Raffaele Ornello
Bianca Raffaelli- 1Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
- 2Department of Neurology, Headache Center, Charité Universitätsmedizin Berlin, Berlin, Germany
Editorial on the Research Topic
Spotlight on resistant and refractory migraine
Migraine is the second cause of disability worldwide and the first in young women (1). While migraine affects more than one billion people worldwide (2), it manifests with a wide spectrum of impact on individuals. This ranges from infrequent occurrences to chronic forms that severely disable those affected.
Migraine management traditionally relies on acute treatments to halt attacks when they occur and on preventive agents to avert future episodes. Failure of migraine preventive treatments is a frequent challenge in clinical practice (3). Many conventional preventive agents were initially designed for other medical conditions and subsequently applied to migraine, resulting in limited effectiveness and poor tolerability (4). The landscape shifted with the introduction of a new generation of migraine-specific treatments designed to antagonize calcitonin gene-related peptide (CGRP) and its receptor. These treatments have achieved high adherence rates and the possibility of long-term persistence due to their improved tolerability (5). In large clinical trials (6–9) and in real-world studies (10, 11), monoclonal antibodies against CGRP and the CGRP-receptor have proven effective even in patients who were previously considered resistant to traditional preventive treatments.
This transition to new migraine-specific preventive treatments prompted a redefinition of the concept of refractory migraine. In 2020, the European Headache Federation revised the definitions of resistant and refractory migraine. According to these updated definitions, migraine is considered “resistant” if an individual experiences at least 3 months of eight or more debilitating headache days monthly, despite attempting at least three classes of preventive medication, which have proven ineffective, intolerable, or contraindicated. When an individual experiences at least 6 months of eight or more debilitating headache days per month and has failed all drug classes of preventive treatment, including CGRP-targeted drugs, the condition is labeled “refractory” (12). These definitions distinguish between conditions that, although disabling, can still benefit from advanced migraine prevention (resistant migraine) and those in which drug treatment is exceedingly challenging (refractory migraine). While less common in the general population, patients with resistant migraine are encountered frequently, at least weekly, in three-quarters of headache centers, while those with refractory migraine are encountered at least weekly in half of these centers (13).
Resistant and refractory migraine are an important object of migraine research due to their representation of the most severe forms of the disorder and their role in understanding migraine pathophysiology and perpetuating factors. The introduction of new definitions may further boost efforts to comprehend the biology of resistance to treatments. This Research Topic provides a comprehensive overview of the diverse range of study designs dedicated to understanding resistant and refractory migraine, encompassing both clinical and preclinical research.
Beginning with a preclinical perspective, Zhang et al. examined fibrinogen levels and vestibular dysfunction in a mouse model of chronic migraine induced by nitroglycerin exposure. The authors observed increased fibrinogen levels and reduced performance in vestibular tests following nitroglycerin application, suggesting that chronic head pain can induce alterations in the central nervous system and even impact coagulation. While chronic migraine itself does not necessarily equate to resistance to preventive treatments, continuous exposure to head pain in chronic migraine can lead to central sensitization to pain (14), potentially resulting in increased resistance to preventive treatments.
A particularly resistant form of chronic migraine is linked to the overuse of acute medication. Research has demonstrated that continuous exposure to high doses of analgesics not only diminishes the efficacy of these drugs but can also exacerbate headaches (15). The introduction of novel migraine-specific medications can be beneficial in reversing the condition of medication overuse (16). To demonstrate the effectiveness of anti-CGRP treatments in chronic migraine with medication overuse, a randomized placebo-controlled clinical trial is currently underway—the RESOLUTION trial involving the use of eptinezumab in patients with chronic migraine and medication overuse headache (Jensen et al.). Eptinezumab, an anti-CGRP monoclonal antibody, is administered intravenously every 12 weeks. The RESOLUTION trial comprises both a placebo-controlled phase and an open-label phase of eptinezumab administration, alongside a counseling intervention known as the Brief Intervention. The aim is to reduce acute medication consumption and manage medication overuse through combined pharmacological and non-pharmacological measures. RESOLUTION started in July 2022 and is supposed to be completed in May 2024.
Monoclonal antibodies targeting the CGRP pathway represent a significant breakthrough in migraine treatment; however, they are not a universal solution. Patients who exhibit resistance to monoclonal antibodies offer an intriguing avenue for investigating the pathophysiology of resistant and refractory migraine, given that monoclonal antibodies are specifically designed to target a pathogenic mechanism of migraine. Additionally, it is worthwhile to explore whether differences exist among monoclonal antibodies, potentially attributable to variations in pharmacokinetics, pharmacodynamics, chemical structure, and interindividual differences in drug metabolism. Two pieces of evidence included in this Research Topic address the switch between different monoclonal antibodies. The report by Overeem et al. explored the switch from antibodies binding to the CGRP molecule (fremanezumab and galcanezumab) to the antibody binding to the CGRP receptor (erenumab). Erenumab was the first licensed monoclonal antibody acting on the CGRP pathway, and previous reports primarily focused on switching between anti-receptor and anti-ligand antibodies. The study by Overeem et al. examined the opposite journey, i.e., from anti-ligand to an anti-receptor antibody. Remarkably, the effectiveness results were comparable to those obtained in studies involving switches between erenumab and anti-ligand antibodies (17–20). Around 30% of patients showed a positive response, defined as ≥30% reduction in monthly headache days, after switching to another antibody class. Switching between antibody classes might therefore be a valuable solution in clinical practice if patients do not respond to the first CGRP(-receptor) antibody. The second paper (Uzun et al.) presented a case study of a patient with chronic migraine treated with all three monoclonal antibodies—erenumab, fremanezumab, and galcanezumab. This patient had initially reported constipation with erenumab and was compelled to switch from fremanezumab to galcanezumab for several months due to logistical reasons. Intriguingly, the patient exhibited distinct responses to all three antibodies and displayed varying tolerability profiles. This case study suggests that monoclonal antibodies targeting the CGRP pathway, despite their shared focus on the same pathway, may exhibit different efficacy and tolerability profiles.
An essential factor to consider in understanding resistant and refractory migraine is the role of comorbidities. Migraine is a complex biopsychosocial disorder wherein individual predisposition interacts with comorbidities and psychosocial factors that can either improve or worsen the condition (21). While the role of comorbidities is well-acknowledged in the transformation of migraine into a chronic disorder (22), their exact influence on resistance to migraine treatments remains an ongoing area of exploration.
Depression is a widely recognized comorbidity of migraine, closely intertwined with migraine-related disability (23). Within our Research Topic, a study explored the issue of comorbidity between depression and migraine, specifically focusing on genetic aspects through a Mendelian randomization approach (Lv et al.). Leveraging data from a genome-wide association study, the authors identified major depression as a risk factor for migraine, with the reverse association being less likely. This study offered an interesting perspective on the relationship between depression and migraine, highlighting shared genetics, particularly among the most severe forms of depression and the most severe forms of migraine.
In conclusion, our Research Topic provided a comprehensive overview of recent innovations across various study designs within the realm of resistant and refractory migraine research. This area continues to evolve, particularly in the era of accessible migraine-specific preventive treatments. The collaboration between preclinical and clinical research in this field promises to yield insights into migraine pathophysiology and the discovery of new treatment targets.
Author contributions
RO: Conceptualization, Writing—original draft, Writing—review and editing. BR: Conceptualization, Writing—original draft, Writing—review and editing.
Conflict of interest
RO reports personal fees from Novartis, Teva, Lilly, and Pfizer, and non-financial support from AbbVie/Allergan, Lilly, Novartis, and Teva. BR received honoraria for consulting and lectures from Abbvie/Allergan, Lilly, Lundbeck, Novartis, and Teva as well as research funding from the German Research Foundation, the German Migraine and Headache Society and Novartis.
The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. Steiner TJ, Stovner LJ, Jensen R, Uluduz D, Katsarava Z. Migraine remains second among the world's causes of disability, and first among young women: findings from GBD2019. J Headache Pain. (2020) 21:137. doi: 10.1186/s10194-020-01208-0
2. Collaborators GBDH. Global, regional, and national burden of migraine and tension-type headache, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. (2018) 17:954–76. doi: 10.1016/S1474-4422(18)30322-3
3. Hepp Z, Dodick DW, Varon SF, Chia J, Matthew N, Gillard P, et al. Persistence and switching patterns of oral migraine prophylactic medications among patients with chronic migraine: a retrospective claims analysis. Cephalalgia. (2017) 37:470–85. doi: 10.1177/0333102416678382
4. Johnson B, Freitag FG. New Approaches to Shifting the Migraine Treatment Paradigm. Front Pain Res. (2022) 3:873179. doi: 10.3389/fpain.2022.873179
5. Lampl C, Maassenvandenbrink A, Deligianni CI, Gil-Gouveia R, Jassal T, Sanchez-Del-Rio M, et al. The comparative effectiveness of migraine preventive drugs: a systematic review and network meta-analysis. J Headache Pain. (2023) 24:56. doi: 10.1186/s10194-023-01594-1
6. Reuter U, Goadsby PJ, Lanteri-Minet M, Wen S, Hours-Zesiger P, Ferrari MD, et al. Efficacy and tolerability of erenumab in patients with episodic migraine in whom two-to-four previous preventive treatments were unsuccessful: a randomised, double-blind, placebo-controlled, phase 3b study. Lancet. (2018) 392:2280–7. doi: 10.1016/S0140-6736(18)32534-0
7. Ferrari MD, Diener HC, Ning X, Galic M, Cohen JM, Yang R, et al. Fremanezumab versus placebo for migraine prevention in patients with documented failure to up to four migraine preventive medication classes (FOCUS): a randomised, double-blind, placebo-controlled, phase 3b trial. Lancet. (2019) 394:1030–40. doi: 10.1016/S0140-6736(19)31946-4
8. Mulleners WM, Kim BK, Lainez MJA, Lanteri-Minet M, Pozo-Rosich P, Wang S, et al. Safety and efficacy of galcanezumab in patients for whom previous migraine preventive medication from two to four categories had failed (CONQUER): a multicentre, randomised, double-blind, placebo-controlled, phase 3b trial. Lancet Neurol. (2020) 19:814–25. doi: 10.1016/S1474-4422(20)30279-9
9. Ashina M, Lanteri-Minet M, Ettrup A, Christoffersen CL, Josiassen MK, Phul R, et al. Efficacy and safety of eptinezumab for migraine prevention in patients with prior preventive treatment failures: subgroup analysis of the randomized, placebo-controlled DELIVER study. Cephalalgia. (2023) 43:3331024231170807. doi: 10.1177/03331024231170807
10. Lambru G, Hill B, Murphy M, Tylova I, Andreou AP. A prospective real-world analysis of erenumab in refractory chronic migraine. J Headache Pain. (2020) 21:61. doi: 10.1186/s10194-020-01127-0
11. Raffaelli B, Kalantzis R, Mecklenburg J, Overeem LH, Neeb L, Gendolla A, et al. Erenumab in chronic migraine patients who previously failed five first-line oral prophylactics and onabotulinumtoxina: a dual-center retrospective observational study. Front Neurol. (2020) 11:417. doi: 10.3389/fneur.2020.00417
12. Sacco S, Braschinsky M, Ducros A, Lampl C, Little P, Van Den Brink AMZ, et al. European headache federation consensus on the definition of resistant and refractory migraine: Developed with the endorsement of the European Migraine and Headache Alliance (EMHA). J Headache Pain. (2020) 21:76. doi: 10.1186/s10194-020-01130-5
13. Sacco S, Lampl C, De Maassen Van, Brink A, Caponnetto V, Braschinsky M, et al. Burden and attitude to resistant and refractory migraine: a survey from the European Headache Federation with the endorsement of the European Migraine and Headache Alliance. J Headache Pain. (2021) 22:39. doi: 10.1186/s10194-021-01252-4
14. Suzuki K, Suzuki S, Shiina T, Kobayashi S, Hirata K. Central sensitization in migraine: a narrative review. J Pain Res. (2022) 15:2673–82. doi: 10.2147/JPR.S329280
15. De Felice, Ossipov M, Wang MH, Lai R, Chichorro J, Meng JG, et al. Triptan-induced latent sensitization: a possible basis for medication overuse headache. Ann Neurol. (2010) 67;325–37. doi: 10.1002/ana.21897
16. Koumprentziotis IA, Mitsikostas DD. Therapies targeting CGRP signaling for medication overuse headache. Curr Opin Neurol. (2022) 35:353–9. doi: 10.1097/WCO.0000000000001061
17. Ziegeler C, May A. Non-responders to treatment with antibodies to the CGRP-Receptor may profit from a switch of antibody class. Headache. (2020) 60:469–70. doi: 10.1111/head.13729
18. Overeem LH, Peikert A, Hofacker MD, Kamm K, Ruscheweyh R, Gendolla A, et al. Effect of antibody switch in non-responders to a CGRP receptor antibody treatment in migraine: a multi-center retrospective cohort study. Cephalalgia. (2022) 42:291–301. doi: 10.1177/03331024211048765
19. Patier Ruiz I, Sánchez-Rubio Ferrández J, Cárcamo Fonfría A, Molina García T. Early experiences in switching between monoclonal antibodies in patients with nonresponsive migraine in spain: a case series. Eur Neurol. (2022) 85:4. doi: 10.1159/000518899
20. Lambru G, Caponnetto V, Hill B, Ratti S, Sacco S, Murphy M, et al. Long-term effect of switching from an anti-cgrp receptor to an anti-cgrp ligand antibody in treatment-refractory chronic migraine: a prospective real-world analysis. Neurotherapeutics. (2023) 3:1394. doi: 10.1007/s13311-023-01394-0
21. Rosignoli C, Ornello R, Onofri A, Caponnetto V, Grazzi L, Raggi A, et al. Applying a biopsychosocial model to migraine: rationale and clinical implications. J Headache Pain. (2022) 23:100. doi: 10.1186/s10194-022-01471-3
22. Torres-Ferrus M, Ursitti F, Alpuente A, Brunello F, Chiappino D, De Vries T, et al. From transformation to chronification of migraine: pathophysiological and clinical aspects. J Headache Pain. (2020) 21:42. doi: 10.1186/s10194-020-01111-8
Keywords: resistant migraine, refractory migraine, migraine prevention, migraine treatment, clinical trials, real-world evidence, experimental model
Citation: Ornello R and Raffaelli B (2023) Editorial: Spotlight on resistant and refractory migraine. Front. Neurol. 14:1291439. doi: 10.3389/fneur.2023.1291439
Received: 09 September 2023; Accepted: 15 September 2023;
Published: 27 September 2023.
Edited and reviewed by: Vincenzo Guidetti, Sapienza University of Rome, Italy
Copyright © 2023 Ornello and Raffaelli. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Raffaele Ornello, cmFmZmFlbGUub3JuZWxsbyYjeDAwMDQwO3VuaXZhcS5pdA==