Different routes of administration in chronic migraine prevention lead to different placebo responses: a meta-analysis.

Placebo response is a powerful determinant of health outcomes in several disorders. Meta-analysis of clinical trials in pain conditions shows that it can contribute up to 75% of the overall treatment effect. Placebo response deriving from different routes of administration is poorly understood in primary headaches' pharmacological prevention. Thus, this meta-analysis aims to analyze how different routes of administration affect the placebo response in chronic migraine (CM). We conducted a meta-analysis with 7 randomized, double-blind, placebo-controlled clinical trials, with 5672 patients older than 18 years who suffer from CM without associated comorbidities. We compared those who received a placebo-administered agent for the preventive treatment of CM subcutaneous, endovenous, or oral against those who received multiple head injections. The primary outcome was reduction in the number of days with migraine in the month assessed at 12, 16, and 24 weeks of treatment compared with baseline. Our study shows that placebo responses were greater when botulinum toxin was applied to the head, followed by intravenous injection of the anti-calcitonin gene-related peptide monoclonal antibody eptinezumab. Oral topiramate and subcutaneous monoclonal showed no difference, being inferior to head injection. Administration route affects placebo responses in CM preventive treatment. Elucidating the underlying mechanisms that mediate a placebo response in migraine treatment is beneficial to clinical practice and drug development, especially when comparing drugs with different routes of administration, with the effect of application to the head being superior to the other routes in this study. In our study the placebo response accounted for approximately 75% of the therapeutic gain in the treatment of CM.