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

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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.

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The authors thank Mrs Evie Delicha, MSc, for her expert statistical advice.


This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

All authors contributed to the study conception and design. Material preparation, literature search, data collection, and analysis were performed by KD and LK. The first draft of the manuscript was written by KD and LK and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Conceptualization: DDM; Methodology: DDM and DP; Formal analysis and investigation KD and LK; Writing—original draft preparation: KD and LK; Writing—review and editing: all authors; Funding acquisition: No founding; Supervision: DDM and DP.

Correspondence to Dimos D. Mitsikostas.

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Conflicts of interest

Dr. L. Kokoti reports no disclosures. Dr. K. Drellia reports no disclosures. Dr. D. Papadopoulos has received consulting, speaking fees and travel grants from Bayer, Genesis Pharma, Merck, Novartis, Roche, Sanofi-Aventis, Specifar and Teva. Prof. D.D. Mitsikostas has received consulting, speaking fees and travel grants from Allergan, Amgen, Bayer, Biogen, Cefaly, ElectroCore, Genesis Pharma, Eli Lilly, Merck-Serono, Merz, Mylan, Novartis, Roche, Sanofi-Genzyme, Specifar and Teva.

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No ethics approval or patient consent was obtained because all data used in this study were collected from previously published peer-reviewed articles.

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Kokoti, L., Drellia, K., Papadopoulos, D. et al. Placebo and nocebo phenomena in anti- CGRP monoclonal antibody trials for migraine prevention: a meta-analysis. J Neurol (2020).

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  • Episodic migraine
  • Chronic migraine
  • Anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies
  • Treatment
  • Topiramate
  • Onabotulinum toxin A