Open dose-ranging trial of flunarizine as add-on therapy in epilepsy

A double-blind placebo-controlled crossover trial of flunarizine as add-on treatment in therapy-resistant epilepsy offered significant evidence of efficacy, but the plasma levels of flunarizine were lower than anticipated, probably due to induction of liver enzymes by comedication. An open dose-ranging trial was therefore undertaken to investigate the relationships among dose, efficacy, side effects, and blood level. With basal medication held constant, flunarizine was added at 3-month intervals in increasing doses of 0, 10, 15, 20, and 25 mg daily, or until side effects occurred or marked seizure reduction was obtained. Forty-seven patients completed the trial; all were adults with therapy-resistant epilepsy who had at least 3 seizures per month. All had complex partial seizures, with additional types in 20. Sixteen patients showed a 50% and 24 a 25% reduction of seizure incidence on flunarizine; 6 and 7, respectively, showed a corresponding increase. The greatest seizure reduction, when observed, occurred generally at a daily dose of 15-20 mg. Side effects, chiefly drowsiness and weight gain, increased markedly between 15 and 20 mg daily. Flunarizine administration produced no change in serum levels of comedication, but flunarizine levels were lower in patients taking more than one other drug. Seizure reduction was obtained most consistently in patients with secondary generalized epilepsy or neurologic deficits. The findings confirm the antiepileptic action of flunarizine in humans and justify further trials.