State of the art in the management of migraine—A response to the American College of Physicians migraine preventive treatment guideline

We appreciate the interest of the American College of Physicians (ACP) in migraine therapy given the critical role that primary care clinicians play in the care of individuals with migraine. ¹ Their recently published guideline for migraine preventive therapy, however, does not align with the evidence‐based approach that is currently practiced by those most knowledgeable and experienced in migraine management. This ACP guideline represents a step backward from widely accepted treatment recommendations recently put forward by the American Headache Society ² and other international headache medicine organizations. ³ , ⁴

A primary problem with the ACP guideline is the reliance on flawed analysis of incomplete data. ⁵ All of the ACP guideline recommendations were made with a low level of confidence. This qualifier is partly because of the remarkably weak evidence supporting the use of several of the therapies recommended in the ACP guideline as “first‐line” for migraine prevention (Table 1). Importantly, the guideline fails to mention the numbers of studies and the numbers of participants involved in the meta‐analysis on which the recommendations are based. This is a critically important piece of information: amitriptyline—one study, venlafaxine—one study, valproate—five studies, topiramate—five studies, beta blockers—six studies, candesartan—two studies, calcitonin gene‐related peptide (CGRP)–targeting monoclonal antibodies—19 studies, and gepants—three studies. For example, for venlafaxine, the single analyzed study included only 41 participants in the drug treatment arm. For the dose that was deemed effective for migraine frequency reduction (150 mg), only 17 participants completed the study. Similarly, there are low patient numbers in the single study included on amitriptyline. This discrepancy is in contrast to the thousands of participants included in Class I graded prospective, placebo‐controlled clinical trials for the CGRP‐targeting migraine preventive therapies. Many large recent studies of the CGRP‐targeting therapies were not included in the ACP analysis, and there is no acknowledgment of the multiple large Class I successful studies of CGRP‐targeting therapies for chronic migraine, leading to their Food and Drug Administration (FDA)‐approved indication for both episodic and chronic migraine. The ACP guidelines do not mention that there are no studies for the therapies they recommend as “first line” chronic migraine.

TABLE 1.

Statements in the ACP guideline and responses on behalf of the AHS.

Statement in ACP guidelines	Response
“Ultimately, because of the lack of a relative net benefit among amitriptyline, the beta‐blockers metoprolol and propranolol, CGRP antagonist‐gepants, CGRP mAbs, valproate, and venlafaxine, the CGC primarily used economic evidence and evidence on patients' values and preferences to prioritize migraine prevention treatments in its recommendations. There were large differences in costs between these medications, with CGRP‐mAbs and CGRP antagonist‐gepants being substantially more costly (Tables S9 and S10). Furthermore, data on patients' values and preferences favored oral over injectable medications. As a result, the CGC suggests that clinicians and patients use a beta‐blocker (metoprolol or propranolol), the antiseizure medication valproate, the SNRI venlafaxine, or the TCA amitriptyline to prevent episodic migraine headache in nonpregnant adults before using a CGRP mAb or a CGRP antagonist‐gepant”	The conclusion that there is a lack of relative net benefit among these therapies is based on flawed analysis of inadequate data (e.g., only single studies with a small number of participants for venlafaxine and amitriptyline). Multiple large RCTs show that CGRP‐targeting therapies are effective in those for whom multiple previous treatments have failed, providing prospective placebo‐controlled evidence of net benefit. The authors did not consider evidence regarding costs of inadequately treated migraine to patients, their families, their employers, and healthcare systems. The preference for oral therapies over injections does not preclude use of the gepants (that are available as oral tablets). Furthermore, the choice of route of therapy should be based on individual patient preference and clinical requirements.
“The CGC also integrated evidence of patients' preferences for oral treatments over injectables (CGRP mAbs) (moderate‐certainty evidence) and considered that people with migraines may place a higher value on the benefits of treatment (such as migraine frequency) over AEs (low‐certainty evidence; see the Values and Preferences section in the Supplement)”	The concept that patients place a higher value on the benefit of treatment over AEs is not supported by real‐world data. The overwhelming majority of patients who are treated with the therapies recommended as first line by the ACP are no longer taking them after 1 year. 7 This poor adherence is largely due to adverse effects. 10
“Adverse event profiles differed across drug classes (Table S7), but most medications were associated with generally mild AEs, such as paresthesia, pain, reduced physical activity, rash, or dizziness. Some treatments, particularly topiramate, were associated with a higher number of AEs, which influenced the CGC's prioritization of less costly treatments with similar efficacy and more favorable AE profiles”	This statement understates the tolerability and safety issues associated with the therapies that are recommended as first line. Valproate, for example, has a host of associated adverse events, some quite serious. 9 The tolerability of the CGRP targeting therapies is significantly greater than the treatments recommended as first line by the ACP.
“Prescribe less costly recommended medications”	This statement falsely implies that the recommended medications are equivalent in terms of efficacy, safety, and appropriateness for individual patients. Medication cost is only one of many important considerations in deciding on an appropriate preventive therapy.

Abbreviations: ACP, American College of Physicians; AE, adverse event; AHS, American Headache Society; CGC, clinical guidelines committee; CGRP, calcitonin gene‐related peptide; mABs, monoclonal antibodies; RCTs, randomized controlled trials; SNRI, serotonin norephinephrine reuptake inhibitor; TCA, Tricyclic antidepressant.

Putting aside the issue of vast differences in the number of participants involved in the clinical trials, there is the issue of the transitivity assumption; that is, for a network analysis to be valid, the analyzed studies must be fundamentally similar. ⁶ The clinical trials supporting the nonspecific migraine preventive therapies recommended in the ACP guideline as “first line” were performed decades ago, with different diagnostic criteria, placebo responses, recording methods, drop‐out rates, and acute medication use among other important differences. The transitivity assumption is clearly not valid for this analysis. Half of the “first line” therapies recommended by the guideline are not FDA‐approved for migraine prevention. For what other disease is this situation the case? All migraine‐specific CGRP targeting therapies are FDA‐approved for migraine prevention.

There is little mention of adverse events and safety concerns in the ACP guideline (Table 1). Poor tolerability is a primary reason for low adherence to nonspecific therapies, by some measures only 17% at 1 year. ⁷ These data are not mentioned in the ACP guideline. Valproate, recommended by the ACP guideline as “first line,” is singled out by the World Health Organization as contraindicated for women of childbearing age, the most common demographic with migraine, because of serious adverse effects associated with exposure during pregnancy. ⁹ Valproate also has black‐box warnings for hepatotoxicity and pancreatitis. Apart from these critically important safety issues, valproate is also notorious for its poor tolerability, with common adverse effects including nausea, significant weight gain, tremor, and hair loss. Valproate is now rarely prescribed by headache specialists, and almost never as first line, because of these safety and tolerability concerns. The implication that there is no difference between the safety and tolerability of valproate as compared with other preventive therapies including CGRP‐targeting therapies is definitively contradicted by extensive clinical experience over decades. Notably absent from the list of recommended therapies is candesartan, which is now prescribed extensively by headache specialists internationally, in part because of its excellent tolerability. ⁸ The efficacy of therapy becomes irrelevant if patients do not adhere to or fear treatments because of poor tolerability and safety.

In addition to the clinical trial end points used in the analysis to support the ACP guideline, there are important new data involving other end points for the CGRP‐targeting therapies, including efficacy in those for whom multiple previous therapies have failed, efficacy in those with acute medication overuse, efficacy in both episodic and chronic migraine, and responder rate analysis. ² None of these parameters are considered in the ACP guideline. Furthermore, there are numerous publications regarding real‐world experience with CGRP‐targeting therapies that do not exist for the “first line” therapies recommended by the ACP. As of July of 2025, a PubMed search with the terms “Migraine prevention,” “CGRP,” and “real world” yields 180 results. These publications are consistent with the extensive experience of headache specialists worldwide which is reflected in the recent recommendations by the American Headache Society and other headache societies. ² , ³ , ⁴

Migraine is a heterogeneous disorder with a broad range of symptoms that occur in the context of multiple comorbidities. The current standard of care in migraine involves tailoring treatment to the specific clinical picture of individual patients. The ACP guideline does not acknowledge this need for an individualized approach and makes multiple questionable recommendations based on incomplete information about “patient preferences” (Table 1). The ACP recommendations also focus extensively on the cost of treatments. What they do not consider, however, are the substantial costs to healthcare systems and to patients, families, and employers that occur when migraine is inadequately controlled, or therapies are poorly tolerated and then discontinued. Best care is not based simply on cost of a medication, but rather matches individual clinical need (including comorbidities) to treatment. Although cost can certainly be a consideration in therapeutic guidelines, the well‐being and safety of the patient should be paramount.

These are exciting times for Headache Medicine, with a variety of remarkably effective and well tolerated migraine‐specific treatment options with improved adherence now available in addition to traditional nonspecific therapies. We look forward to working with the ACP to help inform its members about the spectacular recent progress in Headache Medicine and the new opportunities to reduce disability and improve the lives of the more than one billion individuals worldwide who are impacted by migraine.

AUTHOR CONTRIBUTIONS

Andrew C. Charles: Conceptualization; writing – original draft; writing – review and editing. Stewart J. Tepper: Conceptualization; writing – original draft; writing – review and editing. Jessica Ailani: Conceptualization; writing – original draft; writing – review and editing.

CONFLICT OF INTEREST STATEMENT

Andrew C. Charles has served as a compensated consultant for AbbVie, Aspeya, Lilly, Lundbeck, and Pfizer. He receives royalties from Oxford University Press. He is the immediate past President of the American Headache Society. Jessica Ailani has served as a compensated consultant for AbbVie, Eon, Axsome, Amneal, Dr. Reddy, Eli‐Lilly, Lundbeck, Linpharma, Ipsen, Merz, Pfizer, Gore, Satsuma, Vectura Fertin. Dr. Ailani's institution has received grant support for clinical trials from Parema (2024), Ipsen, Lundbeck, Pfizer, Merz. She has received personal grant support for clinical trials from Mi‐Helper. She is a medical editor for SELF magazine. Stewart J. Tepper has served as a compensated consultant for: AbbVie, Eon, Alphasights, Amgen, Aruene/eNeura, Atheneum, Axsome Therapeutics, Bausch Health, Becker Pharmaceutical Consulting, Catch Therapeutics, ClearView Healthcare Partners, ClickTherapeutics, CoolTech, CRG, Decision Resources, Defined Health, DRG, DocDelta, Dr. Reddy's, Eli Lilly, ExpertConnect, FCB Health, Fenix, Gilmartin Capital, GLG, Guidepoint Global, Health Advances, Health Science Communications, HMP Communications, Impel, Initiator Pharma, InteractiveForums, IQVIA, Keyquest, KiHealth Partners, Krog and Partners, Lundbeck, M3 Global Research, Magellan Health, Magnolia Innovation, Miravo Healthcare, MJH Holdings, Neurofront Therapeutics, Neurolief, Nocira, Novartis, P Value Communications, Pain Insights, Inc., Palion Medical, Perfood, Pfizer, Pulmatrix, Putnam Associates, Rehaler, SAI MedPartners, Satsuma, Scilex, Slingshot Insights, Spherix Global Insights, Strategy Inc., Synapse Medical Communication, System Analytic, Taylor and Francis, Tegus, Teva, Theranica, Third Bridge, Tonix, Trinity Partners, Unity HA, Vial, XOC Salary: Dartmouth‐Hitchcock Medical Center, Thomas Jefferson University, Ki Health Partners. He has been a compensated speaker for AbbVie, Dr. Reddy's, Eli Lilly, Lundbeck, Pfizer, Scilex, Teva, Tonix and has received CME honoraria from American Academy of Neurology, American Headache Society, Annenberg Center for Health Sciences, Catamount Medical Education, Consortium for Research Education Social Awareness and Training In Neurosciences, Diamond Education Foundation, Forefront Collaborative, Haymarket Medical Education, HMP Global, Medical Education Speakers Network, Medical Learning Institute Peerview, Migraine Association of Ireland, Miller Medical Education, National Association for Continuing Education, North American Center for CME, The Ohio State University, Physicians' Education Resource, PlatformQ Education, Primed, Vindico MedicalEducation, WebMD/Medscape. The members of the AHS Board of Directors and their disclosures are listed on the AHS website. The American Headache Society is a nonprofit organization that receives support from industry for educational programming, research, and advocacy. This includes support from multiple companies that are involved in the development, distribution, and marketing of therapies that are addressed in this statement, including (but not limited to) AbbVie, Amgen, Eli Lilly, Lundbeck, Pfizer, and Teva. These companies had no direct or indirect involvement in the development and writing of this perspective.

Charles AC, Tepper SJ, Ailani J, . State of the art in the management of migraine—A response to the American College of Physicians migraine preventive treatment guideline. Headache. 2025;65:1653‐1656. doi: 10.1111/head.15051