Abstract
Resistant versus refractory migraine
The challenge of defining treatment resistance in migraine has long limited both clinical management and research progress. Earlier literature used various thresholds for intractability based on the number of failed preventives, ranging from two to all categories. The European Headache Federation (EHF) 2020 consensus provided the first structured criteria distinguishing resistant from refractory migraine, defining resistant migraine as failure of at least three preventive categories and refractory migraine as a lack of response to all categories (1).
Building on this framework, the 2025 international Delphi consensus published in Cephalalgia by Robblee et al. refined and expanded the EHF definitions to enhance global applicability and facilitate research (2). Both resistant and refractory migraine require not only treatment non-response but clinical burden operationalized by at least two of the following: 1) considerable impairment in personal, educational, or occupational functioning; 2) continuous or near-continuous headache between attacks; and 3) at least eight monthly migraine days (MMD). The Delphi consensus further introduced categories for probable refractory migraine and treatment-responsive migraine to capture the clinical continuum.
Longitudinal data from the REFINE study by Pensato et al. in 2025 provided empirical support for this continuum (3). Over six months, 21.9% of patients with migraine converted to resistant migraine while 40.5% of resistant patients improved, 4.5% progressed to refractory migraine, and nearly one-third of those with refractory migraine improved. These dynamic transitions underscore that refractoriness is neither static nor absolute.
In 2025, several Cephalalgia studies explicitly enrolled individuals with treatment-resistant migraine, reflecting the field's growing focus on this population. Most applied criteria consistent with the 2020 EHF definition of resistant migraine while one adopted a pragmatic threshold of two to four prior preventive failures derived from previous pharmacologic trial conventions. Together, these studies demonstrate a commitment to systematically characterizing and addressing resistant migraine, establishing a reproducible framework for therapeutic innovation, and, ultimately, for extending research to truly refractory disease.
Advances in neurostimulation and procedural options
Several Cephalalgia publications in 2025 highlighted the therapeutic potential of neuromodulation. Clemente et al. evaluated intermittent theta-burst stimulation (iTBS) to the dorsolateral prefrontal cortex in calcitonin gene-related peptide (CGRP) monoclonal antibody non-responders with resistant migraine (n = 12) (4). They showed a trend toward reduced monthly headache day (MHD) and significantly fewer days of acute medication use. Headache intensity was also significantly reduced with a trend towards improvement in cognitive function.
Complementing this study, the TACTIC randomized controlled trial by Ornello et al. examined combined transcranial direct current stimulation (tDCS) with ongoing CGRP monoclonal antibody therapy in patients with resistant migraine (n = 30) (5). The intervention significantly reduced MMD compared with sham, though not MHD, suggesting additive preventive benefit. Collectively, these studies illustrate increasing integration of noninvasive brain stimulation with pharmacologic therapy, moving the field toward circuit-targeted and multimodal management strategies.
Evolving pharmacologic options
The 2025 Cephalalgia portfolio also expanded therapeutic evidence for resistant migraine within and beyond the CGRP pathway. In a six-month prospective real-world study, Russo et al. evaluated atogepant 60 mg daily in 100 individuals with chronic migraine and an average of six prior ineffective preventive classes (6). They met their co-primary endpoints with MMD decreasing by 7.1 days and 53% achieving at least a 50% response at 24 weeks. Similarly, the retrospective RESCUE study by Jaimes et al. investigated atogepant in patients with episodic or chronic migraine unresponsive to CGRP monoclonal antibodies (n = 44). They reported a ≥30% MHD improvement in one-quarter of participants and ≥50% improvement in nearly one-fifth (7). These findings collectively support atogepant as a rational next-line option following CGRP monoclonal antibody failure.
A 2025 six-month prospective study outside the Cephalalgia portfolio evaluated intravenous eptinezumab in patients with at least three prior preventive failures (8), consistent with resistant migraine. Participants had a mean of 10 ± 4.5 failed preventives, indicating that many likely met criteria for refractory migraine. Despite this, 41% achieved ≥50% and 62% achieved ≥30% reductions in MMD. These findings support a deliberate, target-based approach to preventive treatment selection, encouraging trial of multiple agents within the CGRP pathway before deeming migraine refractory.
Beyond CGRP, Johnson et al. reported phase 2 data in Cephalalgia on the pituitary adenylate cyclase-activating peptide (PACAP)-neutralizing monoclonal antibody LY3451838, which enrolled adults with two to four prior preventive failures, bordering the resistant migraine definition (9). Although the study did not achieve superiority over placebo, a subgroup with chronic migraine demonstrated a trend toward MMD reduction. These results complement the 2024 HOPE trial of a PACAP-ligand antibody in The New England Journal of Medicine, collectively positioning PACAP blockade as a potential mechanism for individuals with resistant migraine who have exhausted CGRP-directed options (10). These studies highlight an emerging shift toward pathway-guided treatment selection within and beyond the CGRP system.
Perspective and future directions
The collective 2025 Cephalalgia contributions signal a paradigm shift: from counting trial-and-error medication failures to understanding resistance as a dynamic state with biologic underpinnings and potential for therapeutic response (See Table 1). The field now benefits from standardized definitions, longitudinal validation, and emerging multimodal treatment evidence. Yet the absence of truly refractory migraine trials underscores a key gap.
Refractory and resistant migraine studies from Cephalalgia in 2025.
CGRP mAb = calcitonin gene-related peptide monoclonal antibody; CM = chronic migraine; DLPFC = dorsolateral prefrontal cortex; iTBS = intermittent theta burst stimulation; MHD = monthly headache days; MMD = monthly migraine days; N/A = not applicable; PACAP mAb = pituitary adenylate cyclase-activating peptide; PRNs = acute medication days; RCT = randomized controlled trial; tDCS = transcranial direct current stimulation; w = weeks.
Future research should explicitly stratify participants by resistant and refractory migraine status using standardized definitions to improve interpretability across studies. In addition to industry-led pharmaceutical trials, real-world trials will be particularly important, as these populations often require combination preventive strategies rather than single-agent interventions. Incorporating biomarker and imaging measures could help identify mechanistic differences between treatment-responsive, resistant, and refractory states, while longitudinal and epidemiologic investigations are needed to clarify their natural history and predictors. Cohorts modeled after REFINE can provide an essential framework for tracking these trajectories and guiding personalized therapeutic approaches.
Ultimately, the 2025 literature in Cephalalgia and other journals reflects steady progress toward precision care for those with resistant migraine, while reminding us that the most refractory cases remain the next frontier for discovery.
Footnotes
Acknowledgments
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Funding
The author received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests
The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: J.R. discloses grant support from Barrow Neurological foundation, investigator support from Eli Lilly and Abbvie, as well as paid Editorial relationship with MedLink Neurology and Neurodiem. J.R. has received personal compensation for serving on advisory boards for Allergan/Abbvie. J.R. also discloses that a family member has partial ownership of Scottsdale Providence Recovery Center biomedical company.
