Placebo and nocebo phenomena in anti- CGRP monoclonal antibody trials for migraine prevention: a meta-analysis

High placebo and low nocebo phenomena mirror high positive expectations for a novel treatment, among other reasons. In a meta-analysis aimed to identify placebo and nocebo phenomena in the placebo-controlled randomized trials (RCTs) with the monoclonal antibodies targeting the calcitonin gene-related peptide pathway (anti-CGRP mAbs) all the placebo-treated patients were pooled and compared with the placebo-treated patients in RCTs with topiramate and onabotulinum toxin A (OBTA). In episodic migraine (EM), the proportion of placebo-treated patients who achieved the 50% responder rate (placebo) was 32.7% (95% CI 28.6%–37.0%) in anti-CGRP mAbs vs. 24.4% (95% CI 20.5%–28.5%) in topiramate trials. The proportion of dropouts due to adverse events in placebo-treated patients (nocebo) was 1.9% (95% CI 1.4%–2.6%) in anti-CGRP mAbs vs. 9.9% (95% CI 7.7%–12.3%) in topiramate RCTs. In chronic migraine (CM), the placebo 50% responder rate was 23.6% (95% CI 11.2%–38.8%) in anti-CGRP mAbs RCTs vs. 36.4% (95% CI 32.6%–39.3%) in RCTs with OBTA. The nocebo dropout in anti-CGRP mAbs and OBTA RCTs was 1.4% (95% CI 0.8%–2.1%) and 0.9 (95% CI 0.3%–1.7%), respectively. The stronger placebo and weaker nocebo phenomena in RCTs with anti-CGRP mAbs vs. those with topiramate in the prophylaxis of EM, may decisively determine anti-CGRP mAbs treatment success. No differences were detected between the anti-CGRP mAbs and OBTA in the treatment of CM.