Four anti-CGRP MAbs are currently in use for the prevention of episodic and chronic migraine: erenumab, which targets the CGRP receptor, and fremanezumab, galcanezumab, and eptinezumab, which target the CGRP ligand. In addition, anti-CGRP MAbs have shown some degree of success as preventive treatments for other headache disorders, such as cluster and post-traumatic headaches. There are, however, unmet needs associated with the prophylactic management of these headache disorders, because of inadequate headache frequency reduction in about one-third of migraine patients and an even higher percentage of treatment failure in cluster and post-traumatic headache patients. Significant unmet needs are also present in the symptomatic management of these headache disorders. To overcome these challenges, new acute pharmacological options for headaches have been studied in the last few years, including gepants, a class of small molecules that target the CGRP receptor, and ditans, a class of non-triptan serotonin receptor antagonists. Gepants have been also explored for migraine prevention. This Special Issue summarizes our existing knowledge on the advantages and limitations of modern therapies for headache disorders, highlights open clinical and pathogenetic issues, and explores future directions for research. The Co-Editors and I are confident that it will serve as a reference point for those seeking to understand why, when, and how to treat headache patients with monoclonal antibodies that target CGRP, gepants or ditans.

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