Placebo‐corrected efficacy of modern antiepileptic drugs for refractory epilepsy: Systematic review and meta‐analysis

Abstract

Although adjunctive treatment with modern antiepileptic drugs (AEDs) is standard care in refractory epilepsy, it is unclear how much of the effect can be attributed directly to the AEDs and how much to the beneficial changes seen with placebo. Therefore, we performed a systematic review and meta-analysis of the evidence to determine the placebo-corrected net efficacy of adjunctive treatment with modern AEDs on the market for refractory epilepsy. Of 317 potentially eligible articles reviewed in full text, 124 (39%) fulfilled eligibility criteria. After excluding 69 publications, 55 publications of 54 studies in 11,106 adults and children with refractory epilepsy form the basis of evidence. The overall weighted pooled-risk difference in favor of AEDs over placebo for seizure-freedom in the total sample of adults and children was 6% [95% confidence interval (CI) 4-8, z = 6.47, p < 0.001] and 21% (95% CI 19-24, z = 17.13, p < 0.001) for 50% seizure reduction. Although the presence of moderate heterogeneity may reduce the validity of the results and limit generalizations from the findings, we conclude that the placebo-corrected efficacy of adjunctive treatment with modern AEDs is disappointingly small and suggest that better strategies of finding drugs are needed for refractory epilepsy, which is a major public health problem.

Is the perceived placebo effect comparable between adults and children? A meta-regression analysis

“…Thirty-five reviews, including 179 trials with adult and 117 with pediatric participants, were finally analyzed (15, (Supplementary Table S1 online). From these reviews, 19 assessed the risk of bias (18,20,22,25,26,28,29,32,35,(37)(38)(39)(40)(41)44,46,(49)(50)(51), 6 reported only the Jadad score (15,19,21,36,45,48), 4 assessed only the allocation concealment (34,42,43,47), and 6 did not assess quality (23,24,27,30,31,33). Overall, 13 382 adult and 5 417 pediatric participants were enrolled in the placebo groups.…”

Behavioral intervention as an add-on therapy in epilepsy: Designing a clinical trial

“…This approach, while appropriate for identifying potentially effective treatments, does not control for a placebo effect. In randomized controlled trials in epilepsy, placebo effects are variable and may be of large magnitude [39][40][41]. Adding further variability to outcomes, subjects in a "treatment as usual" arm may benefit from a non-specific improvement due to frequent contact with study personnel, thus falsely enhancing the measured treatment effects.…”

Drug treatment of epilepsy in adults

“…In a recent meta-analysis of 54 randomized controlled add-on trials in 11 106 patients with refractory epilepsy, the benefit in efficacy between adding a new antiepileptic drug and adding placebo was only 6% for freedom from seizures and 21% for a 50% reduction in seizure frequency. 79 This suggests that better strategies for finding more effective antiseizure drugs are needed for refractory epilepsy.…”