Sodium Valproate for Migraine Prevention
Sodium valproate (valproic acid) is a first-line preventive medication for migraine, with strong evidence demonstrating it reduces headache frequency by approximately 4 headaches per month and doubles the responder rate compared to placebo, but it is strictly contraindicated in women of childbearing potential due to teratogenic risk. 1, 2
Indications for Preventive Therapy with Valproate
Initiate valproate when patients meet any of the following criteria:
- ≥2 migraine attacks per month producing disability for ≥3 days 1
- Use of acute medications more than twice weekly (risk of medication-overuse headache) 1
- Failure of or contraindications to acute treatments 1
- Presence of uncommon migraine conditions (prolonged aura, migrainous infarction, hemiplegic migraine) 1
Valproate may be particularly effective in patients with prolonged or atypical migraine aura 1
Dosing and Administration
Start with 250 mg twice daily and titrate to 500-1,500 mg per day in divided doses 1, 3
- Initiate at low dose and increase slowly until benefits are achieved without adverse effects 1
- Most studies used 800-1,500 mg daily for optimal efficacy 1
- Clinical benefits may not become apparent for 2-3 months, so an adequate trial period is essential before declaring treatment failure 1
Evidence of Efficacy
The Cochrane systematic review (2013) provides the strongest evidence:
- Reduces headache frequency by 4.31 headaches per 28 days compared to placebo (MD -4.31; 95% CI -8.32 to -0.30) 2
- Doubles the proportion of responders (≥50% reduction in headache frequency) (RR 2.18; 95% CI 1.28 to 3.72; NNT 4) 2
- Effective in 86.2% of patients for preventing migraine or reducing frequency, severity, and duration 4
Position in Treatment Algorithm
First-line preventive options (choose based on patient factors): 1
- Beta blockers (propranolol 80-240 mg/day, timolol 20-30 mg/day)
- Topiramate 64 mg/day
- Candesartan 65-66 mg/day
- Divalproex sodium/sodium valproate 500-1,500 mg/day
Second-line options (if first-line fails): 1
- Flunarizine
- Amitriptyline
- Sodium valproate (in men only, due to contraindication in women of childbearing potential)
The 2021 Nature Reviews Neurology guidelines downgraded valproate to second-line specifically because of the strict contraindication in women of childbearing potential, which greatly limits its utility 1
Critical Contraindications and Safety Concerns
Absolute contraindication: Women of childbearing potential 1
- Teratogenic effects include neural tube defects 1
- This contraindication is emphasized in the most recent (2021) guidelines and significantly restricts valproate's clinical utility 1
Common adverse effects (NNH 7-14 for clinically important events): 1, 5, 2
- Hair loss
- Tremor
- Weight gain
- Nausea, asthenia, dyspepsia
- Dizziness, somnolence, diarrhea
Most adverse events are mild to moderate in severity 5
Duration of Treatment and Discontinuation
- After 6-12 months of successful treatment, consider pausing therapy to determine if preventive treatment can be stopped 1
- This minimizes unnecessary drug exposure and allows some patients to manage migraine with acute medications only 1
- Measure success by calculating percentage reduction in monthly migraine days 1
Comparative Effectiveness
- Equivalent efficacy to propranolol in patients with migraine alone 1
- No significant difference versus flunarizine in head-to-head comparison 2
- Slightly less effective than topiramate 50 mg (MD -0.90 headaches; 95% CI -1.58 to -0.22) 2
- Amitriptyline may be more effective in patients with mixed migraine and tension-type headache 1