April 17, 2025
To: Editors
Response Statement by the National Headache Foundation (NHF) to Qaseem et al. on the “Prevention of Episodic Migraine Using Pharmacologic Treatments in Outpatient Settings: A Clinical Guideline From the American College of Physicians”
The manuscript by Amir Qaseem and colleagues (1) on the prevention of episodic migraine using pharmacologic treatments in outpatient settings contains several significant limitations that warrant clarification and commentary.
Concerns Regarding Recommendations for Women of Reproductive Age
One of the primary concerns is the recommendation for initiating preventive therapy for women of reproductive age. The inclusion of valproate as a first-line treatment option is particularly problematic due to its well-documented teratogenic effects(1). If a woman of reproductive age were to become pregnant while on valproate, the risk of significant fetal harm is substantial. Additionally, the side effect profile of valproate, including weight gain, further complicates its use in this population (2,3).
Use of Non-Migraine-Specific First-Line Pharmacologic Agents
The first-line recommendations in the manuscript primarily consist of pharmacologic agents originally developed for conditions other than migraine. This approach overlooks the evolution of migraine-specific preventive treatments, particularly the newer calcitonin gene-related peptide (CGRP) antagonists, which have demonstrated strong efficacy and safety profiles. The authors acknowledge that prior to the availability of these newer agents, only 17% of patients were receiving preventive treatment, highlighting the inadequacy of traditional options. Given this historical lack of utilization, prioritizing non-migraine-specific medications fails to address the need for more effective and tolerable treatments. The side effect profile of the CGRP targeted therapies is more favorable than many of the other medications and there needs to be recognition that certain side effects may be less tolerated than others. For example, the weight gain with divalproex would be intolerable to many patients as would be the memory loss with topiramate. Side effects to the CGRP targeted therapies tend to be less frequent and better tolerated (e.g. injection site reactions, constipation, rare hypertension, and Raynaud’s phenomenon with the CGRP monoclonal antibodies (mAbs); and nausea, constipation, rare hypertension, Raynaud’s phenomenon, and somnolence with the gepants). In addition, the long term compliance with the newer CGRP targeted therapies appears to be much better than the non-specific pharmacological agents (4-7).
Lack of Headache Specialist in the "Topic Expert Panel"
The manuscript does not provide any details on the therapeutic area expertise of the “topic expert panel,” raising concerns about the recommendations. It is difficult to ascertain whether the guidelines were formulated by individuals with sufficient expertise in migraine management. The Scientific Committee of the National Headache Foundation providing this response statement is composed of physicians who are board certified and/or fellowship trained in headache medicine.
Overemphasis on Cost Over Clinical Efficacy and Safety
The recommendations appear to be heavily influenced by cost considerations rather than clinical efficacy, tolerability and compliance. The authors themselves concede that if cost were not a factor, CGRP antagonists would be considered first-line treatments. By prioritizing cost over patient tolerability and compliance the manuscript fails to provide an optimal framework for migraine prevention. Furthermore, it is unclear why topiramate is relegated to a third-line option behind valproate when valproate carries greater potential harm of teratogenicity. The decision-making process appears inconsistent and not sufficiently justified.
Failure to Assess Functional Outcomes and Emergency Department Visits
Another limitation of the manuscript is the lack of assessment of key clinical outcomes such as physical function and emergency department visits. In fact, there are numerous studies demonstrating improved disability and quality-of-life in studies with the CGRP targeted therapies (4,7,8). One study showed improved frequency, disability and quality of life for the composite population in those receiving erenumab as compared to those with topiramate (8). These factors are critical in evaluating the true impact of preventive migraine treatments, as they directly correlate with patient quality of life and healthcare burden. The omission of these considerations weakens the strength of the recommendations.
Negative Impact on Insurance Coverage for CGRP Antagonist Gepants and Monoclonal Antibody Therapies
The cost-centered approach taken in the manuscript may have significant consequences for insurance coverage determination policies. By failing to recommend CGRP antagonist gepants and monoclonal antibodies (mAbs) as first-line options, the manuscript indirectly supports restrictive insurance policies that limit access to these highly effective treatments. Many insurance providers base coverage decisions on published guidelines, and when cost-saving measures take precedence over clinical efficacy, patients are often forced to try and fail multiple older, less effective treatments before gaining access to migraine-specific options. This delays appropriate care, increases patient suffering, and contributes to the overall burden of migraine-related disability.
Reliance on Low-Certainty Evidence
All the recommended treatments in the manuscript are based on “low-certainty evidence.” This undermines the reliability of the recommendations, and raises concerns about their applicability in clinical practice. In contrast, newer migraine-specific agents, such as CGRP antagonist gepants and monoclonal antibodies (mAbs), have been supported by robust clinical trials demonstrating their efficacy and safety.
Disregard for American Headache Society Guidelines
Finally, the authors did not incorporate the comprehensive recommendations from the American Headache Society, which reviewed all preventive options (9). Given the thorough and migraine-focused approach of the American Headache Society, this consensus position statement should have been a cornerstone of any discussion on preventive treatment strategies. The omission of these expert-driven recommendations further weakens the credibility of the manuscript.
Conclusion
Given these substantial limitations, the recommendations set forth by Qaseem et al. do not adequately address the needs of patients with episodic migraine. The prioritization of cost over clinical efficacy, the reliance on low-certainty evidence, the lack of transparency in expert selection, and the failure to consider functional outcomes all contribute to a set of recommendations that do not reflect the current best practices in migraine prevention. Migraine-specific agents such as gepants and CGRP antibody therapy should be considered first-line therapies due to their superior efficacy and safety profiles. We would also recommend that divalproex be relegated to a lower tier and that topiramate be moved to a first line preventive medication. Given the complexity and evolution of migraine therapeutics, clinical guidelines should be generated by and in collaboration with headache and migraine specialists and their respective organizations, which in this case includes the American Headache Society and the National Headache Foundation.
National Headache Foundation Scientific Committee:
- Dr. Fred Cohen, MD
- Dr. Merle Diamond, MD, FACEP
- Dr. Jaclyn R. Duvall, MD, FAAN, FAHS
- Dr. Mark Green, MD, FAAN, FWHS
- Dr. Vincent T. Martin, MD, FACP, FAHS
- Dr. Paul G. Mathew, MD, DNBPAS, FAAN, FAHS
- Dr. Hope O’Brien, MD, MBA, FAHS, FAAN
- Dr. Timothy R. Smith, MD, RPh, FACP, FAHS