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Objective Background Methods Results Conclusion To compare the rate and extent of absorption of zavegepant 10 mg (therapeutic dose) or 20 mg (supratherapeutic dose) nasal spray during a migraine attack versus non‐migraine period, assess safety, and explore efficacy and the relationship between zavegepant concentration and therapeutic response.Physiologic changes occurring during a migraine attack could affect the pharmacokinetics of treatments for migraine.This was a Phase 1, multicenter, open‐label, randomized, single‐dose, two‐period, fixed‐sequence, comparative bioavailability study. Participants with a history of 2–8 migraine attacks per month of moderate or severe pain intensity were randomized to a single dose of zavegepant 10 or 20 mg, administered intranasally during a migraine attack (Period 1) and in a non‐migraine period (Period 2). Blood samples were collected pre‐dose and at pre‐specified intervals up to 24 h post‐dose for plasma zavegepant concentration measurement. Safety was monitored throughout, and efficacy (migraine pain intensity score, nausea, photophobia, phonophobia, aura, and functional disability) assessed during Period 1. Plasma zavegepant pharmacokinetic parameters were calculated by standard noncompartmental methods, including maximum plasma concentration (Cmax), area under plasma concentration–time curve from time zero to infinity (AUC0–inf), and time of Cmax (Tmax).A total of 37 participants were evaluable for pharmacokinetics. Following administration of zavegepant 10 mg, geometric mean ratios for Period 1/Period 2 were 82.8% (90% confidence interval [CI] 60.5–113.2) for Cmax and 90.1% (90% CI 70.2–115.5) for AUC0–inf. Following administration of zavegepant 20 mg, geometric mean ratios for Period 1/Period 2 were 72.5% (90% CI 57.9–90.8) for Cmax and 73.4% (90% CI 58.8–91.7) for AUC0–inf. Averaging over the study period, geometric mean ratios for zavegepant 20 mg/10 mg were 142.5% (90% CI 118.6–171.4) for Cmax and 157.0% (90% CI 133.6–184.5) for AUC0–inf. Median Tmax was 0.5 h for both doses regardless of Period. Zavegepant was well tolerated in both study periods and effective during Period 1 at both dose levels. There was no apparent correlation between concentration at 0.5 h or 2 h post‐dose and efficacy outcomes.Zavegepant exposure was comparable during a migraine attack and a non‐migraine period, particularly at the therapeutic dose of 10 mg. When averaging over migraine and non‐migraine periods, there was a less‐than‐dose proportional increase in zavegepant exposure when the dose was doubled from 10 to 20 mg. The median Tmax was 0.5 h regardless of migraine attack or dose. Zavegepant 10 and 20 mg exhibited favorable safety profiles during migraine attacks and non‐migraine periods, and were effective to relieve pain, associated symptoms, and functional disability during migraine attacks, with no apparent correlation between zavegepant concentration and efficacy outcomes. [ABSTRACT FROM AUTHOR]

Objective: To assess the real‐world effectiveness of ubrogepant by evaluating self‐reported satisfaction with pain relief, ability to think clearly, and return to normal function in individuals who had used ubrogepant to treat a migraine episode within the preceding 14 days. Background: Ubrogepant is an oral calcitonin gene–related peptide receptor antagonist approved for the acute treatment of migraine in adults. Few studies have evaluated the real‐world effectiveness of ubrogepant. Methods: The UNIVERSE study was an observational, cross‐sectional survey conducted between February 2021 and April 2021 in US adult Migraine Buddy application (app) users currently treated with ubrogepant. Individuals who were 18 years of age or older and reported at least one dose of ubrogepant in the previous 14 days completed a 30‐question survey in the app. The survey assessed respondent demographics, migraine history, acute treatment patterns, and treatment satisfaction with ubrogepant. Respondents also reported prior acute medication use and reasons for switching to ubrogepant. Results: Of the 1303 ubrogepant users contacted, 302 (23.2%; 50 mg, 120 participants; 100 mg, 182 participants) were included in this study. The mean (standard deviation) age was 41.9 (11.2) years, and 90.1% (272/302) were female. Satisfaction with migraine relief at 2, 4, and 24 h post‐dose was reported by 75.8% (229/302), 83.4% (252/302), and 78.5% (237/302) of participants, respectively. Satisfaction with the ability to think clearly after taking ubrogepant was reported by 85.1% (257/302) of participants, and 83.8% (253/302) were satisfied with their ability to return to normal function. Furthermore, 90.7% (274/302) of participants reported that they were likely to continue using ubrogepant to treat their migraine. Most participants (n = 264 [87%]) reported switching to ubrogepant due to inadequate treatment response with their previous treatment. In this subgroup, comparable outcomes were observed with respect to satisfaction with migraine relief, ability to think clearly, and return to normal function. Conclusions: Ubrogepant demonstrated real‐world effectiveness in the acute treatment of migraine, as evidenced by high levels of treatment satisfaction and a strong indication of their intent to continue using the medication. Plain Language Summary: Ubrogepant is approved for the acute treatment of migraine in adults. In this study, adults who had used ubrogepant to treat a migraine attack in the previous 14 days responded to survey questions regarding their satisfaction with pain relief, ability to think clearly, and return to normal function. Results indicated that the majority of participants experienced high levels of satisfaction with ubrogepant because most of them said that these areas of their life improved after treatment. [ABSTRACT FROM AUTHOR]

Objective: To study if galcanezumab is effective for vestibular migraine (VM). Background: There are currently no placebo‐controlled trials showing that treatment is effective for VM. Therefore, we performed the first placebo controlled, randomized clinical trial of a calcitonin gene–related peptide–targeted monoclonal antibody for VM. Methods: This was a single site, prospective, double‐blind placebo controlled randomized clinical trial. Key inclusion criteria were as follows: participants aged 18–75 years with a diagnosis of VM or probable VM per Barany Society criteria. The primary outcome was change in VM‐PATHI (Vestibular Migraine Patient Assessment Tool and Handicap Inventory) score, and secondary outcomes included change in DHI (Dizziness Handicap Inventory) score, and count of definite dizzy days (DDDs). Participants were randomized 1:1 to 3 months of treatment with galcanezumab or placebo via subcutaneous injection with a pre‐filled syringe, 240 mg the first month, and 120 mg for the second and third months. Results: Forty participants were randomized, and 38 participants were in the modified intent to treat analysis. VM‐PATHI score was reduced 5.1 points (95% confidence interval [CI] −13.0 to 2.7) for placebo (N = 21), and 14.8 points (95% CI −23.0 to −6.5) for galcanezumab (N = 17), a difference of −9.6 (95% CI −20.7 to 1.5, p = 0.044). DHI dropped 8.3 points in the placebo arm (95% CI −15.0 to 1.6), and 22.0 points in the galcanezumab arm (95% CI −31.9 to −12.1), a difference of −13.7 (95% CI −20.4 to −8.5, p = 0.018). The count of DDDs per month dropped from 18 days (standard deviation [SD] 7.6) in the baseline month to 12.5 days (SD 11.2) in month 4 for those in the placebo arm, and from 17.9 days (SD 7.9) in the baseline month to 6.6 days (SD 7.3) in month 4 for those in the galcanezumab arm, a difference of −5.7 days (95% CI −10.7 to −0.7, p = 0.026). No serious adverse events were observed. Conclusions: In this pilot study, galcanezumab was effective in treating VM. Plain Language Summary: Vestibular migraine is a common cause of dizziness. In this study, we investigated whether treatment with a drug called galcanezumab worked better than placebo for treating dizziness. We found that galcanezumab reduced dizziness more than placebo in patients with vestibular migraine. [ABSTRACT FROM AUTHOR]

Objective: To develop machine learning models using patient and migraine features that can predict treatment responses to commonly used migraine preventive medications. Background: Currently, there is no accurate way to predict response to migraine preventive medications, and the standard trial‐and‐error approach is inefficient. Methods: In this cohort study, we analyzed data from the Mayo Clinic Headache database prospectively collected from 2001 to December 2023. Adult patients with migraine completed questionnaires during their initial headache consultation to record detailed clinical features and then at each follow‐up to track preventive medication changes and monthly headache days. We included patients treated with at least one of the following migraine preventive medications: topiramate, beta‐blockers (propranolol, metoprolol, atenolol, nadolol, timolol), tricyclic antidepressants (amitriptyline, nortriptyline), verapamil, gabapentin, onabotulinumtoxinA, and calcitonin gene‐related peptide (CGRP) monoclonal antibodies (mAbs) (erenumab, fremanezumab, galcanezumab, eptinezumab). We pre‐trained a deep neural network, "TabNet," using 145 variables, then employed TabNet‐embedded data to construct prediction models for each medication to predict binary outcomes (responder vs. non‐responder). A treatment responder was defined as having at least a 30% reduction in monthly headache days from baseline. All model performances were evaluated, and metrics were reported in the held‐out test set (train 85%, test 15%). SHapley Additive exPlanations (SHAP) were conducted to determine variable importance. Results: Our final analysis included 4260 patients. The responder rate for each medication ranged from 28.7% to 34.9%, and the mean time to treatment outcome for each medication ranged from 151.3 to 209.5 days. The CGRP mAb prediction model achieved a high area under the receiver operating characteristics curve (AUC) of 0.825 (95% confidence interval [CI] 0.726, 0.920) and an accuracy of 0.80 (95% CI 0.70, 0.88). The AUCs of prediction models for beta‐blockers, tricyclic antidepressants, topiramate, verapamil, gabapentin, and onabotulinumtoxinA were: 0.664 (95% CI 0.579, 0.745), 0.611 (95% CI 0.562, 0.682), 0.605 (95% CI 0.520, 0.688), 0.673 (95% CI 0.569, 0.724), 0.628 (0.533, 0.661), and 0.581 (95% CI 0.550, 0.632), respectively. Baseline monthly headache days, age, body mass index (BMI), duration of migraine attacks, responses to previous medication trials, cranial autonomic symptoms, family history of headache, and migraine attack triggers were among the most important variables across all models. A variable could have different contributions; for example, lower BMI predicts responsiveness to CGRP mAbs and beta‐blockers, while higher BMI predicts responsiveness to onabotulinumtoxinA, topiramate, and gabapentin. Conclusion: We developed an accurate prediction model for CGRP mAbs treatment response, leveraging detailed migraine features gathered from a headache questionnaire before starting treatment. Employing the same methods, the model performances for other medications were less impressive, though similar to the machine learning models reported in the literature for other diseases. This may be due to CGRP mAbs being migraine‐specific. Incorporating medical comorbidities, genomic, and imaging factors might enhance the model performance. We demonstrated that migraine characteristics are important in predicting treatment responses and identified the most crucial predictors for each of the seven types of preventive medications. Our results suggest that precision migraine treatment is feasible. Plain Language Summary: Currently, there is no way to predict whether preventive medications, which are medications that may reduce the frequency and severity of headaches, will be helpful to all patients. We used novel artificial intelligence techniques and developed effective tools that can predict how a patient responds to seven different types of migraine preventive medications before the medication is started. We also found that the ways in which patients describe their headache and the types of symptoms they have is important to predict whether the medication will work. [ABSTRACT FROM AUTHOR]

Objective: To analyze the specificity of calcitonin gene–related peptide (CGRP) levels, we measured alpha‐CGRP circulating levels in a large series of patients with a recent diagnosis of inflammatory bowel disease (IBD) who were interviewed regarding comorbid headache. Background: Several studies have found an association between migraine and IBD. Methods: In this cross‐sectional study performed in an IBD clinic, morning serum alpha‐CGRP levels were measured by enzyme‐linked immunosorbent assay in 96 patients who were recently diagnosed with IBD and compared to those from 50 similar patients with chronic migraine (CM) and 50 healthy controls (HC). Results: Alpha‐CGRP levels were higher in patients with IBD (median [interquartile range] 56.9 [35.6–73.9] pg/mL) and patients with CM (53.0 [36.7–73.9] pg/mL) compared to HC (37.2 [30.0–51.8] pg/mL; p = 0.003; p = 0.019, respectively). Regarding IBD diagnostic subtypes, alpha‐CGRP levels for ulcerative colitis (67.2 ± 49.3 pg/mL; 57.0 [35.6–73.4] pg/mL) and Crohn's disease (54.9 ± 27.5 pg/mL; 57.7 [29.1–76.1] pg/mL) were significantly higher than those of HC (p = 0.013, p = 0.040, respectively). Alpha‐CGRP levels were further different in patients with IBD with migraine (70.9 [51.8–88.7] pg/mL) compared to HC (p < 0.001), patients with IBD without headache (57.5 [33.3–73.8] pg/mL; p = 0.049), and patients with IBD with tension‐type headache but without migraine (41.7 [28.5–66.9] pg/mL; p = 0.004), though alpha‐CGRP levels in patients with IBD without migraine (53.7 [32.9–73.5] pg/mL) remained different over HC (p = 0.028). Conclusion: Together with CM, circulating alpha‐CGRP levels are different in patients with IBD, perhaps reflecting a chronic inflammatory state. IBD is an example of how alpha‐CGRP levels are not a totally specific migraine biomarker. However, alpha‐CGRP levels were further increased in patients with IBD who have a history of migraine, which reinforces its role as a biomarker in migraine patients, always bearing in mind their comorbidities. Plain Language Summary: Alpha‐calcitonin gene–related peptide (CGRP) levels may be a potential migraine biomarker, but it is unclear if this is the case because changes in CGRP concentrations can also be present in other conditions. We measured morning serum alpha‐CGRP levels in 96 patients with a recent inflammatory bowel disease (IBD) diagnosis, and compared them to 50 matched healthy participants and 50 matched patients with chronic migraine (CM). We found a significant increase in serum alpha‐CGRP levels in both patients with IBD and CM compared to healthy controls, which we think may reflect chronic inflammation found in IBD; these results offer another example that alpha‐CGRP concentrations are not totally specific for migraine. [ABSTRACT FROM AUTHOR]

The small molecule calcitonin gene–related peptide receptor antagonists (gepants) are the only drug class with medicines indicated for both the acute and preventive treatment of migraine. Given this dual capacity to both treat and prevent, along with their favorable tolerability profiles and lack of an association with medication‐overuse headache, headache specialists have begun to use gepants in ways that transcend the traditional categories of acute and preventive treatment. One approach, called situational prevention, directs patients to treat during the interictal phase, before symptoms develop, in situations of increased risk for migraine attacks. Herein, we present three patients to illustrate scenarios of gepant use for situational prevention. In each case, a gepant was started in anticipation of a period of increased headache probability (vulnerability) and continued for a duration of 1 day to 5 consecutive days. Although this approach may expose patients to medication when headache may not have developed, the tolerability and safety profile and preventive effect of gepants may represent a feasible approach for some patients. Situational prevention is an emerging strategy for managing migraine before symptoms develop in individuals who can identify periods when the probability of headache is high. This paper is intended to increase awareness of this strategy and stimulate future randomized, placebo‐controlled trials to rigorously assess this strategy. Plain Language Summary: A new class of migraine medicines, the gepants, does not cause medication‐overuse headache; these drugs can be taken in periods of increased headache risk, even before symptoms begin, to keep headaches from coming on. This new way of treating migraine is called "situational prevention." Experience in clinical practice suggests that treating migraine patients without current symptoms during times of increased headache risk, for example in connection with the menstrual cycle, travel, stress, or relaxation after stress, may be good times for situational prevention, but studies are needed to confirm when this strategy is most likely to be beneficial. [ABSTRACT FROM AUTHOR]

Objective: To compare calcitonin gene–related peptide monoclonal antibodies (CGRP mAbs) versus nonspecific oral migraine preventives (NOEPs). Background: Insurers mandate step therapy with NOEPs before approving CGRP mAbs. Methods: Databases were searched for class I or II randomized controlled trials (RCTs) comparing CGRP mAbs or NOEPs versus placebo for migraine prevention in adults. The primary outcome measure was monthly migraine days (MMD) or moderate to severe headache days. Results: Twelve RCTs for CGRP mAbs, 5 RCTs for topiramate, and 3 RCTs for divalproex were included in the meta‐analysis. There was high certainty that CGRP mAbs are more effective than placebo, with weighted mean difference (WMD; 95% confidence interval) of −1.64 (−1.99 to −1.28) MMD, which is compatible with small effect size (Cohen's d −0.25 [−0.34 to −0.16]). Certainty of evidence that topiramate or divalproex is more effective than placebo was very low and low, respectively (WMD −1.45 [−1.52 to −1.38] and −1.65 [−2.30 to −1.00], respectively; Cohen's d −1.25 [−2.47 to −0.03] and −0.48 [−0.67 to −0.29], respectively). Trial sequential analysis showed that information size was adequate and that CGRP mAbs had clear benefit versus placebo. Network meta‐analysis showed no statistically significant difference between CGRP mAbs and topiramate (WMD −0.19 [−0.56 to 0.17]) or divalproex (0.01 [−0.73 to 0.75]). No significant difference was seen between topiramate or divalproex (0.21 [−0.45 to 0.86]). Conclusions: There is high certainty that CGRP mAbs are more effective than placebo, but the effect size is small. When feasible, CGRP mAbs may be prescribed as first‐line preventives; topiramate or divalproex could be as effective but are less well tolerated. The findings of this study support the recently published 2024 position of the American Headache Society on the use of CGRP mAbs as the first‐line treatment. Plain Language Summary: Insurance companies often do not approve calcitonin gene–related peptide monoclonal antibodies (CGRP mAbs) for the treatment of migraine until patients have tried other medicines first. We reviewed and summarized data from studies that reported how well different migraine medications worked, including CGRP mAbs, and found evidence that CGRP mAbs are more effective than placebo and just as effective as other migraine drugs. This suggests that CGRP mAbs should be offered as a first‐line preventive therapy at the discretion of the clinician and the individual patient. Answer questions and earn CME credit: https://wileyhealthlearning.com/#/online‐courses/d524dd0e‐d6b3‐4fd3‐b298‐230b74599848 [ABSTRACT FROM AUTHOR]

Objective: To provide a position statement update from The American Headache Society specifically regarding therapies targeting calcitonin gene‐related peptide (CGRP) for the prevention of migraine. Background: All migraine preventive therapies previously considered to be first‐line treatments were developed for other indications and adopted later for migraine. Adherence to these therapies is often poor due to issues with efficacy and tolerability. Multiple new migraine‐specific therapies have been developed based on a broad foundation of pre‐clinical and clinical evidence showing that CGRP plays a key role in the pathogenesis of migraine. These CGRP‐targeting therapies have had a transformational impact on the management of migraine but are still not widely considered to be first‐line approaches. Methods: Evidence regarding migraine preventive therapies including primary and secondary endpoints from randomized placebo‐controlled clinical trials, post hoc analyses and open‐label extensions of these trials, and prospective and retrospective observational studies were collected from a variety of sources including PubMed, Google Scholar, and ClinicalTrials.gov. The results and conclusions based upon these results were reviewed and discussed by the Board of Directors of The American Headache Society to confirm consistency with clinical experience and to achieve consensus. Results: The evidence for the efficacy, tolerability, and safety of CGRP‐targeting migraine preventive therapies (the monoclonal antibodies: erenumab, fremanezumab, galcanezumab, and eptinezumab, and the gepants: rimegepant and atogepant) is substantial, and vastly exceeds that for any other preventive treatment approach. The evidence remains consistent across different individual CGRP‐targeting treatments and is corroborated by extensive "real‐world" clinical experience. The data indicates that the efficacy and tolerability of CGRP‐targeting therapies are equal to or greater than those of previous first‐line therapies and that serious adverse events associated with CGRP‐targeting therapies are rare. Conclusion: The CGRP‐targeting therapies should be considered as a first‐line approach for migraine prevention along with previous first‐line treatments without a requirement for prior failure of other classes of migraine preventive treatment. [ABSTRACT FROM AUTHOR]

Background: Erenumab is a monoclonal antibody that targets the calcitonin gene‐related peptide (CGRP) receptor and is approved for the preventative treatment of migraine in adults. CGRP is involved in the regulation of vasomotor tone under physiologic and pathologic conditions, including hypertension. While there has not been evidence of hypertension in preclinical models or clinical trials, post‐marketing data suggest erenumab may be associated with hypertension. This led to a warning in the United States Food and Drug Administration prescribing information for erenumab. Objective: To determine the frequency of worsening blood pressure (BP) after initiation of erenumab in patients with migraine and how this is associated with hypertension. Methods: This is an observational retrospective cohort study evaluating patients at a tertiary headache or neurology department. Systolic and diastolic BPs were compared between the initial visit prior to initiation of erenumab, and follow‐up visit while on erenumab. Worsening BP was defined as moving from a lower stage to a higher stage of BP, as defined by the American Heart Association. Serious adverse vascular events were also recorded. Results: A total of 335 patients were included in the final analysis (mean [SD] age of 45.7 [14.40] years, 83.9% [281/335] female). At baseline, 20.9% (70/335) of patients had a prior diagnosis of hypertension. The median (interquartile range) time to follow‐up appointment from initial appointment was 20.5 (13.3–35.3) weeks. The mean (SD) BP at baseline was systolic 124.7 (15) mmHg and diastolic 77 (11) mmHg, and at follow‐up was systolic 124.0 (15) mmHg and diastolic 77.8 (9) mmHg. Overall, 23.3% (78/335) of all patients had worsening BP, whereas 13/225 (3.9%) patients had improvement in their BP. Patients with atrial fibrillation were more likely to develop worsening BP (odds ratio, 4.9, 95% confidence interval 1.12–21.4; p = 0.035). There was no association between worsening BP and pre‐existing hypertension, sex, body mass index, or age. One patient had non‐ST elevation myocardial infarction attributed to a hypertensive emergency while on erenumab. Conclusion: We found that 23.3% of patients initiated on erenumab may have developed worsening BP, suggesting the need for BP monitoring in patients initiated on erenumab. Plain Language Summary: This study aimed to determine how often blood pressure (BP) increases in patients with migraine after initiation of erenumab, a migraine preventative treatment. We compared patients' BP before starting erenumab versus while on erenumab. We found that nearly a quarter of patients developed higher BP, suggesting the need for BP monitoring in patients taking erenumab. [ABSTRACT FROM AUTHOR]

Objective: To determine the effect of the introduction of the calcitonin gene–related peptide monoclonal antibodies (CGRP mAbs) in 2018 on the prescribing of older medications for the prevention of chronic migraine. Background: Prior to 2018, the preventive treatment of migraine borrowed from medications intended to treat other illnesses with the last medication, onabotulinumtoxinA, receiving Food and Drug Administration (FDA) approval for the prevention of chronic migraine in 2010. The FDA approval of three CGRP mAbs in 2018 provided the ideal natural experiment to assess how the introduction of these medications, and a fourth in 2020, affected the generally stable migraine preventive medications market. Methods: We performed a retrospective cohort analysis using the aggregated de‐identified data of 6595 patients. The percentage of patients with chronic migraine who had been prescribed one of ten most prescribed oral preventive medications or onabotulinumtoxinA, or any of the four CGRP mAbs, were calculated relative to the total number of patients with chronic migraine who received a prescription for any medication from our clinic during the pre‐CGRP mAb years of 2015–2017 and post‐approval years of 2019–2021. Results: We observed a statistically significant decrease in the prescription of the top 10 most prescribed medications after the introduction of the CGRP mAbs overall (1456/3144, 46.3%, to 1995/4629, 43.1%, p = 0.001), as well as with most individual medications, including large decreases in verapamil (230/3144, 7.3%, to 125/4629, 2.7%; p < 0.001), the tricyclic antidepressants (494/3144, 15.7%, to 532/4629, 11.5%; p < 0.001), topiramate (566/3144, 18.0%, to 653/4629, 14.1%; p < 0.001), and onabotulinumtoxinA (861/3144, 27.4%, to 1134/4629, 24.5%; p = 0.001). Conclusion: The introduction of the CGRP mAbs during 2018 resulted in a decrease in utilization of most oral medications and onabotulinumtoxinA for the prevention of migraine. Future work should continue to observe how the prescription patterns of these medications evolve with time. [ABSTRACT FROM AUTHOR]

Objective: To evaluate response to anti‐calcitonin gene–related peptide (CGRP) migraine preventives in a real‐world community cohort of persons living with migraine and to identify clinical and genetic characteristics associated with efficacious response. Background: Erenumab‐aooeb, fremanezumab‐vrfm, and galcanezumab‐gnlm target CGRP or its receptor; however, many patients are non‐responsive. Methods: In this retrospective clinical and genetic study, we identified 1077 adult patients who satisfied the International Classification of Headache Disorders, 3rd edition, criteria for migraine without aura, migraine with aura, or chronic migraine and who were prescribed an anti‐CGRP migraine preventive between May 2018 and May 2021. Screening of 558 patients identified 289 with data at baseline and first follow‐up visits; data were available for 161 patients at a second follow‐up visit. The primary outcome was migraine days per month (MDM). In 198 genotyped patients, we evaluated associations between responders (i.e., patients with ≥50% reduction in MDM at follow‐up) and genes involved in CGRP signaling or pharmacological response, and genetic and polygenic risk scores. Results: The median time to first follow‐up was 4.4 (0.9–22) months after preventive start. At the second follow‐up, 5.7 (0.9–13) months later, 145 patients had continued on the same preventive. Preventives had strong, persistent effects in reducing MDM in responders (follow‐up 1: η2 = 0.26, follow‐up 2: η2 = 0.22). At the first but not second follow‐up: galcanezumab had a larger effect than erenumab, while no difference was seen at either follow‐up between galcanezumab and fremanezumab or fremanezumab and erenumab. The decrease in MDM at follow‐up was generally proportional to baseline MDM, larger in females, and increased with months on medication. At the first follow‐up only, patients with prior hospitalization for migraine or who had not responded to more preventive regimens had a smaller decrease in MDM. Reasons for stopping or switching a preventive varied between medications and were often related to cost and insurance coverage. At both follow‐ups, patient tolerance (1: 92.2% [262/284]; 2: 95.2% [141/145]) and continued use (1: 77.5% [224/289]; 2: 80.6% [116/145]) were high and similar across preventives. Response consistency (always non‐responders: 31.7% [46/145]; always responders: 56.5% [82/145], and one‐time only responders: 11.7% [17/145]) was also similar across preventives. Non‐responder status had nominally significant associations with rs12615320‐G in RAMP1 (odds ratio [95% confidence interval]: 4.7 [1.5, 14.7]), and rs4680‐A in COMT (0.6[0.4, 0.9]). Non‐responders had a lower mean genetic risk score than responders (1.0 vs. 1.1; t(df) = −1.75(174.84), p = 0.041), and the fraction of responders increased with genetic and polygenic risk score percentile. Conclusions: In this real‐world setting, anti‐CGRP preventives reduced MDM persistently and had similar and large effect sizes on MDM reduction; however, clinical and genetic factors influenced response. [ABSTRACT FROM AUTHOR]

Objective: To systematically investigate previously examined biomarkers in blood, urine, cerebrospinal fluid, tear fluid, and saliva of patients with cluster headache. Background: Cluster headache is a condition with extensive clinical challenges in terms of diagnosis and treatment. Identification of a biomarker with diagnostic implications or as a potential treatment target is highly warranted. Methods: We conducted a systematic review including peer reviewed full text of studies that measured biochemical compounds in either blood, urine, cerebrospinal fluid, tear fluid, or saliva of patients with cluster headache diagnosed after the implementation of the International Classification of Headache Disorders (1988) written in English, Danish, Swedish, or Norwegian. Inclusion required a minimum of five participants. The search was conducted in PubMed and EMBASE, in September 2022, and extracted data were screened by two authors. Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines for reporting systematic reviews were followed. The Newcastle–Ottawa Scale was used to assess the risk of bias in case–controlled studies. Results: We included 40 studies involving 832 patients with cluster headache and 872 controls, evaluating 80 potential biomarkers. The risk of bias for case–controlled studies was a median of 6 (range: 3–8) and 20 studies out of 40 (50%) were of fair or good quality. Most studies were identified within three groups: hypothalamic‐regulated hormones, inflammatory markers, and neuropeptides. Among the hypothalamic hormones, cortisol was the most frequently investigated (N = 7) and was elevated in cluster headache in most of the studies. The most frequently examined inflammatory marker was interleukin 1 (N = 3), but findings were divergent. Calcitonin gene–related peptide was the most investigated neuropeptide (N = 9) and all studies found increased levels during attacks. Conclusion: Biomarker findings have been inconsistent and widely non‐specific for cluster headache, which explains why none of the previous studies succeeded in identifying a unique biomarker for cluster headache, but instead contributed to substantiating the underlying pathophysiologic mechanisms. Several of the examined biomarkers could hold promise as markers for disease activity but are unfit for a clear distinction from both controls and other headaches. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to determine the number needed to treat (NNT), number needed to harm (NNH), and likelihood of being helped or harmed (LHH) in a post hoc analysis of the phase 3b FOCUS trial. Background: Fremanezumab, a humanized monoclonal antibody that selectively targets calcitonin gene–related peptide (CGRP), has demonstrated efficacy, tolerability, and safety in adults with episodic migraine (EM) or chronic migraine (CM), with documented previous inadequate response to two to four classes of migraine preventive medications. Methods: In the 12‐week double‐blind period of the FOCUS study, patients were randomized (1:1:1) to quarterly fremanezumab, monthly fremanezumab, or matched monthly placebo. NNT was based on responder analysis, defined as ≥50% reduction in monthly average number of migraine days at 12 weeks. NNH was based on discontinuations due to adverse events (AEs). Results: Among patients with CM (n = 509), response rates and discontinuation rates were 27% (45/169) and 0 for quarterly fremanezumab, 29% (50/173) and 2% (3/173) for monthly fremanezumab, and 8% (13/167) and <1% (1/167) for placebo, respectively. These results translated to NNTs of 5.3 and 4.7, NNHs of 1000 and 88, and LHHs of 188 and 19 for quarterly and monthly fremanezumab, respectively. Among patients with EM (n = 328), response rates were 47% (50/107) for quarterly fremanezumab, 43% (47/110) for monthly fremanezumab, and 10% (11/111) for placebo. Discontinuation rates were <1% (n = 1) in all three groups. These results translated to NNTs of 2.7 and 3.0, NNHs of 1000 and 1000, and LHHs of 368 and 328 for quarterly and monthly fremanezumab, respectively. Conclusions: The NNT, NNH, and LHH for quarterly and monthly fremanezumab compare favorably with those for traditional oral preventive medications, including topiramate, valproate, and propranolol. [ABSTRACT FROM AUTHOR]

Objective: To describe the pattern of anti‐calcitonin gene–related peptide monoclonal antibodies (anti‐CGRP mAbs) utilization in the Tuscany region, Italy, and the variation of triptan consumption after treatment initiation. Background: Given the recent commercialization of anti‐CGRP mAbs as migraine preventive medications, real‐world evidence on their patterns of utilization and their impact on migraine abortive medication use is still limited. Methods: A retrospective, descriptive, cohort study on the real‐world utilization of anti‐CGRP mAbs was performed using the population‐based regional administrative database of Tuscany. Patients with ≥1 anti‐CGRP mAb dispensing (namely erenumab, galcanezumab, fremanezumab) between April 1, 2019, and September 30, 2021, were identified. The first dispensing was the cohort entry (CE). New users (NUs) were patients with no anti‐CGRP mAb dispensing before CE. Kaplan–Meier (KM) curves were plotted to describe the cumulative probability of remaining with the initial anti‐CGRP mAb during a 15‐month follow‐up period as a measure of treatment persistence. Among NUs with ≥2 triptan dispensings during the 6 months before CE (i.e., baseline), the mean monthly number of triptan dosage units dispensed was measured in five consecutive follow‐up time windows (months 1–3, 4–6, 7–9, 10–12, 13–15) and the difference from the baseline was calculated. Results: A total of 624 NUs (erenumab = 295, galcanezumab = 223, fremanezumab = 106) were identified, of whom 188 (78%) were women. Mean age was 49.2 years (standard deviation [SD] = 12.6). The survival to discontinuation at 6, 12, and 15 months was about 69%, 48%, and 6%, respectively. The survival to switch was about 6% at 15 months. The observed variation of triptan consumption at 3/6/9/12/15 months and the corresponding SD was −4.4 [8.2]/−5.2 [9.0]/−5.5 [9.2]/−5.4 [9.2]/−4.5 [10.0], respectively. Conclusion: Patient demographics reflect the place of these medications in therapy. Overall, findings seem to indicate a favorable tolerability and effectiveness profile. Further studies are warranted to better establish the long‐term comparative effectiveness, safety, and cost effectiveness of anti‐CGRP mAbs compared to other preventive medications. [ABSTRACT FROM AUTHOR]

Objective: To evaluate an alternative method of defining acute treatment success in migraine by combining multiple indicators into a single dichotomous measure of success. Background: Migraine is characterized by a symptom complex; combining these features as a single endpoint may improve the measurement of treatment effects and better predict patient satisfaction with treatment. Methods: We used a confirmatory latent class model (LCM) with two latent classes interpreted as treatment success and treatment failure. Pooled data for placebo and ubrogepant 50 mg from the ACHIEVE I and ACHIEVE II trials and data for ubrogepant 100 mg from ACHIEVE I were used. LCM inputs included pre‐dose and 2‐h post‐dose measures of pain severity (0–3), the presence/absence of associated symptoms (nausea, photophobia, and phonophobia [0 or 1]), and functional disability (0–3). All definitions were validated against satisfaction with study medication (SWSM) at 24 h post‐dose; results were compared with 2‐hour pain freedom (2hPF). Results: This pooled analysis included 2247 participants. At 2 h post‐dose in the ubrogepant 50 and 100 mg dose groups, 53.2% (472/887) and 54.9% (246/448) of participants, respectively, were classified as achieving treatment success using the LCM‐based approach, compared to 39.0% (356/912) of participants in the placebo group. The results for treatment success using the 2hPF endpoint were 20.7% (184/887) and 21.5% (96/447) in the ubrogepant 50 and 100 mg dose groups, respectively, compared to 12.7% (116/912) for placebo. Using 24‐h SWSM as an external validator, the LCM approach sensitivity and correct classification rates were higher than for 2hPF. Conclusion: The LCM approach led to higher rates of treatment success and greater separation between ubrogepant and placebo and was a more sensitive predictor of treatment satisfaction than the regulatory endpoint of 2hPF. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Hemiplegic migraine (HM) is a subtype of migraine with aura that includes motor weakness; such headaches can be excruciating. The presence of not only headache but also aura symptoms of HM increase the burden on patients, and the treatment of HM is sometimes challenging. Monoclonal antibodies (mAbs) targeting the calcitonin gene‐related peptide (CGRP) pathway are novel migraine preventive treatments that have shown promising efficacy in patients with migraine; however, there have been no reports regarding their efficacy in HM to date. Six patients with HM were treated with galcanezumab in a tertiary‐care headache center. After 3 months of treatment, the number of monthly days with headache of at least moderate severity was reduced in three patients. The number of days each month with weakness was also reduced in four patients. Furthermore, the Patient's Global Impression of Change and change in Migraine Disability Assessment total score, were improved in five of the six patients after the treatment; however, the change from baseline in days with bothersome symptoms did not show any specific trends in our patients. Notably, no adverse events were reported during the treatments. The mechanism underlying the improvement in aura symptoms in our patients is not clear; however, we speculate that a small amount of CGRP mAbs have a direct mode of action in the central nervous system; alternatively, blocking the CGRP pathway in the periphery may secondarily inhibit cortical spreading depression. While prudence must be practiced, galcanezumab was still generally effective in HM and well tolerated. Further prospective clinical studies will more clearly elucidate the effects of CGRP mAbs in patients with HM. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effect of treatment with anti‐calcitonin gene–related peptide (CGRP; receptor) antibodies on visual hypersensitivity in patients with migraine. Background: Increased visual sensitivity can be present both during and outside migraine attacks. CGRP has been demonstrated to play a key role in light‐aversive behavior. Methods: In this prospective follow‐up study, patients treated for migraine with erenumab (n = 105) or fremanezumab (n = 100) in the Leiden Headache Center were invited to complete a questionnaire on visual sensitivity (the Leiden Visual Sensitivity Scale [L‐VISS]), pertaining to both their ictal and interictal state, before starting treatment (T0) and 3 months after treatment initiation (T1). Using a daily e‐diary, treatment effectiveness was assessed in weeks 9–12 compared to a 4‐week pre‐treatment baseline period. L‐VISS scores were compared between T0 and T1. Subsequently, the association between the reduction in L‐VISS scores and the reduction in monthly migraine days (MMD) was investigated. Results: At 3 months, the visual hypersensitivity decreased, with a decrease in mean ± standard deviation (SD) ictal L‐VISS (from 20.1 ± 7.7 to 19.2 ± 8.1, p = 0.042) and a decrease in mean ± SD interictal L‐VISS (from 11.8 ± 6.6 to 11.1 ± 7.0, p = 0.050). We found a positive association between the reduction in MMD and the decrease in interictal L‐VISS (β = 0.2, p = 0.010) and the reduction in ictal L‐VISS (β = 0.3, p = 0.001). Conclusion: A decrease in visual hypersensitivity in patients with migraine after treatment with anti‐CGRP (receptor) antibodies is positively associated with clinical response on migraine. [ABSTRACT FROM AUTHOR]

Objective: To assess the effect of single and multiple doses of rimegepant 75 mg dose on the pharmacokinetics of an oral contraceptive containing ethinyl estradiol (EE)/norgestimate (NGM) in healthy females of childbearing potential or non‐menopausal females with tubal ligation. Background: Females of childbearing age experience the highest prevalence of migraine and frequently inquire about the concomitant use of anti‐migraine medications and contraceptives. Rimegepant, a calcitonin gene–related peptide receptor antagonist, demonstrated efficacy and safety for treating an acute migraine attack and preventing migraine. Methods: This open‐label, single‐center, phase 1, drug–drug interaction study explored the effects of rimegepant 75 mg daily dose on the pharmacokinetics of an oral contraceptive containing EE/NGM 0.035 mg/0.25 mg in healthy females of childbearing potential or non‐menopausal females with tubal ligation. During cycles 1 and 2, participants received EE/NGM once daily for 21 days followed by placebo tablets with inactive ingredients for 7 days. Rimegepant was administered during only cycle 2 for 8 days, from days 12 through 19. The primary endpoint was the effect of single and multiple doses of rimegepant on the pharmacokinetics of EE and norelgestromin (NGMN), an active metabolite of NGM, at steady state, including area under the concentration‐time curve for 1 dosing interval (AUC0−τ,ss) and maximum observed concentration (Css[max]). Results: The study enrolled 25 participants, with pharmacokinetic data assessed for 20 participants. A single 75 mg dose of rimegepant co‐administered with EE/NGM increased exposures of EE and NGMN by ≤16% (geometric mean ratio [GMR], 1.03; 90% confidence interval [CI], 1.01–1.06; and GMR, 1.16; 90% CI, 1.13–1.20, respectively). After 8 days of co‐administering EE/NGM with rimegepant, EE pharmacokinetic parameters, AUC0−τ,ss and Css(max), increased by 20% (GMR, 1.20; 90% CI, 1.16–1.25) and 34% (GMR, 1.34; 90% CI, 1.23–1.46), respectively, and NGMN pharmacokinetic parameters increased by 46% (GMR, 1.46; 90% CI, 1.39–1.52) and 40% (GMR, 1.40; 90% CI, 1.30–1.51), respectively. Conclusions: The study identified modest elevations in overall EE and NGMN exposures after multiple doses of rimegepant, but these elevations are unlikely to be clinically relevant in healthy females with migraine. [ABSTRACT FROM AUTHOR]

Objective: We hypothesized that the response of trigeminal dermal blood flow (DBF) in the trigeminal system and consecutive expansion of flare response to capsaicin would differ from the somatosensory system (arm). We also investigated whether there are differences between patients with migraine and healthy controls (HC). Background: Functional differences between the trigeminal and extracephalic somatosensory systems may partly explain the susceptibility for headaches in patients with migraine. Capsaicin‐induced activation of nociceptive C‐fibers in the skin is mainly mediated by calcitonin gene‐related peptide (CGRP) and induces cutaneous vessel dilatation and flare response. Methods: Female patients with migraine (n = 38) and age‐matched HC (n = 35) underwent DBF measurement at baseline and after topical capsaicin administration using laser speckle imaging. DBF before and after capsaicin stimulation was analyzed over ophthalmic nerve/maxillary nerve/mandibular nerve (V1/V2/V3) dermatomes and the forearm as an extracephalic control. Results: Capsaicin‐induced DBF increased more in the trigeminal dermatomes than on the forearm. The V1 dermatome showed a smaller increase of DBF in patients with migraine compared to HC. Conclusion: Our results suggest that the trigeminovascular system reacts differently from extracephalic areas, which may explain the trigeminal susceptibility to CGRP‐mediated pain attacks. By demonstrating a different reactivity of the V1 dermatome in patients with migraine, our finding suggests that the first trigeminal branch is functionally different from the second and third branches; however, only in patients with migraine. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The article examines changes in prescription practices for CGRP monoclonal antibodies and onabotulinumtoxinA at the beginning of the COVID-19 pandemic, finding that providers initially switched to CGRP mAbs when onabotulinumtoxinA treatments were disrupted but later reverted to pre-pandemic patterns, indicating a preference for onabotulinumtoxinA when available for treating chronic migraine patients.

Objectives/Background: Treatment of migraine in the setting of either renal or hepatic disease can be daunting for clinicians. Not only does the method of metabolism have to be considered, but also the method of elimination/excretion of the parent drug and any active or toxic metabolites. Furthermore, it is difficult to think about liver or kidney disease in isolation, as liver disease can sometimes contribute to impaired renal function and renal disease can sometimes impair hepatic metabolism, through the cytochrome P450 system. Methods: A detailed search for terms related to liver disease, renal disease, and migraine management was performed in PubMed, Ovid Medline, Embase, and the Cochrane Library.For each medication, product labels were retrieved and reviewed using the US FDA website, with additional review of IBM Micromedex, LiverTox, and the Renal Drug Handbook. Results: This manuscript provides an overview of migraine drug metabolism and how it can be affected by liver and renal impairment. It reviews the standard terminology recommended by the US Food and Drug Administration for the different stages of hepatic and renal failure. The available evidence regarding the use of abortive and preventative medicines in the setting of organ failure is discussed in detail, including more recent therapies such as lasmiditan, gepants, and calcitonin gene‐related peptide antibodies. Conclusions: For acute therapy, the use of NSAIDS should be limited, as these carry risk for both severe hepatic and renal disease. Triptans can be selectively used, often with dose guideline adjustments. Ubrogepant may be used in severe hepatic disease with dose adjustment and lasmiditan can be used in end stage renal disease. Though non‐medicine strategies may be the most reasonable initial approach, many preventative medications can be used in the setting of hepatic and renal disease, often with dose adjustment. This review provides tables of guidelines, including reduced dosing recommendations, for the use of abortive and preventative migraine medications in hepatic and renal failure. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: To summarize the pharmacology of the calcitonin peptide family of receptors and explore their relationship to migraine and current migraine therapies. Background: Therapeutics that dampen calcitonin gene‐related peptide (CGRP) signaling are now in clinical use to prevent or treat migraine. However, CGRP belongs to a broader peptide family, including the peptides amylin and adrenomedullin. Receptors for this family are complex, displaying overlapping pharmacologic profiles. Despite the focus on CGRP and the CGRP receptor in migraine research, recent evidence implicates related peptides and receptors in migraine. Methods: This narrative review summarizes literature encompassing the current pharmacologic understanding of the calcitonin peptide family, and the evidence that links specific members of this family to migraine and migraine‐like behaviors. Results: Recent work links amylin and adrenomedullin to migraine‐like behavior in rodent models and migraine‐like attacks in individuals with migraine. We collate novel information that suggests females may be more sensitive to amylin and CGRP in the context of migraine‐like behaviors. We report that drugs designed to antagonize the canonical CGRP receptor also antagonize a second CGRP‐responsive receptor and speculate as to whether this influences therapeutic efficacy. We also discuss the specificity of current drugs with regards to CGRP isoforms and how this may influence therapeutic profiles. Lastly, we emphasize that receptors related to, but distinct from, the canonical CGRP receptor may represent underappreciated and novel drug targets. Conclusion: Multiple peptides within the calcitonin family have been linked to migraine. The current focus on CGRP and its canonical receptor may be obscuring pathways to further therapeutics. Drug discovery schemes that take a wider view of the receptor family may lead to the development of new anti‐migraine drugs with favorable clinical profiles. We also propose that understanding these related peptides and receptors may improve our interpretation regarding the mechanism of action of current drugs. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to explore patient preference for attributes of calcitonin gene‐related peptide (CGRP) inhibitors for the preventive treatment of migraine and to describe differences in treatment preferences between patients. Background: CGRP inhibitors are a novel class of migraine drugs specifically developed for the preventive treatment of migraine. Clinicians should understand patient preferences for CGRP inhibitors to inform and support prescribing choices. Methods: Patients with migraine in the US and Germany were recruited to participate in an online discrete choice experiment (DCE) survey, which presented hypothetical treatment choices using five attributes: mode of administration, side effects, migraine frequency, migraine severity, and consistency of treatment effectiveness. Attribute selection was informed by a literature review and semi‐structured patient interviews (n = 35), and evaluated using patient cognitive debriefing interviews (n = 5). Results: Of 680 who consented to participate, 506 participants completed the survey and were included in the study (US = 257; Germany = 249). Overall, participants placed highest importance (preference weight, beta = 1.65, p < 0.001) on the treatment's ability to reduce the severity of migraine (mild vs. unchanged severity), followed by consistent treatment effectiveness (beta = 1.13, p < 0.001), and higher chance of reduced migraine frequency (beta = 1.00, p < 0.001). Participants preferred an oral tablet every other day (beta = 1.00, p < 0.001) over quarterly infusion, quarterly injections (p = 0.019), or monthly injection (p < 0.001). Preference for all treatment attributes were heterogeneous, and the subgroup analyses found that participants naïve to CGRP monoclonal antibody treatments had a stronger preference for oral therapy compared to those with such experience (p = 0.006). Conclusion: In this DCE assessing CGRP inhibitors attributes, the main driver of patient choice was treatment effectiveness, specifically reduced migraine severity, and consistent treatment effectiveness. Further, patients exhibited an overall preference for an oral tablet every other day over injectables. Patients' experience with previous treatments informs the value they place on treatment characteristics. [ABSTRACT FROM AUTHOR]

Objective: Evaluate the efficacy, safety, and tolerability of zavegepant nasal spray in the acute treatment of migraine. Background: Calcitonin gene‐related peptide‐targeting agents are a novel class of therapeutics for migraine, but none are currently available as a nonoral option for acute treatment. Zavegepant, a high‐affinity, selective, and structurally unique calcitonin gene‐related peptide‐receptor antagonist in late‐stage development, is formulated as a nasal spray for the acute treatment of migraine. Methods: This randomized, dose‐ranging, placebo‐controlled, Phase 2/3 trial in adults aged ≥18 years with migraine (NCT03872453) was conducted at US study sites. Participants were randomized by an interactive web response system and treated a single attack of moderate to severe pain intensity with zavegepant nasal spray 5, 10, 20 mg, or placebo. Coprimary efficacy endpoints were pain freedom and freedom from the most bothersome symptom at 2 h postdose. Results: Of the 1673 participants aged 18 to 79 years who were randomized, 1588 were treated with study medication, and 1581 (mean age 40.8 years, 85.5% female) were analyzed for efficacy: zavegepant 5 mg (n = 387), 10 mg (n = 391), 20 mg (n = 402), and placebo (n = 401). Zavegepant 10 and 20 mg were more effective than placebo on the coprimary endpoints of pain freedom at 2 h postdose (placebo: 15.5% [98.3% confidence interval (CI), 11.1, 19.8]; 10 mg: 22.5% [98.3% CI, 17.5, 27.6; p = 0.0113]; 20 mg: 23.1% [98.3% CI, 18.1, 28.2; p = 0.0055]) and freedom from the most bothersome symptom at 2 h postdose (placebo: 33.7% [98.3% CI, 28.0, 39.3]; 10 mg: 41.9% [98.3% CI, 36.0, 47.9; p = 0.0155]; 20 mg: 42.5% [98.3% CI, 36.6, 48.4; p = 0.0094]). Findings for the 5 mg dose were not significant. The most common treatment‐emergent adverse events with zavegepant 10 and 20 mg and placebo were dysgeusia (13.5% to 16.1% vs. 3.5%), nausea (2.7% to 4.1% vs. 0.5%), and nasal discomfort (1.3% to 5.2% vs. 0.2%). Most adverse events were mild or moderate and resolved without treatment. There was no signal of hepatotoxicity. Conclusion: Zavegepant nasal spray, in single doses of 10 or 20 mg, was effective for the acute treatment of migraine, with a favorable safety profile. Additional research is needed to confirm its potential as a nonoral medication for the acute treatment of migraine. [ABSTRACT FROM AUTHOR]

Plain language summary: Idiopathic intracranial hypertension (IIH) is a condition of high pressure in the spinal fluid that is common in young women who are overweight or obese. Headache happens in most individuals with IIH and can continue after the early phase of IIH has resolved. We studied the use of a newer type of medication developed for migraine called calcitonin gene‐related peptide antibodies and we found that these medications can be helpful for patients who have had IIH, although studies with more patients will be helpful. [ABSTRACT FROM AUTHOR]

Objective: To characterize the effects of blocking calcitonin gene‐related peptide (CGRP) activity in a mouse model of gastrointestinal transport. Background: Migraine management using CGRP modulating therapies can cause constipation of varying frequency and severity. This variation might be due to the different mechanisms through which therapies block CGRP activity (e.g., blocking CGRP, or the CGRP receptor) with antibodies or receptor antagonists. The charcoal meal gastrointestinal transit assay was used to characterize constipation produced by these modes of therapy in transgenic mice expressing the human receptor activity–modifying protein 1 (hRAMP1) subunit of the CGRP receptor complex. Methods: Male and female hRAMP1 mice were dosed with compound or vehicle and challenged with a charcoal meal suspension via oral gavage. The mice were then humanely euthanized and the proportion of the length of the large intestine that the charcoal meal had traveled indicated gastrointestinal transit. Results: Antibody to the CGRP receptor produced % distance traveled (mean ± standard deviation) of 31.8 ± 8.2 (4 mg/kg; p = 0.001) and 33.2 ± 6.0 (30 mg/kg; p < 0.001) compared to 49.7 ± 8.3 (control) in female mice (n = 6–8), and 35.6 ± 13.5 (30 mg/kg, p = 0.019) compared to 50.2 ± 14.0 (control) in male mice (n = 10). Telcagepant (5 mg/kg, n = 8) resulted in % travel of 30.6 ± 14.7 versus 41.2 ± 8.3 (vehicle; p = 0.013) in male mice. Atogepant (3 mg/kg, n = 9) resulted in % travel of 30.6 ± 12.0, versus 41.2 ± 3.7 (control; p = 0.030) in female mice. The CGRP antibody galcanezumab (n = 7–10; p = 0.958 and p = 0.929) did not have a statistically significant effect. Conclusions: These results are consistent with reported clinical data. Selectively blocking the CGRP receptor may have a greater impact on gastrointestinal transit than attenuating the activity of the ligand CGRP. This differential effect may be related to physiologically opposing mechanisms between the CGRP and AMY1 receptors, as the CGRP ligand antibody could inhibit the effects of CGRP at both the CGRP and AMY1 receptors. [ABSTRACT FROM AUTHOR]

Objective: This post hoc analysis in patients medically diagnosed with chronic migraine (CM) and medication‐overuse headache (MOH) evaluated reductions in the use of acute headache medication (AHM) and sustained changes in the diagnostic status of CM and MOH following eptinezumab treatment in the PROMISE‐2 study. Background: Eptinezumab, a monoclonal antibody that inhibits calcitonin gene‐related peptide, is approved in the United States for the preventive treatment of migraine. A previous analysis showed that eptinezumab reduced monthly migraine days and was well tolerated in the subgroup of PROMISE‐2 patients diagnosed with both CM and MOH. Methods: The phase 3, double‐blind, placebo‐controlled PROMISE‐2 study (NCT02974153) randomized adults with CM to eptinezumab 100 mg, 300 mg, or placebo (administered intravenously every 12 weeks for up to two doses). MOH was prospectively diagnosed at screening by trained physicians based on 3 months of medication history and International Classification of Headache Disorders‐3β criteria. This post hoc analysis evaluated changes in total and class‐specific days of AHM usage, the percentage of patients using AHM at or above MOH diagnostic thresholds, and the percentage of patients experiencing monthly headache and migraine day frequency below diagnostic thresholds for MOH and/or CM. Results: In PROMISE‐2, 431/1072 (40.2%) patients with CM were diagnosed with MOH (eptinezumab 100 mg, n = 139; 300 mg, n = 147; placebo, n = 145) and were included in this analysis. Total monthly AHM use decreased from 20.6 days/month at baseline to 10.6 days/month over 24 weeks of treatment (49% decrease) with eptinezumab 100 mg, from 20.7 to 10.5 days/month (49% decrease) with eptinezumab 300 mg, and from 19.8 to 14.0 days/month (29% decrease) with placebo. Numerically greater decreases from baseline with eptinezumab were also observed for individual drug classes. In each study month, the percentages of patients who were below MOH thresholds were numerically higher for both eptinezumab doses compared with placebo, as were the percentages of patients experiencing headache and migraine frequency below CM thresholds. Of patients with available data across the entire treatment period, 29.0% (58/200) of patients treated with eptinezumab stopped meeting and remained below diagnostic thresholds for both CM and MOH during Weeks 1–24, as well as 6.3% (6/96) of patients who received placebo. Conclusions: Across 24 weeks of treatment, eptinezumab reduced AHM use in patients diagnosed with CM and MOH. More than one‐fourth (29%) of patients treated with eptinezumab did not meet the diagnostic thresholds for either CM or MOH for the entire treatment period. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy and safety of two dosing regimens of fremanezumab in Japanese and Korean patients with episodic migraine. Background: Episodic migraine, which accounts for more than 90% of migraine cases, is inadequately addressed by widely available preventive therapies. Fremanezumab, a monoclonal antibody that selectively targets the trigeminal sensory neuropeptide calcitonin gene‐related peptide involved in migraine pathogenesis, has demonstrated efficacy in international Phase 3 trials of patients with both chronic and episodic migraine. Methods: This Phase 3 randomized, placebo‐controlled trial randomly assigned patients with episodic migraine to receive subcutaneous fremanezumab monthly (225 mg at baseline, week 4, and week 8), fremanezumab quarterly (675 mg at baseline and placebo at weeks 4 and 8), or matching placebo. The primary endpoint was the mean change from baseline in the monthly average number of migraine days during the 12‐week treatment period after the first dose. Results: Of 357 patients enrolled (safety set, n = 356; full analysis set, n = 354), the least‐squares mean (±standard error) reductions in the average number of migraine days per month during 12 weeks were significantly greater with fremanezumab monthly (−4.0 ± 0.4, n = 121) and fremanezumab quarterly (−4.0 ± 0.4, n = 117) than with placebo (−1.0 ± 0.4, n = 116; p < 0.0001 for both comparisons). The proportion of patients reaching at least a 50% reduction in the monthly average number of migraine days during the 12‐week period after initial administration was also significantly improved with fremanezumab (fremanezumab monthly, 41.3%; fremanezumab quarterly, 45.3%; placebo, 11.2%; p < 0.0001 for both comparisons) as were other secondary endpoints (p < 0.001 for all comparisons between fremanezumab and placebo). Injection‐site reactions were more common in fremanezumab‐treated patients (fremanezumab monthly, 25.6%; fremanezumab quarterly, 29.7%; placebo, 21.4%). Conclusion: Fremanezumab prevents episodic migraine in Japanese and Korean patients to a similar extent than in previously reported populations with no new safety concerns. [ABSTRACT FROM AUTHOR]

Objective: To determine the efficacy and safety of fremanezumab administration in Japanese and Korean patients with chronic migraine (CM). Background: Available preventive treatments for CM are limited by various efficacy and safety issues. Fremanezumab, a monoclonal antibody that targets the calcitonin gene‐related peptide pathway involved in migraine pathogenesis, has been shown to be effective and well tolerated in large‐scale, international Phase 3 trials. Methods: Randomized, placebo‐controlled trial of patients with CM who received subcutaneous fremanezumab monthly (675 mg at baseline and 225 mg at weeks 4 and 8), fremanezumab quarterly (675 mg at baseline and placebo at weeks 4 and 8), or matching placebo. Primary endpoint was the mean change from baseline in the monthly (28‐day) average number of headache days of at least moderate severity during the 12 weeks after the first dose. Results: Among 571 patients randomized (safety set, n = 569; full analysis set, n = 566), the least‐squares mean (±standard error [SE]) reduction in the average number of headache days of at least moderate severity per month during 12 weeks was significantly greater with fremanezumab monthly (–4.1 ± 0.4) and fremanezumab quarterly (–4.1 ± 0.4) than with placebo (–2.4 ± 0.4). The difference from the placebo group in the mean change (95% confidence interval [CI]) was −1.7 days (−2.54, −0.80) for the fremanezumab monthly group and −1.7 days (−2.55, −0.82) for the fremanezumab quarterly group (p < 0.001 vs. placebo for both fremanezumab groups). The percentage of patients with a ≥50% reduction in the average number of headache days of at least moderate severity per month (response rate) was higher with fremanezumab monthly (29.0%) and fremanezumab quarterly (29.1%) than with placebo (13.2%) in addition to other improvements in secondary endpoints, including reduction of acute medication use (mean change from baseline during 12‐week period ± SE: fremanezumab monthly, –3.7 ± 0.4; fremanezumab quarterly, –3.9 ± 0.4; placebo, –2.4 ± 0.4) and improvements in disability scores (mean change from baseline in six‐item Headache Impact Test score at 4 weeks after third injection ± SE: fremanezumab monthly, –8.1 ± 0.7; fremanezumab quarterly, –8.0 ± 0.7; placebo, –6.5 ± 0.7). Fremanezumab was well tolerated with a similar incidence of adverse events including injection‐site reactions as placebo (patients with at least one treatment‐emergent adverse event: fremanezumab total, n = 232 [61.4%]; placebo, n = 118 [61.8%]). Conclusion: Fremanezumab effectively prevents CM in Japanese and Korean patients and was well tolerated. No safety signal was detected. [ABSTRACT FROM AUTHOR]

Objective: To review the pharmacokinetics of major classes of migraine preventives and the clinical implications of drug–drug interactions (DDIs) with the use of these therapies in migraine management. Background: Preventive treatments for migraine are recommended for a large proportion of patients with frequent migraine attacks. These patients often exhibit a number of comorbidities, which may lead to the introduction of multiple concomitant therapies. Potential DDIs must be considered when using polytherapy to avoid increased risk of adverse events (AEs) or inadequate treatment of comorbid conditions. Methods: A literature search was performed to identify pharmacokinetic properties and potential DDIs of beta‐blockers, antiepileptic drugs, antidepressants, calcium channel blockers, gepants, and monoclonal antibody therapies targeting the calcitonin gene‐related peptide pathway with medications that may be used for comorbid conditions. Results: Most DDIs occur through alterations in cytochrome P450 isoenzyme activity and may be complicated by genetic polymorphism for metabolic enzymes. Additionally, drug metabolism may be altered by grapefruit juice ingestion and smoking. The use of migraine preventive therapies may exacerbate symptoms of comorbid conditions or increase the risk of AEs associated with comorbid conditions as a result of DDIs. Conclusions: DDIs are important to consider in patients with migraine who use multiple medications. The development of migraine‐specific evidence‐based preventive treatments allows for tailored clinical management that reduces the risk of DDIs and associated AEs in patients with comorbidities. [ABSTRACT FROM AUTHOR]

A correction to the article "Long-Term Safety Evaluation of Ubrogepant for the Acute Treatment of Migraine: Phase 3, Randomized, 52-Week Extension Trial," by J. Ailani, R. B. Lipton, S. Hutchinson, K. Knievel, K. Lu, M. Butler, S. Y. Yu, M. Finnegan, L. Severt and J. M. Trugman which appeared in a 2020 issue is presented.

Objective: To determine the potential efficacy of ubrogepant for acute treatment of migraine based on historical experience with triptans. Background: Although triptans have improved migraine treatment, their efficacy and tolerability may limit their utility in some individuals. Ubrogepant is a small‐molecule, oral calcitonin gene–related peptide receptor antagonist approved by the Food and Drug Administration for acute treatment of migraine in adults. Methods: This post hoc analysis of pooled data from the pivotal trials ACHIEVE I and II, identically designed, randomized, double‐blind, phase 3, single‐attack trials of ubrogepant in adults with a history of migraine with/without aura, examined the efficacy and tolerability of ubrogepant 50 mg versus placebo based on participants' historical experience with triptans: triptan responder, triptan‐insufficient responder, and triptan naïve. Co‐primary efficacy endpoints were pain freedom and absence of most bothersome migraine‐associated symptom (MBS) 2 h post initial dose. Adverse events (AEs) within historical triptan experience subgroups were evaluated. Results: In the pooled analysis population (n = 1799), 682 (placebo, n = 350; ubrogepant 50 mg, n = 332), 451 (placebo, n = 223; ubrogepant, n = 228), and 666 (placebo, n = 339; ubrogepant, n = 327) participants were triptan responders, triptan‐insufficient responders, and triptan‐naïve, respectively. Response rates on co‐primary efficacy endpoints were higher for ubrogepant versus placebo across all groups. Treatment‐by‐subgroup interaction p values based on odds ratios for pain freedom (p = 0.290) and absence of MBS (p = 0.705) indicated no significant impact of historical triptan experience on ubrogepant efficacy. AE incidence for ubrogepant did not differ appreciably across historical triptan experience subgroups. Conclusions: Ubrogepant efficacy and tolerability did not differ for the acute treatment of migraine in participants classified as triptan responders, triptan‐insufficient responders, and triptan‐naïve based on their historical experience with triptans. [ABSTRACT FROM AUTHOR]

Background: Calcitonin gene‐related peptide (CGRP) inhibitors were introduced in the United States (US) in 2018. To understand the changing patterns of preventive treatment following the introduction of these new agents, we must first characterize the patterns which preceded their introduction. Objective: To characterize the burden, unmet need, and treatment patterns in patients with migraine initiating preventive migraine medications before the introduction of CGRP inhibitors in the US. Methods: Between March 2016 and October 2017, we enrolled episodic (EM) and chronic migraine (CM) patients initiating or changing preventive treatment at primary care or neurology clinic visits in the US, in a real‐world observational study using a prospective cohort design. At baseline and monthly thereafter for 6 months, we collected data from study sites and patients on migraine frequency, treatment modifications, migraine impact on functioning, and work productivity for a descriptive analysis of migraine patient experience and treatment patterns. Results: From the sample of 234 completers, 118 had EM (50.4%) and 116 had CM (49.6%). Mean age at enrollment was 41 years (SD = 12) and mean age at first migraine diagnosis was 22 years (SD = 11). Most participants were females (n = 204/234; 87.2%) and white (n = 178/234; 76.1%). The majority (n = 164/234; 70.1%) had not used preventive migraine treatment in the 5 years prior to enrollment (treatment naïve). At baseline, mean monthly migraine days were 9.6 days (SD = 5.0) for the preventive treatment naïve group and 12.4 days (SD = 7.0) for treatment experienced patients. The majority had severe Migraine Disability Assessment (Grade IV, total score ≥21), including 67.1% (n = 110/164) of the preventive treatment naïve and 77.1% (n = 54/70) of the preventive treatment experienced patients. Headache Impact Test total scores indicating severe impairment (score >59) occurred in 88.4% (n = 145/164) of the treatment naïve and 88.6% (n = 62/70) of treatment experienced patients. Mean work productivity loss as measured by the Work Productivity and Activity Impairment questionnaire in the subsample of employed patients was 53.3% loss. The most used acute medications at baseline were nonsteroidal anti‐inflammatory agents (n = 124/234; 53.0%), acetaminophen‐based products (n = 112/234; 47.9%), and triptans (n = 105/234; 44.9%). The most commonly initiated preventive treatments were topiramate (n = 100/234; 42.7%), tricyclic antidepressants (n = 39/234; 16.7%), beta‐blockers (n = 26/234; 11.1%), and onabotulinumtoxinA (n = 24/234; 10.3%). Over the 6‐month follow‐up period, almost half of patients (n = 116/234, 49.6%) modified their preventive treatment and discontinued treatment (n = 88/312 total modifications; 28.2%) or modified their pattern of use by increasing, decreasing, or skipping doses (n = 224/312 total modifications; 71.8%), often without seeking medical advice. Avoiding side effects was the main reason reported among patients who discontinued (n = 52/88; 59.1%), decreased frequency or dose (n = 37/89; 41.6%), and skipped doses (n = 29/86; 33.7%). Perceived lack of efficacy was another frequent reason reported among those who discontinued (n = 20/88; 22.7%), decreased frequency or dose (n = 15/89; 16.9%), and skipped doses (n = 18/86; 20.9%). Despite initiation of preventive treatment and improvements observed in number of headache and migraine days, migraine patients continued to experience substantial disability, headache impact, and reduced productivity throughout the 6‐month follow‐up period. Conclusions: Prior to 2018, the burden of migraine was high for patients initiating preventive treatments. Despite having more than 9 days of migraine per month on average, the majority (70.1%) of patients initiating prevention had been treatment naïve, indicating underuse of preventive treatments. The preventive treatments used in this study were poorly tolerated and were reported by patients to lack efficacy, resulting in suboptimal adherence. The high discontinuation rates suggest that the preventive medications being offered during the period of the study did not meet the treatment needs of patients. In addition, the decisions by about half of patients to alter their prescribed treatment plan without consulting their provider can pose substantial health risks. These findings pertain to the broad set of preventive treatments initiated in this study and do not support inferences about individual preventive treatments, due to limitations in sample size. These findings suggest the need for more effective and better tolerated preventive treatment options. [ABSTRACT FROM AUTHOR]

An editorial is presented on the relationship between headache disorders and cerebrovascular (CV) disease, discussing potential causal links, mechanisms, and implications for headache treatment. Topics include the connection between migraine and ischemic processes, the impact of headache on CV events, and the cardiovascular risks associated with migraine therapeutics.

Objective: To evaluate the efficacy, tolerability, and safety of eptinezumab 100 and 300 mg compared with placebo in patients with the dual diagnosis of chronic migraine (CM) and medication‐overuse headache (MOH). Background: Eptinezumab, a humanized monoclonal antibody targeting calcitonin gene‐related peptide, may be effective for treating patients with a dual diagnosis of CM and MOH. Methods: PROMISE‐2 (NCT02974153) was a double‐blind, randomized, placebo‐controlled, phase 3 study that comprised a screening visit, a 28‐day pretreatment period, and a 32‐week study duration. Patients in this exploratory analysis of a prespecified subgroup had confirmed diagnoses of both CM and MOH at screening. Patients were randomly assigned to receive intravenous eptinezumab 100, 300 mg, or placebo every 12 weeks. Efficacy outcomes included mean changes from baseline in monthly migraine days (MMDs) during weeks 1–12, migraine responder rates at week 12, and percentages of patients below International Classification of Headache Disorders thresholds for CM and MOH over weeks 1–24. Results: There were 431 patients who were diagnosed with CM and MOH as specified in the protocol and received eptinezumab 100 mg (n = 139), 300 mg (n = 147), or placebo (n = 145). During the baseline period, these patients experienced an average of 16.7 migraine days across treatment arms. Over weeks 1–12, eptinezumab‐treated patients experienced greater reductions from baseline in MMDs than placebo patients (100 mg, change from baseline = −8.4, difference from placebo [95% confidence interval (CI)] = −3.0 [−4.56, −1.52], p < 0.0001 vs. placebo; 300 mg, change from baseline = −8.6, difference from placebo [95% CI] = −3.2 [−4.66, −1.78], p < 0.0001 vs. placebo; placebo, −5.4). Compared with placebo, more eptinezumab‐treated patients were ≥50% migraine responders (100 mg, 84/139 [60.4%]; 300 mg, 91/147 [61.9%]; placebo, 50/145 [34.5%]) or ≥75% responders (100 mg, 38/139 [27.3%]; 300 mg, 44/147 [29.9%]; placebo, 21/145 [14.5%]) over weeks 1–12. Therapeutic benefits with eptinezumab were observed from day 1 after dosing, and improvements were sustained with an additional dose. For the full 24‐week treatment period, 71/139 (51.1%), 80/147 (54.4%), and 47/145 (32.4%) of 100, 300 mg, and placebo‐treated patients, respectively, were below CM thresholds, and of the patients who provided sufficient acute medication data, 47/93 (50.5%), 53/107 (49.5%), and 26/96 (27.1%), respectively, were below medication‐overuse thresholds. Conclusions: In patients diagnosed with both CM and MOH, eptinezumab treatment resulted in greater reductions in MMDs, higher responder rates, and fewer patients meeting CM and MOH criteria, thus demonstrating the efficacy and clinical utility of eptinezumab in this patient population. [ABSTRACT FROM AUTHOR]

Objective: To evaluate whether quarterly or monthly administration of fremanezumab for migraine prevention exhibits a pattern of decreased efficacy toward the end of the dosing interval (wearing‐off effect). Background: The main goals of migraine preventive treatment are to reduce the frequency, severity, and duration of migraine attacks, and migraine‐associated disability. Wearing‐off refers to the phenomenon whereby clinical symptoms return or worsen before the next dose of a drug is due and has been reported previously with migraine preventive medications. Design and Methods: This was a long‐term, 12‐month, multicenter, randomized, double‐blind, parallel‐group phase 3 study (NCT02638103) that included chronic (CM) and episodic migraine (EM) patients who rolled over from the 12‐week phase 3 HALO CM (NCT02621931) and EM trials (NCT02629861), as well as an additional subset of 312 new patients. Patients with CM or EM received fremanezumab either monthly or quarterly. In this post hoc analysis, for selected months, the difference in the average number of migraine days between weeks 1‐2 and weeks 3‐4, between weeks 1‐3 and week 4, and between weeks 1‐2 and weeks 11‐12 were calculated. Results: A total of 1890 patients (CM, 1110; EM, 780) were enrolled. At months 3, 6, 9, and 15, there were no substantial differences in mean weekly migraine days between weeks 1‐2 and weeks 3‐4 or between weeks 1‐3 and week 4 with quarterly or monthly fremanezumab in the CM or EM subgroups. There were no substantial increases in mean weekly migraine days between weeks 1‐2 and weeks 11‐12 during the first quarter of treatment (months 1‐3) or the second quarter of treatment (months 4‐6) with quarterly or monthly fremanezumab in the CM or EM subgroups. Across both dosing subgroups in CM and EM patients, the mean weekly number of migraine days decreased substantially (30%‐42%) during the first 2 weeks; decreases in weekly migraine days remained steady during the last 2 weeks of the first quarter, with a similar maintenance of response during the second quarter. Conclusions: This analysis of data from a long‐term, phase 3 study showed that patients receiving quarterly fremanezumab or monthly fremanezumab did not experience a wearing‐off effect toward the end of the dosing interval. [ABSTRACT FROM AUTHOR]

Objective: To determine the effectiveness and safety of erenumab in patients with chronic migraine in the real‐world setting of 3 headache centers in Australia. Methods: Patients with migraine were prescribed erenumab (70 or 140 mg) in the setting of either a product familiarization program or paid access to the medication in 3 headache centers in Australia. We obtained baseline and monthly prospective data on monthly headache days, monthly migraine days, monthly triptan use days, monthly codeine use days, Headache Impact Test‐6 scores, and adverse reactions. In this paper, we present our data at 3 and 6 months in our subgroup of patients with chronic migraine with and without medication overuse. Results: A total of 170 patients with chronic migraine were prescribed erenumab in the 3 headache centers. At 3 months, 100/170 (58.8%) had 50% or greater reduction in monthly migraine days. At 6 months, 79/170 (46.5%) had 50% or greater reduction in monthly migraine days. At 6 months, there was a mean reduction in monthly headache days of 9.2 days, a mean reduction in monthly migraine days of 10.2 days. There were few adverse events reported. Conclusion: This is the first report from 3 Australian headache centers about erenumab in the real world. Our analysis has supported erenumab as an effective and well‐tolerated migraine preventative therapy for patients with chronic migraine who have failed many preventative therapies. [ABSTRACT FROM AUTHOR]

Objective: A hallmark of migraine is photophobia. In mice, photophobia‐like behavior is induced by calcitonin gene‐related peptide (CGRP), a neuropeptide known to be a key player in migraine. In this study, we sought to identify sites within the brain from which CGRP could induce photophobia. Design: We focused on the posterior thalamic region, which contains neurons responsive to both light and dural stimulation and has CGRP binding sites. We probed this area with both optogenetic stimulation and acute CGRP injections in wild‐type mice. Since the light/dark assay has historically been used to investigate anxiety‐like responses in animals, we measured anxiety in a light‐independent open field assay and asked if stimulation of a brain region, the periaqueductal gray, that induces anxiety would yield similar results to posterior thalamic stimulation. The hippocampus was used as an anatomical control to ensure that light‐aversive behaviors could not be induced by the stimulation of any brain region. Results: Optogenetic activation of neuronal cell bodies in the posterior thalamic nuclei elicited light aversion in both bright and dim light without an anxiety‐like response in an open field assay. Injection of CGRP into the posterior thalamic region triggered similar light‐aversive behavior without anxiety. In contrast to the posterior thalamic nuclei, optogenetic stimulation of dorsal periaqueductal gray cell bodies caused both light aversion and an anxiety‐like response, while CGRP injection had no effect. In the dorsal hippocampus, neither optical stimulation nor CGRP injection affected light aversion or open field behaviors. Conclusion: Stimulation of posterior thalamic nuclei is able to initiate light‐aversive signals in mice that may be modulated by CGRP to cause photophobia in migraine. [ABSTRACT FROM AUTHOR]

The article discusses treatment choices, offering greater chances for improvement in the quality of life for people with migraine, based on a deeper understanding of migraine physiology. Topics include a case-based approach for learning allows to analyze individual patient factors, at available data from clinical trials; and Food and Drug Administration approved kit for preventative management of patients with chronic migraine has included onabotulinumtoxinA.

The article focuses on the Institute for Clinical and Economic Review final evidence report on the clinical and economic value of novel acute treatments for migraine, rimegepant, and lasmiditan. Topics include the randomized trials of acute therapies for migraine has designed to assess the primary outcomes, and the U.S. Food and Drug Administration guidance and the guidelines for clinical trials of drugs has issued by the International Headache Society Clinical Trial Standing Committee.

Objective: To synthesize the evidence on the efficacy of calcitonin gene‐related peptide receptor antagonists (gepants) from all clinical trials addressing nausea treatment for episodic migraine. Introduction: Nausea is one of the most bothersome symptoms in patients with migraine. The most bothersome symptom is part of the outcomes explored in clinical trials. Methods: Published clinical trials for this project were identified via searches of 4 bibliographic databases: PubMed (includes MEDLINE), Embase, Web of Science, and the Cochrane Library. Individual search strategies included terms related to calcitonin gene‐related peptide, nausea, and vomiting. Random‐effects meta‐analysis was conducted to estimate the overall efficacy of gepants for nausea treatment. Heterogeneity, publication bias, small‐study bias, and potential confounders were explored using Galbraith plot, sensitivity analysis, meta‐regression, and Egger's regression tests. Cumulative meta‐analysis was done to detect temporal trend from accumulating trials. Results: The meta‐analysis involved 23,008 participants in 65 clinical trials from 14 published articles; 10,770 subjects participated in gepant treatment arms while 12,238 subjects participated in placebo or non‐gepant arms (85% females, mean age 41 years in both arms). Nearly all studies used a 2‐hour incidence of nausea as an outcome measure. An overall combined effect size with an odds ratio of 1.29 (95% CI 1.18, 1.40, P =.001; I2 = 42.8%) showed the efficacy of gepants for the treatment of nausea in episodic migraine. Galbraith plot demonstrated that 98.4% of studies were within 2 standard deviations from the regression line, indicating lack of significant heterogeneity and outliers. Meta‐analysis results were robust to sensitivity analysis, small‐study bias, and publication bias (Kendall's Tau −0.09, P =.29; Egger's regression P =.67). Meta‐regression showed that both age and sex ratio were not confounding the meta‐analysis (omnibus P =.69). Cumulative meta‐analysis indicated that the effect size remained stable for studies conducted after 2011, with accumulating evidence continuing to favor efficacy of gepants for the treatment of nausea in episodic migraine. Conclusion: There is sufficient evidence to support the efficacy of gepants for the treatment of nausea in episodic migraine. Future research may focus on examining this efficacy in under‐represented patient populations (males, older age groups) and in chronic migraine. [ABSTRACT FROM AUTHOR]

Objective: To narratively review the pathophysiological rationale of dual therapy with anti‐calcitonin gene‐related peptide monoclonal antibodies and botulinum toxin type A in treatment‐resistant chronic migraine prevention. Background: For the prevention of chronic migraine, several pharmacological therapies are available, including oral medications, botulinum toxin type A, and the newly approved monoclonal antibodies targeting calcitonin gene‐related peptide or its receptor. However, monotherapy does not yield benefits in some affected individuals, which raises the question of whether dual therapy with monoclonal antibodies and botulinum toxin type A hold promise in patients with treatment‐resistant chronic migraine. Method: We searched MEDLINE for articles published from database inception to December 31st, 2019. Publications were largely selected from the past 10 years but commonly referenced and highly regarded older publications were not excluded. Results: Preclinical data suggest that anti‐calcitonin gene‐related peptide monoclonal antibodies and botulinum toxin type A have synergistic effects within the trigeminovascular system. Of note, findings indicate that fremanezumab – an antibody targeting the calcitonin gene‐related peptide – mainly prevents the activation of Aδ‐fibers, whereas botulinum toxin type A prevents the activation of C‐fibers. Conclusion: There is currently only indirect preclinical evidence to support a rationale for dual therapy with anti‐calcitonin gene‐related peptide monoclonal antibodies and botulinum toxin type A for chronic migraine prevention. Rigorous studies evaluating clinical efficacy, safety, and cost‐effectiveness are needed. [ABSTRACT FROM AUTHOR]

Objective: The monoclonal antibodies against calcitonin gene‐related peptide (CGRP) or its receptor are new antimigraine drugs from which many patients already benefit. Very few side effects have been reported from the antibody trials, including very few gastrointestinal (GI) side effects. The current data derive from a double‐blind cross‐over study of CGRP infusion for 2 hours. We present the GI side effects of the infusion and raise the question if underreporting of GI symptoms in CGRP antibody trials has occurred. We also discuss why constipation may be more likely with CGRP receptor blockade than with CGRP neutralizing antibodies. Methods: Thirty healthy volunteers were recruited to receive a 2‐hour infusion of CGRP 1.5 µg/minutes on 2 different days. The participants were pretreated with sumatriptan tablets (2 × 50 mg) 1 day and with placebo the other day. During the infusion, the participants were asked about side effects including a detailed description about their GI symptoms. Clinical observations like flatulence, rumbling, and use of bedpan were also noted. After the infusion, the participants filled out a questionnaire about side effects at home until 12‐hour after the infusion start. The study was conducted at the Danish Headache Center at Rigshospitalet Glostrup in the period February 2018 to July 2018. Results: On both study days 93% (27/29 participants) experienced symptoms from the GI system during the infusion. Rumbling, stomach pain, nausea, diarrhea, and an urge to defecate were the most commonly experienced GI side effects. There was no difference in symptoms between placebo and sumatriptan pretreatment. Conclusion: We conclude that a 2‐hour infusion of CGRP causes frequent and sometimes severe symptoms from the GI system. The symptoms are not antagonized by sumatriptan. More attention should be paid to constipation as a possible side effect of CGRP receptor antagonists. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy of ubrogepant on patient‐reported functional disability, satisfaction with study medication, and global impression of change. Background: Ubrogepant is a small‐molecule, oral calcitonin gene‐related peptide receptor antagonist indicated for the acute treatment of migraine. In 2 phase 3 trials (ACHIEVE I and II), ubrogepant demonstrated efficacy vs placebo on the 2 co‐primary endpoints of headache pain freedom and absence of the most bothersome migraine‐associated symptom at 2 hours post dose for the 50 and 100 mg doses. Patient‐reported outcomes, such as functional disability, satisfaction, and patient global impression of change, can provide additional evidence of the efficacy of an acute treatment for migraine on clinically meaningful and patient‐relevant outcomes. Methods: ACHIEVE I and ACHIEVE II were multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group, single‐attack trials in adults (18‐75 years) with migraine. In ACHIEVE I, participants were randomized 1:1:1 to placebo or ubrogepant 50 or 100 mg; in ACHIEVE II, participants were randomized 1:1:1 to placebo or ubrogepant 25 or 50 mg to treat a migraine attack with moderate or severe headache pain. Participants rated ability to perform daily activities on the Functional Disability Scale, before dosing and at 1, 2, 4, and 8 hours after the initial dose; satisfaction with study medication at 2 and 24 hours; and impression of overall change in migraine on the Patient Global Impression of Change scale at 2 hours. In prespecified analyses for each trial, each outcome was compared between each ubrogepant dose group and the relevant placebo group. Data were pooled from the ubrogepant 50 mg and placebo groups of the 2 trials in a post hoc analysis. Results: In ACHIEVE I, 559 participants were randomized to placebo, 556 to ubrogepant 50 mg, and 557 to ubrogepant 100 mg; in ACHIEVE II, 563 were randomized to placebo, 561 to ubrogepant 25 mg, and 562 to ubrogepant 50 mg. At 2 hours post dose, significantly higher proportions of ubrogepant‐treated participants vs placebo‐treated participants reported being able to function normally (ACHIEVE I: ubrogepant 50 mg, 40.6% [171/421], P =.0012 vs placebo; ubrogepant 100 mg, 42.9% [192/448], P <.0001 vs placebo; placebo, 29.8% [136/456]; ACHIEVE II: ubrogepant 25 mg, 42.6% [185/434], P =.0015 vs placebo; ubrogepant 50 mg, 40.5% [188/464], P =.0118 vs placebo; placebo, 34.2% [156/456]; pooled 50 mg, 40.6% [359/885], vs pooled placebo, 32.0% [292/912]; P <.0001), were satisfied/extremely satisfied with study medication (ACHIEVE I: 50 mg, 36.3% [147/405], P <.0001 vs placebo; 100 mg, 35.8% [149/416], P =.0002 vs placebo; placebo, 24.1% [104/432]; ACHIEVE II: 25 mg, 35.1% [141/402], P =.0018 vs placebo; 50 mg, 37.8% [163/431], P <.0001 vs placebo; placebo, 24.8% [106/427]; pooled ubrogepant 50 mg, 37.1% [310/836], vs pooled placebo, 24.5% [210/859]; P <.0001), and indicated that their migraine was much/very much better on the Patient Global Impression of Change scale (ACHIEVE I: 50 mg, 34.4% [103/299], P =.0006 vs placebo; 100 mg, 34.3% [102/297], P =.0009 vs placebo; placebo, 22.0% [69/313]; ACHIEVE II: 25 mg, 34.1% [124/364], P <.0001 vs placebo; 50 mg, 33.4% [131/392], P =.0002 vs placebo; placebo, 20.7% [78/376]; pooled 50 mg, 33.9% [234/691], vs pooled placebo, 21.3% [147/689]; P <.0001). Conclusions: A significantly higher proportion of participants treated with ubrogepant were able to function normally, were satisfied with the study medication, and reported clinically meaningful improvement compared with those receiving placebo. The results reinforce the potential benefits of ubrogepant on patient‐centered outcomes in the acute treatment of migraine. [ABSTRACT FROM AUTHOR]