Placebo or active comparator in chronic migraine trials: Balancing evidence and practicality

This debate addresses the choice of placebo versus active comparator in randomized controlled trials (RCTs) for chronic migraine (CM), a disabling condition with high global burden. Placebo-controlled designs have traditionally been considered the gold standard for new treatments, allowing quantification of placebo and pharmacological effects, ensuring internal validity, smaller sample sizes, and regulatory acceptance. Yet, ethical concerns arise from the possibility that participants may be denied effective treatments. The emergence of migraine-specific therapies targeting the calcitonin gene-related peptide (CGRP) pathway has prompted calls for active comparator designs. Such trials may enhance clinical relevance, support recruitment, and better mirror clinical practice compared with placebo-controlled RCTs. However, defining a universal standard of care may be challenging given global disparities in access, cost, and treatment preferences, limiting the feasibility of RCTs with active comparators. Placebo-controlled trials remain valuable, but alternative strategies, including short placebo phases with open-label extensions, add-on designs, or three-arm trials (investigational treatment, placebo, active comparator) may reconcile scientific rigor with ethical considerations. Ultimately, the optimal trial design depends on the research question, regulatory requirements, and evolving definitions of standard care in CM prevention.