Safety of divalproex sodium in migraine prophylaxis: an open-label, long-term study. Long-term Safety of Depakote in Headache Prophylaxis Study Group

Headache. 1999 Oct;39(9):633-43. doi: 10.1046/j.1526-4610.1999.3909633.x.


Context: The adverse event profile of long-term divalproex therapy for epilepsy is well established, but little is known about the tolerability or safety of divalproex in long-term migraine prophylaxis.

Objective: Evaluate the long-term safety and efficacy of divalproex sodium in migraine prophylaxis.

Design: Open-label, long-term study, of up to 3 years, of patients who completed one of two multicenter, double-blind, randomized, placebo-controlled studies.

Setting: Eighteen headache/neurology centers throughout the United States.

Patients: One hundred sixty-three patients: 46 treated with placebo, 117 treated with divalproex for migraine in previous studies.

Intervention: Divalproex therapy initiated at 500 mg/day (250 mg twice daily), with adjustment in dose and dosing frequency possible after 1 to 3 days.

Main outcome measures: Number and proportion of patients reporting treatment-emergent adverse events, prevalence and incidence for each treatment-emergent adverse event, vital signs, body weight, 4-week migraine rates and proportion of patients with 50% or greater reduction in rate over time.

Results: Treatment lasted more than 180 days for 71% of patients and more than 360 days for 48% of patients. Improvements in the 4-week, change-from-baseline migraine rates were seen during each of the 3- and 6-month time intervals.

Conclusions: Divalproex is effective for migraine prophylaxis, and initial benefits are maintained for periods in excess of 1080 days.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Female
  • GABA Agents / adverse effects*
  • GABA Agents / therapeutic use
  • Humans
  • Longitudinal Studies
  • Male
  • Middle Aged
  • Migraine Disorders / prevention & control*
  • Randomized Controlled Trials as Topic
  • Safety
  • Valproic Acid / adverse effects*
  • Valproic Acid / therapeutic use


  • GABA Agents
  • Valproic Acid