidelines make no mention of lamotrigine in their recommendations for episodic migraine prevention. 5 The recommended algorithm is:
First-Line Agents:
- Beta-blockers (metoprolol or propranolol)
- Valproate
- Venlafaxine
- Amitriptyline 5
Second-Line Agents (if first-line fails or not tolerated):
- CGRP antagonists (atogepant, rimegepant) or CGRP monoclonal antibodies (eptinezumab, erenumab, fremanezumab, galcanezumab) 5
Third-Line Agent:
- Topiramate (if both first-line and CGRP agents fail) 5
Clinical Pitfalls
- Do not prescribe lamotrigine for general migraine prevention—it lacks efficacy for reducing headache frequency or intensity. 1
- Skin rashes are common with lamotrigine, occurring more frequently than with placebo; slow dose-escalation (starting at 25 mg/day for 2 weeks, then 50 mg/day for 2 weeks) reduces but does not eliminate this risk. 1
- Lamotrigine may benefit aura frequency in select patients but will not reduce the associated headache, so patients need realistic expectations. 3
- If a patient has both frequent auras AND frequent headaches requiring prophylaxis, lamotrigine alone is insufficient—combine it with a proven migraine preventive agent. 3