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. 2025 Sep;45(9):3331024251367767.
doi: 10.1177/03331024251367767. Epub 2025 Sep 15.

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

Jennifer Robblee  1 , Fawad A Khan  2   3 , Michael J Marmura  4 , Hope L O'Brien  5 , Lawrence D Robbins  6 , Marielle Kabbouche Samaha  7 , Morris Levin  8 , Simona Sacco  9 , Raffaele Ornello  9 , Stephanie J Nahas  4 , Heike Hesse  10 , Annika Ehrlich  11 , Adam S Sprouse-Blum  12 , Christina Sun-Edelstein  13 , Bronwyn Jenkins  14 , Elizabeth K Seng  15 , Shivang Joshi  16 , Meredith J Barad  17   18 , Mi Ji Lee  19 , Sheena K Aurora  20 , Mario Fernando Prieto Peres  21
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Free article

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

Jennifer Robblee et al. Cephalalgia. 2025 Sep.
Free article

Abstract

AimDespite its frequency in tertiary headache centers, the International Classification of Headache Disorders, 3rd edition (ICHD-3) does not include refractory migraine. Multiple definitions have been proposed with a recent 2020 proposal for both refractory migraine and resistant migraine by the European Headache Federation (EHF). The aim is to reach an international consensus on the definition of refractory migraine.MethodsThis study is a Delphi consensus carried out by a group of international experts in headache medicine. Following a focus group, a panel of 20 experts and one facilitator reviewed the EHF proposed criteria to build upon their definitions. The Delphi consensus was conducted across five rounds. Questions with >70% consensus were deemed to have strong agreement, 60-70% consensus was deemed minor agreement, and <60% deemed no agreement. A final meeting was held to discuss any concerns and specific wording.ResultsThe Delphi consensus led to the development of four key categories: refractory migraine, probable refractory migraine, resistant migraine, and treatment-responsive migraine. Similar to the EHF 2020 definitions, refractory migraine requires treatment failure of all evidence-based classes, and resistant migraine requires failure of at least three classes. Probable refractory migraine criteria were designed to account for situations where treatment access barriers may prevent trials of certain medication classes (e.g. pediatrics, low to middle-income countries, lack of insurance coverage). Finally, treatment-responsive migraine criteria were developed to allow for standardization in research studies comparing refractory or resistant migraine to migraine that is treatment-responsive.ConclusionsThese four categories may aid in enrollment for studies on pathophysiology, biomarkers, and new treatment targets. Clinically, the criteria for refractory and resistant migraine will help with clinical decision-making by reinforcing the need to try evidence-based treatments and by providing guidance regarding when to try more aggressive treatment approaches. These criteria may also increase attention to this population's disease burden to help advocate for them as a specific migraine subgroup. Field testing in diverse clinical settings will be needed, but it is recommended that ICHD-3 considers inclusion of these four categories in their appendix.

Keywords: chronic daily headache; diagnostic criteria; intractable; migraine; refractory migraine; resistant migraine.

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Conflict of interest statement

Declaration of conflicting interestsDr Jennifer Robblee 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. Dr. Robblee has received personal compensation for serving on advisory boards for Tonix and Allergan/Abbvie. Dr Robblee also discloses that a family member has partial ownership of Scottsdale Providence Recovery Center.Dr Fawad Khan discloses receiving institutional research support from Marinus, Biohaven, Teva, Lundbeck and UCB; advisory fees from Eisai, Neurelis, Marinus, Epitel, Pfizer; honorarium for speaker engagements from Amgen, UCB, SK Life Science, Lundbeck, Allergan, Lilly USA, Impel Pharmaceuticals, AbbVie; honorarium for educational programs from Natus and Stratus. He serves on the Louisiana State Medical Advisory Board in a non-paid position. In non-compensated roles, and he is a board member of the Deccan Alumni Association of North America, a non-profit professional society.Dr Michael Marmura discloses receiving institutional research support from AbbVie and Teva, and advisory fees from Lundbeck, Theranica,Dr Hope O’Brien discloses participating in a speaker bureau for AbbVie, Eli Lilly, Pfizer, Biohaven (past), BDSI (past) and Scimed; participating on an advisory board for AbbVie, Eli Lilly, Pfizer, Biohaven (past), BDSI (past); participating as a consultant for Medscape and Guidepoint; Editorial Royalties for UpToDate, Research Funding from AbbVie, Eli Lilly and Vector Psychometric Group. She also reports being the American Academy of Neurology Vice-chair MMC and an Invited Speaker; American Headache Society committee member, past chair for Underrepresented committee and an invited Speaker; United Council of Neurological Subspecialties accreditation committee member; National Headache Foundation Board member; UC Master of Health Administration Program Advisory board member; Cincinnati Eye Institute Foundation Board member; and Medscape Migraine Center of Excellence Faculty consultant.Dr Lawrence Robbins discloses being a speaker for Abbvie, Impel and IdorsiaDr Marielle Kabbouche Samaha discloses investigator support to the institution for research studies from Eli Lilly, Abbvie, Teva, NIH and PICORI direct pay to her institution. Dr Kabbouche has received direct pay as a speaker from Theranica in the last two years and as a consultant for Merz pharmaceutical.Dr Morris Levin discloses an advisor role in one-day advisory board meetings with AbbVie, Biohaven, Theranica, BDSI and Linpharma; he serves as a consultant for Percept and Neurolytics. He is a member of no speakers’ boards and has no stock shares or options in any biomedical company.Dr Simona Sacco discloses personal fees as speaker or advisor for Abbott, Allergan-Abbvie, AstraZeneca, Bayer, Boheringer, Eli Lilly, Lundbeck, Pfizer and Teva. Other roles include President for the European Stroke Organisation, editor-in-chief for Cephalalgia and Cephalalgia Reports, and assistant editor for Stroke.Dr Raffaele Ornello discloses personal fees for presentations or Advisory Boards from AbbVie, Eli Lilly, Lundbeck, Novartis, Organon, Pfizer and Teva. He is an Editorial Board Member for The Journal of Headache and Pain and Associate Editor for Frontiers in Neurology.Dr Stephanie Nahas discloses receiving honoraria for consulting from AbbVie, Amneal (ended June 2024), Axsome (ended May 2024), Eli Lilly (ended November 2024), Lundbeck (ended October 2023), Pfizer and Tonix (ended November 2023). She has received honoraria for work in education or publishing from American Academy of Neurology, American Headache Society, Diamond Headache Clinic Research and Educational Foundation, MedLink Neurology, Springer, WebMD/Medscape and Wolters-Kluwer.Dr Heike Hesse reports no disclosures.Dr Annnika Ehrlich discloses serving as a consultant, on an advisory board and on a speaker bureau for Abbvie. She has consulted for Pfizer, and served on advisory boards for eNeura, Lundbeck and Theranica. She is the advance practice provider representative to the American Headache Society board. She received an honorarium for serving on the Headache Cooperative of the Pacific board. She serves as President of the Alliance for Headache Disorders Advocacy and The Headache Alliance.Dr Adam Sprouse-Blum discloses serving as a consultant for Guidepoint.Dr Christina Sun-Edelstein discloses honoraria for speaking and consulting/advisory board participation from Teva, Lundbeck, Lilly and Pfizer. She also receives royalties from UpToDate.Dr Bronwyn Jenkins discloses educational honoraria and advisory fees from Abbvie/Allergan, Eli Lilly, Teva, Lundbeck and Pfizer; with travel grants from Care Pharmacy and Pfizer. Other roles include being Immediate Past President of the Australian and New Zealand Headache Society (ANZHS) and on the subcommittees of ethics and education for IHS.Dr Elizabeth Seng discloses serving as a consultant or on an advisory board for GlaxoSmithKline, Click Therapeutics, Theranica and Abbvie, and received research funding from the NINDS (NS096107 Principal Investigator [PI]: Seng), National Center for Complementary and Integrative Health (R01AT011005-01A1 Multiple PIs: Seng and Shallcross), the Veteran's Health Administration (the Headache Center of Excellence Research and Evaluation Center and VA HSR&D, IRP 20-002 PI: Damush) and the American Heart Association.Dr Shivang Joshi discloses honoraria for speaking from Abbvie, Scilex and Lundbeck. He has been an advisor for Abbvie, Lundbeck, Lilly, Axsome and Sermo.Dr Meredith Barad discloses consultant work for Abbvie–Migraine and Eli Lilly.Dr Mi Lee discloses personal fees as speaker or advisor from Abbvie, Eli Lilly, Lundbeck, Pfizer, Teva, Organon, CKD, SK Chemical, YuYu and NuEyne; research supports from Abbvie, Pfizer, Eli Lilly, Pfizer, Lundbeck, Novartis, Teva, Otsuka, BioHaven, Ildong, Yuhan, NuEyne, Teva and YuYu; research grants from National Research Foundation of Korea(NRF), Medical Device Development Fund grant funded by the Korea government, Korean Headache Society and Seoul National University. She is an associate editor for Cephalalgia and Headache and Pain Reports.Dr Sheena Aurora discloses being the VP for C2N diagnostics.Dr Mario Peres discloses personal fees from Ache, Allergan/AbbVie, Eli Lilly, Eurofarma, Libbs, Lundbeck, Novartis, Pfizer, Sanofi and Teva, and has received research support from Allergan/AbbVie, Eli Lilly, Eurofarma, Janssen-Cilag, Libbs, Natura, Novartis and Teva.

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