BackgroundThis study compared persistence of patients initiating rimegepant versus oral triptans for the acute treatment of migraine.MethodsA retrospective cohort analysis was conducted using US MarketScan claims data (1 March 2019 to 30 June 2023) among commercially- and US federal Medicare-insured migraine patients initiating rimegepant or oral triptans. Persistence was defined as having ≥1 refill within 12 months of initial prescription and was compared between propensity score-matched rimegepant and triptan cohorts.ResultsBefore matching, 13,599 patients were identified in the rimegepant cohort and 38,127 in the triptan cohort. After matching, each cohort included 9909 patients. Significantly more rimegepant patients were persistent (75.8%) versus triptan patients (53.5%) (odds ratio [OR] 2.72, 95% confidence interval [CI] 2.56-2.90). Subgroup analyses showed similar trends for rimegepant versus specific triptans (rizatriptan: OR 2.49 [95% CI 2.33-2.67], and sumatriptan: OR 2.92 [95% CI 2.73-3.12]) and in patients with chronic migraine (OR 2.86 [95% CI 2.53-3.23]).ConclusionsThis study provides compelling evidence that rimegepant is associated with greater persistence than oral triptans for real-world acute treatment of migraine. Rimegepant is a favorable option for patients seeking effective and tolerable long-term treatment, particularly for those with insufficient response, intolerability, or contraindications to triptans.

Cluster headache, characterized by bouts of excruciating pain attacks, detrimentally affects health and quality of life. Eptinezumab is an anticalcitonin gene-related peptide monoclonal antibody approved for migraine prevention. To evaluate the efficacy and safety of eptinezumab in the preventive treatment of episodic cluster headache. This double-blind, placebo-controlled, randomized (1:1) clinical trial (Eptinezumab in Participants With Episodic Cluster Headache [ALLEVIATE]) was conducted between December 2020 and October 2023. Results are from the initial 4-week randomized phase. The study took place at 64 sites across Europe, the US, and Japan. Included were adults (aged 18-75 years) with a history of episodic cluster headache for 1 or more years (with bouts lasting ≥6 weeks when untreated) and previous acute and preventive medication use. Eptinezumab, 400 mg, or placebo (intravenous infusion). The primary end point was the change from baseline in the number of weekly attacks in weeks 1 to 2. Safety was assessed using treatment-emergent adverse events. Of 628 total participants screened, 320 entered the second screening period, and 231 met eligibility criteria. Of the 231 participants randomized (eptinezumab, n = 118; placebo, n = 113), 215 (93%) completed the placebo-controlled period. The participant mean (SD) age was 44 (11) years, and 178 of 229 were male (78%). At baseline, the mean (SD) weekly attacks were 15.2 (8.1) in the eptinezumab group and 15.7 (8.3) in the placebo group. There was no statistically significant difference between eptinezumab and placebo in the change from baseline in the number of weekly attacks over weeks 1 to 2 (least-squares mean [SE], −4.0 [0.93] vs −4.6 [0.89]; between-group difference, 0.7; 95% CI, −1.3 to 2.6; P = .50). More eptinezumab-treated participants achieved 50% or greater response vs placebo over week 2 (50.9% [54 of 106] vs 37.3% [41 of 110]; odds ratio [OR], 1.77; 95% CI, 1.03-3.07; P =.04), week 3 (62.5% [65 of 104] vs 43.8% [49 of 112]; OR, 2.26; 95% CI, 1.30-3.97; P =.004), and week 4 (66.7% [68 of 102] vs 50.5% [54 of 107]; OR, 2.14; 95% CI, 1.21-3.83; P =.009). Eptinezumab showed numerically larger improvements than placebo for 75% or greater response, average daily pain scores, and across other patient-reported outcomes. Treatment-emergent adverse events occurred in 25.0% of patients (28 of 112) receiving eptinezumab and 26.5% of patients (31 of 117) receiving placebo. Among adults with episodic cluster headache, eptinezumab did not significantly reduce the number of attacks vs placebo, although it was associated with numerically higher responder rates and improvements in average daily pain and patient-reported outcomes. Eptinezumab was generally well tolerated. ClinicalTrials.gov Identifier: NCT04688775

BACKGROUND:Erenumab-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. METHODS:Participants 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. RESULTS:Overall, 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%]). CONCLUSIONS:Erenumab 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 REGISTRATION:NCT03971071.

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.

BACKGROUND:Chronic cluster headache is an uncommon but highly debilitating primary headache disorder characterised by excruciating head pain recurring in daily attacks and without remission periods longer than 3 months. Treatment is challenging due to the few strategies available. Eptinezumab, approved for migraine prevention, is a humanised monoclonal antibody that targets calcitonin gene-related peptide, which has been implicated in the pathophysiology of cluster headaches. The CHRONICLE trial evaluated the long-term safety and efficacy of eptinezumab for the treatment of chronic cluster headache. METHODS:CHRONICLE was a 60-week, open-label, fixed-dose trial conducted in 28 specialist headache centres in nine countries (Denmark, Finland, France, Germany, Italy, Netherlands, Spain, the UK, and the USA). Participants were aged 18-75 years with a diagnosis of chronic cluster headache according to the International Classification of Headache Disorders, 3rd edition. Eptinezumab 400 mg was administered intravenously every 12 weeks. The primary objective was to evaluate the long-term safety and tolerability of eptinezumab by assessing treatment-emergent adverse events. The efficacy of eptinezumab was assessed by attack frequency, pain severity, and patient-reported outcomes. CHRONICLE is registered on ClinicalTrials.gov (NCT05064397) and EudraCT (2020-001968-28) and is completed. FINDINGS:From Sept 17, 2021, to June 29, 2023, 131 participants were enrolled and treated, of whom 108 (82%) completed the trial. The participants were primarily male (n=84 [64%]), with a mean age of 45·2 years (SD 10·8), and a mean time since diagnosis of 7·3 years (5·8). Treatment-emergent adverse events were reported in 106 participants (81%), with few leading to treatment withdrawal (four participants) or infusion interruption (one participant). The three most common treatment-emergent adverse events were COVID-19 (n=29; 22%), nasopharyngitis (n=24; 18%), and fatigue (n=23; 18%, most commonly on the first day of infusion). There were no treatment-related serious adverse events and no deaths during the trial. Consistent improvements in attack frequency, pain severity, and patient-reported outcomes were observed. INTERPRETATION:Eptinezumab was generally well tolerated in participants with chronic cluster headache, with a similar safety profile as previously seen in participants with migraine. Although clinical efficacy over 12 months was observed, randomised controlled trials (when feasible) or trials with an innovative design are needed to confirm the clinical relevance of these observations. FUNDING:H Lundbeck A/S.

ImportanceCluster headache, characterized by bouts of excruciating pain attacks, detrimentally affects health and quality of life. Eptinezumab is an anticalcitonin gene-related peptide monoclonal antibody approved for migraine prevention. ObjectiveTo evaluate the efficacy and safety of eptinezumab in the preventive treatment of episodic cluster headache. Design, Setting, and ParticipantsThis double-blind, placebo-controlled, randomized (1:1) clinical trial (Eptinezumab in Participants With Episodic Cluster Headache [ALLEVIATE]) was conducted between December 2020 and October 2023. Results are from the initial 4-week randomized phase. The study took place at 64 sites across Europe, the US, and Japan. Included were adults (aged 18-75 years) with a history of episodic cluster headache for 1 or more years (with bouts lasting >= 6 weeks when untreated) and previous acute and preventive medication use. InterventionsEptinezumab, 400 mg, or placebo (intravenous infusion). Main Outcomes and MeasuresThe primary end point was the change from baseline in the number of weekly attacks in weeks 1 to 2. Safety was assessed using treatment-emergent adverse events. ResultsOf 628 total participants screened, 320 entered the second screening period, and 231 met eligibility criteria. Of the 231 participants randomized (eptinezumab, n = 118; placebo, n = 113), 215 (93%) completed the placebo-controlled period. The participant mean (SD) age was 44 (11) years, and 178 of 229 were male (78%). At baseline, the mean (SD) weekly attacks were 15.2 (8.1) in the eptinezumab group and 15.7 (8.3) in the placebo group. There was no statistically significant difference between eptinezumab and placebo in the change from baseline in the number of weekly attacks over weeks 1 to 2 (least-squares mean [SE], -4.0 [0.93] vs -4.6 [0.89]; between-group difference, 0.7; 95% CI, -1.3 to 2.6; P = .50). More eptinezumab-treated participants achieved 50% or greater response vs placebo over week 2 (50.9% [54 of 106] vs 37.3% [41 of 110]; odds ratio [OR], 1.77; 95% CI, 1.03-3.07; P =.04), week 3 (62.5% [65 of 104] vs 43.8% [49 of 112]; OR, 2.26; 95% CI, 1.30-3.97; P =.004), and week 4 (66.7% [68 of 102] vs 50.5% [54 of 107]; OR, 2.14; 95% CI, 1.21-3.83; P =.009). Eptinezumab showed numerically larger improvements than placebo for 75% or greater response, average daily pain scores, and across other patient-reported outcomes. Treatment-emergent adverse events occurred in 25.0% of patients (28 of 112) receiving eptinezumab and 26.5% of patients (31 of 117) receiving placebo. Conclusions and RelevanceAmong adults with episodic cluster headache, eptinezumab did not significantly reduce the number of attacks vs placebo, although it was associated with numerically higher responder rates and improvements in average daily pain and patient-reported outcomes. Eptinezumab was generally well tolerated. Trial RegistrationClinicalTrials.gov Identifier: NCT04688775

OBJECTIVE:This pooled analysis of data from four randomized placebo-controlled trials summarizes the efficacy and safety of rimegepant for acute treatment of migraine. METHODS:In all studies, participants were aged ≥18 years and had a ≥ 1-year history of migraine, two to eight migraine attacks of moderate or severe pain intensity per month, and attacks lasting 4-72 hours if untreated. Participants were provided with a single dose of rimegepant 75 mg or placebo to treat a single migraine attack of moderate or severe pain intensity within the next 45 days. Co-primary endpoints at 2 hours post-dose were pain freedom and freedom from the most bothersome symptom (MBS). Treatment comparisons utilized Mantel-Haenszel risk estimation with stratification by study and prophylactic migraine medication use randomization stratum; p values are nominal. On-treatment adverse events (AEs) were also assessed. RESULTS:Overall, 4,895 participants received rimegepant (n = 2,439) or placebo (n = 2,456). For the co-primary endpoints, the proportion of participants with pain freedom 2 hours post-dose (20.0% vs. 11.8%; p < 0.0001) and MBS freedom 2 hours post-dose (40.2% vs. 29.2%; p < 0.0001) was higher in the rimegepant vs. the placebo group. Rimegepant also demonstrated improvements over placebo in nearly all secondary and exploratory efficacy endpoints. AEs were reported in 11.1% and 9.6% of participants in the rimegepant and placebo groups, respectively. The only AE reported in > 1% of participants was nausea (rimegepant = 1.4%, placebo = 1.3%). Severe AEs occurred in 0.3% and 0.1% of participants in the rimegepant and placebo groups, respectively. Serious AEs occurred in 0.1% of participants in both groups; none were deemed related to study treatment. CONCLUSION:In this pooled analysis of four randomized placebo-controlled trials, a single dose of rimegepant 75 mg demonstrated efficacy and a favorable safety profile for the acute treatment of a migraine attack with moderate or severe pain.

ObjectiveTo develop evidence-based clinical practice guidelines for non-invasive neuromodulation devices in acute and preventive migraine treatment.MethodsA 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.ResultsFrom 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.ConclusionNon-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.

Medication overuse headache (MOH) is a secondary headache characterized by frequent use of acute or symptomatic migraine medications at a sufficient frequency to transform patients from episodic to chronic migraine. MOH represents a significant medical problem, with a serious burden on patients' lives and on society as a whole. MOH patients often have additional comorbidities, and the clinical challenge of helping patients reduce acute medication use and revert to episodic headache can be marked. Treatment includes education and prevention; withdrawal programs; pharmacological prophylaxis; multidisciplinary therapies with behavioral and noninvasive neuromodulation options; and scheduled, frequent follow-up to prevent relapses. The advent of anti-CGRP therapy monoclonal antibodies may provide an alternative to more extensive programs for less complex patients. This review also provides guidance for which patients may benefit most from coordinated integrated programs.