Abstracts

Given the ability of anticonvulsants such as topiramate (TPM) to reduce neuronal hyperexcitability, it is reasonable to expect that at least some may be useful in paroxysmal disorders other than epilepsy, eg, migraine. In double-blind, placebo-controlled trials, 44-48% of valproate (VPA)-treated patients had [ge]50% migraine reduction vs. 14-21% of placebo-treated patients (23-34% net increase in responder rate with VPA treatment). VPA and TPM share similar broad-spectrum profiles in epilepsy, but have different mechanisms of action. Nonetheless, in open-label studies, TPM, like VPA, prevented migraine headache. Two double-blind, placebo-controlled dose-response trials assessed the potential usefulness of TPM as migraine prophylaxis.
TPM was evaluated in the absence of other preventive medications in adolescents/adults (12-65 yrs) with an established history of migraine ([ge]6 mos), with or without aura, who had previously failed no more than 2 preventive regimens. In the prospective 28-day baseline after other migraine preventives had been withdrawn, patients had to have at least 3-12 migraines. Patients were randomized to placebo, 50, 100, or 200 mg/day TPM. The 8-wk titration phase was followed by an 18-wk maintenance phase. The 25-mg/day starting dose was increased weekly in 25-mg increments to assigned target dose or maximum tolerated dose. Primary efficacy variable was mean change from prospective baseline in monthly migraine frequency during double-blind treatment. Secondary efficacy measures included responder rate (% patients with [ge]50% seizure reduction).
469 patients were randomized in Study 1 (placebo, N=115; TPM 50, 117; TPM 100, 125; TPM 200, 112) and 468 in Study 2 (placebo, 114; TPM 50, 117; TPM 100, 120; TPM 200, 117). Both studies showed significant differences between placebo and TPM 100 (Study 1, P[lt]0.001; Study 2, P=0.008) and TPM 200 (P[lt]0.001, both studies), but not TPM 50, in mean migraine frequency reduction. In Study 1, responder rates were placebo, 23%; TPM 50, 36% (P=0.04); TPM 100, 54% (P[lt]0.001), and TPM 200, 52% (P[lt]0.001). In Study 2, responder rates were placebo, 23%; TPM 50, 39% (P=0.01); TPM 100, 49% (P[lt]0.001) and TPM 200, 52% (P[lt]0.001). Discontinuations due to adverse events (AEs) (combined studies): placebo, 11%; TPM 50, 17%; TPM 100, 23%; TPM 200, 27%. The most common adverse AEs ([ge]10% incidence) with TPM 100 as target dose: paresthesia (TPM 100, 48%; placebo, 6%); fatigue (13%, 10%) and appetite decrease (13%, 6%).
TPM 100 mg/day as a target dose is effective and well tolerated for migraine prophylaxis. With TPM 100 mg, the net difference from placebo in responder rate was 26% and 31%, which compares favorably with VPA.
[Supported by: Johnson [amp] Johnson Pharmaceutical Research [amp] Development]