The results of two multicenter, randomized, double-blind, placebo-controlled clinical trials established the effectiveness of divalproex sodium in the prophylactic treatment of migraine headache.

Both studies employed essentially identical designs and recruited patients with a history of migraine with or without aura (of at least 6 months in duration) who were experiencing at least 2 migraine headaches a month during the 3 months prior to enrollment. Patients with cluster headaches were excluded. Women of childbearing potential were excluded entirely from one study, but were permitted in the other if they were deemed to be practicing an effective method of contraception.

In each study following a 4 week single-blind placebo baseline period, patients were randomized, under double blind conditions, to divalproex sodium or placebo for a 12 week treatment phase, comprised of a 4 week dose titration period followed by an 8 week maintenance period. Treatment outcome was assessed on the basis of 4 week migraine headache rates during the treatment phase.

In the first study, a total of 107 patients (24 M, 83 F), ranging in age from 26 to 73 were randomized 2:1, divalproex sodium to placebo. Ninety patients completed the 8 week maintenance period. Drug dose titration, using 250 mg tablets as valproic acid, was individualized at the investigator's discretion. Adjustments were guided by actual/sham trough total serum valproate levels in order to maintain the study blind. In patients on divalproex sodium doses ranged from 500 to 2,500 mg as valproic acid a day. Doses over 500 mg as valproic acid were given in three divided doses (TID). The mean dose during the treatment phase was 1,087 mg/day as valproic acid resulting in a mean trough total valproate level of 72.5 mcg/mL, with a range of 31 to 133 mcg/mL.

The mean 4 week migraine headache rate during the treatment phase was 5.7 in the placebo group compared to 3.5 in the divalproex sodium group (see Figure 4). These rates were significantly different.

In the second study, a total of 176 patients (19 males and 157 females), ranging in age from 17 to 76 years, were randomized equally to one of three divalproex sodium dose groups (500, 1,000, or 1,500 mg/day) as valproic acid or placebo. The treatments were given in two divided doses (BID). One hundred thirty-seven patients completed the 8 week maintenance period. Efficacy was to be determined by a comparison of the 4 week migraine headache rate in the combined 1,000/1,500 mg/day as valproic acid group and placebo group.

The initial dose was 250 mg as valproic acid daily. The regimen was advanced by 250 mg as valproic acid every 4 days (8 days for 500 mg/day as valproic acid group), until the randomized dose was achieved. The mean trough total valproate levels during the treatment phase were 39.6, 62.5, and 72.5 mcg/mL in the divalproex sodium 500, 1,000, and 1,500 mg/day as valproic acid groups, respectively.

The mean 4 week migraine headache rates during the treatment phase, adjusted for differences in baseline rates, were 4.5 in the placebo group, compared to 3.3, 3, and 3.3 in the divalproex sodium 500, 1,000, and 1,500 mg/day as valproic acid groups, respectively, based on intent-to-treat results (see Figure 4). Migraine headache rates in the combined divalproex sodium 1,000/1,500 mg as valproic acid group were significantly lower than in the placebo group.

Figure 4 Mean 4 week Migraine Rates

1 Mean dose of divalproex sodium was 1,087 mg/day as valproic acid.

2 Dose of divalproex sodium was 500 or 1,000 mg/day as valproic acid.