BACKGROUND: Calcitonin gene-related peptide (CGRP) is a key mediator in migraine pathophysiology, and the development of gepants, novel CGRP receptor antagonists, has expanded therapeutic options for both acute and preventive treatment. This scoping review aims to synthesize current evidence on the pharmacology, clinical applications, safety, and combination strategies of gepants. METHODS: A scoping review was conducted following PRISMA-ScR recommendations. A comprehensive search of PubMed/MEDLINE and Scopus was performed from database inception to July 2025, with an additional search in January 2026 for real-world studies. Data were extracted and summarized narratively without quantitative synthesis. RESULTS: Second- and third-generation gepants, including ubrogepant, rimegepant, atogepant, and zavegepant, overcome the hepatotoxicity and bioavailability limitations of earlier compounds. Pharmacokinetic properties determine their suitability for both acute and preventive use, and their lack of vasoconstrictive activity makes them suitable for patients with cardiovascular comorbidities. Most are metabolized by cytochrome 3A4 and are substrates for efflux transporters, necessitating awareness of drug-drug interactions, although no clinically significant interactions with common migraine preventive medications have been reported. Preclinical and preliminary clinical evidence indicates a low likelihood of gepants inducing medication-overuse headache. Combination therapy with other migraine treatments is mechanistically plausible and supported by early pharmacokinetic and safety data, though robust clinical trial evidence remains limited. CONCLUSION: Gepants represent an effective and well-tolerated class of CGRP-targeted therapies with flexible use in acute and preventive migraine management. Their pharmacological properties support individualized treatment strategies and potential combination approaches; however, long-term safety, optimal positioning, and the efficacy of combination regimens require further investigation.
Iannone et al. (Tue,) studied this question.