Calcitonin Gene-Related Peptide-targeted Therapies in Migraine: A Critical Appraisal of Current Evidence, Clinical Advances and Future Perspectives

Migraine is among the leading causes of years lived with disability worldwide, yet for several decades its preventive pharmacology was borrowed from cardiology, epilepsy and psychiatry. Therapies directed at calcitonin gene-related peptide and its receptor constitute the first preventive class designed from migraine-specific biology, and eight agents belonging to two structural families, injectable monoclonal antibodies and small-molecule receptor antagonists known as gepants, are now in clinical use. This critical narrative review examines what the accumulated randomised, observational and pharmacovigilance evidence does and does not establish about this class in adults. Literature was identified through structured searching of biomedical and multidisciplinary scholarly databases and indexes, supplemented by backward and forward citation tracking and by examination of professional guidance, with a final search date of 15 July 2026. Studies were appraised for design adequacy, comparator choice, outcome definition, generalisability and consistency, and the evidence was organised thematically rather than study by study. Across pivotal trials the class produces reproducible but numerically modest reductions in monthly migraine days relative to placebo, typically between one and three days, while responder analyses and real-world cohorts identify a substantial subgroup deriving much larger benefit. The most defensible advantage over established oral preventive drugs lies in tolerability, treatment persistence and speed of onset rather than in average efficacy, and head-to-head and network meta-analytic evidence supports this reading. Several uncertainties persist: the biological basis of non-response, the interpretation of circulating peptide concentrations, the durability of benefit after treatment cessation, vascular safety in populations excluded from trials, the near absence of paediatric and pregnancy evidence, and the concentration of both research and access in high-income settings. Confidence in short-term efficacy and tolerability is high, whereas confidence in long-term safety, disease modification and equitable applicability remains limited. Research priorities include mechanistic stratification, pragmatic active-comparator trials, structured discontinuation studies and evidence generation beyond high-income health systems.