Commentary on 2022 guidelines on clinical trial design in cluster headache and further suggestions.

BACKGROUND: New guidelines for cluster headache clinical trials were recently published. We welcome these new guidelines and raise additional considerations in trial methodologies. MAIN BODY: We present non-inferiority trials to overcome ethical issues with placebo use, and additionally discuss issues with trial recruitment. CONCLUSIONS: We highlight some possible issues and solutions to be considered with the recently published cluster headache trial guidelines.

Management of medication overuse headache.

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.

Eptinezumab Demonstrated Efficacy Regardless of Prior Preventive Migraine Treatment Failure Type: Post Hoc Analyses of the DELIVER Study.

INTRODUCTION: In the DELIVER study, eptinezumab reduced monthly migraine days (MMDs) more than placebo in patients with 2-4 prior preventive migraine treatment failures. This post hoc analysis evaluated the efficacy of eptinezumab across the 24-week placebo-controlled period of the DELIVER study in subgroups defined by prior treatment failure type. METHODS: DELIVER (NCT04418765) randomized adults with migraine to eptinezumab 100 mg, 300 mg, or placebo, administered intravenously every 12 weeks. Changes from baseline in MMDs and percentages of patients with ≥ 50% reduction from baseline in MMDs (≥ 50% migraine responder rates [MRRs]) were summarized in subgroups of patients defined by prior treatment failure type. Subgroups were not mutually exclusive and included patients for whom topiramate, beta blockers (metoprolol, propranolol), amitriptyline, and/or flunarizine had failed. RESULTS: Across Weeks 1-12 in all subgroups, patients treated with eptinezumab experienced greater reductions from baseline in MMDs than those receiving placebo (reductions ranged from 4.5-5.5 vs 1.6-2.4, respectively), with larger reductions over Weeks 13-24. Similarly, ≥ 50% MRRs were consistently higher with eptinezumab than placebo and increased following a second infusion. CONCLUSION: In all subgroups, regardless of prior preventive treatment failure type, eptinezumab demonstrated greater reductions in MMDs and higher MRRs compared with placebo. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT04418765).

Long-term effectiveness of eptinezumab in patients with migraine and prior preventive treatment failures: extension of a randomized controlled trial.

BACKGROUND: Eptinezumab demonstrated efficacy in adults with migraine and prior preventive treatment failures in the placebo-controlled phase of the DELIVER clinical trial; its long-term effectiveness in this population has not yet been reported. The objective of this study was to evaluate the long-term effectiveness of eptinezumab in a migraine patient population during the 48-week extension phase of DELIVER. METHODS: DELIVER was conducted June 1, 2020 to September 15, 2022. 865 adults with migraine, with documented evidence of 2-4 prior preventive migraine treatment failures and with completion of the 24-week placebo-controlled period of DELIVER received eptinezumab (100 or 300 mg) during the dose-blinded extension, either continuing their randomized dose or, if originally receiving placebo, were randomized 1:1 to an eptinezumab dose (100 or 300 mg). A mixed model for repeated measures was used to evaluate changes from baseline in the number of monthly migraine days (MMDs). RESULTS: Of 865 patients entering the extension (eptinezumab 100 mg, n = 433; 300 mg, n = 432), 782 (90.4%) completed and 11 (1.3%) discontinued due to an adverse event. Eptinezumab was associated with early and sustained reductions in migraine frequency. Mean MMDs at baseline were approximately 14 days across groups. Mean (standard error) change from baseline in MMDs over the final dosing interval (weeks 61-72) was -6.4 (0.50) with placebo/eptinezumab 100 mg, -7.3 (0.49) with placebo/eptinezumab 300 mg, -7.1 (0.39) with eptinezumab 100 mg, and -7.0 (0.39) with eptinezumab 300 mg. During weeks 61-72, 63-70% of patients demonstrated ≥ 50% reduction in MMDs, and 36-45% demonstrated ≥ 75% reduction. Headache severity and acute medication use reductions, and patient-reported improvements in most bothersome symptom, disease status, quality of life, and work productivity, were observed. Adverse events were generally mild, transient, and similar in frequency/type to previous eptinezumab trials. CONCLUSIONS: The long-term effectiveness and safety/tolerability of eptinezumab in patients with migraine and 2-4 prior preventive treatment failures was demonstrated by high completion rates and migraine-preventive benefits sustained for up to 18 months, implying that eptinezumab is a viable long-term treatment option for patients still seeking successful migraine treatments. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT04418765; URL: https://www. CLINICALTRIALS: gov/ct2/show/NCT04418765 ); EudraCT (Identifier: 2019-004497-25; URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-004497-25 ).

Serotonin syndrome in the acute treatment landscape of migraine: the lasmiditan experience.

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.

Healthcare costs and resource utilization in patients with migraine treated with erenumab: A retrospective, non-interventional study using claims data from the United States.

OBJECTIVE: To assess healthcare costs and healthcare resource utilization (HCRU) among adult patients who newly initiated erenumab in the United States. METHODS: This retrospective, non-interventional analysis included adult patients (aged ≥18 years) newly initiating erenumab and who had three consecutive monthly claims for erenumab (11/1/2017-9/1/2019) from the Komodo Health database. Outcomes included migraine-related and all-cause costs, use of other preventive/acute migraine medications, and HCRU. All outcomes were compared during the 180-day pre- versus the 180-day post-index periods. Cost outcomes were also assessed for longer periods including post-index Days 91-270 and monthly mean post-index costs for the longest time of continuous insurance enrollment. RESULTS: Overall, 1839 patients with migraine were included for analysis. Compared to the 180-day pre-index period, an increase in total migraine-related costs (+$2639; p < 0.0001), migraine-related prescription costs (+$3435, p < 0.0001), all-cause total costs (+$2977; p < 0.001), and all-cause prescription costs (+$4102; p < 0.0001) were observed during the 180-day post-index period after adjusting for covariates. Conversely, reduction in migraine-related medical costs (-$896; p < 0.0001), and significantly lower odds of migraine-related emergency room visits (odds ratio [OR] 0.60, 95% confidence interval [CI] 0.44-0.82; p = 0.001), migraine-related office visits (OR 0.58, 95% CI 0.53-0.64; p < 0.0001), and migraine-related neurologist visits (OR 0.69, 95% CI 0.63-0.75; p < 0.0001) were observed during the 180-days post-index period. There were significant decreases in the odds of having overall preventive migraine medications (OR 0.81, 95% CI 0.75-0.87; p < 0.0001), acute-migraine medications (OR 0.92, 95% CI 0.85-1.00; p = 0.038), and triptan (OR 0.79, 95% CI 0.73-0.85; p < 0.0001) during the 180-day post-index period. Sensitivity analyses on cost outcomes found no statistically significant differences in pre-index migraine-related costs compared to post-index migraine-related costs when assessing longer post-index follow-up periods. CONCLUSION: Initiation of therapy with a novel treatment is often associated with an increase in overall healthcare costs due to the entrance costs associated with novel therapy. For a chronic condition such as migraine, cost versus health benefits should be evaluated over a long period (e.g., ≥2 years) to better understand the true benefits of therapy. Data from this study suggest that the entrance cost for erenumab, the primary driver of the high post-index prescription costs gets mitigated by reduced medical costs over long-term follow-up. The results indicate better disease management in adult patients with migraine, which should be an important consideration for both patients and payors, as these findings have shown an offset between migraine-related prescription and medical costs.

Multimodal Migraine Management and the Pursuit of Migraine Freedom: A Narrative Review.

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.

A Brief Review of Gepants.

PURPOSE OF REVIEW: Gepants are small molecules that antagonize calcitonin gene-related peptide (CGRP) receptors. Due to their favorable side effect profile and versatility in treating headaches acutely and preventively, gepants are preferred over triptans. We will cover the indications for the four FDA-approved gepants in adults: rimegepant, atogepant, ubrogepant, and zavegepant. This review will illustrate how gepants will continue to revolutionize the acute and preventive treatment of headaches. RECENT FINDINGS: Gepants are now available in oral tablet, dissolving tablet, and intra-nasal spray formulations. Recent studies have shown promising utility in treating the pre-headache or prodromal phase. They have favorable tolerability, no evidence for association with medication overuse, and remain a safer alternative in those who have cerebrovascular risk factors. Additional research is needed to explore occurrence of Raynaud's phenomenon in participants treated with gepants, as it has been associated with CGRP monoclonal antibodies, but are not extensively studied in gepants. Gepants are expected to play a significant role in the next generation of migraine treatments.

Long-term efficacy and safety of erenumab in patients with chronic migraine and acute medication overuse: A subgroup analysis.

OBJECTIVE: Assess the long-term efficacy and safety of erenumab in patients with chronic migraine with acute medication overuse. BACKGROUND: Overuse of acute medication in patients with chronic migraine has been linked to greater pain intensity and disability and may diminish the effectiveness of preventive therapies. METHODS: This 52-week open-label extension study followed a 12-week double-blind placebo-controlled study in which patients with chronic migraine were randomized 3:2:2 to placebo or once-monthly erenumab 70 mg or 140 mg. Patients were stratified by region and medication overuse status. Patients received erenumab 70 mg or 140 mg throughout or switched from erenumab 70 to 140 mg (based on protocol amendment to augment safety data at higher dose). Efficacy was assessed in patients with and without medication overuse at parent study baseline. RESULTS: Of 609 patients enrolled in the extension study, 252/609 (41.4%) met the criteria for medication overuse at parent study baseline. At Week 52, the mean change in monthly migraine days from parent study baseline was -9.3 (95% confidence interval: -10.4, -8.1 days) in the medication overuse subgroup versus -9.3 (-10.1, -8.5 days) in the non-medication overuse subgroup (combined erenumab doses); proportion of patients achieving ≥50% reduction in monthly migraine days at Week 52 was 55.9% (90/161; 48.2%, 63.3%) versus 61.3% (136/222; 54.7%, 67.4%), respectively. Among baseline users of acute migraine-specific medication, the mean change in monthly migraine-specific medication days at Week 52 was -7.4 (-8.3, -6.4 days) in the medication overuse subgroup versus -5.4 (-6.1, -4.7 days) in the non-medication overuse subgroup. Most patients (197/298; 66.1%) in the medication overuse subgroup transitioned to non-overuse status by Week 52. Erenumab 140 mg was associated with numerically greater efficacy than erenumab 70 mg across all endpoints. No new safety signals were identified. CONCLUSION: Long-term erenumab treatment demonstrated sustained efficacy and safety in patients with chronic migraine with and without acute medication overuse.

The temporal trend of placebo response in migraine prevention from 1990 to 2021: a systematic literature review and meta-analysis with regression.

BACKGROUND: Migraine affects 1.1 billion people globally and is the second leading cause of disability worldwide. In clinical trials, treatment efficacy is evaluated by comparing the differential responses in the treatment and placebo arms. Although placebo response in preventive migraine trials has been studied, there is limited research examining temporal trends. This study evaluates the trend of placebo response over thirty years in migraine prevention trials and investigates the association of potential confounders, such as patient, treatment, and study characteristics on placebo response using meta-analysis with regression. METHODS: We conducted literature searches from January 1990 to August 2021 in bibliographical databases (PubMed, Cochrane Library, and EMBASE). Studies were selected according to PICOS criteria and included randomized, double-blind, placebo-controlled trials evaluating preventive migraine treatments in adult patients diagnosed with episodic or chronic migraine, with or without aura. The protocol was registered with PROSPERO (CRD42021271732). Migraine efficacy outcomes included were either continuous (e.g., monthly migraine days) or dichotomous (e.g., ≥ 50% responder rate (yes/no)). We assessed the correlation of the change in outcome from baseline in the placebo arm, with the year of publication. The relationship between placebo response and year of publication was also assessed after accounting to confounders. RESULTS: A total of 907 studies were identified, and 83 were found eligible. For the continuous outcomes, the change from baseline in mean placebo response showed an increase over the years (rho = 0.32, p = 0.006). The multivariable regression analysis also showed an overall increase in placebo response over the years. The correlation analysis of dichotomous responses showed no significant linear trend between publication year and mean placebo response (rho = 0.08, p = 0.596). Placebo response also varied by route of administration. CONCLUSION: Placebo response increased over the past 30 years in migraine preventive trials. This phenomenon should be considered when designing clinical trials and conducting meta-analyses.

Sustained response of galcanezumab in migraine prevention: Patient-level data from a post hoc analysis in patients with episodic or chronic migraine.

OBJECTIVE: To evaluate, at population and individual patient levels, the sustained response of reduction in migraine headache days in patients with migraine treated with galcanezumab. METHODS: This was a post hoc analysis of double-blind galcanezumab studies in patients with migraine: two 6-month episodic migraine (EM; EVOLVE-1/EVOLVE-2), one 3-month chronic migraine (CM; REGAIN), and one 3-month treatment-resistant migraine (CONQUER). Patients received monthly subcutaneous galcanezumab 120 mg (after 240 mg initial loading dose), galcanezumab 240 mg, or placebo. In the EM and CM studies, the proportions of patients with ≥50% and ≥75% (EM only) reduction from baseline in average monthly migraine headache days from Months 1 to 3 and Months 4 to 6 were evaluated. A mean monthly response rate was estimated. The sustained effect was defined as maintaining ≥50% response for ≥3 consecutive months in the patient-level data for EM and CM. RESULTS: A total of 3348 patients with EM or CM from the EVOLVE-1/EVOLVE-2 (placebo, n = 894, galcanezumab, n = 879), REGAIN (placebo, n = 558, galcanezumab, n = 555), and CONQUER (EM: placebo, n = 132, galcanezumab, n = 137; CM: placebo, n = 98, galcanezumab, n = 95) studies were included. Patients were predominantly female, White, and had monthly migraine headache day averages ranging from 9.1 to 9.5 days (EM) and 18.1 to 19.6 days (CM). In patients with EM and CM, 19.0% and 22.6% of galcanezumab-treated patients, respectively, had significantly higher maintenance of ≥50% response for all months in the double-blind period compared to 8.0% and 1.5% of placebo-treated patients. The odds ratios (OR) of achieving clinical response for EM and CM were double with galcanezumab (OR = 3.0 [95% CI 1.8, 4.8] and OR = 6.3 [95% CI 1.7, 22.7], respectively). At the individual patient level, of patients who had ≥75% response at Month 3 in the galcanezumab 120 and 240 mg dose groups and placebo group, 39.9% (55/138) and 43.0% (61/142), respectively, of galcanezumab-treated patients maintained ≥75% response during Months 4-6 compared to 32.7% (51/156) with placebo. CONCLUSION: More galcanezumab-treated patients achieved ≥50% response within the first 3 months of treatment compared to placebo; responses were sustained during Months 4-6. The odds of achieving ≥50% response were double with galcanezumab.

Adding eptinezumab to brief patient education to treat chronic migraine and medication-overuse headache: Protocol for RESOLUTION-A phase 4, multinational, randomized, double-blind, placebo-controlled study.

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.

Novel Migraine Treatments: A Review

Aims: To present a review of the mechanisms of action, available clinical data, and safety profiles of novel migraine therapeutics to inform practice. Methods: PubMed, Medline, and Google Scholar were searched for randomized controlled trials (24 publications), review articles (15 publications), and other pertinent literature (16 publications) discussing the novel migraine therapeutics available between the years 2010 and 2021. All publications were reviewed to assess the mechanism of action, relevant clinical data, and side effect profile for each novel treatment. Therapeutic gain was also recorded in studies that included a placebo arm. Results: A total of 55 studies were included in the final analysis. In the preventive treatment of migraine, novel medications target calcitonin gene-related peptide (CGRP) and fall into either the monoclonal anti-CGRP or gepant class. For the acute treatment of migraine, novel medications fall into either the ditan or gepant class. Several medical devices have been developed for the acute and preventive treatment of migraine. Conclusion: Novel therapeutics are available for both the prevention and acute treatment of migraine headaches. These new medications and neuromodulatory devices appear overall to be safe and effective in the management of migraine headaches.

Once-daily oral atogepant for the long-term preventive treatment of migraine: Findings from a multicenter, randomized, open-label, phase 3 trial.

OBJECTIVE: To assess long-term safety, tolerability, and efficacy of once-daily oral atogepant 60 mg in adults with migraine. BACKGROUND: Atogepant is an oral, small-molecule, calcitonin gene-related peptide receptor antagonist approved for the preventive treatment of episodic migraine. METHODS: A 52-week, multicenter, randomized, open-label trial of adults (18-80 years) with migraine. Lead-in trial completers or newly enrolled participants with 4-14 migraine days/month were enrolled and randomized (5:2) to atogepant 60 mg once daily or oral standard care (SC) migraine preventive medication. The primary objective was to evaluate the safety and tolerability of atogepant; safety assessments included treatment-emergent adverse events (TEAEs), clinical laboratory evaluations, vital signs, and Columbia-Suicide Severity Rating Scale scores. Efficacy assessments (atogepant only) included change from baseline in mean monthly migraine days (MMDs) and the proportion of participants with reductions from baseline of ≥50%, ≥75%, and 100% in MMDs. RESULTS: The trial included 744 participants randomized to atogepant 60 mg (n = 546) or SC (n = 198). The atogepant safety population was 88.2% female (n = 479/543) with a mean (standard deviation) age of 42.5 (12.0) years. TEAEs occurred in 67.0% (n = 364/543) of participants treated with atogepant 60 mg. The most commonly reported TEAEs (≥5%) were upper respiratory tract infection (10.3%; 56/543), constipation (7.2%; 39/543), nausea (6.3%; 34/543), and urinary tract infection (5.2%; 28/543). Serious TEAEs were reported in 4.4% (24/543) for atogepant. Mean (standard error) change in MMDs for atogepant was -3.8 (0.1) for weeks 1-4 and -5.2 (0.2) at weeks 49-52. Similarly, the proportion of participants with ≥50%, ≥75%, and 100% reductions in MMDs increased from 60.4% (310/513), 37.2% (191/513), and 20.7% (106/513) at weeks 1-4 to 84.2% (282/335), 69.9% (234/335), and 48.4% (162/335), at weeks 49-52. CONCLUSION: Daily use of oral atogepant 60 mg for preventive treatment of migraine during this 1-year, open-label trial was safe, well tolerated, and efficacious.

Remote electrical neuromodulation for migraine prevention: A double-blind, randomized, placebo-controlled clinical trial.

OBJECTIVE: To assess the clinical efficacy of remote electrical neuromodulation (REN), used every other day, for the prevention of migraine. BACKGROUND: Preventive treatment is key to managing migraine, but it is often underutilized. REN, a non-pharmacological acute treatment for migraine, was evaluated as a method of migraine prevention in patients with episodic and chronic migraine. METHODS: We conducted a prospective, randomized, double-blind, placebo-controlled, multi-center trial, with 1:1 ratio. The study consisted of a 4-week baseline observation phase, and an 8-week double-blind intervention phase in which participants used either REN or a placebo stimulation every other day. Throughout the study, participants reported their symptoms daily, via an electronic diary. RESULTS: Two hundred forty-eight participants were randomized (128 active, 120 placebo), of which 179 qualified for the modified intention-to-treat (mITT) analysis (95 active; 84 placebo). REN was superior to placebo in the primary endpoint, change in mean number of migraine days per month from baseline, with mean reduction of 4.0 ± SD of 4.0 days (1.3 ± 4.0 in placebo, therapeutic gain = 2.7 [confidence interval -3.9 to -1.5], p < 0.001). The significance was maintained when analyzing the episodic (-3.2 ± 3.4 vs. -1.0 ± 3.6, p = 0.003) and chronic (-4.7 ± 4.4 vs. -1.6 ± 4.4, p = 0.001) migraine subgroups separately. REN was also superior to placebo in reduction of moderate/severe headache days (3.8 ± 3.9 vs. 2.2 ± 3.6, p = 0.005), reduction of headache days of all severities (4.5 ± 4.1 vs. 1.8 ± 4.6, p < 0.001), percentage of patients achieving 50% reduction in moderate/severe headache days (51.6% [49/95] vs. 35.7% [30/84], p = 0.033), and reduction in days of acute medication intake (3.5 ± 4.1 vs. 1.4 ± 4.3, p = 0.001). Similar results were obtained in the ITT analysis. No serious device-related adverse events were reported in any group. CONCLUSION: Applied every other day, REN is effective and safe for the prevention of migraine.

Variability in recurrence rates with acute treatments for migraine: why recurrence is not an appropriate outcome measure.

BACKGROUND: Headache recurrence is a common feature of acute therapies, whether approved or still in development, and continues to be a significant problem for both the patient and the clinician. Further complicating this issue is lack of standardization in definitions of recurrence used in clinical trials, as well as disparity in patient characteristics, rendering a comparison of different acute medications challenging. Recurrence has serious clinical implications, which can include an increased risk for new-onset chronic migraine and/or development of medication overuse headache. The aim of this review is to illustrate variability of recurrence rates depending on prevailing definitions in the literature for widely used acute treatments for migraine and to emphasize sustained response as a clinically relevant endpoint for measuring prolonged efficacy. BODY: A literature search of PubMed for articles of approved acute therapies for migraine that reported recurrence rates was performed. Study drugs of interest included select triptans, gepants, lasmiditan, and dihydroergotamine mesylate. An unpublished post hoc analysis of an investigational dihydroergotamine mesylate product that evaluated recurrence rates using several different definitions of recurrence common in the literature is also included. Depending on the criteria established by the clinical trial and the definition of recurrence used, rates of recurrence vary considerably across different acute therapies for migraine, making it difficult to compare results of different trials to assess the sustained (i.e., over a single attack) and the prolonged (i.e., over multiple attacks) efficacy of a particular study medication. CONCLUSION: A standardized definition of recurrence is necessary to help physicians evaluate recurrence rates of different abortive agents for migraine. Sustained pain relief or freedom may be more comprehensive efficacy outcome measures than recurrence. Future efficacy studies should be encouraged to use the recommended definition of sustained pain freedom set by the International Headache Society.

Guidelines of the International Headache Society for Controlled Clinical Trials in Cluster Headache.

In 1995, a committee of the International Headache Society developed and published the first edition of the Guidelines for Controlled Trials of Drugs in Cluster Headache. These have not been revised. With the emergence of new medications, neuromodulation devices and trial designs, an updated version of the International Headache Society Guidelines for Controlled Clinical Trials in Cluster Headache is warranted. Given the scarcity of evidence-based data for cluster headache therapies, the update is largely consensus-based, but takes into account lessons learned from recent trials and demands by patients. It is intended to apply to both drug and neuromodulation treatments, with specific proposals for the latter when needed. The primary objective is to propose a template for designing high quality, state-of-the-art, controlled clinical trials of acute and preventive treatments in episodic and chronic cluster headache. The recommendations should not be regarded as dogma and alternative solutions to particular methodological problems should be explored in the future and scientifically validated.

Role of Calcitonin Gene-Related Peptide on the Gastrointestinal Symptoms of Migraine-Clinical Considerations: A Narrative Review.

Calcitonin gene-related peptide (CGRP) is involved in several of the pathophysiological processes underpinning migraine attacks. Therapies that target CGRP or its receptor have shown efficacy as preventive or acute treatments for migraine. Two small-molecule CGRP receptor antagonists (rimegepant and ubrogepant) are approved for the acute treatment of migraine, and four monoclonal antibodies (eptinezumab, erenumab, fremanezumab, and galcanezumab) are approved for migraine prevention; erenumab targets the canonical CGRP receptor, the others CGRP ligand. CGRP plays a role in gastrointestinal nociception, inflammation, gastric acid secretion, and motility. Nausea and vomiting are among the gastrointestinal symptoms associated with migraine, but individuals with migraine may also experience functional upper and lower gastrointestinal comorbidities, such as gastroesophageal reflux disease, gastroparesis, functional diarrhea or constipation, and irritable bowel syndrome. Although gastrointestinal symptoms in migraine can be treatment-related, they may also be attributable to increased CGRP. In this review, we summarize the epidemiological evidence for associations between migraine and gastrointestinal disorders, consider the possible physiological role of CGRP in these associations, and review the clinical occurrence of gastrointestinal events in patients with migraine receiving CGRP-based therapies and other migraine treatments. Because patients with migraine are at an increased risk of comorbid and treatment-related gastrointestinal effects, we also propose a patient-management strategy to mitigate these effects.

Migraine treatment with external concurrent occipital and trigeminal neurostimulation-A randomized controlled trial.

OBJECTIVE: To evaluate the efficacy and safety of concurrent non-invasive stimulation of occipital and trigeminal nerves in acute treatment of migraine with or without aura. BACKGROUND: Non-invasive neuromodulation devices stimulating a single peripheral nerve or anatomic distribution are routinely used by patients with migraine refractory to the first-line drugs or those who opt out of pharmaceutical treatment. Concurrent occipital and trigeminal stimulation was described in an invasive setting, and its safety cost outweighed its efficacy gain. This study evaluated the efficacy and safety of an external concurrent occipital and trigeminal device in acute treatment of migraine. DESIGN AND METHODS: This was a randomized, sham-controlled, double-blind, multi-center trial. Patients 18 years of age or older who met the International Classification of Headache Disorders (2018) diagnostic criteria for migraine with or without aura, reported 1-6 migraine attacks per month, and other headaches no more than 6 days per month were enrolled. Of 131 intention-to-treat participants (67 and 64 in the active and sham groups, respectively), 109 (50 and 59 in the active and sham groups, respectively) treated at least one migraine episode. Reduction of migraine headache (pain relief) 2 h after treatment initiation was the primary efficacy endpoint. Pain relief at 1 h, and pain freedom and relief in most bothersome symptom at 2 h after treatment initiation were the secondary endpoints. Freedom from most bothersome symptom at 2 h and sustained pain freedom 24 h after treatment initiation were among the exploratory endpoints. RESULTS: Sixty percent of participants (30/50) in the active arm reported pain relief at 2 h after initiation of the first eligible treatment (primary outcome) compared to 37% (22/59) in the control arm (difference, 23%; 95% confidence interval [CI], 2%-41%; p = 0.018). Pain freedom at 2 h without rescue medication was reported by 46% (23/50) of participants in the active arm and by 12% (7/59) of participants in the sham arm (p < 0.001). Pain freedom 2 h after the treatment and, subsequently, at 24 h, was reported by 4.25 times more participants in the active arm (36%; 18/50) than in the sham arm (8%; 5/59). The 28% difference was statistically significant (95% CI, 1%-43%; p < 0.001). A 4.25-fold difference was also observed comparing the proportion of participants free from pain and most bothersome symptom 2 h after the stimulation (47% [17/36] and 11% [5/45] in the active and sham arms, respectively; 95% CI, 14%-54%; p < 0.001). Adverse events were not serious or severe. All study-related events resolved without treatment. CONCLUSION: External concurrent occipital and trigeminal neurostimulation is a well-tolerated, safe, and effective migraine treatment that provided a fast and durable relief and freedom from migraine pain and associated symptoms in a randomized setting. The observed safety and performance suggest external concurrent occipital and trigeminal neurostimulation is a viable alternative to the currently available acute migraine treatments. TRIAL REGISTRATION: clinicaltrials.gov identifier NCT03631550.

External Concurrent Occipital and Trigeminal Neurostimulation Relieves Migraine Headache: A Prospective, Randomized, Double-Blind, Sham-Controlled Trial.

INTRODUCTION: Current external peripheral nerve stimulation devices stimulate only one nerve. This prospective, randomized, double-blind, sham-controlled trial assessed efficacy, safety, and tolerability of a novel external combined occipital and trigeminal neurostimulation (eCOT-NS) device as a self-administered home treatment for migraine (Relivion®MG, Neurolief Ltd; Netanya, Israel). METHODS: Episodic and chronic migraine subjects (N = 55) were randomized to receive active (n = 27) or sham (n = 28) treatment. Subjects received eCOT-NS devices and performed 60 ± 20-min home treatments within 45 min of migraine episode onset. The primary endpoint was relative (percent) change in mean baseline VAS pain scores 1 h after treatment initiation. Treatment outcomes assessed at 1-, 2-, and 24-h post-treatment initiation were pain reduction and proportion of pain-free subjects and treatment responders, defined as ≥ 50% pain reduction. Categorical pain ratings (none, mild, moderate, and severe pain) were also analyzed. RESULTS: Active stimulation was significantly more effective than sham stimulation for decreasing pain intensity at 1 h (53% vs. 10%), 2 h (52% vs. 17%), and 24 h (71% vs. 34%). Pain-free ratings were greater for the active treatment arm at 1 h (29.2% vs. 16%), 2 h (41.7% vs. 20%), and 24 h (65.2% vs. 40%). The number of subjects with baseline moderate or severe migraine pain who were pain-free at 2 h was significantly greater among active treatment subjects (43% vs. 10.5%). The responder rate was significantly higher among the active treatment group at 1 h (67% vs. 20%), 2 h (66.7% vs. 32%,), and 24 h (78.3% vs. 48%). Overall headache relief was significantly higher in the active treatment group at 1 h (67% vs. 26%) and 2 h (76% vs. 31.6%). Mild adverse events, reported by a minority of subjects, resolved spontaneously. CONCLUSIONS: eCOT-NS provides superior clinically meaningful relief and freedom from migraine pain, offering an effective and safe therapy for acute treatment of migraine. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03398668.

As current external nerve stimulation devices stimulate only one nerve, this study assessed the effectiveness, safety, and tolerability of a new external nerve stimulation device that stimulates two nerves (occipital and trigeminal) as a self-administered home treatment for migraine (Relivion^®MG, Neurolief Ltd; Netanya, Israel). Fifty-five subjects with episodic and chronic migraine were randomly assigned to active (n = 27) or sham (dummy) treatment (n = 28). Subjects performed a 60-min home treatment within 45 min of migraine onset. The primary endpoint was the change in pain intensity 1 h after treatment initiation. Active treatment was significantly more effective than sham stimulation for decreasing pain intensity at 1 h (53% vs. 10%) and 2 h (52% vs. 17%). Pain-free ratings were also greater for the active treatment arm at 1 h (29.2% vs. 16%) and 2 h (41.7% vs. 20%). Overall headache relief was significantly higher in the active treatment group at 1 h (67% vs. 26%) and 2 h (66.7% vs. 32%). Mild, transient side effects reported by a few subjects resolved without treatment. This new external concurrent occipital and trigeminal neurostimulation (eCOT-NS) device provides superior and meaningful relief and freedom from migraine pain compared to sham treatment.