Topiramate for migraine prevention: a randomized controlled trial

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Brandes JL, Saper JR, Diamond M, Couch JR, Lewis DW, Schmitt J, et al. JAMA 2004;291:965-73

Context Small open-label and controlled trials suggest that the antiepileptic drug topiramate is effective for migraine prevention.

Objective To assess the efficacy and safety of topiramate for migraine prevention in a large controlled trial.

Design A 26-week, randomized, double-blind, placebo-controlled study.

Setting 52 North American clinical centers.

Participants Patients were aged 12 to 65 years and had a 6-month history of migraine (International Headache Society criteria) and 3 to 12 migraines a month but no more than 15 headache days a month during a 28-day prospective baseline phase.

Interventions After a washout period, patients meeting entry criteria were randomized to topiramate (50, 100, or 200 mg/d) or placebo. Topiramate was titrated by 25 mg/wk for 8 weeks to the assigned or maximum tolerated dose, whichever was less. Patients continued receiving that dose for 18 weeks.

Main outcome measures The primary efficacy measure was change from baseline in mean monthly migraine frequency. Secondary efficacy measures included responder rate (proportion of patients with ≥50% reduction in monthly migraine frequency), reductions in mean number of monthly migraine days, severity, duration, and days per month requiring rescue medication, and adverse events. The month of onset of preventive treatment action was assessed.

Results Of 483 patients randomized, 468 provided at least 1 postbaseline efficacy assessment and comprised the intent-to-treat population. Mean monthly migraine frequency decreased significantly for patients receiving topiramate at 100 mg/d (−2.1, P=.008) and topiramate at 200 mg/d (−2.4, P < .001) vs placebo (−1.1). Statistically significant reductions (P < .05) occurred within the first month with topiramate at 100 and 200 mg/d. The responder rate was significantly greater with topiramate at 50 mg/d (39%, P=.01), 100 mg/d (49%, P < .001), and 200 mg/d (47%, P < .001) vs placebo (23%). The number needed to treat (NNT) ranges from 5 to 7, depending on the dosage used. Reductions in migraine days were significant for the 100-mg/d (P=.003) and 200-mg/d (P < .001) topiramate groups. Rescue medication use was reduced in the 100-mg/d (P=.01) and 200-mg/d (P=.005) topiramate groups. Adverse events resulting in discontinuation in the topiramate groups included paresthesia, fatigue, and nausea.

Conclusions Topiramate showed significant efficacy in migraine prevention within the first month of treatment, an effect maintained for the duration of the double-blind phase.

Comment Migraine is a highly prevalent and disabling neurologic disorder that occurs in episodic attacks dominated by symptoms of head pain, sensory hypersensitivity, and autonomic dysregulation. Currently only three medications are marketed in the United States with FDA approval for the indication of migraine prevention, all of which have significant limitations regarding efficacy and tolerability.

Brandes et al report on the use of topiramate (currently FDA-approved for treatment of seizure disorders in children and adults) for migraine prophylaxis. The study notably excluded very impaired subjects (ie, those with chronic daily headache, medication-overuse headache, or migraine unresponsive to at least two preventative medications). Study subjects were 87% female (higher than the female prevalence of migraine), and ranged in age from 12 to 65 years. The number of adolescents included in the trial is not explicitly stated.

This valid study resulted in statistically significant positive results for all endpoints for the 100-mg and 200-mg treatment groups. Migraine period frequencies were reduced by ∼40% for each of the 100-mg and 200-mg groups versus ∼20% for the placebo group. Although the absolute magnitude of this response is modest (ie, reduction of ∼1 migraine period per month between placebo and treatment groups), these efficacy results are comparable with those previously reported for other FDA-approved medications for migraine prophylaxis (eg, divalproex sodium).

The tolerability of topiramate was fair. The actual median dosages attained for the 100-mg and 200-mg groups were only ∼86 mg and ∼150 mg, respectively. Subject withdrawals due to adverse events were relatively high (27% and 21% for 100-mg and 200-mg groups, respectively vs 12% for the placebo group [number need to harm ∼10]). Moreover, although the authors do not state the percentage of subjects reporting any treatment-emergent adverse events, paresthesias alone were reported by ∼50% of subjects in the 100-mg and 200-mg groups. The high frequency of these symptoms raises significant questions as to the success of blinding of the trial and may account for some of the observed differences in efficacy between treatment and placebo groups.