CGRP-Targeted Therapies Reshape Migraine Care: Unanswered Questions on Non-Response, Safety, and Personalization
Key Insights
CGRP monoclonal antibodies and gepants (search) have transformed migraine (search) treatment by targeting the underlying neuropeptide mechanism rather than repurposing older drugs.
Only about half of migraine (search) patients achieve a useful response to CGRP pathway blockers, highlighting the need to identify other transmitters and predictors of non-response.
Key safety questions remain unresolved, including cerebrovascular outcomes, blood pressure effects, reproductive exposure, and use in pediatric and adolescent populations.
The therapeutic landscape for migraine (search) has undergone a fundamental shift, moving from largely repurposed treatments toward mechanism-based interventions targeting calcitonin gene–related peptide (CGRP), a neuropeptide now recognized as a key mediator of migraine pathophysiology. Monoclonal antibodies directed against CGRP or its receptor, together with small-molecule CGRP receptor antagonists known as gepants (search), have expanded both preventive and acute treatment options and reshaped clinical decision-making. Yet despite this progress, treatment response remains heterogeneous, and the biological basis of efficacy and non-response is not fully understood.
The CGRP Revolution and Its Limits
The identification of CGRP as a central player in migraine (search) emerged from work that challenged the once-dominant vascular theory. Peter J. Goadsby, whose research with Lars Edvinsson at Lund University helped establish the role of CGRP, noted that the vascular explanation "didn't make any sense" because migraine is predominantly one-sided, whereas a circulating factor would affect both sides of the head. The subsequent development of CGRP-targeted therapies represents, in Goadsby's words, "one of the clearest examples of translational neuroscience succeeding in medicine."
However, the clinical reality is nuanced. "Only about half of migraine (search) sufferers who are treated will have a useful response, and about 40% will have a spectacular response," Goadsby explained. "So, what that tells you is that there are other aspects of the pathway, other transmitters, that must be involved." This incomplete response rate underscores the heterogeneity of migraine and points to the need for deeper investigation into alternative targets, including PACAP and AMPA, which are being explored as rescue strategies for CGRP non-responders.
Dual Acute and Preventive Roles
One of the most intriguing features of gepants (search) is their ability to function as both acute and preventive treatments, a duality that challenges traditional distinctions in migraine (search) pharmacology. Goadsby argues that "if you attack the right mechanism, or block the right mechanism, then it really becomes a question of pharmacokinetics, absorption, and side effects as to whether you'll be able to use the medicine in both an acute and a preventive fashion." He points to eptinezumab, a monoclonal antibody given intravenously, as a clear example of a preventive treatment that works acutely, with efficacy comparable to an oral gepant.
This convergence has implications for drug development. "It makes early medicine development a lot easier, because you no longer have to think about models and systems in terms of whether they're preventive or acute; it's simply not a relevant concept," Goadsby said.
Unresolved Safety Questions
Important questions persist regarding the safety profile of CGRP-targeted therapies. A dedicated Research Topic in Frontiers highlights concerns about cerebrovascular safety, blood pressure and vascular effects, reproductive and perinatal exposure, and use during childhood and adolescence. The role of CGRP in vascular homeostasis and neurovascular coupling raises particular concern for patients with vascular comorbidities.
"Current clinical trials and real-world studies provide encouraging evidence of effectiveness and generally favourable tolerability, but long-term, comparative and population-specific data remain limited," the Research Topic editors note. They call for further investigation into treatment sequencing, switching, and combination strategies, as well as the positioning of CGRP therapies alongside neuromodulation, ditans, and other emerging approaches.
The Opioid Problem in Migraine (search) Care
Despite the advances represented by CGRP therapies, opioid-containing agents such as codeine remain entrenched in migraine (search) care. Goadsby attributes this partly to familiarity and the tendency to "lump migraine together with other pain conditions, which I think is a mistake because migraine is certainly much more than just pain." He also highlights the biological distinction between dependence risk and medication-overuse headache, noting that the latter can be produced by triptans as well as opioids. A common feature, he suggests, is that these medicines are agonists that activate receptors found in brainstem sensory-modulating regions, potentially driving downstream changes in network function.
Translational Gaps and Future Directions
Among the most pressing translational gaps, Goadsby identifies the need to understand vertigo in migraine (search), particularly vestibular migraine (search), where vertigo is a prominent and disabling component. "Very little systematic work has been done to look at that physiology, and that's one of the translational gaps we're trying to address," he said.
The Research Topic further emphasizes the need for studies on predictors of response and non-response—including clinical, imaging, genetic, and molecular biomarkers—as well as health economics, affordability, access, and implementation in routine care. Safety registries, minimum data elements, and pharmacovigilance standards for long-term follow-up are also identified as priorities.
Looking ahead, Goadsby remains optimistic about the trajectory of migraine (search) therapeutics. Drawing a parallel with triptans, which are now listed by the WHO as essential medicines, he predicts that "the same thing will happen with gepants (search) and the tablet medicines that follow." In the longer term, he suggests, "if we keep developing new medicines, you only have to come up with something really spectacular for a quarter of people every 20 years. In 100 years, you've more or less got the problem figured out."