Photophobia is associated with lower sleep quality in individuals with migraine: results from the American Registry for Migraine Research (ARMR).

BACKGROUND: Patients with migraine often have poor sleep quality between and during migraine attacks. Furthermore, extensive research has identified photophobia as the most common and most bothersome symptom in individuals with migraine, second only to headache. Seeking the comfort of darkness is a common strategy for managing pain during an attack and preventing its recurrence between episodes. Given the well-established effects of daily light exposure on circadian activity rhythms and sleep quality, this study aimed to investigate the relationship between photophobia symptoms and sleep quality in a cohort of patients with migraine. METHODS: A cross-sectional observational study was conducted using existing data extracted from the American Registry for Migraine Research (ARMR). Participants with a migraine diagnosis who had completed the baseline questionnaires (Photosensitivity Assessment Questionnaire (PAQ), Generalized Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-2 (PHQ-2)), and selected questions of the ARMR Sleep questionnaire were included. Models were created to describe the relationship of photophobia and photophilia with various sleep facets, including sleep quality (SQ), sleep disturbance (SDis), sleep onset latency (SOL), sleep-related impairments (SRI), and insomnia. Each model was controlled for age, sex, headache frequency, anxiety, and depression. RESULTS: A total of 852 patients meeting the inclusion criteria were included in the analysis (mean age (SD) = 49.8 (13.9), 86.6% (n = 738) female). Those with photophobia exhibited significantly poorer sleep quality compared to patients without photophobia (p < 0.001). Photophobia scores were associated with SQ (p < 0.001), SDis (p < 0.001), SOL (p = 0.011), SRI (p = 0.020), and insomnia (p = 0.005) after controlling for age, sex, headache frequency, depression, and anxiety, signifying that higher levels of photophobia were associated with worse sleep-related outcomes. Conversely, photophilia scores were associated with better sleep-related outcomes for SQ (p < 0.007), SOL (p = 0.010), and insomnia (p = 0.014). CONCLUSION: Results suggest that photophobia is a significant predictor of poor sleep quality and sleep disturbances in migraine. These results underscore the necessity for comprehensive and systematic investigations into the intricate interplay between photophobia and sleep to enhance our understanding and develop tailored solutions for individuals with migraine.

Safety and tolerability of atogepant for the preventive treatment of migraine: a post hoc analysis of pooled data from four clinical trials.

BACKGROUND: Conventional, non-specific preventive migraine treatments often demonstrate low rates of treatment persistence due to poor efficacy or tolerability. Effective, well-tolerated preventive treatments are needed to reduce migraine symptoms, improve function, and enhance quality of life. Atogepant is a migraine-specific oral calcitonin gene-related peptide receptor antagonist that is indicated for the preventive treatment of migraine in adults. This analysis evaluated the safety and tolerability profile of atogepant for the preventive treatment of migraine, including adverse events (AEs) of interest, such as constipation, nausea, hepatic safety, weight changes, and cardiac disorders. METHODS: This post hoc analysis was performed using data pooled from 2 (12-week) randomized, double-blind, placebo-controlled trials (RCTs) and 2 (40- and 52-week) open-label long-term safety (LTS) trials of oral atogepant for episodic migraine (EM). RESULTS: The safety population included 1550 participants from the pooled RCTs (atogepant, n = 1142; placebo, n = 408) and 1424 participants from the pooled LTS trials (atogepant, n = 1228; standard care [SC], n = 196). In total, 643/1142 (56.3%) atogepant participants and 218/408 (53.4%) placebo participants experienced ≥ 1 treatment-emergent AEs (TEAEs) in the RCTs. In the LTS trials, 792/1228 (64.5%) of atogepant participants and 154/196 (78.6%) of SC participants experienced ≥ 1 TEAEs. The most commonly reported TEAEs (≥ 5%) in participants who received atogepant once daily were upper respiratory tract infection (5.3% in RCTs, 7.7% in LTS trials), constipation (6.1% in RCTs, 5.0% in LTS trials), nausea (6.6% in RCTs, 4.6% in LTS trials), and urinary tract infection (3.4% in RCTs, 5.2% in LTS trials). Additionally, weight loss appeared to be dose- and duration-dependent. Most TEAEs were considered unrelated to study drug and few led to discontinuation. CONCLUSIONS: Overall, atogepant is safe and well tolerated in pooled RCTs and LTS trials for the preventive treatment of EM in adults. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT02848326 (MD-01), NCT03777059 (ADVANCE), NCT03700320 (study 302), NCT03939312 (study 309).

Comparative efficacy, quality of life, safety, and tolerability of atogepant and rimegepant in migraine prevention: A matching-adjusted indirect comparison analysis.

BACKGROUND: Comparative evaluations of preventive migraine treatments can help inform clinical decision making for managing migraine in clinical practice. METHODS: An anchored matching-adjusted indirect comparison analysis was conducted using pooled participant-level data from two phase 3 atogepant trials (ADVANCE and PROGRESS) and one phase 2/3 rimegepant trial (BHV3000-305) to evaluate the relative efficacy and safety/tolerability of atogepant and rimegepant as preventive migraine treatments. Participants receiving atogepant 60 mg once daily, rimegepant orally disintegrating tablet 75 mg once every other day, and placebo were included. Only participants meeting the BHV3000-305 inclusion/exclusion criteria were analyzed: ≥6 monthly migraine days and ≤18 monthly headache days at baseline. The primary efficacy assessment of interest was change in monthly migraine days across weeks 1-12. RESULTS: There were 252 participants in the atogepant group and 348 in the rimegepant group. Across weeks 1-12, atogepant 60 mg demonstrated a significantly greater reduction in mean monthly migraine days compared with rimegepant 75 mg (mean difference [95% CI]: -1.65 [-2.49, -0.81]; p < 0.001). Both atogepant and rimegepant demonstrated similar safety/tolerability profiles. CONCLUSION: In this matching-adjusted indirect comparison analysis, oral atogepant 60 mg once daily demonstrated a significantly greater reduction in monthly migraine days compared with rimegepant 75 mg orally disintegrating tablet once every other day.

Responder rates with eptinezumab over 24 weeks in patients with prior preventive migraine treatment failures: post hoc analysis of the DELIVER randomized clinical trial.

BACKGROUND AND PURPOSE: Eptinezumab reduced monthly migraine days more than placebo in the DELIVER study, a clinical trial with patients with difficult-to-treat migraine and prior preventive treatment failures. This post hoc analysis assesses the sustained response to eptinezumab at the population and patient level and evaluates the potential for response in initial non-responders. METHODS: Adults with chronic or episodic migraine and two to four prior preventive treatment failures were randomized to eptinezumab 100 mg, 300 mg or placebo every 12 weeks. Primary outcomes in this post hoc analysis are the proportion of patients with ≥30%, ≥50% or ≥75% reduction in monthly migraine days (i.e., migraine responder rates [MRRs]) during weeks 1-12 and weeks 13-24 and across 4-week intervals. Secondary outcomes are maintenance and shifts in MRRs from weeks 1-12 to weeks 13-24. RESULTS: Between weeks 1-12 and 13-24, ≥30% MRRs increased from 65.9% to 70.4% (100 mg) and from 71.0% to 74.5% (300 mg), versus 36.9% to 43.1% (placebo). The ≥50% and ≥75% MRRs were sustained or increased over the 24-week period. The largest increase in ≥30% MRRs occurred after the second infusion with eptinezumab. The percentage of initial non-responders (<30% MRRs during weeks 1-12) who experienced response (≥30% MRRs during weeks 13-24) to the second dose was 34.7% (100 mg) and 30.4% (300 mg) with eptinezumab versus 21.1% with placebo. CONCLUSION: Across MRR thresholds, most patients who responded to eptinezumab during weeks 1-12 maintained or improved response during weeks 13-24. More than one-third of initial non-responders became responders after their second infusion.

Safety and efficacy of ubrogepant for the acute treatment of perimenstrual migraine attacks: A post hoc analysis.

OBJECTIVE: To evaluate the efficacy and safety of ubrogepant for the acute treatment of perimenstrual migraine (pmM) attacks. BACKGROUND: Ubrogepant is an oral calcitonin gene-related peptide receptor antagonist approved for the acute treatment of migraine in adults. METHODS: After completing one of two phase 3 trials, participants could enroll in a phase 3, 52-week, open-label, long-term safety extension trial and were re-randomized 1:1:1 to usual care, ubrogepant 50 mg, or ubrogepant 100 mg. This post hoc analysis evaluated the efficacy of ubrogepant in a subset of women who treated ≥1 pmM or non-pmM attack with ubrogepant. A pmM attack started on or between 2 days before and the first 3 days of menstrual bleeding. Mean (standard deviation [SD]) percentages of ubrogepant-treated attacks achieving 2-h pain freedom and pain relief were reported, with outcomes weighted equally by participant. RESULTS: Of 734 women in the modified intent-to-treat population, 354 reported ≥1 menstrual cycle start date and a ubrogepant-treated headache day in the same month. A qualifying pmM and non-pmM attack was reported by 278 and 716 women, respectively. Pain freedom at 2 h was achieved in a mean (SD) of 28.7% (37.4) of pmM attacks and 22.1% (26.9) of non-pmM attacks treated with ubrogepant 50 mg (p = 0.054) and 29.7% (35.2) versus 25.3% (26.3) of attacks treated with ubrogepant 100 mg (p = 0.757). No difference was found in the mean percentage of ubrogepant-treated pmM and non-pmM attacks that achieved 2-h pain relief with ubrogepant 50 mg (64.8% [39.9] vs. 65.2% [32.4]; p = 0.683) and with 100 mg (67.1% [37.4] vs. 68.4% [30.2]; p = 0.273). Treatment-related treatment-emergent adverse events were reported by 8.8% (12/137) and 12.8% (18/141) in the ubrogepant 50 and 100 mg pmM subgroups, respectively. CONCLUSIONS: Ubrogepant demonstrated similar efficacy for the treatment of pmM and non-pmM attacks. No new safety signals were identified.

Atogepant for the preventive treatment of chronic migraine (PROGRESS): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: In this study, we aimed to evaluate the efficacy, safety, and tolerability of atogepant for the preventive treatment of chronic migraine. METHODS: We did this randomised, double-blind, placebo-controlled, phase 3 trial at 142 clinical research sites across the USA, the UK, Canada, China, Czech Republic, Denmark, France, Germany, Italy, Japan, South Korea, Poland, Russia, Spain, Sweden, and Taiwan. Adults aged 18-80 years with a 1-year or longer history of chronic migraine were randomly assigned (1:1:1) to receive oral atogepant 30 mg twice a day, oral atogepant 60 mg once a day, or placebo. The primary endpoint was change from baseline in mean monthly migraine days (MMDs) across the 12-week treatment period. The primary analysis was done in the modified intent-to-treat population and included all randomly assigned participants who received at least one dose of study intervention, had an evaluable baseline period of electronic diary (eDiary) data, and had at least one evaluable post-baseline 4-week period (weeks 1-4, 5-8, and 9-12) of eDiary data during the double-blind period. The safety population consisted of all participants who received at least one dose of study intervention. This trial is registered with ClinicalTrials.gov (NCT03855137). FINDINGS: Between March 11, 2019 and Jan 20, 2022, 1489 participants were assessed for eligibility. 711 were excluded, and 778 participants were randomly assigned to atogepant 30 mg twice a day (n=257), atogepant 60 mg once a day (n=262), or placebo (n=259). Participants in the safety population were aged 18-74 years (mean 42·1 years). 459 (59%) of 773 patients were White, 677 (88%) patients were female, and 96 (12%) were male. 84 participants discontinued treatment during the trial, and 755 comprised the modified intent-to-treat population (atogepant 30 mg twice a day n=253, atogepant 60 mg once a day n=256, and placebo n=246). Baseline mean number of MMDs were 18·6 (SE 5·1) with atogepant 30 mg twice a day, 19·2 (5·3) with atogepant 60 mg once a day, and 18·9 (4·8) with placebo. Change from baseline in mean MMDs across 12 weeks was -7·5 (SE 0·4) with atogepant 30 mg twice a day, -6·9 (0·4) with atogepant 60 mg once a day, and -5·1 (0·4) with placebo. Least squares mean difference from placebo was -2·4 with atogepant 30 mg twice a day (95% CI -3·5 to -1·3; adjusted p<0·0001) and -1·8 with atogepant 60 mg once a day (-2·9 to -0·8; adjusted p=0·0009). Most common adverse events for atogepant were constipation (30 mg twice a day 28 [10·9%]; 60 mg once a day 26 [10%]; and placebo 8 [3%]) and nausea (30 mg twice a day 20 [8%]; 60 mg once a day 25 [10%]; and placebo 9 [4%]). Potentially clinically significant weight decrease (≥7% reduction at any time post-baseline) was observed in each treatment group (atogepant 30 mg twice a day 14 [6%]; atogepant 60 mg once a day 15 [6%]; and placebo 5 [2%]). INTERPRETATION: Atogepant 30 mg twice a day and 60 mg once a day showed clinically relevant reductions in MMDs across 12 weeks in chronic migraine patients. Both atogepant doses were well tolerated, consistent with the known safety profile of atogepant. FUNDING: Allergan (now AbbVie).

Hemiplegic Migraine.

PURPOSE OF REVIEW: In this article, we review recent updates to the epidemiology, diagnostic testing, genetics, pathophysiology, and management of hemiplegic migraine. RECENT FINDINGS: While three genes have been historically associated with hemiplegic migraine, recent studies suggest two additional genes may also be implicated including PPRT2 and SLC1A3. Hemiplegic migraine is a severe subset of migraine with aura with symptoms including reversible hemiparesis in addition to other aura symptoms such as visual, sensory, or speech. The exact pathophysiology of hemiplegic migraine is not clear, but it is thought that this phenomenon is due to neuronal and glial depolarization causing cortical spreading depression. Due to the severity of presentation as well as the numerous mimickers, it is important to know a comprehensive differential and work-up. Given the low prevalence of the disease, most studies regarding treatment are limited to case studies. There is still an important need for further and larger studies regarding management of these cases.

The Safety of Celecoxib as an Acute Treatment for Migraine: A Narrative Review.

INTRODUCTION: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been the first-line choice for the acute treatment of migraine attacks for decades; however, the safety of a particular NSAID is related to its treatment dose, duration, and mechanism of action. Although adverse event (AE) risks differ substantially among individual migraine treatments, increased or prolonged exposure to any NSAID elevates risks and severity of AEs. METHODS: For this narrative review, we conducted a literature search of PubMed until July 2022, focusing on the history, mechanism of action, and treatment guidelines informing the safety and efficacy of celecoxib oral solution for the acute treatment of migraine attacks. RESULTS: Here we discuss the mechanisms of action of nonselective NSAIDs vs. cyclooxygenase-2 (COX-2) inhibitors, and how these mechanisms underlie the AEs associated with these treatments. We review the clinical trials that influenced the regulatory history of NSAIDs, specifically COX-2 inhibitors, the role of traditional and new formulations of NSAIDs including celecoxib oral solution, and special considerations in the acute treatment of migraine attacks. CONCLUSIONS: Low-dose formulations of NSAIDs, such as celecoxib oral solution, provide acute migraine analgesia with similar or fewer associated cardiovascular and gastrointestinal events than previous formulations.

Temporomandibular Joint Disorder Comorbidities.

Comorbidity is a distinct additional condition that either existed or exists during the clinical course of a patient afflicted by the condition/entity in question. The clinician attempting to manage temporomandibular joint disorder (TMD) and TMD pain must realize that recognition and management of the comorbidities are essential to the successful management of the same with optimal pain control. When TMD presents with multiple comorbidities, the task for the clinician becomes more complex. It is the hope of the authors that this condensed version of TMD-associated comorbidities acts as a primer for understanding the significance of the same in pain management.

Evaluation of vascular risk in patients with migraine with and without aura treated with erenumab: Post hoc analysis of pooled long-term clinical trial data.

OBJECTIVE: To assess cardiovascular (CV) safety of erenumab in clinical trial patients associated with degree of CV risk. BACKGROUND: Hypertension has been considered a theoretical risk associated with the inhibition of the calcitonin gene-related peptide pathway in migraine management, particularly in a patient population with pre-existing CV risk factors. METHODS: Data pooled from four double-blind, randomized trials were used to assess blood pressure (BP) changes and CV safety in patients grouped based on 10-year risk of cardiac, cerebrovascular, and peripheral artery disease as no-risk-factors, low-risk (>0% to ≤10%), moderate-risk (>10% to ≤20%), and high-risk (>20%) categories. CV safety was assessed as ischemic cardiovascular and cerebrovascular adverse events (ICCAE). RESULTS: There was no apparent difference between placebo- (N = 1032) and erenumab-treatment groups (70 mg, N = 885; 140 mg, N = 504) in clinical worsening of BP category from baseline to Months 1-3 (14% [143/1032] placebo vs. 13% [114/885] and 14% [71/504] for erenumab 70 and 140 mg, respectively) regardless of baseline BP category. The adverse event (AE) profile of erenumab was similar across CV risk categories throughout the long-term analysis. Erenumab-treated patients with high and moderate 10-year CV risk (N = 107) did not experience any ICCAEs during the double-blind treatment period; there was a single ICCAE (a cerebral dural venous sinus thrombosis) observed in the low-risk erenumab group (N = 273). There were no increases in AEs during the long-term extensions of up to 5 years (N = 2499; 3482 patient-years of exposure to erenumab) with exposure-adjusted incidence rates of cardio/cerebrovascular disorder AEs of 0.4, 0.5, 0.0, and 1.1 (per 100 patient-years) for no risk factor (N = 1805), low (N = 492), moderate (N = 121), and high (N = 81) 10-year CV risk groups, respectively. CONCLUSIONS: Ischemic CV and cerebrovascular AEs were uncommon and the incidence rates were similar across the 10-year CV risk categories. This analysis helps provide more detail on the CV safety of erenumab.

Phase Ib, open-label, fixed-sequence, drug-drug interaction, safety, and tolerability study between atogepant and ubrogepant in participants with a history of migraine.

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.

Open-label trials for CGRP-targeted drugs in migraine prevention: A narrative review.

BACKGROUND: Calcitonin gene-related peptide-targeted drugs have proven safe and effective for migraine prevention in large randomized-controlled, double-blind trials with an average duration of six months. Open-label studies may provide additional information on the long-term safety and efficacy of these substances. METHODS: We searched PubMed for open-label trials with calcitonin gene-related peptide(-receptor) monoclonal antibodies and calcitonin gene-related peptide-receptor antagonists. We summarized and critically analyzed the literature in a narrative way. RESULTS: Overall, 13 open-label trials were included in this review (n = 4 for erenumab, n = 4 for galcanezumab, n = 3 for fremanezumab, n = 1 for eptinezumab, n = 1 for atogepant). Open-label trial duration ranged between 12 and 264 weeks. No safety concerns emerged, and the adverse events profile was similar to the double-blind study phase. Discontinuation rates were generally low with >75% of patients remaining in the trials after one year. Efficacy data showed a sustained reduction of migraine frequency throughout the trials, along with a lasting improvement in quality of life. CONCLUSIONS: The open-label study program for calcitonin gene-related peptide-targeted migraine preventives confirms the favorable safety and efficacy profile of these drugs over time. Treatment adherence appears higher than with previous unspecific migraine preventives. Real-world data and post-marketing surveillance studies may corroborate and complement open-label results.

Post hoc analysis of clinical trial data and pharmacokinetic data to assess wearing-off of erenumab within monthly treatment cycle.

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.

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.

Raynaud's phenomenon associated with calcitonin gene-related peptide receptor antagonists case report.

BACKGROUND: Calcitonin gene-related peptide (CGRP) is a potent vasodilator that regulates the cerebrovascular and peripheral circulation. A new class of migraine therapies decreases CGRP through various mechanisms. One unknown off-target effect is the impact decreasing CGRP will have on the peripheral circulation. The following cases report new onset Raynaud's phenomenon (RP) following the use of CGRP receptor antagonists (-gepants) for both the acute and preventive treatment of migraine. These cases describe the development of RP in two individuals after using each of the currently available gepant medications. To our knowledge these are the first cases reported of RP associated with the use of gepants. RP has previously been reported in association with monoclonal antibodies to the CGRP ligand and CGRP receptor indicated in the prevention of migraine. CASE PRESENTATION: One case involved oral CGRP receptor antagonists for acute treatment inducing RP. In this case, rimegepant and ubrogepant used separately for different migraine attacks each led to RP in the digits. The other case involved oral CGRP receptor antagonist, atogepant, used as a preventive treatment and induced RP in the digits. This patient had a prior history of areolar tissue RP while breastfeeding, but never in her fingers. In both cases, the offending medications were discontinued, and the patients reported no further episodes of RP. CONCLUSION: Two cases are reported of people with migraine with new onset digital RP while taking CGRP receptor antagonists (rimegepant, ubrogepant, atogepant) for acute and preventive treatment.

Pharmacovigilance: reporting requirements throughout a product's lifecycle.

Comprehensive methods for evaluating safety are needed to objectively assess the full risk profile of a medication. The confidence of the prescribing provider in the safety and effectiveness of pharmaceuticals is extremely important. Pharmacovigilance is a key component of drug safety regulatory processes and is paramount for ensuring the safety profile of medications used to treat patients. All participants in the healthcare system, including healthcare providers and consumers, should understand and meaningfully engage in the pharmacovigilance process; healthcare providers should integrate pharmacovigilance into everyday practice, inviting feedback from patients. This narrative review aims to give an overview of the main topics underlying pharmacovigilance and drug safety in pharmaceutical research phase after the authorization of a drug in the United States. The US Food and Drug Administration guidance and post-approval regulatory actions are considered from an industry perspective. Plain language summary: Regulatory processes that ensure the safety of drugs is monitored Government agencies regulate the safe use of medicinal products. By determining and enforcing pharmacovigilance, the monitoring of drugs for potential risks, they safeguard the welfare of consumers of medicines. Comprehensive, documented methods for evaluating the safety of a drug during its development and its subsequent use allow identification of any risks associated with the drug's use throughout its lifetime. The comprehensive identification of safety issues associated with a drug is improved when all parties involved in the development and use of drugs participate in the pharmacovigilance process. For example, clinicians should regularly ask their patients if they are experiencing any issues with their treatment, and patients should be encouraged to report problems they encounter with a particular medication to their healthcare provider. This narrative review provides an overview of the main topics underlying pharmacovigilance and drug safety after approval of a drug in the United States. Guidelines and actions from the US Food and Drug Administration are considered from an industry perspective.

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.

Atogepant for migraine.

Atogepant is a selective oral, small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist that has been approved for preventive treatment of migraine. CGRP is a neuropeptide involved in vasodilation and cerebrovascular regulation. CGRP is the most potent vasoactive constituent of the cerebrovascular trigeminal neuronal system and has a key role in migraine. Medications targeting CGRP are being used as migraine preventive and abortive treatments.

Effect of Galcanezumab on Total Pain Burden in Patients Who Had Previously Not Benefited from Migraine Preventive Medication (CONQUER Trial): A Post Hoc Analysis.

INTRODUCTION: In evaluating therapies for migraine prevention, emphasis is placed on frequency and less attention is paid to duration or severity. Total pain burden (TPB) combines frequency, duration, and severity of migraine headache, and has the potential to further characterize the benefit of preventive treatment using a single composite measure. TPB was previously used to characterize response to galcanezumab (GMB) in patients with migraine. In this post hoc analysis we assessed the impact of GMB in lowering TPB in patients who had previously not benefited from two to four categories of migraine preventive medication. METHODS: CONQUER trial patients (N = 462), 18-75 years old who had previously not benefited from two to four categories of migraine preventive medication, were randomized (1:1) to monthly placebo or GMB 120 mg with 240 mg loading dose. For each patient, monthly TPB in severity-weighted hours was calculated by multiplying migraine headache duration (hours) by maximum severity for each migraine headache day, then summing these daily scores over the month for the monthly score. Changes from baseline in monthly TPB across months 1-3 were analyzed. Spearman correlations between TPB and scores on the Migraine-Specific Quality-of-Life Questionnaire (MSQ) total and Migraine Disability Assessment Scale (MIDAS) were assessed at baseline. RESULTS: Mean (SD) baseline monthly TPB was 192.1 (158.3) and 188.2 (197.4) severity-weighted hours for GMB-treated and placebo-treated patients, respectively. Across the 3-month double-blind period, GMB-treated patients experienced significantly greater mean reductions from baseline in monthly TPB compared with placebo-treated patients, both for mean change (GMB - 82.7, placebo - 15.8, p < 0.001) and percentage change (GMB - 38.6%, placebo 9.4%, p < 0.001). Furthermore, baseline TPB correlated with MSQ score (r = - 0.39) and MIDAS score (r = 0.40), suggesting good association of TPB with functional and disability outcomes. CONCLUSION: GMB reduced mean TPB in patients who had previously not benefited from two to four categories of migraine preventive medication. TRIAL REGISTRATION: NCT03559257.