Monthly Migraine Attacks Research Articles

Long-term safety of zavegepant nasal spray for the acute treatment of migraine: A phase 2/3 open-label study.

Zavegepant is the first small molecule calcitonin gene-related peptide receptor antagonist for intranasal administration for the acute treatment of migraine. The objective of this study was to evaluate the safety and tolerability of zavegepant in the acute treatment of migraine under repeated, as-needed dosing for up to one year. This phase 2/3, one-year open-label safety study of zavegepant 10 mg nasal spray for the acute treatment of migraine enrolled adults aged ≥18 years with a history of two to eight moderate to severe monthly migraine attacks. Participants used one dose of zavegepant as needed to self-treat migraine attacks of any severity, up to eight times per month, for 52 weeks. Participants were enrolled between 29 June and 4 December 2020. Of the 608 participants entering long-term treatment, 603 were treated with study drug. Participants administered a mean (SD) of 3.1 (1.55) zavegepant doses per month. There were no deaths. Of the seven serious adverse events reported, none was considered related to treatment. Altogether, 6.8% (41/603) of treated participants had an adverse event leading to study drug discontinuation. The most frequent adverse event leading to discontinuation was dysgeusia (1.5% [9/603]). The most common treatment-emergent adverse events (≥5% of participants) were dysgeusia (39.1% [236/603]); nasal discomfort (10.3% [62/603]); COVID-19 (7.5% [45/603]); nausea (6.1% [37/603]); nasal congestion and throat irritation (5.5% [33/603] each); and back pain (5.3% [32/603]). Aminotransferases >3x the upper limit of normal occurred in 2.6% [16/603] of participants; none had concurrent elevations in bilirubin >2x upper limit of normal. One year of zavegepant 10 mg nasal spray up to eight times per month was safe and well tolerated.Trial registration: Clinicaltrials.gov: NCT04408794.

The Modern Clinician as an "Argonaut" Guiding Through the "Symplegades" of Evidence for PFO Closure in Patients With Migraine.

Patent foramen ovale (PFO) has been associated with migraine, especially migraine with aura, and 30-50% of individuals with migraine with aura have a PFO, suggesting it could be more than just an "innocent bystander''. Observational data showed a reduction of the frequency and severity of migraine attacks, particularly those with aura, following transcatheter PFO closure for established indications. Three small randomized controlled trials have demonstrated significant benefits of PFO closure in most of their secondary endpoints, such as reductions in the mean number of monthly migraine attacks and migraine days. Since a significant proportion of patients experience important side effects from traditional migraine medications and newer highly effective migraine prevention strategies may need to be instituted. PFO closure could in this regard to be a valuable add-on in the armamentarium of migraine treatment, improving the quality of life by alleviating the need for medications. The effect of percutaneous PFO closure on migraine treatment is needed to be clarified. As the underlying pathophysiology remains poorly understood and largely hypothetical, future investigations, focusing on the causal relationship between PFO and migraine, will help to define the subgroup of patients most likely to benefit from PFO closure. More accurate patient recruitment may lead to greater postprocedural benefits and more significant symptom improvement. Additionally, randomized controlled trials need to be reported adequately with more realistic endpoints, sufficient duration of follow-up, and statistical power to detect differences between closure and placebo groups to ensure precise and reliable findings.

Patent foramen ovale closure reduces migraine burden: a meta-analysis

Abstract Background Patent foramen ovale (PFO) closure has been shown to reduce the risk of recurrent stroke in selected patients. On the other hand, the efficacy of PFO closure in reducing migraine attacks remains a matter of debate. Purpose We performed a systematic review and meta-analysis of randomized controlled trials that compared PFO closure plus medical therapy to medical therapy alone for the management of migraine. Methods A comprehensive search was conducted in PubMed through December 10, 2022. The main efficacy endpoints were the complete cessation of migraine, the mean reduction in monthly migraine days and the mean reduction in monthly migraine attacks. The main safety outcome was the occurrence of major procedure related adverse events. Results Our search retrieved 667 results. Three randomized controlled trials including 448 patients were included in the final analysis. Of these, 231 patients (mean age 43.4±10.5 years) underwent PFO closure, while 217 (43.7±10.6) were treated conservatively with medical therapy. In the medical treatment group, 190 patients underwent a sham procedure. The follow-up period ranged from 6 to 12 months. Overall, no significant association between PFO closure and complete migraine cessation was observed [Hazard Ration 3.31, 95% confidence intervals (CI): 0.72 – 15.17 – Figure 1). On the other hand, PFO closure was associated with a significant reduction in the mean number of migraine days per month [mean difference (MD): 1.23, 95% CI: 0.44-2.10, p=0.024, Figure 2A] as well as with a significant decrease in monthly migraine attacks (MD: 0.58, 95%CI : 0.25-0.91, p=0.017, Figure 2B). In respect of efficacy endpoint, a total of 9 transient, procedure related adverse events, including access-site bleeding, hematoma and tachycardia were reported in the implantation group. Conclusions PFO closure plus medical treatment compared to medical treatment alone was related with fewer and shorter migraine attacks. These results suggest clinical benefit of PFO closure in selected patients with migraine.Figure 1.Figure 2.

A Phase 2/3 Open-label, Long-term, Safety Trial of Zavegepant 10 mg Nasal Spray for the Acute Treatment of Migraine (P9-12.002)

A Phase 2/3 Open-label, Long-term, Safety Trial of Zavegepant 10 mg Nasal Spray for the Acute Treatment of Migraine (P9-12.002)

Medication Preference, Satisfaction, and Clinical Improvement Among Adults Receiving Long-Term Treatment With Rimegepant for Migraine (P10-12.011)

Medication Preference, Satisfaction, and Clinical Improvement Among Adults Receiving Long-Term Treatment With Rimegepant for Migraine (P10-12.011)

Patterns of Medication Utilization and Migraine Frequency in Adults Using Rimegepant for Both Preventive and Acute Treatment for Migraine: Results From a 52-Week, Open-Label Extension Study (P9-12.006)

Patterns of Medication Utilization and Migraine Frequency in Adults Using Rimegepant for Both Preventive and Acute Treatment for Migraine: Results From a 52-Week, Open-Label Extension Study (P9-12.006)

Long-Term Preventive and Acute Treatment of Migraine With Rimegepant Improves Health Related Quality of Life (P12-12.003)

Long-Term Preventive and Acute Treatment of Migraine With Rimegepant Improves Health Related Quality of Life (P12-12.003)

Efficacy and Safety of Zavegepant Nasal Spray for the Acute Treatment of Migraine: Results of a Phase 3 Double-Blind, Randomized, Placebo Controlled Trial (PL5.002)

Efficacy and Safety of Zavegepant Nasal Spray for the Acute Treatment of Migraine: Results of a Phase 3 Double-Blind, Randomized, Placebo Controlled Trial (PL5.002)

Long-Term Safety and Tolerability of Zavegepant 10 mg Nasal Spray During Concomitant Use of CGRP Monoclonal Antibodies: Results From a 1-Year Open-label Safety Trial (P10-12.009)

Long-Term Safety and Tolerability of Zavegepant 10 mg Nasal Spray During Concomitant Use of CGRP Monoclonal Antibodies: Results From a 1-Year Open-label Safety Trial (P10-12.009)

Effects of Rimegepant 75 mg on Monthly Migraine Days: a 52-Week, Open-Label Extension Study (P10-12.010)

Effects of Rimegepant 75 mg on Monthly Migraine Days: a 52-Week, Open-Label Extension Study (P10-12.010)

Safety and Tolerability of Rimegepant Every Other Day for Preventive Treatment of Migraine Plus As-Needed for Acute Treatment of Migraine: Results from A 52-Week, Open-Label Extension Phase (P12-12.006)

Safety and Tolerability of Rimegepant Every Other Day for Preventive Treatment of Migraine Plus As-Needed for Acute Treatment of Migraine: Results from A 52-Week, Open-Label Extension Phase (P12-12.006)

Risk factors of white matter hyperintensities in migraine patients

BackgroundMigraine frequently is associated with White Matter Hyperintensities (WMHs). We aimed to assess the frequency of WMHs in migraine and to assess their risk factors.MethodsThis is cross-sectional study included 60 migraine patients of both genders, aged between 18 and 55 years. Patients with vascular risk factors were excluded. We also included a matched healthy control group with no migraine. Demographic, clinical data, and serum level of homocysteine were recorded. All subjects underwent brain MRI (3 Tesla).ResultsThe mean age was 38.65 years and most of our cohort were female (83.3). A total of 24 migraine patients (40%) had WMHs versus (10%) in the control group, (P < 0.013). Patients with WMHs were significantly older (43.50 + 8.71 versus. 35.92+ 8.55 years, P < 0.001), have a longer disease duration (14.54+ 7.76versus 8.58+ 6.89 years, P < 0.002), higher monthly migraine attacks (9.27+ 4. 31 versus 7.78 + 2.41 P < 0.020) and high serum homocysteine level (11.05+ 5.63 versus 6.36 + 6.27, P < 0.006) compared to those without WMHs. WMHs were more frequent in chronic migraine compared to episodic migraine (75% versus 34.6%; P < 0.030) and migraine with aura compared to those without aura (38.3% versus 29,2; P < 0.001). WMHs were mostly situated in the frontal lobes (83.4%), both hemispheres (70.8%), and mainly subcortically (83.3%).ConclusionOlder age, longer disease duration, frequent attacks, and high serum homocysteine level are main the risk factors for WMHs in this cohort. The severity or duration of migraine attacks did not increase the frequency of WMHs. The number of WMHs was significantly higher in chronic compared to episodic migraineurs.

Patent Foramen Ovale Closure for Treating Migraine: A Meta-Analysis.

Background Observational studies have shown percutaneous patent foramen ovale (PFO) closure to be a safe means of reducing the frequency and duration of migraine. Objective This study evaluated the efficacy and safety of PFO closure in patients with migraine using evidence-based medicine. Methods The Pubmed (MEDLINE), Embase, and Cochrane Library databases were searched for randomized controlled trials (RCTs), cohort studies, and retrospective case series from January 1, 2001, to February 30, 2021. The Jadad scale and R 4.1.0 software were used to assess the quality of the literature and meta-analysis, respectively. Results In total, three randomized controlled trials, one pooled study, and eight retrospective case series including 1,165 participants were included in the meta-analysis. Compared with control intervention in migraine, PFO closure could significantly reduce headache frequency (OR = 1.5698, 95% CI: 1.0465–2.3548, p=0.0293) and monthly migraine attacks and monthly migraine days (OR = 0.2594, 95% CI: 0.0790–0.4398, p=0.0048). Subgroup analysis of patients who all completed PFO surgery showed resolution of migraine headache for migraines with aura (OR = 1.5856, 95% CI: 1.0665–2.3575, p=0.0227). Conclusions Treatment with PFO closure could reduce the frequency of headaches and monthly migraine days and is an efficient treatment for migraine attacks with aura.

Pooled Analysis of PFO Occluder Device Trials in Patients With PFO and Migraine

BackgroundAlthough observational studies have shown percutaneous patent foramen ovale (PFO) closure to be a safe means of reducing the frequency and duration of migraine, randomized clinical trials have not met their primary efficacy endpoints. ObjectivesThe authors report the results of a pooled analysis of individual participant data from the 2 randomized trials using the Amplatzer PFO Occluder to assess the efficacy and safety of percutaneous device closure as a therapy for episodic migraine with or without aura. MethodsThe authors analyzed individual patient-level data from 2 randomized migraine trials (the PRIMA [Percutaneous Closure of Patent Foramen Ovale in Migraine With Aura] and PREMIUM [Prospective Randomized Investigation to Evaluate Incidence of Headache Reduction in Subjects with Migraine and PFO Using the Amplatzer PFO Occluder Compared to Medical Management] studies). Efficacy endpoints were mean reduction in monthly migraine days, responder rate (defined as ≥50% reduction in monthly migraine attacks), mean reduction in monthly migraine attacks, and percentage of patients who experienced complete cessation of migraine. The safety endpoint was major procedure- and device-related adverse events. ResultsAmong 337 subjects, 176 were randomized by blocks to device closure and 161 to medical treatment only. At 12-month follow-up, the analysis met 3 of the 4 efficacy endpoints: mean reduction of monthly migraine days (−3.1 days vs. −1.9 days; p = 0.02), mean reduction of monthly migraine attacks (−2.0 vs. −1.4; p = 0.01), and number of subjects who experienced complete cessation of migraine (14 [9%] vs. 1 [0.7%]; p < 0.001). For the safety analysis, 9 procedure-related and 4 device-related adverse events occurred in 245 subjects who eventually received devices. All events were transient and resolved. ConclusionsThis pooled analysis of patient-level data demonstrates that PFO closure was safe and significantly reduced the mean number of monthly migraine days and monthly migraine attacks, and resulted in a greater number of subjects who experienced complete migraine cessation.

A Head-to-Head Comparison of Percutaneous Mastoid Electrical Stimulator and Supraorbital Transcutaneous Stimulator in the Prevention of Migraine: A Prospective, Randomized Controlled Study

This prospective, randomized, multicenter head-to-head outcome study was performed to compare the efficacy and safety of Percutaneous Mastoid Electrical Stimulator (PMES) and Supraorbital Transcutaneous Stimulator (STS) in migraine prevention. This was a prospective, randomized, head-to-head outcome study that involved three medical centers. After a one-month run-in, episodic patients with at least two migraine attacks/month were randomized to receive PMES daily for 45 min or STS daily for 20 min for three months. The primary outcomes were change in monthly migraine days and the 50% response rate. A total of 90 patients were included in this study. We observed statistically significant reduction of migraine days in the third month treatment both in the PMES group and STS group. The difference between the two groups was not significant (60.5% vs. 53.8%, p = 0.88). Of note, 77.8% patients in the PMES group and 62.2% patients in the STS group had a ≥50% reduction of migraine days in the third month (p = 0.070). The change in monthly migraine days, monthly migraine attacks, severity of migraine days, accompanying symptoms during migraine and monthly acute anti-migraine drug intake were not significantly different between the two groups. The change of Headache Impact Test-6 (HIT-6) from run-in to the third-month treatment in the STS group was more remarkable than that in the PMES group (36.5% vs. 25.6%, p = 0.041). The occurrence of discomfort paresthesia was higher in the STS group (13.3% vs. 0%, p = 0.026). PMES and STS treatment were both effective in migraine prevention. The safety and efficacy of PMES and STS were comparable.

Migraine Frequency Decrease Following Prolonged Medical Cannabis Treatment: A Cross-Sectional Study.

Background: Medical cannabis (MC) treatment for migraine is practically emerging, although sufficient clinical data are not available for this indication. This cross-sectional questionnaire-based study aimed to investigate the associations between phytocannabinoid treatment and migraine frequency. Methods: Participants were migraine patients licensed for MC treatment. Data included self-reported questionnaires and MC treatment features. Patients were retrospectively classified as responders vs. non-responders (≥50% vs. <50% decrease in monthly migraine attacks frequency following MC treatment initiation, respectively). Comparative statistics evaluated differences between these two subgroups. Results: A total of 145 patients (97 females, 67%) with a median MC treatment duration of three years were analyzed. Compared to non-responders, responders (n = 89, 61%) reported lower current migraine disability and lower negative impact, and lower rates of opioid and triptan consumption. Subgroup analysis demonstrated that responders consumed higher doses of the phytocannabinoid ms_373_15c and lower doses of the phytocannabinoid ms_331_18d (3.40 95% CI (1.10 to 12.00); p < 0.01 and 0.22 95% CI (0.05–0.72); p < 0.05, respectively). Conclusions: These findings indicate that MC results in long-term reduction of migraine frequency in >60% of treated patients and is associated with less disability and lower antimigraine medication intake. They also point to the MC composition, which may be potentially efficacious in migraine patients.

Trajectory of migraine-related disability following long-term treatment with lasmiditan: results of the GLADIATOR study

BackgroundMigraine is recognized as the second leading cause of disability globally. Lasmiditan is a novel, selective serotonin 5-HT1F receptor agonist developed for acute treatment of migraine. Here we analyzed effects of lasmiditan on migraine disability assessed with the Migraine Disability Assessment (MIDAS) scale for interim data from a long-term safety study.MethodsCompleters of two single-attack parent studies were offered participation in the 1 year GLADIATOR study, that randomized participants to treatment with lasmiditan 100 mg or 200 mg taken as needed for migraine attacks of at least moderate severity. Changes in MIDAS were modeled using a mixed model repeated measures analysis.ResultsThe sample included 1978 patients who received ≥1 lasmiditan dose and were followed for a median of 288 days. Baseline mean MIDAS scores for the lasmiditan 100-mg and 200-mg groups were 29.4 and 28.9, respectively, indicating severe migraine-related disability. Relative to baseline, MIDAS total scores were significantly lower at 3, 6, 9, and 12 months for both dose groups. At 12 months, changes in MIDAS scores were − 12.5 and − 12.2 for lasmiditan 100 mg and 200 mg, respectively, with 49% and 53% of patients, respectively, achieving at least a 50% decrease in MIDAS total score. Statistically significant improvements were also seen for work and/or school absenteeism and presenteeism, monthly headache days, and mean headache pain intensity at all time points up to 1 year. Findings for patients who completed all visits versus those dropping out early were similar. Responses were generally similar for the lasmiditan 100 mg or 200 mg doses, between subgroups defined based on the number of baseline monthly migraine attacks (≤5 vs. >5), and also between subgroups defined by pain-free response (yes/no) during initial attacks.ConclusionsLong-term treatment with lasmiditan was associated with significant reductions in migraine-related disability, including both work or school absenteeism and presenteeism. The similarity of responses in completers and those who dropped out suggests that selective attrition does not account for the improvements. Benefits were significant at 3 months and maintained through 12 months.Trial registrationclinicaltrials.govNCT02565186; first posted October 1, 2015.

Meta-analysis of randomized trials on percutaneous patent foramen ovale closure for prevention of migraine

Background: The role of percutaneous patent foramen ovale (PFO) closure for prevention of migraine is controversial.Methods: We performed a computerised search of MEDLINE, EMBASE and COCHRANE databases through December 2017 for randomised trials evaluating PFO closure versus control in patients with migraine headaches (with or without aura). The main study outcome was the reduction in monthly migraine attacks after PFO closure compared with the control group.Results: The final analysis included three randomised trials with a total of 484 patients. Reduction in monthly migraine attacks was higher in PFO closure compared with the control group (standardised mean difference-SMD = 0.25; 95% CI: 0.06–0.43; p = .01). There was higher reduction of monthly migraine days in PFO closure group compared with control group (SMD = 0.30; 95% CI: 0.08–0.53; p = .01). There was no statistically significant difference in complete resolution of migraine attacks (OR: 3.67; 95% CI: 0.66–20.41; p = .14) and in responders’ rate (OR: 1.92; 95% CI: 0.76–4.85; p = .17) between PFO closure and control groups. In patients whose majority of migraine attacks are with aura, there was an observed reduction in migraine attacks in PFO closure compared with control groups (SMD = 0.86; 95% CI: 0.07–1.65; p = .03).Conclusion: PFO closure might be beneficial in migraine patients by reducing migraine attacks and migraine days, especially in patients whose majority of migraine attacks are with aura. However, those benefits were not associated with an improvement in responders’ rate or complete resolution of migraine; raising concerns on the magnitude of clinical benefit of PFO closure in migraine prevention.

Effect of percutaneous electrical nerve stimulation for the treatment of migraine.

Background:This study aimed to assess the effectiveness and safety of percutaneous electrical nerve stimulation (PENS) in migraine treatment.Methods:Sixty-two patients with at least 2 migration attacks each month were recruited and randomly divided into a verum PENS group and a sham PENS group in a ratio of 1:1. All patients received verum or sham PENS 30 minutes daily, 5 times weekly for 12 weeks. The primary outcomes were change in monthly migraine days (MMD) and the 50% responder rate (RR). Secondary outcomes were evaluated using the monthly migraine attacks (MMA), monthly headache days (MHD), and monthly acute antimigraine drug intake (MAADI). All outcome measurements were performed at treatment initiation to establish a baseline and again after 12 weeks of treatment.Results:At the end of the 12 weeks, the group receiving verum PENS exhibited statistically significant decrease in the mean MMD compared with the group receiving sham PENS intervention (P < .05). Additionally, the 50% RR was significantly higher in the verum PENS group than that in the sham PENS group (P < .05). Furthermore, the MMA, MHD, and MAADI were also significantly lower in the verum PENS group that those in the sham PENS group (P < .05).Conclusion:The results of this study demonstrated that verum PENS is more effective and safe than Sham PENS for the treatment of migraine.

Functional Changes of the Perigenual Part of the Anterior Cingulate Cortex after External Trigeminal Neurostimulation in Migraine Patients.

To explore the functional reorganization of the pain processing network during trigeminal heat stimulation (THS) after 60 days of external trigeminal neurostimulation (eTNS) in migraine without aura (MwoA) patients between attacks. Using whole-brain BOLD-fMRI, functional response to THS at two different intensities (41 and 51°C) was investigated interictally in 16 adults MwoA patients before and after eTNS with the Cefaly® device. We calculated the percentage of patients having at least a 50% reduction of monthly migraine attacks and migraine days between baseline and the last month of eTNS. Secondary analyses evaluated associations between BOLD signal changes and clinical features of migraine. Before eTNS treatment, there was no difference in BOLD response between MwoA patients and healthy controls (HC) during low-innocuous THS at 41°C, whereas the perigenual part of the right anterior cingulate cortex (ACC) revealed a greater BOLD response to noxious THS at 51°C in MwoA patients when compared to HC. The same area demonstrated a significant reduced BOLD response induced by the noxious THS in MwoA patients after eTNS (p = 0.008). Correlation analyses showed a significant positive correlation between ACC BOLD response to noxious THS before eTNS treatment and the decrease of ACC BOLD response to noxious THS after eTNS. Moreover, a significant negative correlation in the migraine group after eTNS treatment between ACC functional activity changes and both the perceived pain ratings during noxious THS and pre-treatment migraine attack frequency has been found. Our findings suggest that eTNS treatment with the Cefaly® device induces a functional antinociceptive modulation in the ACC that is involved in the mechanisms underlying its preventive anti-migraine efficacy. Nevertheless, further observations to confirm whether the observed fMRI effects of eTNS are both related to clinical improvement and specific to antinociceptive modulation in migraine patients are mandatory.