ACP Issues Guidance for Migraine Headache Prophylaxis

The Clinical Guidelines Committee of the American College of Physicians (ACP) has released a new clinical guideline on the prevention of episodic migraine headache in nonpregnant adults in the outpatient setting.

The guideline is supported by a supplemental review of pharmacologic effectiveness and a summary of patient values and medication preferences. It appears in Annals of Internal Medicine.

The ACP recommended that physicians use monotherapy as initial treatment in outpatient settings. It cautioned, however, that all the recommendations have only conditional strength and are based on low-certainty evidence. Furthermore, patient values and preferences may affect the choice of medication.

Amir Qaseem, MD, PhD, the ACP’s chief science officer and vice president of clinical policy at the Center for Evidence Reviews, called migraine “a core clinical topic for internal medicine physicians and our patients, and hence a priority area for the ACP to develop a clinical guideline. This disabling condition is underdiagnosed and undertreated,” Qaseem, who is also an adjunct professor at Thomas Jefferson University in Philadelphia, told Medscape Medical News. “It impacts females more than males, 21% vs 11%, and is more common in adults between the ages of 18 and 44 and those who are unemployed or have a household income of

The guideline panel defined episodic migraine as 1-14 headache days per month and offered alternatives should initial treatments be poorly tolerated or produce an inadequate response.

The authors noted that migraine ranks second as the leading cause of global disability, expressed as years lived with disability, in all adults and is the top cause in women aged 15-49 years. It affects 16% of people in the United States.

The accompanying systematic review of prophylactic migraine medication effectiveness, led by Johanna A. A. Damen, PhD, an assistant professor in the Julius Center for Health Sciences and Primary Care at University Medical Center Utrecht in Utrecht, the Netherlands, found no high-certainty evidence to favor one pharmacologic preventative treatment over another. That conclusion emerged from a review of 61 studies with almost 21,000 patients assessed for drug efficacy vs placebo on such benefits and harms as migraine frequency and duration, emergency department visits, days of short-term medication, disability, physical functioning, quality of life, scores of migraine severity and daily functional impact, and discontinuations due to adverse events.

Damen’s group noted that most previous studies have focused on one class of drugs such as beta-blockers and head-to-head drug comparisons were scant in the literature. “A network meta-analysis published in 2023 concluded that CGRP [calcitonin gene-related peptide] mAbs [monoclonal antibodies] and gepants are more effective than older drug classes in patients with episodic or chronic migraine. We could not confirm this finding.” Again, the evidence was mostly insufficient or of low certainty.

Commenting on the guidance but not involved in it, Abayomi Ogunwale, MD, a family medicine physician at UTHealth Houston, called the guidance a useful tool “primarily because it provides an update on current evidence on chronic and episodic migraines, conditions which affect millions, whose diagnostic criteria have constantly evolved, and for which multiple abortive and prophylactic therapies have been proposed and investigated.” In his view, the evidence basis is sufficient, “and by listing the treatments and the level of supporting evidence, the guideline simplifies management decisions and provides some needed clarity for everyday practice.”

The following agents were reviewed:

Angiotensin-converting enzyme inhibitor: Lisinopril; antiseizure medications: Topiramate and valproate; angiotensin receptor blockers: Candesartan and telmisartan; beta-adrenergic blockers: Metoprolol and propranolol; CGRP receptor antagonists and gepants: Atogepant and rimegepant; CGRP mAbs: Eptinezumab, erenumab, fremanezumab, and galcanezumab; SSRIs and serotonin/norepinephrine reuptake (SNR) inhibitors: Fluoxetine and venlafaxine; tricyclic antidepressant (TCA): Amitriptyline; as well as a combination of any of these treatments.

ACP Recommendations

Before initiating any pharmacologic treatment, physicians should explore whether patients have modifiable triggers and factors that contribute to an acute migraine headache. They should discuss the importance of lifestyle interventions, such as staying hydrated and maintaining regular and adequate sleep and physical activity, as well as evaluate whether appropriate and adequate-strength medication is being used.

In selecting treatment, clinicians should use an informed decision-making approach and discuss benefits, harms, costs, and patients’ values and preferences. This discussion should include financial burden and mode of administration, contraindications, pregnancy and reproductive status in women, clinical comorbidities, and availability when selecting a pharmacologic treatment to prevent episodic migraine.

• Monotherapy should begin with one of the following five treatments (conditional recommendation; low-certainty evidence): Abeta-blocker, either metoprolol or propranolol, the antiseizure medication valproate, the SNR inhibitor venlafaxine, or the TCA amitriptyline.

• Clinicians should use monotherapy with a CGRP antagonist-gepant (atogepant or rimegepant) or a CGRP mAb (eptinezumab, erenumab, fremanezumab, or galcanezumab) in outpatients who do not tolerate or inadequately respond to a trial or trials of metoprolol or propranolol, valproate, venlafaxine, or amitriptyline (Conditional recommendation; low-certainty evidence).

• Clinicians should consider monotherapy with topiramate in those who do not tolerate or inadequately respond to a first trial or trials of metoprolol or propranolol, valproate, venlafaxine, or amitriptyline. A further CGRP trial with atogepant or rimegepant, or with eptinezumab, erenumab, fremanezumab, or galcanezumab is recommended (Conditional recommendation; low-certainty evidence).

Ogunwale cautioned, “Although current evidence supports the efficacy of emerging CGRP inhibitors, the cost, availability, and route of administration of these monoclonal antibodies limit the utility of this recommendation in everyday clinical practice.”

Theodore Strange, MD, chair of medicine at Northwell Staten Island University Hospital, Staten Island, New York, who specializes in adult primary care, called the recommendations not only useful but also overdue, the latter “in part because of lack of evidence in treating migraines and the diversity of treatment options,” he told Medscape Medical News. “These guidelines give direction and clear up some confusion about how best to approach treatment options, starting with lifestyle changes first.”

Strange added that patient preference, cost, and formularies will play a role, but while some of the initial therapies are inexpensive and generic, “the newer medications, which may have use for more chronic patients and those who fail initial therapies, are more expensive and their long-term efficacy may still be open to discussion and further review.”

The ACP concluded that funding agencies such as the Patient-Centered Outcomes Research Institute or the National Institute of Neurological Disorders and Stroke support comparative clinical effectiveness trials and evaluate the cost-effectiveness of all relevant pharmacologic treatments for episodic migraine prevention. These studies should assess patient-centered outcomes, including utility-based measures of quality of life, and new studies should evaluate the effect of treatments on subgroups determined by age, race, and ethnicity.

Patient Preferences

Because no difference was found in net benefits and harms of all recommended treatments, the ACP considered evidence of patients’ values and preferences and economic evidence, Qaseem said. “CGRPs were substantially higher in cost and are currently unavailable as generics. Expensive medications have an impact on our patients. As a result, medications that are administered orally and at lower cost were prioritized.”

In a summary of patient values and preferences around treatment, Bada Yang, MD, PhD, an assistant professor at Cochrane Netherlands, University Medical Center Utrecht, Utrecht, the Netherlands, and associates suggested patients seem to prefer oral treatments that reduce the severity, frequency, and duration of their migraines, decrease the duration of limitations on daily activity, and lower the risk for migraine post-dosing on day 1. Side effects and reduced need for acute medications may be less important.

“Although migraine frequency is often measured as a primary outcome in trials, trialists should consider the measurement of migraine severity, migraine attack on day 1 post-dosing, and consistency of treatment effectiveness,” Yang’s group wrote. They called for research to reproduce their findings without industry involvement and to compare the importance of all major outcomes within a single study directly.

This clinical guideline and the supplementary reviews were funded by the American College of Physicians.

Qaseem and the other clinical guideline authors disclosed no relevant competing interests. Daman, Bada, and the supplement coauthors disclosed no relevant competing interests. Ogunwale and Strange declared no competing interests.

Diana Swift is an independent medical journalist based in Toronto, Canada.