Tepper, Stewart J.

Objective To develop evidence-based clinical practice guidelines for non-invasive neuromodulation devices in acute and preventive migraine treatment. Methods A systematic review was conducted across six databases from 1946 to April 2025. Randomized controlled trials evaluating Food and Drug Administration-cleared or Conformité Européenne (CE)-marked non-invasive neuromodulation devices were included. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology, and recommendations were developed through consensus following GRADE Evidence-to-Decision frameworks. The working group comprised 15 senior members and six junior members. Results From 1536 initial records, 15 studies met the inclusion criteria and were finally used to develop evidence-based recommendations. Evidence quality ranged from very low to moderate. Weak recommendations were issued for SAVI Dual, Cefaly, Relivion, and Nerivio in the treatment of acute migraine attacks, and for gammaCore Sapphire, Cefaly, and Nerivio in the preventive migraine treatment. Other cleared devices received no recommendations or have no eligible studies for the GRADE assessment. The primary limitations across studies included imprecision due to small sample sizes and various methodological concerns. Additionally, expert consensus recommendations were developed for devices and clinical scenarios not adequately covered by randomized controlled trials, including potential applications in pediatric populations, vestibular migraine, chronic migraine, menstrual migraine, and medication overuse headache. Conclusion Non-invasive neuromodulation devices offer promising alternatives to drug treatment for migraine management. These devices are safe and generally well tolerated and devoid of drug interactions. While current evidence quality varies, ongoing research and technological advancements show encouraging potential. Future studies should adhere to International Headache Society guidelines for neuromodulation device trials, address proper sham controls and blinding assessment, and account for patient adherence challenges in device use. Expanded insurance coverage would enhance cost-effectiveness and device accessibility. These guidelines provide a framework for clinical decision-making while highlighting areas requiring further research.

ABSTRACTBackgroundErenumab‐induced medication overuse headache (MOH) remission in participants with chronic migraine (CM) in a prospective, Phase 4, randomized, placebo‐controlled trial with an open‐label treatment period (OLTP). We present 1‐year results from the combined double‐blind treatment period (DBTP) and OLTP for the stratified nonopioid cohort.MethodsParticipants with CM‐MOH were randomized 1:1:1 to subcutaneous 70 or 140 mg erenumab every 4 weeks (QM) or placebo for the initial 24 weeks (DBTP). Those successfully completing DBTP could continue the 28‐week OLTP, maintaining the same erenumab dose received during DBTP or, if receiving placebo, randomly assigned 1:1 to erenumab 70 or 140 mg QM. OLTP endpoints were exploratory.ResultsOverall, 552 participants received erenumab (70 mg, n = 274; 140 mg, n = 278); 95.3% completed OLTP. One‐year MOH relapse in participants who achieved MOH remission at DBTP Month 6 was 2.7% (3/111) and 2.4% (3/124) with erenumab 70 and 140 mg, respectively; absence of MOH at study end was observed in 69.0% (189/274) and 75.5% (210/278) of participants. Sustained MOH absence over 1 year was reported in 60.5% (107/177) and 68.8% (119/173) of participants, respectively. Sustained improvements in measures of headache days, medication days, and function were observed in both groups. No new safety concerns were identified (grade ≥ 3, 35 [6.3%]; serious, 17 [3.1%]; adverse events leading to treatment discontinuation, 5 [0.9%]).ConclusionsErenumab was effective in inducing and sustaining MOH remission and improving function over 1 year. Treatment compliance remained high, with safety events consistent with erenumab's known safety profile.Trial RegistrationNCT03971071

Abstract Objective To estimate the real‐world risk of cardiovascular events among patients with migraine treated with erenumab and other migraine preventive medications. Background Migraine preventive treatment with calcitonin gene‐related peptide (CGRP) pathway inhibitors, such as erenumab and others, may theoretically result in cardiovascular effects due to a lack of compensatory vasodilation with CGRP pathway inhibition. Methods In this retrospective observational cohort study, we estimated the unadjusted cumulative risk (CR) of new‐onset hypertension, acute myocardial infarction (MI), or stroke among patients with migraine newly treated with erenumab, other anti‐CGRP pathway monoclonal antibodies (mAbs), standard oral preventive medications, and onabotulinumtoxinA using data from the MarketScan® Commercial and Medicare Supplemental medical claims database. Comparative analyses to assess the relative risk (RR) of vascular events were gated on the comparability of treatment groups with respect to baseline demographics and clinical characteristics. Potential bias due to unmeasured confounding was evaluated via negative control outcome (NCO) analyses. Confounding based on measured covariates and differential informative censoring were addressed with inverse probability weights. Results A total of 108,019 new users of migraine preventive medications were included. Unadjusted CR (95% confidence interval [CI]) of hypertension at 12 months of treatment was: erenumab, 9.34% (8.79–9.89%); other anti‐CGRP pathway mAbs, 9.42% (8.92–9.92%); standard oral preventive medications, 9.09% (8.77–9.41%); and onabotulinumtoxinA, 9.10% (8.39–9.81%). NCO analyses identified minimal concerns related to unmeasured confounding in erenumab versus other mAbs and erenumab versus onabotulinumtoxinA comparisons. Adjusted RRs (95% CIs) of acute MI and stroke, respectively, at 36 months of treatment were 1.02 (0.45–1.59) and 0.90 (0.56–1.25) for erenumab versus other mAbs and 0.87 (0.19–1.55) and 0.97 (0.42–1.52) for erenumab versus onabotulinumtoxinA. Conclusions In this analysis of the MarketScan medical claims database, we found no difference in the risk of vascular events in patients treated with erenumab versus other anti‐CGRP pathway mAbs or onabotulinumtoxinA.

ImportancePatients with chronic migraine and medication overuse headaches (CM-MOH) represent a particularly burdened subpopulation. This trial provides first, to our knowledge, American Academy of Neurology class I evidence for a preventive therapy in CM-MOH.ObjectiveTo assess erenumab efficacy and safety in patients with nonopioid CM-MOH.Design, Settings, and ParticipantsThis randomized, double-blind, parallel-group, placebo-controlled trial took place at 67 centers in North America, Europe, and Australia from October 7, 2019, to November 2, 2022. This report reflects the primary analysis conducted in January 2023, using a database snapshot from December 1, 2022, which contains the complete dataset of the double-blind treatment period (DBTP). Participants included adults with CM-MOH who had 1 or more preventive treatment failure(s). There were 992 participants screened and 620 participants enrolled (584 in nonopioid cohort and 36 in opioid cohort)InterventionsErenumab, 70 mg, 140 mg, or placebo, once monthly for 24 weeks.Main Outcomes and MeasuresThe primary end point was MOH remission at month 6. Secondary end points included change from baseline in mean monthly acute headache medication days (AHMD) at month 6 and sustained MOH remission throughout the DBTP. Safety end points were adverse events and changes in vital signs.ResultsThe primary analysis population included 584 participants in the nonopioid-treated cohort with a mean age of 44 years and 482 participants were female (82.5%). Baseline demographics and disease characteristics were balanced across groups. At month 6, 134 participants in the erenumab, 140 mg group (69.1%) (odds ratio [OR], 2.01; 95% CI, 1.33-3.05; P < .001 vs placebo) and 117 in the erenumab, 70 mg group (60.3%) (OR, 1.37; 95% CI, 0.92-2.05; P = .13 vs placebo) achieved MOH remission vs 102 participants in the placebo group (52.6%). AHMD use was also reduced in the erenumab groups vs placebo. Least squares mean (standard error) change from baseline in average monthly AHMD was –9.4 (0.4) days in the erenumab, 140 mg group (difference from placebo, –2.7; 95% CI, –3.9 to –1.6; P < .001) and –7.8 (0.4) days in the erenumab, 70 mg group (difference from placebo, –1.2; 95% CI, –2.4 to –0.1; P = .03), vs –6.6 (0.4) days in the placebo group. MOH remission throughout the DBTP was sustained in 119 participants (61.3%,) 96 participants (49.5%), and 73 participants (37.6%) in the erenumab, 140 mg, 70 mg, and placebo groups, respectively. Adverse events were consistent with the known safety profile of erenumab. Treatment-emergent adverse events incidence in the combined erenumab group was 66.8% (259 participants; constipation 15.2% (59 participants) and COVID-19 13.9% (54 participants) were most common.Conclusions and RelevanceIn this study, monthly, 140 mg, erenumab injections safely and effectively achieved MOH remission in patients with nonopioid CM-MOH within 6 months.Trial RegistrationClinicalTrials.gov Identifier: NCT03971071

Abstract The small molecule calcitonin gene–related peptide receptor antagonists (gepants) are the only drug class with medicines indicated for both the acute and preventive treatment of migraine. Given this dual capacity to both treat and prevent, along with their favorable tolerability profiles and lack of an association with medication‐overuse headache, headache specialists have begun to use gepants in ways that transcend the traditional categories of acute and preventive treatment. One approach, called situational prevention , directs patients to treat during the interictal phase, before symptoms develop, in situations of increased risk for migraine attacks. Herein, we present three patients to illustrate scenarios of gepant use for situational prevention. In each case, a gepant was started in anticipation of a period of increased headache probability (vulnerability) and continued for a duration of 1 day to 5 consecutive days. Although this approach may expose patients to medication when headache may not have developed, the tolerability and safety profile and preventive effect of gepants may represent a feasible approach for some patients. Situational prevention is an emerging strategy for managing migraine before symptoms develop in individuals who can identify periods when the probability of headache is high. This paper is intended to increase awareness of this strategy and stimulate future randomized, placebo‐controlled trials to rigorously assess this strategy.