Pharmacological mechanisms underlying neurovascular alterations related to resistant and refractory migraine: CGRP pathways and beyond

Background: Migraine is the fourth leading cause of disability worldwide. It impairs patients’ physical, emotional and social functioning, as well as their productivity. This is also due to poor pharmacological control of attacks in difficult-to-treat patients. Despite several therapeutic strategies available, including the game-changing calcitonin gene-related peptide (CGRP)-targeted small-molecule and biotechnological drugs, 40% of patients remain resistant or even refractory. The aim of this review is to highlight the neurovascular mechanisms underlying poor response or nonresponse to antimigraine drugs, with particular focus on the phenomena related to the CGRP pathway. Methods: Eligibility criteria, search strategy and information sources were established a priori: PubMed, Scopus, Cochrane Library, Web of Science and ScienceDirect were searched for studies published from database inception to the date of the last search on July 05th, 2025. Results: Non-response to antimigraine treatment is closely linked to clinical and neurobiological factors that increase the overall disease burden. Underlying these challenges are mechanisms involving genetic and epigenetic modifications that contribute to inter-individual variability in pharmacokinetics and pharmacodynamics. Additionally, CGRP as well as other neuropeptides, implicated in the neurovascular basis of migraine, may play a significant role. Targeting these mechanisms may help overcome treatment resistance and refractoriness, as defined by the European Headache Federation. Combination therapies, including the latest available treatments, might represent a promising strategy. Thus, they deserve further investigation to confirm efficacy without worsening the safety profile. Conclusions: A deeper understanding of the neurovascular pharmacology and pathophysiology of migraine is essential to pave the way for more personalized and effective treatments. tudies are needed to clarify the neuropharmacological, genetic, and epigenetic mechanisms that underlie resistance and refractoriness to pharmacological therapies, affecting the CGRP pathway both directly and indirectly. Clinical trial number: Not applicable.