Calcium antagonists as an add-on therapy for drug-resistant epilepsy

As up to 30% of patients with epilepsy do not have their seizures controlled with current treatments, there have been continuous attempts to find new antiepileptic drugs based on increasing knowledge of cellular and molecular biology involved in the genesis of epilepsy and seizures. Calcium has been established to play a major role in seizure occurrence, thus, calcium antagonists that can alter the effects of calcium on brain cells have been investigated for effect on epileptic seizures.

To evaluate the effects of calcium antagonists on seizures, side effects, quality of life and cognition, when used as an add-on therapy for patients with drug-resistant epilepsy.

We searched MEDLINE from 1966 to 2000 and the Cochrane Epilepsy Group trials register, the Cochrane Controlled Trials Register (The Cochrane Library Issue 1, 2001).

Randomized placebo-controlled add-on trials of any calcium antagonists in patients with drug-resistant epilepsy.

Two reviewers independently selected trials for inclusion and extracted data. Outcomes were: (a) 50% or greater reduction in seizure frequency; (b) treatment withdrawal (any reason); (c) side effects. For crossover trials, the first treatment period was treated as a parallel trial. Analyses were by intention to treat. Due to problems acquiring the data needed from crossover trials, overall results from these trials were summarised in tables.

Eleven trials were included. One parallel and seven crossover trials of flunarizine, two crossover trials of nimodipine and one crossover trial of nifedipine. For flunarizine, the odds ratio (OR) (95% Confidence Intervals (CIs)I) for a 50% or greater reduction in seizure frequency for the parallel trial was 1.64 (0.55, 4.94) indicating a non-significant advantage for flunarizine. We were unable to acquire data for this outcome from the seven crossover trials. The overall OR (95% CI) for treatment withdrawal for flunarizine was 5.83 (2.06, 16.45) indicating patients were significantly more likely to have flunarizine withdrawn than placebo. No side effects were statistically associated with flunarizine. For nifedipine we were unable to acquire the data we required from the two crossover trials for our specified outcomes. For the outcomes reported in the trials, nifedipine had no significant effect in seizures frequency. For nimodipine, we only had data from the first treatment period from one of the two crossover trials (17 subjects). The ORs (95% CIs) for a 50% or greater reduction in seizure frequency was 11.34 (1.00, 128.03) and for treatment withdrawal was 2.46 (0.22, 27.75).

Flunarizine may have a weak effect on seizure frequency, but had a significant withdrawal rate probably due to side effects, and should not be recommended for use as an add-on treatment. Similarly, there is no convincing evidence to support the use of nifedipine or nimodipine as add-on treatments for epilepsy.