LAUSR

ABSTRACT Introduction Migraine is the leading cause of years lived with disability in people under 50. Electrophysiological phenomena at the basis of prodromal and headache attack phases and of chronification processes involve calcitonin-gene related peptide (CGRP) as a fundamental player become a game changer of migraine pharmacotherapy. Areas covered The purpose of the present review is to retrace fundamental stages of CGRP from its discovery to the role in migraine pathogenesis and therapy to underscore the change of paradigm offered by the newly approved small molecules to antagonize CGRP receptor, the gepants. In particular, the development of this new class is gone over from the initial synthesis of C-terminus truncated CGRP antagonists to the development of the first generation of gepants ending with Zavegepant that can be considered the third generation. Expert opinion The history of CGRP in migraine draws the successful road to follow for key signaling pathways of modulation of nociceptive facilitation by diencephalic and brainstem nuclei, including dopaminergic neurotransmission, orexin A and the large-conductance calcium-activated potassium (BKCa) and ATP-sensitive potassium (KATP) channels also investigating the potential of essential oils and the role of polymorphisms. Real-world post marketing long-term data are needed for gepants.