Combination behavioral and pharmacological interventions through telehealth platforms: Opportunities for increasing access and optimizing migraine outcomes

Migraine is a disease process that is characterized by disabling attacks of headache, hypersensitivity to sensory stimulation, gastrointestinal symptoms, as well as other cognitive and affective symptoms. Treatment options should be personalized and can be pharmacological, non-pharmacological, or both based on a variety of factors including patient preference, efficacy, and adherence. Non-pharmacologic treatments are especially underutilized for many reasons, including access barriers. Options tend to be binary, either medication or behavioral intervention, without concomitant approaches. This Perspective article explores the promising potential of integrated preventive treatments for migraine management, combining behavioral therapies, specifically acceptance and commitment therapy (ACT), with pharmacological interventions targeting the calcitonin gene-related peptide (CGRP) pathways. Our objective is to discuss the therapeutic potential and practical research considerations of this integrative approach for enhancing optimal patient outcomes. Based on research evidence, the American Headache Society (AHS) has endorsed various types of behavioral therapies for migraine, including in combination.1 Randomized controlled studies to support these recommendations include a well-designed pediatric trial investigating the combined use of cognitive behavioral therapy (CBT) and amitriptyline for chronic migraine,2 and an adult study investigating propranolol, behavioral management, or its combination.3 In a recent systematic review, Treadwell et al.4 underwent a thorough evaluation of behavioral interventions for migraine prevention in adults and children, as part of a Patient-Centered Outcomes Research Institute and Agency for Healthcare Research and Quality publication, prepared by the Evidence-based Practice Centers. In their review of 45 behavioral interventions for migraine, the authors highlight few rigorous well-designed trials that study behavioral interventions for migraine, let alone in concert with pharmacologic treatment.4 Collectively, the analysis demonstrated that behavioral interventions reduce migraine/headache attack frequency in adults. However, the strength of evidence was low, which may be because these studies were structured for pharmacologic clinical trials, which do not necessarily translate to behavioral trials.5 Many of the combined biobehavioral and pharmacological studies reviewed permitted the use of various pharmacological preventives.4 This variability often complicates the ability to attribute effects specifically to the interventions under study, which is a notable limitation. Historically, the impact of targeted migraine-specific preventives could not be fully assessed due to the reliance on older non-specific medications; however, the introduction of new pharmacological treatments targeting the CGRP pathways has significantly altered this landscape. According to the AHS, CGRP inhibitors should be considered as a first-line treatment for migraine prevention.6 These newer medications have been shown to reduce migraine burden and associated disability, with impressive responder rates of 50–75%. Additionally, these drugs are characterized by their excellent safety profiles, tolerability, and high levels of patient adherence. Taken together, there is a need for rigorous comparative effectiveness studies, including those that investigate CGRP monoclonal antibodies (mAbs), innovative research designs (e.g., multiphasic optimization strategies, SMART designs) that will facilitate the optimization of bio-behavioral intervention components, and/or sequencing of evidence-based interventions. We believe ACT has a therapeutic potential for migraine. While understudied, it is currently being studied for its efficacy in reducing migraine disability.7 The effects of ACT in treating migraine are primarily based on its ability to enhance psychological flexibility, helping individuals to accept their pain without judgment and commit to actions that align with their values, despite patients’ discomfort. ACT is a third-wave biobehavioral modality that focuses on cognitive defusion. It varies from CBT in that patients learn to integrate the diagnosis into their lives, and to focus on their capacity to live a full life, as opposed to pain reduction more directly. ACT is used for depression and other medical illnesses and has been found to improve patients’ relationships, work, and personal growth.8 Our group performed a pilot study and has published our outcomes data.9 We incorporated these principles into our pilot study, “Acceptance and Commitment Therapy for Migraine,” conducted at Brigham and Women's Hospital.10 Originally, we had planned an in-person group intervention for this study, allowing participants on varied or no preventive medications; however, due to the COVID-19 pandemic, we transitioned to delivering the intervention remotely via a secure Zoom platform. Through a qualitative review and validated surveys, we found that patients preferred the remote format and were able to complete the full sequence of treatments. There is a critical need for telehealth-based interventions given the scarcity of behavioral medicine providers with expertise in migraine/pain management. In addition, telehealth is especially crucial for individuals in rural or underserved areas who face substantial barriers to accessing effective treatments. Further studies are necessary to determine the benefits and potential harm of digital health/telehealth strategies, especially in terms of increasing access, adherence, and health equity.4 Based on this, we are planning a feasibility study; our intention is to include a diverse participant pool with representation by age, sex, gender, socioeconomic status, and geography to ensure the study's findings are widely applicable. Presently, there are disparities in technological access, influenced by health equity factors that limit some groups’ participation in telehealth-based interventions. Although these barriers are challenging, they are crucial to address in our study design to improve migraine treatment practices and accessibility. Further, we propose a feasibility study to assess the utility of these new injectable CGRP mAbs, specifically combined with ACT. In the meantime, a well-designed study focused on recruitment and retention of individuals with migraine using CGRP mAbs and offered ACT could yield promising results, setting a foundation for best practices in migraine management. While rimegepant and atogepant are also considered first-line treatments, we will standardize the use of CGRP mAbs for the proposed clinical trial to maintain consistency. Furthermore, we hope to conduct a fully powered trial with a robust sample size, designed specifically to interrogate efficacy rather than relying on pilot-level data. Recognizing that the field has often been constrained by overdependence on small-sample pilot studies, our approach focuses on constructing a trial that meets stringent statistical power requirements to yield significant results.4 This shift is important as preliminary studies, while useful for refining feasibility and intervention delivery, do not provide the comprehensive data needed for conclusive outcomes. To address the episodic nature of migraine, which introduces complexity in outcome measurement due to variability in attack frequency, intensity, and duration, we are integrating methods like diary-based tracking and episodic trend modeling. This approach ensures that our data capture reflects the real-world experiences of people living with migraine. Moreover, our trial will employ validated, reliable outcome measures, both patient-reported and clinician-assessed, to enhance the generalizability of our findings. We are also implementing strategies to mitigate bias, such as blinding and standardized intervention protocols, to maintain the integrity of our results. Our piloting phase is deliberately focused on optimizing recruitment strategies, adherence measures, and intervention delivery, setting a solid foundation for a subsequent Phase 3 efficacy trial. The insights gained from our preliminary work are instrumental in informing power and feasibility metrics, essential for scaling up to a large-scale, multi-site trial that can provide definitive answers and potentially transform migraine treatment protocols. In conclusion, innovative research is needed to explore the role of combination therapy, including biobehavioral and pharmacological interventions, in the treatment of migraine. We believe remote telehealth delivery methods may help improve access and optimize the lives of people living with migraine. Teshamae S. Monteith: Conceptualization; writing – original draft; writing – review and editing. Asimina Lazaridou: Conceptualization; writing – original draft; writing – review and editing. Carolyn Bernstein: Conceptualization; writing – original draft; writing – review and editing. Teshamae S. Monteith has the following disclosures over the past 3 years: clinical trial site principal investigator for studies sponsored by Abbvie, Eli Lilly, Ipsen, and Rehaler; participation in advisory board/consultancy for AbbVie, Teva, Linpharma, e-Neura, Lundbeck, Novartis, Axsome, Merz, and Pfizer; Educational grant from Amgen and AbbVie; personal fees from Medscape, Massachusetts Medical Society, American Headache Society, American Academy of Neurology, Neurodiem, Academic CME, AbbVie, and Novartis; unpaid co-author for research funded by AbbVie, Pfizer/Biohaven, and Theranica. She is an Associate Editor for Cephalalgia and Continuum Audio, and is on the editorial board for Neurology, American Migraine Foundation, and Brain and Life Magazine. Teshamae S. Monteith has provided unpaid service on the board of directors for the International Headache Society (2021–2023) and currently on the executive board for the Florida Society of Neurology. Carolyn Bernstein consults for Percept, reviewers of UpToDate, and receives research support from Teva. Asimina Lazaridou reports no disclosures.