Valproic Acid is More Indicated for Migraine Prophylaxis
Valproic acid (divalproex sodium/sodium valproate) is the more indicated agent for migraine prophylaxis, with strong evidence supporting its efficacy as a first-line preventive therapy, while levetiracetam (Keppra) lacks guideline support and has only modest evidence suggesting it may be comparable but not superior to established agents. 1, 2
Evidence-Based Positioning
Valproic Acid: Established First-Line Agent
The American Academy of Family Physicians and American College of Physicians establish valproic acid as a first-line preventive agent for migraine prophylaxis, with strong support from five controlled studies demonstrating efficacy. 1, 2
Effective dosing ranges from 500-1,500 mg per day, with most guidelines recommending 800-1,500 mg daily for optimal migraine prevention. 2, 3
Valproic acid is particularly effective in patients with prolonged or atypical migraine aura, offering specific advantages in this subpopulation. 2
Research demonstrates that lower doses (500-600 mg daily) with serum levels less than 50 mcg/mL may be equally or more effective than higher doses, with better tolerability. 3
Levetiracetam: Insufficient Evidence
Levetiracetam is not mentioned in established migraine prophylaxis guidelines and lacks the evidence base required for first-line recommendation. 1
The only available evidence for levetiracetam in migraine comes from small open-label studies showing modest efficacy (46% responder rate with >50% reduction in attacks), which is not superior to established anticonvulsants. 4, 5
One randomized controlled trial found levetiracetam comparable to valproate (63% vs 65.6% responder rates), but this single study is insufficient to establish it as a guideline-recommended agent. 5
Critical Safety Considerations
Valproic Acid Contraindications
Valproic acid is absolutely contraindicated in women of childbearing potential due to teratogenic risk, specifically neural tube defects. 2
Additional contraindications include liver disease and thrombocytopenia. 2
Common adverse effects include hair loss, tremor, and weight gain, though these are generally well-tolerated. 2
Valproic acid increases risk of grade 3-4 hematologic toxicities when combined with chemotherapy agents like temozolomide. 1
Levetiracetam Safety Profile
Levetiracetam demonstrates better tolerability with fewer adverse drug reactions and higher retention rates compared to older anticonvulsants. 1
Most common side effects are somnolence, nausea, and weight gain, all typically mild and transient. 4
Levetiracetam may be preferred when valproic acid is contraindicated due to its more favorable side effect profile. 1
Clinical Decision Algorithm
First-Line Choice: Valproic Acid
Use valproic acid 500-1,500 mg daily as first-line therapy for migraine prophylaxis in appropriate candidates (excluding women of childbearing potential). 1, 2
Start with 500 mg daily and titrate based on response and tolerability, targeting serum levels less than 50 mcg/mL for optimal efficacy with minimal side effects. 2, 3
Allow 2-3 months at therapeutic dosing before declaring treatment failure. 2
When to Consider Levetiracetam
Consider levetiracetam only when valproic acid is contraindicated or not tolerated, recognizing it lacks guideline support. 1
If using levetiracetam, dose at 1,000 mg twice daily (starting at 500 mg and titrating up). 4
Levetiracetam may show better efficacy in patients with migraine with aura and those with less frequent baseline attacks. 4
Important Clinical Pitfalls
Do not use valproic acid in women of childbearing potential without reliable contraception—this is an absolute contraindication. 2
Avoid premature discontinuation of preventive therapy; adequate trials require 2-3 months at therapeutic doses. 2
Limit acute rescue medications to less than twice per week to prevent medication overuse headache, which worsens migraine frequency. 6, 7
Monitor for thrombocytopenia and hepatotoxicity with valproic acid, particularly in patients on concurrent chemotherapy. 1