May 1, 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” (ACP)
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 of the NHF is the ACP’s 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 was to become pregnant while taking 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 included in the guideline 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 from numerous clinical trials. The guideline authors acknowledge that prior to the availability of these newer agents only 17% of patients were receiving preventive migraine treatment, highlighting the inadequacy of traditional options.
Given this historical lack of utilization, prioritizing the use of non-migraine specific medications fails to address the need for more effective and tolerable treatments. The side effect profile associated with CGRP-targeted therapies is more favorable than for 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 associated with the use of divalproex would be intolerable to many patients as would be the memory loss associated with topiramate therapy. Side effects related to CGRP-targeted therapies tend to be less frequent and moderate in nature (e.g., injection site reactions, constipation, rare hypertension, and Raynaud phenomenon associated with the CGRP monoclonal antibodies [mAbs]; and nausea, constipation, rare hypertension, Raynaud phenomenon, and somnolence associated with the gepants). In addition, reported long-term patient compliance seen with the newer CGRP-targeted therapies appears to be much better than that reported for non-specific pharmacological agents (4-7).
A Headache Specialist is Essential in a Migraine Management "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 authoring this response statement is comprised 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 guideline authors themselves concede that if cost were not a factor, CGRP antagonists would be considered first-line treatments for migraine. By prioritizing cost over patient tolerability and compliance, the ACP guideline 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. From our perspective, the ACP’s decision-making process appears to be 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 associated with migraine such as physical function and emergency department visits. In fact, there are numerous studies demonstrating improved disability and quality-of-life outcomes in studies of CGRP-targeted therapies for migraine (4,7,8). One study showed improvements in reported migraine frequency, disability, and quality of life for the composite population in those receiving erenumab as compared to those taking topiramate therapy (8). These factors are critical to consider when 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 in our assessment.
Negative Impact on Insurance Coverage for CGRP Antagonist Gepants and Monoclonal Antibody Therapies
The cost-centered approach taken in the ACP guideline 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 guideline 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 strategy 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 included in the ACP guideline are based on “low-certainty evidence.” This undermines the reliability of the recommendations and raises concerns about their applicability in clinical practice. In contrast, the use of newer migraine-specific agents, such as CGRP antagonist gepants and monoclonal antibodies (mAbs), are supported by robust clinical trials demonstrating their efficacy and safety.
Disregard for American Headache Society Guidelines
Finally, the authors of the ACP guideline did not incorporate recent 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 recommendations, 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, FASH
- Dr. Paul G. Mathew, MD, DNBPAS, FAAN, FAHS
- Dr. Hope O’Brien, MD, MBA, FAHS, FAAN
- Dr. Timothy R. Smith, MD, RPh, FACP, FAHS