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Introduction: Combination use of atogepant and onabotulinumtoxinA has the potential to be more effective than either alone for the preventive treatment of chronic migraine (CM) due to their complementary mechanisms of action. This analysis collected real-world data to evaluate the safety, tolerability, and effectiveness of adding atogepant to onabotulinumtoxinA as a combination preventive treatment for CM., Methods: This retrospective, longitudinal, multicenter chart review included adults with CM who received ≥ 2 consecutive cycles of onabotulinumtoxinA before ≥ 1 month of onabotulinumtoxinA and atogepant combination treatment. Charts at atogepant prescription (index date) and two subsequent onabotulinumtoxinA treatment visits (~ 3 and ~ 6 months post-index) were reviewed for change from baseline in monthly headache days (MHDs), ≥ 50% reduction in MHDs, discontinuation rates, and adverse events (AEs)., Results: Of the 55 charts that met safety analysis criteria, 31 had data on headache days at index and first post-index visit and were eligible for effectiveness analysis (mean age 46.7 years, 94.5% female). For those with data available prior to onabotulinumtoxinA treatment (n = 25), the mean MHD was 24.0 days, reduced by 8.15 days after onabotulinumtoxinA treatment. After atogepant was added, MHD was incrementally reduced by 4.53 days and 8.75 days from index date to the first (N = 31) and second (N = 23) post-index onabotulinumtoxinA treatment visit, respectively. A ≥ 50% reduction in MHDs was achieved by 45.2% of patients ~ 3 months post-index. Atogepant and onabotulinumtoxinA were discontinued by 16.1% and 6.5% of patients, respectively. In the safety population, 32.7% of patients experienced ≥ 1 AE. No serious AEs were reported., Conclusions: This real-world study of patients with CM demonstrated that adding atogepant to onabotulinumtoxinA as a combination preventive treatment for CM was effective by providing an additional reduction in MHDs over ~ 3 and ~ 6 months of combination treatment. Safety results were consistent with the known safety profiles of onabotulinumtoxinA and atogepant, with no new safety signals identified., (© 2024. The Author(s).)

Objective: This post hoc analysis of the PREVAIL study explored the effectiveness of eptinezumab for up to 2 years of open-label treatment in the subgroup of patients with chronic migraine who had a confirmed diagnosis of medication-overuse headache (MOH) at screening., Background: MOH is a disabling and costly secondary headache disorder characterized by increased headache frequency and/or severity with increased acute headache medication use. Eptinezumab, an anti-calcitonin gene-related peptide monoclonal antibody, reduces headache frequency, severity, and associated disability and improves functioning and health-related quality of life as a preventive migraine therapy; short-term benefits in patients with concurrent MOH have also been reported., Methods: Participants received up to eight quarterly intravenous infusions of eptinezumab 300 mg in the phase 3, single-arm, open-label PREVAIL study. Safety and patient-reported outcome measures (Migraine Disability Assessment [MIDAS], 6-item Headache Impact Test [HIT-6], patient-identified most bothersome symptom [PI-MBS], Patient Global Impression of Change [PGIC], and 36-item Short-Form Health Survey [SF-36]) were conducted at predefined intervals. Patients were observed up to 20 weeks after their last infusion (Week 104)., Results: A total of 49/128 (38.3%) patients enrolled in PREVAIL had an MOH diagnosis at screening. In the MOH subgroup, long-term eptinezumab treatment was associated with reductions in headache frequency (43/49 [87.8%] patients reported ≥50% reduction in MIDAS-derived headache days at ≥1 visit), severity (2.2-point reduction [on a 10-point scale]), disability (mean MIDAS total score reduction of 51.9 points), and impact (mean HIT-6 total score reduction of 9.7 points) at Week 104. Most patients described a "much improved" or "very much improved" status by Week 48 (PI-MBS, 31/46 [67.4%]) and Week 104 (PGIC, 31/36 [86.1%]). Health-related quality of life improvements in the SF-36 were also observed., Conclusion: Eptinezumab preventive therapy in patients with chronic migraine showed benefits that extended to the subset of patients with concomitant MOH., (© 2024 The Author(s). Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

Objective: To collect real-world data to evaluate the effectiveness, safety, and tolerability of adding atogepant to onabotulinumtoxinA as combination preventive treatment for chronic migraine (CM)., Background: Combination use of atogepant and onabotulinumtoxinA has the potential to be more effective than either alone for the preventive treatment of CM., Design/methods: This retrospective, longitudinal, multi-center chart review included adults with CM receiving ≥2 consecutive onabotulinumtoxinA cycles before ≥3mo of onabotulinumtoxinA and atogepant combination treatment. Charts at first atogepant prescription (index date) and 2 onabotulinumtoxinA injection visits (~3 and 6mo post-index) were reviewed for change from baseline in monthly headache days (MHDs), ≥50% reduction in MHDs, and rates and types of adverse events (AEs). Charts with CGRP agents for migraine prevention during baseline (~3mo pre-index) were excluded., Results: 31 charts met eligibility criteria (mean age 46.7 years, 94% female). Atogepant 60 mg and 30 mg were administered QD to 30 and 1 patients, respectively. Throughout the study, patients received a mean dose of 170U onabotulinumtoxinA. Pre-onabotulinumtoxinA, the mean MHD was 24.0d, reduced by a mean -8.15d (95%CI -11.44,-4.85; n=25) after onabotulinumtoxinA pre-index (mean 3.97yr). MHD additionally decreased by mean -4.53d [95%CI -7.44,-1.61] after ~3mo of combination treatment (n=31) and -8.75d total [95%CI -13.21, -4.29] after ~6mo of combination treatment in patients with data available (n=23). Nearly half of patients (n=14/31) achieved ≥50% reduction in MHDs ~3mo post-index. Overall, 95% CIs indicate that reductions from baseline were statistically significant. No new safety signals were identified when atogepant was added to onabotulinumtoxinA. The most commonly reported AEs (≥5%) were constipation and fatigue., Conclusions: This real-world pilot study of patients with CM demonstrated clinically meaningful treatment benefit in the reduction of headache days with onabotulinumtoxinA alone and additive benefits with co-administration of atogepant. Safety results were consistent with the known safety profiles of onabotulinumtoxinA and atogepant. Disclosure: Dr. Blumenfeld has received personal compensation for serving as an employee of The Los Angeles Headache Center. Dr. Blumenfeld has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Allergan. Dr. Blumenfeld has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Best Doctors. Dr. Blumenfeld has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Guidepoint. Dr. Blumenfeld has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for GLG. Dr. Blumenfeld has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Theranica. Dr. Blumenfeld has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Aeon. Dr. Blumenfeld has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Revance. Dr. Blumenfeld has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Lilly. Dr. Blumenfeld has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Pfizer. Dr. Blumenfeld has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Lundbeck. Dr. Blumenfeld has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Teva. Dr. Blumenfeld has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Abbvie. Dr. Blumenfeld has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Allergan. Dr. Blumenfeld has received personal compensation in the range of $100,000-$499,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Aeon. Dr. Blumenfeld has received personal compensation in the range of $100,000-$499,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Revance. Dr. Blumenfeld has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Theranica. Dr. Blumenfeld has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Axsome. Dr. Blumenfeld has received personal compensation in the range of $100,000-$499,999 for serving on a Speakers Bureau for Allergan. Dr. Blumenfeld has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Amgen. Dr. Blumenfeld has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Teva. Dr. Blumenfeld has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Lilly. Dr. Blumenfeld has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Biohaven. Dr. Blumenfeld has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Lundbeck. Dr. Mechtler has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Jushi Inc. Dr. Mechtler has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Amgen. Dr. Mechtler has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Novartis. Dr. Mechtler has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Allergan. Dr. Mechtler has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Eli Lilly. Dr. Mechtler has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Teva. Dr. Mechtler has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Biohaven. Dr. Mechtler has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Lundbeck. Dr. Mechtler has received stock or an ownership interest from Jushi Co.. The institution of Dr. Mechtler has received research support from The Harry Dent Family Foundation, Inc. The institution of Dr. Mechtler has received research support from Amgen/Novartis. The institution of Dr. Mechtler has received research support from Alder/ Lundbeck. The institution of Dr. Mechtler has received research support from Abbvie/Allergan. The institution of Dr. Mechtler has received research support from Miles for Migraine. The institution of Dr. Mechtler has received research support from American Migraine Foundation. The institution of Dr. Mechtler has received research support from Charlotte's Web. Dr. Cook has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Abbvie. Dr. Cook has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Teva. Dr. Cook has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Impel. The institution of Dr. Cook has received research support from Abbvie . The institution of Dr. Cook has received research support from Aeon. The institution of Dr. Cook has received research support from Axsome . The institution of Dr. Cook has received research support from Lilly . Dr. Rhyne has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abbvie/Allergan. Dr. Rhyne has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Abbvie/Allergan. Dr. Rhyne has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Abbvie/Allergan. Dr. Rhyne has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Amgen. Dr. Rhyne has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Teva. Dr. Rhyne has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Biohaven. Dr. Rhyne has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Lilly. Dr. Rhyne has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Theranica. Dr. Rhyne has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Lundbeck. Dr. Rhyne has received personal compensation in the range of $5,000-$9,999 for serving as a Speaker with Diamond Headache Clinic Research and Education Foundation. Dr. Rhyne has received personal compensation in the range of $500-$4,999 for serving as a Speaker with National Headache Foundation. Dr. Jenkins has received personal compensation for serving as an employee of Abbvie. Dr. Jenkins has received personal compensation for serving as an employee of Allergan. Dr. Jenkins has received personal compensation for serving as an employee of Teva. Dr. Jenkins has received personal compensation for serving as an employee of Biohaven. Dr. Jenkins has received personal compensation for serving as an employee of Lundbeck . Dr. Jenkins has received personal compensation for serving as an employee of Amgen and Novartis. Dr. Jenkins has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Abbvie. Dr. Jenkins has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Allergan . Dr. Jenkins has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Teva. Dr. Jenkins has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biohaven . Dr. Jenkins has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Lundbeck . Dr. Jenkins has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Amgen and Novartis. Dr. Jenkins has stock in Prevacus. Dr. Jenkins has received intellectual property interests from a discovery or technology relating to health care. Ms. Hughes has received personal compensation for serving as an employee of ICON plc. Dr. Dabruzzo has received personal compensation for serving as an employee of AbbVie. Dr. Dabruzzo has stock in AbbVie. Dr. Manack Adams has received personal compensation for serving as an employee of Abbvie. Dr. Manack Adams has stock in Abbvie. Merle Diamond has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Allergan/AbbVie . Merle Diamond has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lundbeck Pharmaceutical . Merle Diamond has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amgen. Merle Diamond has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Teva. Merle Diamond has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Impel NeuroPharma. Merle Diamond has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eli Lilly. Merle Diamond has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Promius. Merle Diamond has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Lundbeck Pharmaceuticals . Merle Diamond has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Amgen. Merle Diamond has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Allergan/AbbVie. Merle Diamond has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Assertio. Merle Diamond has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Eli Lilly . Merle Diamond has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Promius Pharma. Merle Diamond has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Supernus . Merle Diamond has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Teva Pharma. Merle Diamond has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Upsher-Smith . Merle Diamond has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Impel Neuro Pharma . Merle Diamond has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Axsome. Merle Diamond has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Assertio. Merle Diamond has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Amgen. Merle Diamond has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Axsome Pharma . Merle Diamond has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Assertio Therapeutics . Merle Diamond has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Eli Lilly . Merle Diamond has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Lundbeck . Merle Diamond has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Supernus Pharma. Merle Diamond has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Teva . Merle Diamond has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Upsher Smith. Merle Diamond has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Impel Neuro Pharma. Merle Diamond has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Allergan/AbbVie. Merle Diamond has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Lundbeck . Merle Diamond has received research support from Amgen . Merle Diamond has received research support from Lundbeck. Merle Diamond has received research support from Teva . Merle Diamond has received research support from Eli Lilly. Merle Diamond has received research support from Allergan. Merle Diamond has received personal compensation in the range of $500-$4,999 for serving as a Course Directory, Speaker with Diamond Research & Educational Foundation.

Background: Serotonin syndrome (SS) symptoms overlap with adverse events associated with lasmiditan, a 5-HT (serotonin) 1F receptor agonist for acute treatment of migraine. Because SS symptoms are heterogeneous, diagnosis can be challenging, and potential cases observed with lasmiditan treatment led to questions about SS pathophysiology. Here, we provide an overview of the potential risk of SS based on experience with lasmiditan., Methods: Results of eight phase 2 and phase 3 lasmiditan trials ( n  = 5,916) and a controlled intravenous trial of lasmiditan ( n  = 88) were analyzed for symptomatology consistent with SS. Post-marketing surveillance data from lasmiditan's US launch date (January 2020) until data cut-off (April 2021) were also examined. Established Sternbach and Hunter diagnostic criteria were used for formal determination of SS., Results: Of 6,004 lasmiditan-treated clinical trial patients, 15 reported ≥1 treatment-emergent adverse event consistent with signs and symptom(s) of SS. After review, one case met Sternbach and Hunter criteria, two cases potentially met Sternbach criteria, and three cases reported as SS had limited/no information to determine if either criterion was met. During post-marketing surveillance (approximately 13,400 lasmiditan prescriptions), 17 cases with symptom complexes consistent with SS were reported; 3/17 cases had adequate case descriptions to apply predefined criteria. Of these, two met Sternbach and Hunter criteria, and one met Sternbach criteria., Conclusion: Awareness of clinical symptomatology and diagnostic criteria of SS can help clinicians with recognition of rare instances of SS that may occur with lasmiditan., Clinical Trial Registration: NCT03670810, NCT00384774, NCT00883051, NCT02565186., Competing Interests: RK, ED, MV, and SM are full-time employees of Eli Lilly and Company and are company stockholders. ST: Research funding—Aeon, Abbvie, Eli Lilly, Lundbeck, Neurocrine, Neurolief, Pfizer, Suven, UCB Advisor, consultant, Advisory Board, and/or Scientific Board (honoraria): Aeon, Abbvie, Alphasights, Amgen, Aruene, Atheneum, Axsome Therapeutics, Becker Pharmaceutical Consulting, ClearView Healthcare Partners, ClickTherapeutics, CoolTech, CRG, Decision Resources, Defined Health, DRG, Eli Lilly, ExpertConnect, FCB Health, Fenix, GLG, Guidepoint Global, Health Advances, Health Science Communications, HMP Communications, Impel, Initiatior Pharma, InteractiveForums, Keyquest, Ki Health Partners, Krog and Partners, Lundbeck, M3 Global Research, Magnolia Innovation, MJH Holdings, Miravo Healthcare, Neurofront Therapeutics, Neurolief, Novartis, P Value Communications, Pain Insights, Inc., Palion Medical, 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, Trinity Partners, Unity HA, Vial, and XOC. Salary—Dartmouth-Hitchcock Medical Center, Thomas Jefferson University, and The New England Institute for Neurology and Headache. Honoraria lecture fees/Speaker Bureau—AbbVie, Eli Lilly, Pfizer, Scilex, and Teva. Travel—AbbVie, American Headache Society, Diamond Headache Clinic, Eli Lilly, Pfizer, and Scilex. Honoraria lecture fees, Continuing Medical Education (CME)—American Academy of Neurology, American Headache Society, Annenberg Center for Health Sciences, Catamount Medical Education, Diamond Headache Clinic, Forefront Collaborative, Haymarket Medical Education, HMP Global, Medical Education Speakers Network, Medical Learning Institute Peerview, Miller Medical Education, National Association for Continuing Education, North American Center for CME, The Ohio State University, Physicians’ Education Resource, PlatformQ Education, Primed, Vindico Medical Education, and WebMD/Medscape. AB: Advisory Board—Allergan, Aeon, Alder, Amgen, Biohaven, Lilly, Lundbeck, Novartis, Pfizer, Revance, Teva, Theranica, and Zoscano. Speaker—Allergan, Amgen, Lilly, Teva, and Lundbeck. Consultant—Allergan, Alder, Amgen, Biohaven, Lilly, Lundbeck, Pfizer, Novartis, Teva, Theranica, and Zoscano. Grant support—Allergan and Amgen. Contributing author—Novartis, Teva, Allergan, Abbvie, Biohaven, Lilly, and Lundbeck., (Copyright © 2023 Blumenfeld, Tepper, Khanna, Doty, Vincent and Miller.)

Migraine is a neurologic disease with a complex pathophysiology that can be controlled with current treatment options but not cured. Therefore, treatment expectations are highly variable. The concept of migraine freedom was recently introduced and can mean different things, with some, for example, expecting complete freedom from headache and associated symptoms and others accepting the occasional migraine attack if it does not impact functioning. Therefore, migraine management should be optimized so that patients can have the best opportunity to achieve their optimal treatment goals. With migraine freedom as a goal and, given the complex pathophysiology of migraine and the high incidence of comorbidities among individuals with migraine, treatment with a single modality may be insufficient, as it may not achieve migraine freedom in those with more frequent or disabling attacks. In this clinical perspective article, we have identified four key, partially overlapping principles of multimodal migraine treatment: (1) manage common comorbidities; (2) control modifiable risk factors for progression by addressing medication and caffeine overuse; (3) diagnose and treat secondary causes of headache, if present; and (4) individualize acute and preventive treatments to minimize pain, functional disability, and allodynia. There are many barriers to pursuing migraine freedom, and strategies to overcome them should be optimized. Migraine freedom should be an aspirational goal both at the individual attack level and for the disease overall. We believe that a comprehensive and multimodal approach that addresses all barriers people with migraine face could move patients closer to migraine freedom., (© 2023. The Author(s).)

BACKGROUND: Chronic migraine (CM) is a common neurologic disorder that imposes substantial burden on payers, patients, and society. Low rates of persistence to oral migraine preventive medications have been previously documented; however, less is known about persistence and costs associated with innovative nonoral migraine preventive medications. OBJECTIVE: To evaluate real-world persistence and costs among adults with CM treated with onabotulinumtoxinA (onabotA) or calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs). METHODS: This was a retrospective, longitudinal, observational study analyzing the IBM MarketScan Commercial and Medicare databases. The study sample included adults with CM initiating treatment with either onabotA or a CGRP mAb on or after January 1, 2018. Persistence and costs over 12 months after treatment initiation were evaluated using chi-square and Student's t-tests. Persistence to onabotA was compared with CGRP mAbs as a weighted average of the class and by individual CGRP mAbs. Mean pharmacy (acute and preventive), medical (inpatient, emergency department, and outpatient), and total costs are reported. Multivariate regression analyses were conducted to generate adjusted estimates of persistence and costs after controlling for potential confounders (age, sex, region, insurance type, number of baseline comorbidities, Charlson Comorbidity Index, and number of previously used oral migraine preventive medications). RESULTS: Of 66,303 individuals with onabotA or CGRP mAb claims, 2,697 with CM met the inclusion/exclusion criteria. In the total population, individuals were primarily female (85.5%), lived in the South (48.5%), and had a mean (SD) age of 44 (12) years, which was consistent across the onabotA and CGRP mAb cohorts. Common comorbid conditions included anxiety (23.9%), depression (18.2%), hypertension (16.5%), and sleep disorders (16.9%). After adjusting for potential confounding variables, persistence to onabotA during the 12-month follow-up period was 40.7% vs 27.8% for CGRP mAbs (odds ratio [OR] = 0.683; 95% CI = 0.604-0.768; P < 0.0001). Persistence to erenumab, fremanezumab, and galcanezumab was 25.5% (OR = 0.627; 95% CI = 0.541-0.722; P < 0.0001), 30.3% (OR = 0.746; 95% CI = 0.598-0.912; P = 0.0033), and 33.7% (OR = 0.828; 95% CI = 0.667-1.006; P = 0.058). All-cause ($18,292 vs $18,275; P = 0.9739) and migraine-related ($8,990 vs $9,341; P = 0.1374) costs were comparable between the onabotA and CGRP mAb groups. CONCLUSIONS: Among adults with CM receiving onabotA and CGRP mAbs, individuals initiating onabotA treatment had higher persistence compared with those receiving CGRP mAbs. Total all-cause and migraine-related costs over 12 months were comparable between those receiving onabotA and CGRP mAbs. DISCLOSURES: This study was sponsored by Allergan (prior to its acquisition by AbbVie), they contributed to the design and interpretation of data and the writing, reviewing, and approval of final version. Writing and editorial assistance was provided to the authors by Dennis Stancavish, MS, of Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ, and was funded by AbbVie. The opinions expressed in this article are those of the authors. The authors received no honorarium/fee or other form of financial support related to the development of this article. Dr Schwedt serves on the Board of Directors for the American Headache Society and the American Migraine Foundation. Within the prior 12 months he has received research support from Amgen, Henry Jackson Foundation, Mayo Clinic, National Institutes of Health, Patient-Centered Outcomes Research Institute, SPARK Neuro, and US Department of Defense. Within the past 12 months, he has received personal compensation for serving as a consultant or advisory board member for AbbVie, Allergan, Axsome, BioDelivery Science, Biohaven, Collegium, Eli Lilly, Ipsen, Linpharma, Lundbeck, and Satsuma. He holds stock options in Aural Analytics and Nocira. He has received royalties from UpToDate. Dr Lee and Ms Shah are employees of AbbVie and may hold AbbVie stock. Dr Gillard was an employee of AbbVie and may hold AbbVie stock. Dr Knievel has served as a consultant for AbbVie, Amgen, Eli Lilly, and Biohaven; conducted research for AbbVie, Amgen, and Eli Lilly; and is on speaker programs for AbbVie and Amgen. Dr McVige has served as a speaker and/or received research support from Allergan (now AbbVie Inc.), Alder, Amgen/Novartis, Avanir, Biohaven, Eli Lilly, Lundbeck, and Teva. Ms Wang and Ms Wu are employees of Genesis Research, which provides consulting services to AbbVie. Dr Blumenfeld, within the past 12 months, has served on advisory boards for Allergan, AbbVie, Aeon, Alder, Amgen, Axsome, BDSI, Biohaven, Impel, Lundbeck, Lilly, Novartis, Revance, Teva, Theranica, and Zosano; as a speaker for Allergan, AbbVie, Amgen, BDSI, Biohaven, Lundbeck, Lilly, and Teva; as a consultant for Allergan, AbbVie, Alder, Amgen, Biohaven, Lilly, Lundbeck, Novartis, Teva, and Theranica; and as a contributing author for Allergan, AbbVie, Amgen, Biohaven, Novartis, Lilly, and Teva. He has received grant support from AbbVie and Amgen. AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual, and trial-level data (analysis data sets), as well as other information (eg, protocols, clinical study reports, or analysis plans), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications. These clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan and execution of a Data Sharing Agreement. Data requests can be submitted at any time after approval in the United States and Europe and after acceptance of this manuscript for publication. The data will be accessible for 12 months, with possible extensions considered. For more information on the process, or to submit a request, visit the following link: https://www.abbvieclinicaltrials.com/hcp/data-sharing/.

Aim: To evaluate the onset, magnitude and persistence of efficacy of remote electrical neuromodulation (REN) compared with placebo for the preventive treatment of migraine. Materials & methods: Analysis was conducted on data from a prospective, double-blind, placebo-controlled clinical trial, which assessed the efficacy of REN for the prevention of migraine. The number of monthly migraine days (MMD) per group was calculated in 2-week intervals and compared between the groups. Results: Differences between the active (N = 95) and placebo (N = 84) groups reached significance at 2 weeks: therapeutic gain 0.84 MMD; p = 0.036. 4 weeks gain 1.59 MMD; p = 0.025, 6 weeks gain 2.27 MMD; p < 0.001, 8 weeks gain 2.68 MMD; p < 0.001. Conclusion: REN provides rapid and consistent efficacy in preventive treatment of migraine.

Background: The objective is to review the technique of onabotulinumtoxinA injection treatment in the glabellar and frontal regions using the PREEMPT (Phase III REsearch Evaluating Migraine Prophylaxis Therapy) paradigm, with review of the aesthetic issues related to the procedure. OnabotulinumtoxinA is an effective medication for the prevention of chronic migraine. The PREEMPT injection paradigm has been validated in randomized clinical trials and real-world settings. This treatment includes injections in the forehead and glabella area. In addition, for aesthetic uses, glabella onabotulinumtoxinA injections are done in similar muscles specifically the procerus, corrugator supercilii, and frontalis muscles. Often patients who have been injected with onabotulinumtoxinA for chronic migraine have concerns about their appearance and will ask if they can see an aesthetic injector to improve this. This is a difficult issue as onabotulinumtoxinA should be injected with an interval of 10-12 weeks to avoid development of antibodies against onabotulinumtoxinA, so all injections (migraine and aesthetic) should ideally be done close together; however, if an aesthetic injection is done on the same day as a PREEMPT injection, the effect of the PREEMPT injection will not yet be visible as it takes time for onabotulinumtoxinA effects to be seen. Thus, there is a risk of a potential overdose in a particular area if aesthetic injections are done without input from the PREEMPT injector., Methods: This is a narrative review supported by photographic documentation showing the technique of onabotulinumtoxinA injection of the upper face, considering anatomical differences between patients, and combining the needs in neurology and aesthetic medicine fields., Results: Practitioners treating chronic migraine often modify some of the principles of the PREEMPT paradigm. Many practitioners are unsure about injections in the glabellar and frontal areas. The authors present a technique for using the PREEMPT protocol and adapting this to the individual patient's anatomy to prevent an unsightly appearance or ptosis. In addition, sites are provided where an aesthetic injector could inject to improve the patient's appearance without overlapping with the PREEMPT injection sites., Conclusion: Adherence to the PREEMPT injection protocol provides an evidence-based approach to achieving clinical benefit for patients with chronic migraine. Aesthetic elements of the treatment of the glabella and forehead require additional attention. The authors provide practical considerations and recommendations regarding this., (© 2023 American Headache Society.)

Objective: To evaluate potential drug-drug interactions of ubrogepant and atogepant., Background: Ubrogepant and atogepant, calcitonin gene-related peptide (CGRP) receptor antagonists, are recently approved drugs for acute and preventive treatment of migraine, respectively. For patients with migraine who are prescribed atogepant for the preventive treatment of migraine, health care providers could prescribe ubrogepant for the acute treatment of breakthrough migraine attacks., Methods: A phase Ib, multi-center, open-label, fixed-sequence study was conducted in participants diagnosed with migraine for at least 1 year. To assess the primary objective of pharmacokinetic interactions in this phase I trial, the highest United States Food and Drug Administration-approved individual dose strengths of atogepant (60 mg once daily) and ubrogepant (100 mg) were utilized, with ubrogepant being administered on a fixed-dose schedule every 3 days, regardless of whether a participant was experiencing a migraine attack. Secondary endpoints included safety and tolerability. Clinical safety measurements were monitored throughout the study., Results: Of the 31 participants enrolled, 26 completed the study. A single dose of ubrogepant had no statistically significant effect on atogepant pharmacokinetics. Co-administration of ubrogepant with atogepant resulted in a 19% increase (geometric mean ratio 118.80, 90% confidence interval [CI] 108.69-129.84) in the ubrogepant area under the plasma concentration-time curve and a 26% increase (geometric mean ratio 125.63, 90% CI 105.58-149.48) in the ubrogepant maximum plasma concentration. These statistically significant changes in ubrogepant exposure were not clinically meaningful, and no new safety concerns were identified for the combination., Conclusion: The combination use of atogepant and ubrogepant was safe and well tolerated in adult participants with a history of migraine enrolled in the study. Pharmacokinetic changes during co-administration were not clinically meaningful., (© 2023 AbbVie Inc and The Authors. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

Introduction: Migraine is a highly prevalent and disabling neurological disease. Excessive use of acute medications can lead to medication-overuse headache (MOH), occurring when a patient experiences an increasing number of headache and migraine days, despite taking greater amounts of acute medication. To treat MOH, a preventive migraine treatment and/or withdrawal of the overused medication(s) are advised. Brief Educational Intervention (BEI) has been shown to be an effective tool with promising results for MOH. Here, we report the design of a clinical trial that aims to evaluate the efficacy of eptinezumab, an anti-calcitonin gene-related peptide preventive migraine treatment, as an add-on to BEI for treatment of MOH in those with chronic migraine., Methods and Analysis: RESOLUTION will be a phase 4, multi-national, randomized, double-blind, placebo-controlled study. This study will enroll approximately 570 participants with dual diagnoses of chronic migraine and MOH. Eligible patients will be randomly allocated to one of two treatment groups, BEI and eptinezumab (100 mg; n = 285) or BEI and placebo ( n = 285), in a 1:1 ratio. The primary endpoint is the change from baseline in monthly migraine days over weeks 1-4. Secondary and exploratory endpoints will assess monthly migraine days over weeks 1-12, MOH remission, transition from chronic to episodic migraine, health-related quality of life, work productivity, and the safety and tolerability of eptinezumab in this patient population., Ethics and Dissemination: This study will be conducted in accordance with good clinical practice. All patients will be fully informed about the study, including the risks and benefits of participation, and all participants will provide informed consent for participation in the trial and dissemination of results., Competing Interests: RJ has given lectures for Pfizer, Berlin-Chemie, Norspan, Merck, Autonomic Technologies, Teva, Allergan/AbbVie, Lundbeck, and Novartis and she is or has been a principal investigator on clinical trials sponsored by Eli Lilly, Lundbeck, and Autonomic Technologies. HS has received personal fees from Novartis, Lilly, Allergan/AbbVie, Teva, and Lundbeck and research support from Novartis, has served on advisory boards for Teva and Lundbeck, and is affiliated with BMJ Open as a reviewer. CT has received funding for participation in Advisory Boards or for scientific presentations from Allergan/AbbVie, Eli Lilly, Lundbeck, Novartis, and Teva and is or has been a principal investigator in clinical trials sponsored by Allergan, Eli Lilly, Lundbeck, Novartis, and Teva. GT is a board member for the Dutch Headache Society and the CGRP Education and Research Forum and is an advisory member for the Dutch Headache Alliance; she has received personal fees from Consultancy: Novartis, Teva, Allergan, Lilly, and Lundbeck, received research support from the Dutch Brain Foundation, Dutch Heart Foundation, Dutch Research Council, IRRF, and Dioraphte (all to institution), has a pending patent for an eDiary collaboration with Interactive Studios, is involved with the clinical trial WHATstudy on the effect of hormonal treatment in migraine, is a National Primary Investigator in the ALLEVIATE and CHRONICLE studies by Lundbeck, and is also a presenter for satellite symposia/webinars with Springer Media (Mednet)/Ashfield MedComms. LC has received grants from the Danish Health Authority. AM is a current employee of Lundbeck. OØ was previously an employee of Lundbeck and is now employed by Biogen. RL has been a consultant, advisory board member, and/or has received honoraria from Lundbeck Seattle BioPharmaceuticals, Allergan, American Academy of Neurology, American Headache Society, Amgen, Biohaven Pharmaceuticals, BioVision, Boston Scientific, Dr. Reddy's Laboratories, electroCore Medical, Eli Lilly, eNeura Therapeutics, GlaxoSmithKline, Merck, Pernix, Pfizer, Supernus, Teva Pharmaceuticals, Trigemina, Vector, and Vedanta, received compensation from eNeura and Biohaven Pharmaceuticals, has stock or stock options in Biohaven Pharmaceuticals and Manistee, and has received research support from Amgen, Migraine Research Foundation, and National Headache Foundation. ST reports grants for research (no personal compensation) from Allergan/AbbVie, Amgen, Eli Lilly, Lundbeck, Neurolief, Novartis, Satsuma, and Zosano, is a consultant and/or on advisory boards (honoraria) for Aeon, Allergan/AbbVie, Alphasights, Amgen, Aruene, Atheneum, Axsome Therapeutics, Becker Pharmaceutical Consulting, BioDelivery Sciences International, Biohaven, ClearView Healthcare Partners, Click Therapeutics, Collegium, CoolTech, CRG, Decision Resources, Defined Health, DRG, Eli Lilly, ExpertConnect, FCB Health, Fenix, GLG, Guidepoint Global, Health Advances, Health Science Communications, HMP Communications, Impel, InteractiveForums, Keyquest, Krog and Partners, Lundbeck, M3 Global Research, Magnolia Innovation, MJH Holdings, Neurofront Therapeutics, Neurolief, Novartis, P Value Communications, Pain Insights Inc, Palion Medical, Pulmatrix, Putnam Associates, SAI MedPartners, Satsuma, Slingshot Insights, Spherix Global Insights, Strategy Inc, System Analytic, Taylor and Francis, Teva, Theranica, Tremeau, Unity HA, XOC, and Zosano, and reports salary from Dartmouth-Hitchcock Medical Center and Thomas Jefferson University, and CME honoraria from the American Academy of Neurology, American Headache Society, Catamount Medical Education, Diamond Headache Clinic, Forefront Collaborative, Haymarket Medical Education, Peerview, Medical Education Speakers Network, Migraine Association of Ireland, National Association for Continuing Education, North American Center for CME, The Ohio State University, Physicians' Education Resource, PlatformQ Education, Primed, Vindico Medical Education, and WebMD/Medscape. AB has served on advisory boards for Allergan, AbbVie, Aeon, Alder, Amgen, Axsome, Biohaven, Impel, Lundbeck, Lilly, Novartis, Revance, Teva, Theranica, and Zosano; has received funding for speaking from Allergan, AbbVie, Amgen, Biohaven, Lundbeck, Lilly, and Teva; has served as a consultant for Allergan, AbbVie, Alder, Amgen, Biohaven, Lilly, Lundbeck, Novartis, Teva, and Theranica, received grant support from Allergan and Amgen, and has been a contributing author for Allergan, AbbVie, Amgen, Novartis, Teva, Lilly, and Biohaven. CL has participated on an advisory board and received payment for lectures arranged by AbbVie Pharma AS, Lundbeck, Novartis AS, and Roche AS, Norway and he has received research sponsorship from AbbVie Pharma, and is a regular reviewer with BMJ., (Copyright © 2023 Jensen, Schytz, Tassorelli, Terwindt, Carlsen, Mittoux, Østerberg, Lipton, Tepper, Blumenfeld and Lundqvist.)

Background and Objectives: The oral calcitonin gene-related peptide receptor antagonist atogepant is indicated for the preventive treatment of episodic migraine. We evaluated changes in patient-reported outcomes with atogepant in adults with migraine., Methods: In this phase 3, 12-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial (ADVANCE), adults with 4-14 migraine days per month received atogepant (10, 30, or 60 mg) once daily or placebo. Secondary endpoints included changes from baseline in Migraine-Specific Quality-of-Life Questionnaire (MSQ) version 2.1 Role Function-Restrictive (RFR) domain at week 12 and mean monthly Activity Impairment in Migraine-Diary (AIM-D) Performance of Daily Activities (PDA) and Physical Impairment (PI) domains across the 12-week treatment period. Exploratory endpoints included change in MSQ Role Function-Preventive (RFP) and Emotional Function (EF) domains; AIM-D total scores; and change in Headache Impact Test (HIT)-6 scores., Results: Of 910 participants randomized, 873 comprised the modified intent-to-treat population (atogepant: 10 mg [n = 214]; 30 mg [n = 223]; and 60 mg [n = 222]; placebo [n = 214]). All atogepant groups demonstrated significantly greater improvements vs placebo in MSQ RFR that exceeded minimum clinically meaningful between-group difference (3.2 points) at week 12 (least-square mean difference [LSMD] vs placebo: 10 mg [9.9]; 30 mg [10.1]; 60 mg [10.8]; all p < 0.0001). LSMDs in monthly AIM-D PDA and PI scores across the 12-week treatment period improved significantly for the atogepant 30 (PDA: -2.54; p = 0.0003; PI: -1.99; and p = 0.0011) and 60 mg groups (PDA: -3.32; p < 0.0001; PI: -2.46; p < 0.0001), but not for the 10 mg group (PDA: -1.19; p = 0.086; PI: -1.08; p = 0.074). In exploratory analyses, atogepant 30 and 60 mg were associated with nominal improvements in MSQ RFP and EF domains, other AIM-D outcomes, and HIT-6 scores at the earliest time point (week 4) and throughout the 12-week treatment period. Results varied for atogepant 10 mg., Discussion: Atogepant 30 and 60 mg produced significant improvements in key patient-reported outcomes including MSQ-RFR scores and both AIM-D domains. Nominal improvements also occurred for other MSQ domains and HIT-6, reinforcing the beneficial effects of atogepant as a new treatment for migraine prevention., Trial Registration Information: ClinicalTrials.gov NCT03777059. Submitted: December 13, 2018; First patient enrolled: December 14, 2018., Clinicaltrials: gov/ct2/show/NCT03777059., Classification of Evidence: This study provides Class II evidence that daily atogepant is associated with improvements in health-related quality-of-life measures in patients with 4-14 migraine days per month., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Treatment wearing-off has been reported for calcitonin gene-related peptide-pathway monoclonal antibodies, including erenumab, specifically in the last week of the monthly dosing cycle., Objective: We sought to determine the consistency of erenumab effect throughout the monthly treatment cycle., Methods: In this post hoc analysis of four pivotal double-blind, randomized controlled studies of erenumab in episodic and chronic migraine, we assessed wearing-off based on change in weekly migraine days at week 4 versus average over weeks 1-3 in each monthly dosing cycle. Analyses were conducted at each monthly dosing cycle in all patients, in responders (≥50% reduction in weekly migraine days), and in consistent responders (response in ≥2monthly cycles)., Results: There was no evidence of wearing-off in the full study populations of two global studies (N = 946 and N = 656) and two Japan studies (N = 475 and N = 261). In the full study population, mean change in weekly migraine days at week 4 compared with the average over week 1-3 ranged from 0.15 days improvement to 0.19 days worsening in the placebo group and 0.08 days improvement to 0.20 days worsening in the erenumab groups. A subgroup of responders experienced wearing-off, but the extent of wearing-off did not differ between erenumab and placebo groups. The mean change in weekly migraine days at week 4 compared with the average over weeks 1-3 ranged from 0.34 to 0.61 days worsening in the placebo group and 0.27 to 0.78 days worsening in the erenumab groups. Few patients had persistent wearing-off in ≥2 consecutive monthly treatment cycles. For erenumab-treated responders, serum erenumab concentrations were similar among patients experiencing wearing-off and those maintaining response., Conclusion: No systematic wearing-off with erenumab was identified. Further research is needed to determine if wearing-off reported for some patients in clinical practice reflects a true treatment response pattern or normal fluctuations in migraine frequency., (© 2022 The Authors. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

Introduction: Through 2018, three calcitonin gene-related peptide pathway-targeted monoclonal antibodies (CGRP mAbs) had received US Food and Drug Administration (FDA) approval for migraine prevention: erenumab, fremanezumab, and galcanezumab., Methods: This retrospective analysis evaluated adverse events (AEs) spontaneously reported to the FDA Adverse Event Reporting System (FAERS) safety surveillance database during the first 6 months post-approval of erenumab (May 2018 to November 2018), fremanezumab (September 2018 to March 2019), and galcanezumab (September 2018 to March 2019). Reporting rates (RR) per 1000 exposed patients were calculated from number of reported events (when product classified as "primary suspect") in each AE category and estimated number of treated patients based on de-identified prescription data (IQVIA database) and were ranked on the basis of frequency for each product., Results: RR per 1000 exposed patients for "migraine" (erenumab, 4.89; fremanezumab, 1.01; galcanezumab, 2.99), "headache" (3.32, 1.27, 3.07), and "drug ineffective" (3.68, 1.14, 1.69) were commonly reported for all three products, as were migraine-associated symptoms ("nausea": 2.94, 0.91, 1.09) and "injection-site" reactions ("pain": 2.94, 0.8, 4.9; "swelling": 0.56, 0.53, 1.25; "pruritus": 0.26, 0.63, 1.14; "erythema": 0.58, 0.71, 1.58). "Constipation" ranked second for erenumab (4.90) but did not make the top ten events for fremanezumab (0.46) or galcanezumab (0.76); cardiovascular events did not rank in the top ten AEs for any product. The frequency of serious outcomes was low, with ≤ 2% of AEs categorized as serious across the CGRP mAbs., Conclusion: These results aid in supporting the safety profile of CGRP mAbs in the real-world setting and may provide clinicians and patients with additional insight when considering migraine preventive treatments., (© 2022. The Author(s).)

Introduction: Numerous medications are used for the preventive treatment of chronic migraine (CM), including oral treatments, onabotulinumtoxinA (onabotA; BOTOX), and calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs). Despite substantial clinical trial evidence, less is published about the real-world experience of these treatments based on data routinely collected from a variety of sources. This systematic review assessed real-world evidence on the effectiveness and safety of preventive treatments for CM in adults., Methods: A systematic search of MEDLINE, Embase, and the Cochrane library with back-referencing and supplementary searches retrieved data published between January 2010 and February 2020. Publications were screened, extracted, and quality assessed. Data were narratively synthesized. Search criteria included preventive medications for CM. Evidence was available for topiramate, onabotulinumtoxinA, CGRP mAbs (erenumab, galcanezumab, and fremanezumab). OnabotulinumtoxinA was most commonly assessed (55 studies), followed by erenumab (six studies), multiple CGRP mAbs (one study), and topiramate (one study). Long-term data (> 1 year) were available for onabotulinumtoxinA only, with erenumab reported up 6 months, topiramate up to 3 months, and multiple CGRP mAbs up to 12 months., Results: Substantial data demonstrated that onabotulinumtoxinA reduces the number/frequency of headaches, concomitant acute medication use, and impact of headaches on well-being and daily activity. More limited evidence showed benefits for the same parameters with erenumab. Single studies suggested topiramate and multiple CGRP mAbs decrease the number/frequency of headaches and impact of headaches. To date, onabotulinumtoxinA is the only preventive treatment for CM that has long-term safety data in real-world settings reporting treatment-related adverse events of up to 3 years., Conclusion: While substantial real-world evidence supports the long-term effectiveness and safety of onabotulinumtoxinA, real-world data on other preventive treatments of CM are currently limited to short term effectiveness due to their more recent approvals., (© 2022. The Author(s).)

Background: This post-hoc analysis from three phase 3 treatment trials of rimegepant 75 mg - an oral small molecule calcitonin gene-related peptide receptor antagonist for acute and preventive treatment of migraine - assessed efficacy in adults with migraine based on triptan treatment experience., Methods: Participants were assigned to one of four groups based on triptan treatment experience: insufficient response (e.g. lack of efficacy and/or poor tolerability) to 1 triptan, insufficient response to ≥2 triptans, current triptan users, and triptan-naïve participants. The co-primary efficacy endpoints were pain freedom and most bothersome symptom freedom at two hours postdose., Results: In the three trials (N = 3507; rimegepant n = 1749, placebo n = 1758), 1235 (35.2%) participants had a history of insufficient response to 1 triptan (n = 910 [25.9%]) or ≥2 triptans (n = 325 [9.3%]), and 2272 (64.8%) had no history of insufficient response to triptans (current use = 595 [17.0%], naïve = 1677 [47.8%]). Rimegepant was effective on the co-primary endpoints in all subgroups ( p  ≤ 0.013), except for freedom from the most bothersome symptom in the triptan-naïve group ( p  = 0.06). No differences on co-primary endpoints were found in pairwise comparisons of rimegepant-treated participants., Conclusions: Rimegepant was effective for the acute treatment of migraine in adults with a history of insufficient response to 1 or ≥2 triptans and in current triptan users. Efficacy on co-primary endpoints did not differ based on the number of insufficient triptan responses.Trial registration: Clinicaltrials.gov: NCT03235479, NCT03237845, NCT03461757.

Background: Eptinezumab is an anti-calcitonin gene-related peptide humanized monoclonal antibody approved for the preventive treatment of migraine in adults. The PREVAIL study demonstrated a favorable safety profile with sustained reductions in overall migraine-related burden in patients with chronic migraine (CM). This post hoc analysis aimed to examine item-level changes in the Migraine Disability Assessment (MIDAS) questionnaire over 2 years in participants with CM on eptinezumab treatment., Methods: PREVAIL was an open-label, phase 3 trial that included 96 weeks of treatment where 128 adults received intravenous eptinezumab administered over 30 min every 12 weeks (wks) for up to 8 doses of 300 mg. MIDAS was administered at baseline, Wk12, and every 12wks thereafter. Two supplementary MIDAS items not included in the total score calculation assessed number of headache days in the past 3 months (MIDAS headache) and average headache pain severity (from 0 [none] to 10 [worst]). MIDAS total scores were summed from 5 items, each quantifying the number of days in the past 3 months with migraine-related disability. Items 1, 3, and 5 assessed absenteeism, namely how many days the patient missed work/school (Q1), household work (Q3), or family/social/leisure activities (Q5). Items 2 and 4 were measures of presenteeism, namely how many days the patient had reduced productivity in work/school (Q2) or household work (Q4)., Results: Mean MIDAS headache days decreased from 47.4 (baseline) to 17.1 (Wk12) and 16.3 (Wk104). The average headache pain severity score (0‒10) decreased from a mean of 7.3 (baseline) to 5.5 (Wk12) to 4.5 (Wk104). Mean MIDAS scores measuring absenteeism (Q1, 3, 5) changed from 9.7 days at baseline to 3.2 days (Wk12) and to 3.9 days (Wk104). Mean MIDAS scores measuring presenteeism (Q2, 4) at Wk12 decreased from 14.2 days at baseline to 5.2 days (Wk12, 104). Patients categorized with very severe MIDAS disability had a mean total MIDAS score of 84.8, with an average reduction of 56.7 days (Wk12), which was maintained at 32 days at Wk104., Conclusions: Long-term treatment with eptinezumab in patients with CM suggested sustained reductions in MIDAS-quantified disability, consistent with the sustained reductions in headache frequency and pain severity., Trial Registration: ClinicalTrials.gov identifier: NCT02985398 ., (© 2022. The Author(s).)

Chronic migraine (CM) is one of the most disabling diseases, and it is commonly misdiagnosed and mistreated. Despite the importance of a timely and accurate diagnosis for the effective management of CM, recent surveys have shown that only 20-25% of individuals with CM receive a correct diagnosis. The obvious consequences of misdiagnosed CM are prolongation of symptoms and their associated effects on disability and health-related quality of life. Additionally, mistreatment of CM can lead to acute medication overuse headache with escalation of headache and end organ damage. Ideally, a diagnosis of CM should be made in the primary care setting, based on a thorough medical history including detailed descriptions of headaches occurring earlier in life as well as current headaches, and the range of headaches (not just the worst headaches). In our experience, it is often equally informative to ask the patient about the number of headache-free days (HFDs) and no accompanying symptoms (i.e., crystal-clear days) to quantify headache days and accurately estimate headache frequency/impact. Headache frequency is important, as this count is one key means of diagnosing CM, which requires ≥ 15 headache days/month, noting that these do not need to be migraine days. A headache day is defined as more than 4 h a day of headache. Comorbidities are common in CM and may affect the treatment choice and increase disability. Every CM patient should be offered a preventive migraine treatment. In this commentary, we provide practical insights and tips for diagnosing CM and cover issues of medication overuse, patient communication, diagnostic testing, and when to make a referral. Our key message to physicians for a patient who comes to the clinic with frequent disabling headaches having features of migraine is to assume CM until proven otherwise., (© 2022. The Author(s).)

Recently approved migraine preventive therapies facilitate rapid control of migraine activity, potentially improving patients' lives and minimizing the societal burden of migraine. This review synthesizes available evidence on rates and timing of early onset of migraine prevention and identifies patient-level outcomes related to early onset prevention. This evidence-based scoping review identified all available clinical trial evidence regarding the early onset of prevention of migraine, under the hypothesis 'Patients with migraine (episodic or chronic) report additional benefits when receiving an approved migraine preventive treatment that demonstrates an early onset of prevention '. Early onset of prevention was defined as migraine preventive benefits within 30 days post-administration. PubMed, EMBASE, and CINAHL were searched for publications between 1988 and 2020. Overall, 16 publications described 18 studies. All studies were conducted in approved treatments [four anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies and one chemodenervation agent] in patients with episodic/chronic migraine; no publications were identified for traditional oral agents for early migraine prevention. Compared to placebo, erenumab (three studies) reduced weekly migraine days within 1 week; fremanezumab (six studies) increased reports of no headache of at least moderate severity on Day 1 and significantly reduced migraine frequency within 1 week; galcanezumab (three studies) significantly reduced the mean number of patients with migraine beginning Day 1 and each day of the first week; eptinezumab (four studies) significantly reduced migraine attack likelihood on Day 1 by > 50% versus baseline; and onabotulinumtoxinA (two studies) reduced headache and migraine days within 1 week. Four publications described function, disability, and quality of life improvements as early as Week 4; none reported cost-benefit. Anti-CGRP monoclonal antibodies (erenumab, fremanezumab, galcanezumab, and eptinezumab) and a chemodenervation agent (onabotulinumtoxinA) provide clinically relevant benefits during the first treatment week. Literature describing clinically relevant benefits regarding early onset of prevention in patients with migraine is limited., Competing Interests: Declaration of Conflicting Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: C.G. has been a paid consultant for Alder/Lundbeck, Biohaven, Amgen/Novartis, Theranica, Axsome, Upsher Smith, Spherix Global Insights, and Vorso and has been a past member of speaker bureaus for Amgen/Novartis, Allergan/AbbVie, Biohaven, Lilly, Theranica, and Upsher Smith. He served as an Associate Editor of Headache until 2020 and is a board member of the Headache Cooperative of New England (HCNE). D.C.B. has received grant support from the Food and Drug Administration and the National Headache Foundation and grant support and honoraria from Allergan, Amgen, Lilly, Lundbeck, and Teva. She serves on the editorial board of Current Pain and Headache Reports. M.J.M. has received compensation for consultation from Lundbeck and Theranica. He has participated in speaker bureaus for Lilly and Amgen/Novartis. He has received salary support for serving as principal investigator from Teva, GammaCore, and Allergan/AbbVie. He has received payments for authorship or royalties from Demos Medical, Cambridge University Press, and MedLink. B.T. has received compensation for consulting from Amgen, Novartis, Biohaven, Lilly, Lundbeck, Teva, and Theranica. He has participated in speaker bureaus with Allergan/AbbVie, Amgen, Biohaven, Lilly, Lundbeck, and Teva, and he has received financial compensation for serving as principal investigator with Amgen and Theranica. J.M.P. has received grant support from the National Institutes of Health and compensation for consulting from Alder/Lundbeck, Allergan/AbbVie, Amgen/Novartis, and Biohaven. P.K.D. has received grant support from Amgen/Novartis, Allergan/AbbVie, and Lilly. She serves as Editor in Chief of Migraine Again, Editor at Large of Everyday Health, and Co-Producer/Co-Owner of Migraine World Summit, which is supported by Lundbeck, Impel, Lilly, Allergan/AbbVie, Axon Optics, and Teva. N.L. has no compensation or conflicts to report. All funding or sponsorships are directed to the American Migraine Foundation. A.B. serves as a consultant and/or a promotional speaker for Alder, Allergan, Amgen, Biohaven, electroCore, Lilly, Lundbeck, Novartis, Promius, Supernus, Teva, and Theranica., (© The Author(s), 2022.)

Objective: To assess the nocioceptive input of habitual nocturnal jaw clenching that acts as a contributing factor in migraine pathogenesis., Background: Habitual nocturnal jaw clenching has been implicated as a trigger, particularly in those whose headaches are present upon waking or shortly thereafter. Nocturnal EMG studies of patients diagnosed with migraine show nearly twice the temporalis clenching EMG levels and double the bite force as matched asymptomatic controls, leading to the speculation that parafunctional clenching activity may have some role in headache pathogenesis. The NTI (Nociceptive Trigeminal Inhibition) oral device is a dental splint designed to reduce nocturnal jaw clenching intensity and is FDA approved for the prevention of medically diagnosed migraine pain based on open label studies. There are no prior placebo-controlled trials to assess the migraine prevention efficacy of the NTI splint. This is the first placebo-controlled cross-over study to assess the efficacy of the NTI splint in patients with Chronic Migraine., Method: A placebo controlled, single-blinded cross-over study was done with IRB oversight assessing the efficacy of the NTI splint compared to placebo using the change in the HIT-6 score as the outcome measure., Results: 68% of refractory chronic migraine sufferers using the NTI as measured by sequential HIT 6 scores had at least a one-category improvement (severe to substantial, or substantial to some, or some to none) compared to 12% when using a placebo device. 36% of subjects using the NTI device reported a two-category improvement in their HIT-6 score, compared to 0% when using placebo., Conclusion: The improvement in HIT-6 scores produced by the NTI device, suggests that patients with Chronic Migraine may have intense nocturnal jaw clenching as a contributing factor to their headache related disability. An NTI device is one method of assessing whether jaw-clenching is a contributing factor to ongoing migraine., Trial Registration: Current Controlled Trials NCT04871581. 04/05/2021. Retrospectively registered., (© 2022. The Author(s).)

Introduction: Ubrogepant is a calcitonin gene-related peptide receptor antagonist indicated for acute treatment of migraine that can be used to treat breakthrough attacks in individuals taking preventive treatment for migraine. We evaluated the impact of preventive medication use on the efficacy and safety of ubrogepant for the acute treatment of migraine., Methods: This was an analysis of pooled efficacy data from the ACHIEVE I and ACHIEVE II phase 3 trials, in which efficacy of ubrogepant was assessed at 2 h after taking study medication for pain freedom, absence of most bothersome symptom (MBS), and pain relief. In addition, a long-term safety (LTS) extension trial was completed where safety was assessed on the basis of incidence and severity of treatment-emergent adverse events (TEAEs). Outcomes were compared between participants with or without prior (within 6 months) preventive medication use (anticonvulsants, beta blockers, antidepressants, or onabotulinumtoxinA). For efficacy analyses, data were pooled across ACHIEVE trials for the 50 mg and placebo groups; for safety analyses, data for all dose groups (50 mg and 100 mg) in the LTS trial were pooled., Results: Preventive treatments were used by 417 of 2247 (18.6%) participants analyzed in the ACHIEVE trials and by 143 of 813 (17.5%) participants in the LTS trial. Responder rates for all outcomes were similar between participants with or without preventive treatment within each dose group (p > 0.05). No significant differences were noted across the different preventive medications. Rates and types of TEAEs were similar between participants with or without preventive treatment. No serious treatment-related adverse events were reported., Conclusion: Efficacy and safety of ubrogepant for the acute treatment of migraine were similar between participants with or without prior or current use of concomitant preventive medication., Trial Registration: ClinicalTrials.gov identifiers: NCT02828020 (ACHIEVE I), NCT02867709 (ACHIEVE II), and NCT02873221 (long-term safety trial)., (© 2021. The Author(s).)

Introduction: Combination use of onabotulinumtoxinA and calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) has the potential to be more effective than either therapy alone for migraine prevention., Methods: This retrospective, longitudinal chart review included adults with chronic migraine treated at one clinical site with ≥ 2 consecutive cycles of onabotulinumtoxinA and ≥ 1 month of subsequent combination treatment with CGRP mAbs. Charts at time of mAb prescription (baseline) and up to four visits ~ 3, 6, 9, and 12 months post-baseline were reviewed for safety, tolerability, and outcome measures (monthly headache days [MHDs], headache intensity, and migraine-related disability [MIDAS])., Results: Of 300 charts reviewed, 257 patients met eligibility criteria (mean age: 50 years; 82% women). Average headache frequency was 21.5 MHDs before initiation of onabotulinumtoxinA and 12.1 MHDs before adding CGRP mAb therapy. Prescribed mAbs were erenumab (78%), fremanezumab (6%), and galcanezumab (16%). Over the entire study, patients discontinued CGRP mAb more frequently than onabotulinumtoxinA (23 vs. 3%). Adverse events occurred in 28% of patients, most commonly constipation (9%). Compared with onabotulinumtoxinA alone (baseline), MHDs decreased significantly at all visits (mean decrease: 3.5-4.0 MHDs over ~ 6-12 months of combination treatment); 45.1% of patients had clinically meaningful improvement in migraine-related disability (≥ 5-point reduction in MIDAS score) after ~ 6 months., Conclusions: In this real-world study, combination treatment with onabotulinumtoxinA and CGRP mAbs was well tolerated, with no new safety signals identified, and was associated with additional clinically meaningful benefits. More real-world and controlled trials should be considered to further assess safety and potential benefits of combination treatment. Video abstract: Real-world data suggests that CGRP inhibitors improve onabotulinumtoxinA efficacy for chronic migraine (MP4 20,067 kb)., (© 2021. The Author(s).)

Migraine involves brain hypersensitivity with episodic dysfunction triggered by behavioral or physiological stressors. During an acute migraine attack the trigeminal nerve is activated (peripheral sensitization). This leads to central sensitization with activation of the central pathways including the trigeminal nucleus caudalis, the trigemino-thalamic tract, and the thalamus. In episodic migraine the sensitization process ends with the individual act, but with chronic migraine central sensitization may continue interictally. Increased allostatic load, the consequence of chronic, repeated exposure to stressors, leads to central sensitization, lowering the threshold for future neuronal activation (hypervigilance). Ostensibly innocuous stressors are then sufficient to trigger an attack. Medications that reduce sensitization may help patients who are hypervigilant and help to balance allostatic load. Acute treatments and drugs for migraine prevention have traditionally been used to reduce attack duration and frequency. However, since many patients do not fully respond, an unmet treatment need remains. Calcitonin gene-related peptide (CGRP) is a vasoactive neuropeptide involved in nociception and in the sensitization of peripheral and central neurons of the trigeminovascular system, which is implicated in migraine pathophysiology. Elevated CGRP levels are associated with dysregulated signaling in the trigeminovascular system, leading to maladaptive responses to behavioral or physiological stressors. CGRP may, therefore, play a key role in the underlying pathophysiology of migraine. Increased understanding of the role of CGRP in migraine led to the development of small-molecule antagonists (gepants) and monoclonal antibodies (mAbs) that target either CGRP or the receptor (CGRP-R) to restore homeostasis, reducing the frequency, duration, and severity of attacks. In clinical trials, US Food and Drug Administration-approved anti-CGRP-R/CGRP mAbs were well tolerated and effective as preventive migraine treatments. Here, we explore the role of CGRP in migraine pathophysiology and the use of gepants or mAbs to suppress CGRP-R signaling via inhibition of the CGRP ligand or receptor., (© 2021. The Author(s).)

Introduction: OnabotulinumtoxinA is approved in the USA for the prevention of headache in adults with chronic migraine, a debilitating neurologic disease characterized by headaches occurring on ≥ 15 days per month for > 3 months and including migraine features on ≥ 8 days per month., Objective: The COMPEL Study (NCT01516892), a 108-week, multi-center, open-label study, evaluated the long-term efficacy and safety of onabotulinumtoxinA in adults with chronic migraine. The objective of this subanalysis was to examine the safety and tolerability of onabotulinumtoxinA after each of nine treatment cycles., Methods: OnabotulinumtoxinA 155 U was administered every 12 weeks. Safety and tolerability, overall and by treatment cycle, were assessed. Treatment-emergent adverse events reported between successive treatments were attributed to the preceding treatment. The safety population received one or more doses of onabotulinumtoxinA. The primary efficacy outcome was the reduction in headache days at week 108 compared with baseline., Results: Of 716 patients enrolled, 373 patients (52.1%) completed the study and 343 (47.9%) withdrew; 481 patients (67.2%) received 60 weeks of treatment and 402 (56.1%) received 108 weeks of treatment. In total, 436 (60.9%) patients reported treatment-emergent adverse events; most were mild/moderate in severity. Thirty-two patients (4.5%) discontinued the study after experiencing treatment-emergent adverse events. The incidence of treatment-emergent adverse events typically decreased with repeated onabotulinumtoxinA treatment: first cycle, 24.2%; fourth cycle, 18.4%; ninth cycle, 12.2%. Neck pain (2.7%), eyelid ptosis (1.8%), musculoskeletal stiffness (1.4%), injection-site pain (1.3%), and headache (1.3%) were the most common treatment-emergent adverse events after the first cycle. Seventy-five patients (10.5%) reported serious treatment-emergent adverse events, 13 (1.8%) withdrew. Treatment-related adverse events were reported by 131 patients (18.3%), one was considered serious. OnabotulinumtoxinA significantly reduced headache day frequency by 10.7 (6.4) days per 28-day period (p < 0.0001) at week 108., Conclusions: OnabotulinumtoxinA treatment was well tolerated over 108 weeks; no new safety signals were identified. The overall incidence of treatment-emergent adverse events and the most common individual events decreased with repeated onabotulinumtoxinA administration., Clinical Trial Registration: ClinicalTrials.gov; NCT01516892.

Small RNAs regulate gene expression and most genes in the worm Caenorhabditis elegans are subject to their regulation. Here, we analyze small RNA data sets and use reproducible features of RNAs present in multiple data sets to discover a new class of small RNAs and to reveal insights into two known classes of small RNAs--22G RNAs and 26G RNAs. We found that reproducibly detected 22-nt RNAs, although are predominantly RNAs with a G at the 5' end, also include RNAs with A, C, or U at the 5' end. These RNAs are synthesized downstream from characteristic sequence motifs on mRNA and have U-tailed derivatives. Analysis of 26G RNAs revealed that they are processed from a blunt end of double-stranded RNAs and that production of one 26G RNA generates a hotspot immediately downstream for production of another. To our surprise, analysis of RNAs shorter than 18 nt revealed a new class of RNAs, which we call NU RNAs (pronounced "new RNAs") because they have a NU bias at the 5' end, where N is any nucleotide. NU RNAs are antisense to genes and originate downstream from U bases on mRNA. Although many genes have complementary NU RNAs, their genome-wide distribution is distinct from that of previously known classes of small RNAs. Our results suggest that current approaches underestimate reproducibly detected RNAs that are shorter than 18 nt, and theoretical considerations suggest that such shorter RNAs could be used for sequence-specific gene regulation in organisms like C. elegans that have small genomes., (© 2016 Blumenfeld and Jose; Published by Cold Spring Harbor Laboratory Press for the RNA Society.)

Chronic migraine is a recognized complication of episodic migraine. A high frequency of attacks and frequent use of abortive medications are important risk factors associated with conversion to a chronic condition. Prophylaxis is therefore recommended for patients with frequent episodic migraine. The agents approved for migraine prophylaxis are the anti-epileptic agents divalproex and topiramate, and the beta-adrenergic antagonists propranolol and timolol. However, a wide range of other systemic agents and local injections of botulinum toxin have also been used in migraine prophylaxis. The anticipated benefits must be weighed against the adverse effects associated with each agent in determining the optimal preventive regimen for individual patients.