Prophylactic efficacy and safety of valproate versus topiramate for migraine: a systematic review

Migraine prophylaxis options commonly include valproate and topiramate. Although several randomised trials have directly compared these agents, their relative efficacy and safety remain underexplored. Existing reviews have largely focused on placebo-controlled or indirect comparisons and have not comprehensively synthesised the available head-to-head evidence. This systematic review, therefore, evaluates the comparative efficacy and safety of valproate versus topiramate using a comprehensive, multilingual search METHODS: This review has been registered on the Open Science Framework (DOI: https://doi.org/10.17605/OSF.IO/ZC3S6 ). Databases and registers were searched to 9 September 2025. We included randomised controlled trials (RCTs) comparing valproate with topiramate in adult migraineurs. Due to the high risk of bias, evaluated at the outcome level using the revised Cochrane Risk of Bias 2 tool, a descriptive approach was adopted.

Eight trials were included (1659 participants; 72.2% female; mean ages 29.2-42.1 years). Two studies were in Chinese, one in Persian, and the rest were in English. Both drugs appeared to reduce migraine frequency meaningfully. Reductions in migraine duration, pain intensity, and disability measures (HIT-6, MIDAS) improved similarly with both drugs. The evidence base was insufficient to support a definitive efficacy advantage for either drug. Adverse events were common but mostly mild. Valproate use was often associated with increased appetite, drowsiness, and tremor, while topiramate use was commonly associated with paraesthesia and appetite loss.

The head-to-head randomized evidence appears to suggest that both valproate and topiramate may be effective for migraine prophylaxis. However, the current evidence is insufficient to support definitive claims of superiority for either drug. Differences in adverse- event profiles may therefore play a key role in guiding individualised treatment decisions. High- quality, well-powered trials are needed.