Reaching international consensus on the definition of refractory migraine using the Delphi method.

BackgroundNew treatments are currently offering new opportunities and challenges in clinical management and research in the migraine field. There is the need of homogenous criteria to identify candidates for treatment escalation as well as of reliable criteria to identify refractoriness to treatment. To overcome those issues, the European Headache Federation (EHF) issued a Consensus document to propose criteria to approach difficult-to-treat migraine patients in a standardized way. The Consensus proposed well-defined criteria for resistant migraine (i.e., patients who do not respond to some treatment but who have residual therapeutic opportunities) and refractory migraine (i.e., patients who still have debilitating migraine despite maximal treatment efforts).The aim of this study was to better understand the perceived impact of resistant and refractory migraine and the attitude of physicians involved in migraine care toward those conditions.MethodsWe conducted a web-questionnaire-based cross-sectional international study involving physicians with interest in headache care.ResultsThere were 277 questionnaires available for analysis. A relevant proportion of participants reported that patients with resistant and refractory migraine were frequently seen in their clinical practice (49.5% for resistant and 28.9% for refractory migraine); percentages were higher when considering only those working in specialized headache centers (75% and 46% respectively). However, many physicians reported low or moderate confidence in managing resistant (8.1% and 43.3%, respectively) and refractory (20.7% and 48.4%, respectively) migraine patients; confidence in treating resistant and refractory migraine patients was different according to the level of care and to the number of patients visited per week. Patients with resistant and refractory migraine were infrequently referred to more specialized centers (12% and 19%, respectively); also in this case, figures were different according to the level of care.ConclusionsThis report highlights the clinical relevance of difficult-to-treat migraine and the presence of unmet needs in this field. There is the need of more evidence regarding the management of those patients and clear guidance referring to the organization of care and available opportunities.

There are a number of reasons to attempt to define and classify refractory headache disorders. Particularly important are the potential benefits in the areas of research, treatment, and medical cost reimbursement. There are challenges in attempting to classify refractory forms of headaches, including the lack of biological or other objective markers and a lack of consensus among practitioners as to what qualifies as refractoriness, or even if a separate category for refractory migraine and other refractory headaches needs to be established. A definition of refractory migraine has been proposed by Schulman et al in this issue ("Defining Refractory Migraine [RM] and Refractory Chronic Migraine [RCM]: Proposed Criteria for the Refractory Headache Special Interests Section of the American Headache Society"), which should be tested for validity and usefulness. It seems reasonable to consider adding this defined syndrome to the International Classification of Headache Disorders, second edition (ICHD-II). In this article, options for adding refractory headache syndromes to the ICHD are discussed with pros and cons for each. Two "best" options for adding the disorder "refractory migraine" to the ICHD are presented along with an illustrative case example.

BackgroundSome individuals with migraine fail to respond adequately to preventive treatments, bearing most of migraine burden. The European Headache Federation (EHF) classifies these individuals into resistant migraine (ResM) or refractory migraine (RefM) according to treatment failures, debilitating headache days, and disease duration. We investigated the evolution of these categories over six months in patients treated at tertiary headache centers and whether they accurately reflect disability and burden.MethodsParticipants from the multicenter, prospective REFINE study were classified into three categories of treatment responsiveness, namely RefM, ResM, and non-refractory non-resistant migraine (NRNRM). The primary objective was to determine the trajectories of category changes over six months. Secondary outcomes included changes in the 6-item Headache Impact Test (HIT-6), Headache-Attributed Lost Time (HALT), and Hospital Anxiety and Depression Scale (HADS-A and HADS-D) scores.ResultsOverall, 489 participants were included with a median age of 45 years (IQR = 36–53); 389 participants (79.7%) were female; 256 (52.4%) had NRNRM, 178 (36.4%) ResM, and 55 (11.2%) RefM. At follow-up, 200/256 (78.1%) NRNRM remained stable, while 56/256 (21.9%) progressed to ResM. Among those with ResM, 98/178 (55.1%) remained stable, 72/178 (40.5%) improved to NRNRM, and 8/178 (4.5%) worsened to RefM. Among participants with RefM, 37/55 (67.3%) remained stable, while 18/55 (32.7%) improved to NRNRM. Participants with RefM and ResM presented significantly higher scores at baseline than those with NRNRM. Over time, HIT-6, HALT, and HADS-A scores improved substantially in the overall cohort (p < 0.001, p < 0.001, and p = 0.006, respectively). Improvements were observed in participants with ResM across all scores and HIT-6 and HALT for NRNRM, but no improvement was noted in participants with RefM.ConclusionsOver six months, ~ 40% of ResM and ~ 30% of RefM individuals improved to NRNRM, while ~ 20% of NRNRM developed treatment resistance after receiving care in tertiary headache centers. Participants with ResM had a better prognosis than those with RefM. While both ResM and RefM reflect high migraine disability burden, they might present relevant differences in their management and prognosis.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-025-02126-9.

Migraine is one of the main causes of disability in modern world. Treatment of chronic refractory migraine (RCM) would be a challenge even for experienced physician. The aim of this study was to analyze the effect of combination therapy for RCM: greater occipital nerve’s (GON) pulsed radiofrequency (PRF) and botulinum toxin injections. We observed 6 female patients, suffering from RCM according to the European Headache Federation criteria. All patients had long history of migraine (5–44 years) with conservative treatment failure (at least three medication groups). Their migraine could be classified as refractory for long period of time (1–10 years). All of our patients passed a combination of PRF and BTA injection as consecutive 1-day treatments. Botulinum toxin type A injections were done in accordance to the PREEMPT protocol, followed by ultrasound-guided PRF of GONs bilateral. The observation period was 6 months after the procedure. We observed a positive response to treatment in all patients with dramatic reduction of pain intensity (from 7 ± 1 to 2 ± 2 on NRS scale) and significant decrease in the number of headache days (from 22 ± 5 to 4 ± 4) during first month after treatment. Two patients (30%) were pain free after the treatment until the end of the observation. No adverse effects were registered. Bilateral GON’s PRF followed by botulinum toxin therapy as 1-day treatment may be a useful option for the treatment of refractory chronic migraine. These interventional procedures are effective, minimally invasive, inexpensive, safe, and well-tolerated and can be performed on an outpatient basis.

Physicians, researchers and clinical trial developers from around the world, working in the headache field, speak a common language based on the International Classification of Headache Disorders (ICHD). The current ICHD-3 does not include a definition of refractoriness for primary headaches. To fill the gap, the European Headache Federation (EHF) developed new consensus criteria for refractory chronic migraine (rCM) and refractory chronic cluster headache (rCCH) particularly for the purposes of randomized-controlled trials (RCTs) involving experimental medications and neuromodulation, but they may also help for referral from a primary care provider to a headache specialist and for medical cost reimbursement. EHF definitions of rCM and rCCH have to be considered as a useful and mandatory tool in any multidisciplinary or innovative therapeutic approach.

To gauge consensus regarding a proposed definition for refractory migraine proposed by Refractory Headache Special Interest Section, and where its use would be most appropriate. Headache experts have long recognized that a subgroup of headache sufferers remains refractory to treatment. Although different groups have proposed criteria to define refractory migraine, the definition remains controversial. The Refractory Headache Special Interest Section of the American Headache Society developed a definition through a consensus process, assisted by a literature review and initial membership survey. A 12-item questionnaire was distributed at the American Headache Society meeting in 2007 during a platform session and at the Refractory Headache Special Interest Section symposium. The same questionnaire was subsequently sent to all American Headache Society members via e-mail. A total of 151 responses from AHS members form the basis of this report. The survey instrument was designed using Survey Monkey. Frequencies and percentages of the survey were used to describe survey responses. American Headache Society members agreed that a definition for refractory migraine is needed (91%) that it should be added to the International Classification of Headache Disorders-2 (86%), and that refractory forms of non-migraine headache disorders should be defined (87%). Responders believed a refractory migraine definition would be of greatest value in selecting patients for clinical drug trials. The current refractory migraine definition requires a diagnosis of migraine, interference with function or quality of life despite modification of lifestyle factors, and adequate trials of acute and preventive medicines with established efficacy. The proposed criteria for the refractory migraine definition require failing 2 preventive medications to meet the threshold for failure. Although 42% of respondents agreed with the working definition of refractory migraine, 43% favored increasing the number to 3 (50%) or 4 (26%) preventive treatment failures. When respondents were asked if they felt that the proposed definition was appropriate to select patients for invasive procedures (patent foramen ovale repair or stimulators) only 44% agreed. There is a consensus for a need for a definition for refractory migraine and that it should be added to the International Classification of Headache Disorder-2. There was also general agreement by the responders that refractory forms of non-migraine headache disorders should be defined.

The debate on the clinical definition of refractory Chronic Migraine (rCM) is still far to be concluded. The importance to create a clinical framing of these rCM patients resides in the complete disability they show, in the high risk of serious adverse events from acute and preventative drugs and in the uncontrolled application of therapeutic techniques not yet validated.The European Headache Federation Expert Group on rCM presents hereby the updated definition criteria for this harmful subset of headache disorders. This attempt wants to be the first impulse towards the correct identification of these patients, the correct application of innovative therapeutic techniques and lastly aim to be acknowledged as clinical entity in the next definitive version of the International Classification of Headache Disorders 3 (ICHD-3 beta).

In this letter, we present the Austrian proposal for diagnostic criteria of refractory chronic migraine and we discuss the consensensus statement of the European Headache Feaderation. We focus in particular on the definition of adequate prophylactic treatment, the management of medication overuse and the requirement for CSF analyses in patients with refractory chronic migraine. In our proposal, the criteria for adequate treatment and recommendations for dealing with medication overuse are more explicit than in the EHF proposal, whereas the requirements for CSF analyses and measurement of CSF pressure are not as strict.

Background: Despite the emergence of novel targeted therapies, refractory migraine remains a major clinical challenge. According to the 2020 European Headache Federation (EHF) Consensus, patients experiencing ≥8 debilitating headache days per month are classified as "resistant" if they have failed at least three classes of preventive treatments, and as "refractory" if they have failed all available classes. Notably, treatments targeting the calcitonin gene-related peptide (CGRP) pathway—monoclonal antibodies and small-molecule antagonists—are currently grouped together within this classification. However, recent real-world evidence suggests that atogepant, a small-molecule CGRP receptor antagonist, may be effective in patients with resistant migraine phenotypes, including those who have failed anti-CGRP monoclonal antibodies. This study aimed to evaluate the effectiveness, safety, and tolerability of atogepant 60 mg daily over 24 weeks in patients with refractory migraine. Methods: This was an observational, prospective, non-randomized, open-label study conducted over a 24-week period. Twenty patients with treatment-refractory chronic migraine received atogepant 60 mg once daily. The co-primary effectiveness endpoints were: (i) change in monthly migraine days (MMDs) from baseline to Weeks 12 and 24; and (ii) the proportion of responders, defined as patients achieving a ≥50% reduction in MMDs from baseline at each time point. Results: MMDs decreased by a mean of 3.7 days at Week 12 (SD 5.8; p=0.049) and 4.1 days at Week 24 (SD 6.0; p=0.047). The proportion of patients achieving a ≥50% reduction in MMDs was 30% at Week 12 and 35% at Week 24. Conclusion: These findings support the effectiveness of atogepant 60 mg daily as a preventive treatment in patients with refractory migraine. Notably, the observed clinical benefit in individuals who had failed all available migraine preventive drug classes challenges current EHF criteria, suggesting that atogepant and CGRP-targeting monoclonal antibodies should be considered as distinct therapeutic options. Several molecular mechanisms may explain the enhanced inhibition of CGRP signalling with atogepant. Unlike monoclonal antibodies, atogepant is co-internalized with the CGRP receptor, allowing it to inhibit signalling within endosomes. Additionally, atogepant binds to receptors for amylin and adrenomedullin, neuropeptides implicated in migraine pathophysiology, as supported by provocation studies.

The proposed definitions for refractory migraine (RM) and refractory chronic migraine (R-CM) comprise 5 key components that must be operationalized for epidemiologic research. Persons with RM or R-CM must meet the second edition of the International Classification of Headache Disorders criteria for migraine or chronic migraine. They must experience significant interference with function or quality of life due to headaches. This interference must be present despite adequate treatment in 3 domains: modification of triggers and lifestyle factors, acute medication, and preventive medicines. The epidemiologic data which address these 5 components will be reviewed herein though specifically designed studies will be required to fully explore RM and R-CM. In addition, 2 "modifiers" of RM and R-CM have been proposed; one addresses medication overuse and the other considers disability based on a Migraine Disability Assessment score of 11 or greater. The epidemiology of these modifiers is discussed.

Correspondence/Findings We appreciated the Comment Letter from the Austrian colleagues referring to the recently published Consensus Statement on clinical definition of refractory Chronic Migraine (rCM), authored by the European Headache Federation (EHF) Expert Group [1,2]. In this Comment Letter [3] the authors present Chronische Migrane: Therapie, Therapieresistenz und Neuromodulation – Ein Konsensus-Statement, a consensus statement on CM with and without medication overuse, therapeutic options, with particular focus on patients selection for Occipital Nerve Stimulation (ONS). This article was published in a non-indexed national journal, supported by the device manufacturer [4]. We would like to underline the structural difference existing between the EHF paper and the Austrian one: the first one is finalized to the clinical definition of rCM and the proposal of criteria to be evaluated for a future inclusion of rCM as 3-digit diagnosis of CM in the next ICHD-3 (1.3.1 Refractory Chronic Migraine). The latter mostly targets to patients selection for ONS: “Diagnostic criteria for rCM and guidelines for managing targets patients with rCM and selecting candidates for invasive neuromodulation are crucial issues [4]”. In contrast, the EHF Consensus clearly states “The European Headache Federation felt to develop new consensus criteria that define rCM, particularly for the purposes of controlled clinical trials that involve experimental medication and neuromodulation independently from the non-invasive therapies or the implantable devices [1,5]”. In particular four points should be addressed:

Frecuencia e impacto del trastorno por estrés postraumático y los eventos vitales traumáticos en pacientes con migraña

Looking for the identikit of refractory chronic migraine patients in the CGRP-monoclonal antibodies scenario: Insight from the real-word experience

Refractory migraine is a poorly described complication of migraine in which migraine has chronified and become resistant to standard treatments. The true prevalence is unknown, but medication resistance is common in headache clinic patient populations. Given the lack of response to treatment, this patient population is extremely difficult to treat with limited guidance in the literature. To review the diagnostic, pathophysiological, and management challenges in the refractory migraine population. There are no accepted, or even ICHD-3 appendix, diagnostic criteria for refractory migraine though several proposed criteria exist. Current proposed criteria often have low bars for refractoriness while also not meeting the needs of pediatrics, lower socioeconomic status, and developing nations. Pathophysiology is unknown but can be hypothesized as a persistent "on" state as a progression from chronic migraine with increasing central sensitization, but there may be heterogeneity in the underlying pathophysiology. No guidelines exist for treatment of refractory migraine; once all guideline-based treatments are tried, treatment consists of n-of-1 treatment trials paired with non-pharmacologic management. Refractory migraine is poorly described diagnostically, its pathophysiology can only be guessed at by extension of chronic migraine, and treatment is more the art than science of medicine. Navigating care of this refractory population will require multidisciplinary care models and an emphasis on future research to answer these unknowns.

In the absence of a biological marker and expert consensus on the best approach to classify chronic migraine (CM), recent revised criteria for this disease has been proposed by the Headache Classification Committee of the International Headache Society. This revised criteria for CM is now presented in the Appendix. Herein we field test the revised criteria for CM. We included individuals with transformed migraine with or without medication overuse (TM+ and TM–), according to the criteria proposed by Silberstein and Lipton, since this criterion has been largely used before the Second Edition of the International Classification of the Headache Disorders (ICHD-2). We assessed the proportion of subjects that fulfilled ICHD-2 criteria for CM or probable chronic migraine with probable medication overuse (CM+), as well as the revised ICHD-2 (ICHD-2R) criteria for CM (15 days of headache, 8 days of migraine or migraine-specific acute medication use—ergotamine or triptans). We also tested the ICHD-2R vs. three proposals. In proposal 1, CM/CM+ would require at least 15 days of migraine or probable migraine per month. Proposal 2 required 15 days of headache per month and at least 50% of these days were migraine or probable migraine. Proposal 3 required 15 days of headache and at least 8 days of migraine or probable migraine per month. Of the 158 patients with TM–, just 5.6% met ICHD-2 criteria for CM. According to the ICHD-2R, a total of 92.4% met criteria for CM (P < 0.001 vs. ICHD-2). The ICHD-2R criterion performed better than proposal 1 (47.8% of agreement, P < 0.01) and was not statistically different from proposals 2 (87.9%) and 3 (94.9%). Subjects with TM+ should be classified as medication overuse headache (MOH), and not CM+, according to the ICHD-2R. Nonetheless, we assessed the proportion of them who had 8 days of migraine per month. Of the 399 individuals with TM+, just 10.2% could be classified as CM+ in the ICHD-2. However, most (349, 86.9%) had 8 days of migraine per month and could be classified as MOH and probable CM in the ICHD-2R(P < 0.001 vs. ICHD-2). We conclude that the ICHD-2R addresses most of the criticism towards the ICHD-2 and should be adopted in clinical practice and research. In the population where use of specific acute migraine medications is less common, the agreement between ICHD-2R CM and TM may be less robust.