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Review
. 2024 Jan:99:104943.
doi: 10.1016/j.ebiom.2023.104943. Epub 2023 Dec 23.

Resistant and refractory migraine: clinical presentation, pathophysiology, and management

Raffaele Ornello  1 , Anna P Andreou  2 , Eleonora De Matteis  1 , Tim P Jürgens  3 , Mia T Minen  4 , Simona Sacco  5
Affiliations
Review

Resistant and refractory migraine: clinical presentation, pathophysiology, and management

Raffaele Ornello et al. EBioMedicine. 2024 Jan.

Abstract

Migraine is a leading cause of disability worldwide. A minority of individuals with migraine develop resistant or refractory conditions characterised by ≥ 8 monthly days of debilitating headaches and inadequate response, intolerance, or contraindication to ≥3 or all preventive drug classes, respectively. Resistant and refractory migraine are emerging clinical definitions stemming from better knowledge of the pathophysiology of migraine and from the advent of migraine-specific preventive treatments. Resistant migraine mostly results from drug failures, while refractory migraine has complex and still unknown mechanisms that impair the efficacy of preventive treatments. Individuals with resistant migraine can be treated with migraine-specific preventive drugs. The management of refractory migraine is challenging and often unsuccessful, being based on combinations of different drugs and non-pharmacological treatment. Future research should aim to identify individuals at risk of developing treatment failures, prevent the condition, investigate the mechanisms of refractoriness to treatments, and find effective treatment strategies.

Keywords: CGRP; Migraine-related disability; Non-pharmacological treatments; Refractory migraine; Resistant migraine.

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Conflict of interest statement

Declaration of interests RO reports consulting fees from Teva, direct payments from Teva, Eli Lilly, Novartis, AbbVie, and Pfizer, support for attending meetings and/or travel from Novartis and Teva, participation to advisory boards from Eli Lilly, and other support from Novartis and Allergan-AbbVie; he is a Junior Editorial Board member of The Journal of Headache and Pain. SS reports grants from Novartis and Uriach, consulting fees from Abbott, Allergan, AbbVie, Novartis, Teva, Eli Lilly, Pfizer, Lundbeck, Novo Nordisk, and AstraZeneca, direct payment from Abbott, Allergan-AbbVie, Novartis, Teva, Eli Lilly, Pfizer, Lundbeck, Novo Nordisk, and AstraZeneca, support for attending meetings and/or travel from Eli Lilly, Novartis, Teva, and Lundbeck, receipt of equipment from Allergan-AbbVie and Novo Nordisk; she is President Elect of the European Stroke Organisation and Editor-in-Chief of Cephalalgia. APA received grants or contracts from Brain Research UK, Medical Research Council, Medical Research Foundation, Rosetrees, and Migraine Trust, consulting fees from Eli Lilly and AbbVie, direct payment from Eli Lilly, AbbVie, eNeura, Autonomic Technologies, and Novartis, participation to advisory boards from Eli Lilly and AbbVie; she is Chair of the Communications Committee of the International Headache Society and Chair of the Headache SIG of the British Pain Society. TPJ reports grants from the European Regional Development Funds (ERDF), Innovation Fund of the Federal Joint Committee (Germany) and Novartis; compensation from Allergan, Abbvie, Chordate, Grünenthal, Hormosan, Lilly, Lundbeck, Novartis, Pfizer, Teva and Sanofi for consultant services and/or speaker honoraria; he is President of the German Migraine and Headache Society and member of the Educational Committee of the German Pain Society. EDM and MTM report no conflict of interest.

Figures

Fig. 1
Fig. 1
Definitions of difficult-to-treat migraine proposed through the years. Definitions of refractory migraine changed over time. The most recent European Headache Federation consensus distinguishes resistant and refractory migraine according to the number of contraindication or failure of prior preventative classes and of consecutive months with at least 8 debilitating headaches. Treatment failure is declared after an adequate attempt (i.e., adequate dose and duration: 2 months for oral preventatives, 3 months for monoclonal antibodies targeting the calcitonin gene-related peptide, 6 months for onabotulinumtoxinA). An attack is debilitating when causes serious impairment to daily activities despite the use of an adequate dose of symptomatic medication. Abbreviations: AHS: American Headache Society; EHF: European Headache Federation; ICHD: International Classification of Headache Disorders; MO: medication overuse; MIDAS: Migraine Disability Assessment.
Fig. 2
Fig. 2
a. Characteristics of resistant and refractory migraine. b. The importance of residual monthly migraine days. c. Prevalence of resistant and refractory migraine in headache centres.a. Individuals with high frequency episodic or chronic migraine might meet definition of resistant and refractory migraine when reporting a high disability burden and failures of different classes of preventatives. Most individuals with refractory migraine have chronic migraine. Resistant migraine still has therapeutic options to ameliorate the condition, but may also eventually evolve to refractory migraine. b. The residual burden of migraine after prevention could be significant even if the preventative has a high relative efficacy; in those subjects, the residual burden of migraine could be similar to that of individuals with low response to preventive treatments. c. Proportion of clinicians reporting frequent (weekly to daily) visits to individuals with resistant or refractory migraine. Data from the Burden and Attitude towards Resistant and Refractory migraine (BARR) survey.
Fig. 3
Fig. 3
Factors leading to or promoting resistance and refractoriness to preventative migraine drugs. Main factors that can play a role in the onset and progression of resistant and refractory migraine. Those factors can be related to the drug (light green), individual comorbidities (light yellow), lifestyle (light red) and the disease (dark green) such as misdiagnosis of migraine—i.e., correct diagnosis many years from onset—and delayed care, which can also contribute to resistance to treatments. See sections 4 and 5 of the text for references.
Fig. 4
Fig. 4
Management of resistant and refractory migraine. Approaches to resistant and refractory migraine, which includes a correct diagnosis, an adequate management of medication overuse and a proper choice of preventative strategies according to individuals' characteristics. The proposed approaches are not specific to either resistant or refractory migraine but represent priorities to each condition.
See this image and copyright information in PMC

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