Cephalalgia[JOURNAL]
Sun
200 papers
Neck pain in migraine: A narrative review and steps to correct evaluation and treatment.
Rees TA, Doukhi D, Wang VS … +10 more , Balcerbula A, Bravo M, Fathi H, Holmuratova B, Kodounis M, Seyoum SA, Tasdelen S, Vekilyan H, Caronna E, Pozo-Rosich P
Cephalalgia · 2025 Oct · PMID 41134815 · Publisher ↗
BackgroundNeck pain is common in migraine patients, occurring during all migraine phases and between attacks. It can be a migraine symptom, trigger or a coexisting condition, and is associated with greater disability and...
BackgroundNeck pain is common in migraine patients, occurring during all migraine phases and between attacks. It can be a migraine symptom, trigger or a coexisting condition, and is associated with greater disability and poorer treatment response. There is evidence that neck pain associated with headaches can be frequently incorrectly diagnosed as a cervical disorder rather than migraine, resulting in a lack of appropriate treatment. Accurately assessing the connection between neck pain and migraine is crucial for effective treatment.MethodsThis narrative review aims to summarise existing research on the role and contribution of neck pain in migraine, both as a symptom and a trigger, and outlines future research needed to deepen our understanding of this relationship. It also proposes a structured approach for assessing neck pain in migraine and a treatment algorithm, offering guidance for clinical evaluation and treatment. For this purpose, a comprehensive narrative review was conducted using PubMed, covering preclinical, clinical, neurophysiological and imaging evidence on migraine and neck pain.ResultsMigraine patients frequently exhibit cervical dysfunction, tenderness and altered posture, with overlapping neuroanatomical pathways of the neck and trigeminal systems, suggesting shared mechanisms of nociception and migraine initiation. Clinical assessment involves a thorough history, physical exam and exclusion of secondary causes. Standard migraine therapies, such as amitriptyline and onabotulinumtoxinA, may help reduce neck pain and non-pharmacological treatments, such as physical therapy, acupuncture and behavioural strategies, show some promise. However, evidence on neck pain relief is limited.ConclusionsAccurately distinguishing whether neck pain is a symptom, trigger or comorbid condition in migraine is essential for guiding effective treatment strategies. Both pharmacological and non-pharmacological approaches may help manage migraine-associated neck pain. However, few studies have assessed the effects of acute or preventive migraine therapies, particularly calcitonin gene-related peptide-targeted treatments, on neck pain, highlighting a significant gap in our current knowledge. Future research should evaluate the effectiveness of these therapies on neck pain, both alone and in combination with non-pharmacological interventions.
Efficacy of different cannabinoid compounds on migraine-like responses in female rats.
da Luz FMR, Kaup AO, Baggio DF … +2 more , Costa FHR, Chichorro JG
Cephalalgia · 2025 Oct · PMID 41129688 · Publisher ↗
AIM: To investigate the effect of different cannabinoid compounds on the periorbital mechanical allodynia and photosensitivity in acute and chronic migraine models. METHODS: Female Wistar rats were treated systemically w...
AIM: To investigate the effect of different cannabinoid compounds on the periorbital mechanical allodynia and photosensitivity in acute and chronic migraine models. METHODS: Female Wistar rats were treated systemically with different cannabinoid compounds (cannabidiol, CBD, 30 mg/kg; CBD and cannabigerol, CBD/CBG - 2:1; CBD and 0.3% tetrahydrocannabinol (CBD/THC); or CBD/CBG/THC) followed by injection of calcitonin-gene-related peptide (CGRP) or pituitary adenylate cyclase-activating polypeptide (PACAP) into the trigeminal ganglion to induced immediate periorbital mechanical allodynia and late photosensitivity. The effect of CBD and CBD/THC was also assessed on periorbital mechanical allodynia and photosensitivity in the chronic migraine model induced by repeated nitroglycerin (NTG) injections. RESULTS: Periorbital mechanical allodynia induced by CGRP was significantly reduced by CBD alone and combined with THC or CBG. CBD/THC was the most effective treatment in this condition since it presented the longer effect (up to three hours) and was the only treatment capable of reducing late photosensitivity associated with CGRP. All four compounds presented antinociceptive effect on acute migraine-like responses induced by PACAP, with CBD alone presenting the longer effect (from 30 minutes up to two hours). Except for CBD/CBG, all compounds also reduced (up to two hours) late photosensitivity associated with PACAP. In the chronic migraine model induced by NTG, CBD reduced periorbital mechanical allodynia on days 5, 7 and 11, while CBD/THC suppressed the development of periorbital allodynia up to day 13 and significantly reduced photosensitivity up to three hours. CONCLUSION: Altogether, these results suggest that cannabinoid compounds may represent effective alternatives for the treatment of episodic and chronic migraine.
Introducing a risk score for predicting ischemic stroke in migraine with or without visual aura.
McCain CR, Parrish MH, Melikov P … +6 more , Rosamond WD, Sengupta S, Spinale F, Trivedi T, Wood S, Sen S
Cephalalgia · 2025 Oct · PMID 41117320 · Publisher ↗
AimMigraine with aura is a risk factor for ischemic stroke. To further assess this risk factor in relation to ischemic stroke, along with other risk factors, we created the migraine associated risk of stroke score (MARS+...
AimMigraine with aura is a risk factor for ischemic stroke. To further assess this risk factor in relation to ischemic stroke, along with other risk factors, we created the migraine associated risk of stroke score (MARS+), making it applicable to migraineurs. The risk score includes vascular risk factors, migraine characteristics and medications used in migraine patients.MethodsWe prospectively evaluated participants in Atherosclerosis Risk in Communities Cohort (ARIC) with a history of migraine. In this population, we tested the association of potential risk factors for ischemic stroke using a Cox proportional hazards model. The coefficient of each variable was divided by the lowest β value and rounded to the nearest integer. The sum of the weighted score of the reported risk factors was found and categorized into two prognostic groups.ResultsWe assessed migraine characteristics (aura, migraine frequency and duration) and medications that were in current use by participants, mean ± SD age 58 ± 5.5 years, 86% white, 14% black and 77% women (ergot alkaloids, triptans, hormone replacement therapy, sympathomimetics, steroids, selective serotonin reuptake inhibitors and opioids), in addition to traditional risk factors. Based on the points derived from the significant factors we assigned age ≥65 years = 1, non-white race = 2, hypertension = 2, diabetes = 3, body mass index ≥30 = 2, atrial fibrillation = 2, use of steroid medications = 3, use of selective serotonin reuptake inhibitor medications = 1, opioids = 2, presence of aura = 2 and duration <5 years = 1 to total 21 points. A cut-off of MARS+ ≥5 was considered as a lifetime high risk for ischemic stroke based on receiver operating characteristic curve and Youden's index. Of the 1485 participants with migraine, 112 had an ischemic stroke. MARS+ ≥5 revealed a hazard ratio of 4.09 (95% confidence interval = 2.67-6.26).ConclusionsThe MARS+ score is used to predict ischemic stroke in middle-aged migraine sufferers. This risk score, in addition to generalizability, includes factors such as migraine characteristics and medications that may increase stroke risk.
International Headache society evidence-based guidelines on the use of non-invasive neuromodulation devices for the acute and preventive treatment of migraine.
Yuan H, Orr SL, Al-Karagholi MAM … +18 more , Ashina M, Cohen F, Diener HC, Dodick DW, Jensen RH, Marmura MJ, Martinelli D, Matharu MS, Petersen AS, Pozo-Rosich P, Sacco S, Simmonds L, Tassorelli C, Tepper SJ, Terwindt GM, Wang SJ, Yeh JT, Silberstein SD
Cephalalgia · 2025 Oct · PMID 41117312 · Publisher ↗
ObjectiveTo develop evidence-based clinical practice guidelines for non-invasive neuromodulation devices in acute and preventive migraine treatment.MethodsA systematic review was conducted across six databases from 1946...
ObjectiveTo develop evidence-based clinical practice guidelines for non-invasive neuromodulation devices in acute and preventive migraine treatment.MethodsA systematic review was conducted across six databases from 1946 to April 2025. Randomized controlled trials evaluating Food and Drug Administration-cleared or Conformité Européenne (CE)-marked non-invasive neuromodulation devices were included. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology, and recommendations were developed through consensus following GRADE Evidence-to-Decision frameworks. The working group comprised 15 senior members and six junior members.ResultsFrom 1536 initial records, 15 studies met the inclusion criteria and were finally used to develop evidence-based recommendations. Evidence quality ranged from very low to moderate. Weak recommendations were issued for SAVI Dual, Cefaly, Relivion, and Nerivio in the treatment of acute migraine attacks, and for gammaCore Sapphire, Cefaly, and Nerivio in the preventive migraine treatment. Other cleared devices received no recommendations or have no eligible studies for the GRADE assessment. The primary limitations across studies included imprecision due to small sample sizes and various methodological concerns. Additionally, expert consensus recommendations were developed for devices and clinical scenarios not adequately covered by randomized controlled trials, including potential applications in pediatric populations, vestibular migraine, chronic migraine, menstrual migraine, and medication overuse headache.ConclusionNon-invasive neuromodulation devices offer promising alternatives to drug treatment for migraine management. These devices are safe and generally well tolerated and devoid of drug interactions. While current evidence quality varies, ongoing research and technological advancements show encouraging potential. Future studies should adhere to International Headache Society guidelines for neuromodulation device trials, address proper sham controls and blinding assessment, and account for patient adherence challenges in device use. Expanded insurance coverage would enhance cost-effectiveness and device accessibility. These guidelines provide a framework for clinical decision-making while highlighting areas requiring further research.
What does ChatGPT know about Migraine? A comparative-descriptive analysis.
Garcia LB, Ferreira AJ, Hussein MA … +1 more , Kowacs PA
Cephalalgia · 2025 Oct · PMID 41105723 · Publisher ↗
BackgroundThe integration of artificial intelligence (AI) into medical education and clinical decision-making is rapidly expanding. ChatGPT-4o, a multimodal AI model, offers real-time access to a vast corpus of biomedica...
BackgroundThe integration of artificial intelligence (AI) into medical education and clinical decision-making is rapidly expanding. ChatGPT-4o, a multimodal AI model, offers real-time access to a vast corpus of biomedical knowledge. Nonetheless, concerns persist regarding the scientific accuracy and interpretive reliability of its responses when applied to clinical subjects such as migraine.AimTo assess the reliability and factual accuracy of ChatGPT-4o when addressing key clinical questions regarding migraine.MethodsEight clinically relevant questions were submitted to ChatGPT-4o, covering migraine pathophysiology, diagnosis and treatment. Each response was compared with current evidence from high-impact medical literature and rated as satisfactory, partially satisfactory or unsatisfactory. Classifications were based on conceptual accuracy, reference validity and clinical coherence.ResultsOf the eight responses analyzed, 62.5% were classified as satisfactory, while 37.5% were deemed partially satisfactory. No response was considered entirely unsatisfactory. The most common limitations included reference-related AI hallucinations and insufficient technical depth in selected answers.ConclusionsChatGPT-4o demonstrates potential as a support tool in the dissemination of structured medical information about migraine. However, its clinical use must remain supervised by professionals, given its limitations in bibliographic precision and interpretive nuance.
Cervical musculoskeletal dysfunctions in pediatric migraine: A cross-sectional study.
Silva NVD, Bevilaqua-Grossi D, Pradela J … +2 more , Dach F, Pinheiro-Araujo CF
Cephalalgia · 2025 Oct · PMID 41105568 · Publisher ↗
BackgroundWhile the association between migraine, neck pain, and cervical musculoskeletal dysfunctions is well established in adults, such a relationship remains unclear in the pediatric population. This gap limits our u...
BackgroundWhile the association between migraine, neck pain, and cervical musculoskeletal dysfunctions is well established in adults, such a relationship remains unclear in the pediatric population. This gap limits our understanding of early pathophysiological mechanisms and hinders the development of targeted interventions.ObjectiveTo assess self-reported neck pain, pressure pain threshold (PPT), global cervical range of motion (ROM), and upper cervical mobility in children and adolescents with and without migraine.MethodsA cross-sectional study was conducted with 102 participants in total (51 with migraine - MG - and 51 controls - CG), aged six to 16 years. Neck pain characteristics (presence, frequency, intensity, and duration) were recorded. Cervical ROM was measured in flexion, extension, lateral flexion, and rotation. Upper cervical mobility was evaluated using the Flexion Rotation Test (FRT), and PPT was bilaterally assessed in the sternocleidomastoid, levator scapulae, suboccipital, upper trapezius, and anterior scalene muscles. Comparisons between groups were made using Student's t-test, Mann-Whitney U test, or Chi-square test, with a significance level set at 5%.ResultsCompared to the control group, the MG showed a higher prevalence of neck pain (39.2% vs. 5.9%; p < 0.001) and longer average duration (19 ± 8.6 vs. 8 ± 3.4 h; p = 0.046). Reduced lateral flexion (p < 0.001) and reduced upper cervical mobility (p < 0.001) were observed in the MG. Additionally, all evaluated muscles exhibited significantly lower PPT values in the MG (p < 0.001) than controls, indicating increased pain sensitivity.ConclusionSimilar to adults, children and adolescents with migraine demonstrate cervical musculoskeletal impairments, including neck pain, reduced cervical mobility-especially in lateral flexion and upper cervical rotation-and heightened sensitivity in craniocervical muscles. These findings support the routine inclusion of cervical musculoskeletal assessments in the clinical management of pediatric migraine.
The clinical outcome of patients starting monoclonal antibodies anti-CGRP with concomitant migraine preventive treatments.
Fofi L, Altamura C, Marcosano M … +9 more , Brunelli N, Iannone LF, Doretti A, Viticchi G, De Cesaris F, Alesina A, Silvestrini M, Peresson M, Vernieri F
Cephalalgia · 2025 Oct · PMID 41105547 · Publisher ↗
BackgroundThe management and role of standard preventive treatments (SPTs) in patients co-treated with monoclonal antibodies (mAbs) directed towards calcitonin gene-related peptide (CGRP) has been poorly investigated. Th...
BackgroundThe management and role of standard preventive treatments (SPTs) in patients co-treated with monoclonal antibodies (mAbs) directed towards calcitonin gene-related peptide (CGRP) has been poorly investigated. The present study aimed to prospectively compare the clinical profile of patients co-treated with SPTs and anti-CGRP mAbs with patients with anti-CGRP mAb monotherapy and to assess the possible SPT influence on their outcome. The SPT withdrawal or a new SPT prescription during the 12-month treatment period with anti-CGRP mAbs and their possible relation with comorbidities were also evaluated.MethodsOur Italian multicentric, prospective observational cohort study enrolled patients with migraine receiving the first prescription of subcutaneous anti-CGRP mAbs. Only patients who completed the annual cycle of therapy were included in the analyses. At baseline, the population was divided into two groups: with (SPT+ patients) or without concomitant SPTs (SPT- patients). At baseline (T0), T6 (after six months of therapy) and T12 (at the end of the one-year treatment period), we collected migraine clinical data (monthly migraine days (MMDs) and/or the pain intensity, by a numerical rating scale (NRS)); disability (Migraine Disability Assessment (MIDAS) score); and the type and the presence of SPTs at baseline, the beginning of a new SPT or its withdrawal. The primary endpoint was to compare the clinical outcome (variation of MMDs at T6) of baseline SPT+ patients with that of baseline SPT- patients. Secondary endpoints were: (i) to describe the percentage of concomitant SPTs from T0 to T12 in the SPT+ group; (ii) to investigate the factors (i.e. comorbidities, demographics, migraine burden), if any, influencing the persistence of concomitant SPTs from T0 to T12; (iii) to evaluate whether baseline SPT presence influences pain intensity (NRS) and disability (MIDAS) at T0, T6 and T12.ResultsWe enrolled 599 patients who started a new treatment with anti-CGRP mAbs. The analysis was conducted on 555 patients who started galcanezumab (260; 46.8%), erenumab 140 mg (167; 30.0%) or fremanezumab (128; 23.1%). Patients with baseline concomitant SPTs presented lower T0 MMDs than SPT+ patients (18.6 ± 7.8 vs. 20.3 ± 7.2; = 0.007) and a lower MMD reduction from T0 to T6 (-10.4 ± 7.2 vs -12.4 ± 7.4, = 0.007), reaching similar MMD numbers at T6 ( = 0.984). Baseline SPTs were not associated with MMD 50% response rate at T6 (odds ratio = 0.779, 95% confidence interval = 0.534-1.138; = 0.205). Moreover, the changes in MIDAS score ( = 0.919) and NRS (p = 0.664) from T0 to T6 and T6 to T12 did not differ according to baseline concomitant SPTs. During the 12-month treatment period, anti-CGRP mAbs SPT+ patients progressively decreased from 35.0% at baseline to 28.8% at T6 and to 19.6% at T12. A comorbid condition, although neither MMD 50% response rate nor T12 MMDs, influenced the use of concomitant SPTs at T12 (odds ratio = 3.132, 95% confidence interval = 1.981-4.954; < 0.001). The introduction of a new SPT during 12-month mAb therapy occurred only in seven subjects. Overall, 13% of patients reported at least one adverse event.ConclusionsOur study confirms that concomitant SPTs at baseline do not influence the clinical outcome of CGRP mAbs after six months of treatment. A progressive withdrawal of SPTs during 12-month anti-CGRP therapy was observed, dissimilar among preventive classes, with persistence of SPTs at T12, mainly in patients with comorbid conditions.
Migraine-related disability according to headache frequency subclassifications: A systematic review and meta-analysis.
Matharu MS, Silberstein S, Yuan H … +5 more , Edgar D, Colman R, Schwedt TJ, Lanteri-Minet M, Obermann M
Cephalalgia · 2025 Oct · PMID 41105531 · Publisher ↗
BackgroundThis systematic review and meta-analysis synthesized migraine-related disability outcomes according to headache frequency subclassifications, including low-frequency episodic migraine (LFEM), high-frequency epi...
BackgroundThis systematic review and meta-analysis synthesized migraine-related disability outcomes according to headache frequency subclassifications, including low-frequency episodic migraine (LFEM), high-frequency episodic migraine (HFEM) and chronic migraine (CM).MethodsWe searched the PubMed and Cochrane Library (CENTRAL) up to 16 October 2024 for peer-reviewed non-interventional studies reporting migraine-related disability outcomes in CM and subclassifications of episodic migraine (e.g. LFEM and HFEM). Eligible studies with an HFEM subgroup were grouped by headache frequency measure (monthly migraine days [MMD] or monthly headache days [MHD]), HFEM subgroup, disability parameter and study setting. Random-effects meta-analyses were conducted on groups with three or more studies, with the results presented in forest plots. Risk of bias was assessed using Joanna Briggs Institute tools.ResultsOf the 32 included studies, 27 were grouped, yielding five meta-analysis groups containing three or more studies. All five groups had an HFEM subgroup of 8-14 MHD. Accordingly, we classified LFEM as 0-7 MHD and CM as ≥15 MHD. Ten studies contributed data to the five meta-analysis groups. Estimated pooled values are reported by headache frequency subgroup for each meta-analysis group: LFEM (95% confidence interval [CI]), HFEM (95% CI) and CM (95% CI). For meta-analysis group 1, four population-based studies reported Migraine Disability Assessment (MIDAS) Grade IV proportions, with pooled values of 11.1% (7.1-17.1), 43.9% (31.8-56.9) and 57.5% (42.7-71.1), respectively. For meta-analysis group 2, five population-based studies documented Work Productivity and Activity Impairment (WPAI) outcomes. Pooled mean overall work productivity impairment (OWPI) scores were 36.9% (30.8-43.1), 44.7% (38.4-51.0) and 52.0% (47.7-56.3), respectively. Pooled mean activity impairment (AI) scores were 36.4% (33.7-39.1), 46.4% (42.8-50.0) and 53.5% (52.1-54.8), respectively. For meta-analysis group 3, three clinic-based studies presented MIDAS Grade IV proportions. Pooled values were 15.0% (4.4-40.5), 42.4% (17.1-72.4) and 65.7% (30.3-89.4), respectively. For meta-analysis group 4, three clinic-based studies reported WPAI outcomes. Pooled mean OWPI scores were 28.8% (21.6-35.9), 40.2% (36.2-44.2) and 49.6% (46.3-52.9), respectively. Pooled mean AI scores were 29.4% (21.9-36.9), 43.5% (39.0-48.1) and 51.6% (48.8-54.4), respectively. For meta-analysis group 5, three clinic-based studies detailed MIDAS scores. Pooled mean scores were 10.7 (3.9-17.5), 23.9 (9.4-38.4) and 49.6 (15.8-83.3), respectively.ConclusionsThis study showed a pattern of increasing migraine-related disability with rising headache frequency. Regardless of study setting, our meta-analyses also suggested a severe level of disability in many individuals (42%-44%) with HFEM, highlighting an unmet need for more effective migraine management. Disability burden and headache frequency should both be considered when determining treatment needs and therapy access, particularly for patients with HFEM.Study Registration: INPLASY2024120039.
Abstracts from the 22 International Headache Congress, 11-13 September 2025, São Paulo, Brazil.
Cephalalgia · 2025 Oct · PMID 41102623 · Publisher ↗
Abstract loading — click title to view on PubMed.
Adjunctive occipital nerve block for emergency treatment of acute migraine: A randomized, controlled trial.
Tamayo de Leon CD, Gama-Reyes EG, Paredes Moreno FA … +1 more , Galnares-Olalde JA
Cephalalgia · 2025 Oct · PMID 41100185 · Publisher ↗
AimTo evaluate the efficacy and safety of greater occipital nerve (GON) block combined with triple therapy versus triple therapy alone in the treatment of acute migraine in the emergency department for severe or refracto...
AimTo evaluate the efficacy and safety of greater occipital nerve (GON) block combined with triple therapy versus triple therapy alone in the treatment of acute migraine in the emergency department for severe or refractory cases setting.MethodsWe conducted a prospective, randomized, controlled trial without use of placebo control in adult patients with migraine according to International Classification of Headache Disorders, 3rd editon criteria. Patients were randomly assigned (1:1), without blinding method, to receive either a GON block (methylprednisolone 80 mg + lidocaine 20 mg) plus triple intravenous therapy (ketorolac, paracetamol, metoclopramide) or triple therapy alone. The primary outcome was the proportion of patients achieving ≥50% reduction in headache intensity on a visual analog scale (VAS) two hours post-treatment. Secondary outcomes included changes in monthly migraine days, pain-free days, Headache Impact Test-6 (HIT-6) scores and hospital readmissions at 30-day follow-up.ResultsForty-two patients were enrolled (21 per group). A ≥50% VAS reduction at two hours occurred in 95.2% of patients receiving the GON block versus 47.6% in the control group ( = 0.0003). Median pain reduction was 6.0 vs. 3.0 points, respectively ( < 0.001). At 30 days, the intervention group reported fewer migraine days (median 3.0 vs. 7.0 days; = 0.0355), more pain-free days (14.0 vs. 5.0 days; = 0.0379) and lower HIT-6 scores (59.0 vs. 65.0; = 0.1584). Readmission rates were lower in the intervention group (9.5% vs. 23.8%) but not statistically significant. Adverse events associated with the GON block were mild and transient, including local pain (47.6%) and minor bleeding (14.3%).ConclusionsGON block as an adjunct to triple therapy is effective and well tolerated for the acute treatment of migraine, providing significant short-term relief and improving outcomes at 30-day follow-up. Our failure to blind the outcome assessors limit the validity of our results, which supports the use of GON block as an adjunct to parenteral therapy for patients with migraine in the emergency department.Trial RegistrationThis study was not registered in a public trial registry.
Disrupted functional network topology in tension-type headache: A cross-sectional magnetoencephalography study.
Xiong Z, Qiu D, Liang J … +6 more , Li X, Guo Z, Zhang M, Liu G, Gao T, Wang Y
Cephalalgia · 2025 Oct · PMID 41091912 · Publisher ↗
BackgroundTension-type headache (TTH) is the most common primary headache, yet its neural basis remains unclear. Magnetoencephalography (MEG) combined with graph-theoretical analysis enables precise mapping of functional...
BackgroundTension-type headache (TTH) is the most common primary headache, yet its neural basis remains unclear. Magnetoencephalography (MEG) combined with graph-theoretical analysis enables precise mapping of functional brain networks. This study aimed to identify network-level connectivity alterations in TTH using resting-state MEG and graph-based metrics.MethodsWe analyzed resting-state MEG data from 27 TTH patients during the interictal period and 37 age- and gender-matched healthy controls, all with eyes closed. Functional connectivity (FC) across 1-45 Hz was mapped and analyzed using graph theory. Network topology metrics were computed, and their associations with clinical symptoms were assessed.ResultsTTH patients showed increased FC across 1-45 Hz, notably between the right somatomotor and frontal operculum and insula (FrOperIns), and between the temporo-occipital-parietal (TempOccPar) and visual regions, with the latter positively correlated with Headache Impact Test-6 scores. Frequency-specific increases were observed between the left prefrontal and right orbitofrontal cortices (delta, theta), somatomotor and FrOperIns (theta), and TempOccPar and visual areas (beta). Graph theory analysis revealed nodal abnormalities, particularly in the left precuneus and posterior cingulate and prefrontal cortices, along with elevated local efficiency and clustering coefficient.ConclusionsThese findings indicate that TTH is associated with frequency-specific alterations in functional connectivity and disrupted network topology, particularly involving regions implicated in pain processing and cognitive control. Graph-theoretical MEG analysis may offer valuable insights into the neural mechanisms of TTH and support the development of network-based biomarkers. ClinicalTrials.gov Identifier: NCT05334927.
Efficacy and safety of eptinezumab in a predominantly Asian population with chronic migraine: Results of the randomized, double-blind, placebo-controlled SUNRISE trial.
Yu S, Matsumori Y, Kim BK … +9 more , Gryglas-Dworak A, Giorgadze G, Pozo-Rosich P, Krog Josiassen M, Ranc K, Ettrup A, Mittoux A, Sperling B, Takeshima T
Cephalalgia · 2025 Oct · PMID 41091746 · Publisher ↗
AimWe aimed to evaluate the efficacy and safety of eptinezumab for the preventive treatment of chronic migraine in a predominantly Asian population.MethodsThe multi-regional, randomized, double-blind, placebo-controlled,...
AimWe aimed to evaluate the efficacy and safety of eptinezumab for the preventive treatment of chronic migraine in a predominantly Asian population.MethodsThe multi-regional, randomized, double-blind, placebo-controlled, phase 3 SUNRISE trial randomly assigned adults with chronic migraine to receive eptinezumab 100 mg, 300 mg, or placebo. The primary endpoint was change from baseline in monthly migraine days (MMDs) during Weeks 1-12. Key secondary efficacy endpoints were 50% reduction in MMDs (Weeks 1-12) and 75% reduction in MMDs (Weeks 1-4, Weeks 1-12), and the percentage of participants experiencing migraine on Day 1.ResultsOverall, 978 participants received treatment, including 621 (63.5%) from Asia. Both eptinezumab doses met the primary and all key secondary efficacy endpoints. The mean change from baseline in MMDs (Weeks 1-12) was -7.2 for eptinezumab 100 mg, -7.5 for eptinezumab 300 mg, and -4.8 for placebo. Between-group differences were -2.4 for eptinezumab 100 mg versus placebo ( < 0.0001) and -2.7 for eptinezumab 300 mg versus placebo ( < 0.0001). Both eptinezumab doses also demonstrated an odds ratio of >2 versus placebo for all migraine responder rates ( < 0.0001), and a lower percentage of participants experiencing migraine on Day 1 versus placebo ( ≤ 0.01). Safety outcomes were similar across treatment groups.ConclusionsEptinezumab demonstrated statistically significant greater reductions in MMDs compared with placebo, beginning on Day 1 and sustained through Week 12, with a well-tolerated safety profile consistent with prior clinical trials.Trial registrationClinicalTrials.gov (Identifier: NCT04921384); EudraCT (Identifier: 2020-001657-42).
OnabotulinumtoxinA for the preventive treatment of episodic migraine: Results from the phase 3, multicenter randomized, double-blind, placebo-controlled phase of the PRECLUDE trial.
Pozo-Rosich P, Blumenfeld AM, Lipton RB … +6 more , DeGryse RE, Li B, Adams AM, Nguyen T, James L, Brin MF
Cephalalgia · 2025 Oct · PMID 41091731 · Publisher ↗
BackgroundMigraine is a complex disabling neurological disease characterized by recurrent headache attacks lasting 4-72 h with moderate to severe intensity and other accompanying symptoms. While chronic migraine (CM) and...
BackgroundMigraine is a complex disabling neurological disease characterized by recurrent headache attacks lasting 4-72 h with moderate to severe intensity and other accompanying symptoms. While chronic migraine (CM) and episodic migraine (EM) are primarily differentiated by the frequency of headache and migraine days, underlying clinical and functional differences have been described. OnabotulinumtoxinA (onabotA) has been approved as a preventive treatment for CM with controlled clinical and real-world evidence suggesting potential benefits for treatment of EM. Given the lack of randomized controlled trial data, PRECLUDE, a prospective phase 3 trial was designed to evaluate the efficacy and safety of onabotA for the preventive treatment of EM.MethodsThe PRECLUDE trial was a phase 3 multicenter, randomized, double-blind, placebo-controlled, parallel-group trial with an open-label onabotA 195 U extension phase. In total, 775 patients aged 18-65 years with a history of migraine attacks were randomized (1:1:1) to receive placebo, onabotA 155 U, or onabotA 195 U. Patients recorded daily headache data and medication use via an electronic diary (eDiary) during a four-week screening phase, 24-week double-blind phase, followed by a 24-week open-label extension phase. The primary endpoint was the change in the frequency of monthly migraine days from baseline across months 5 and 6.ResultsAll treatment groups showed a reduction in the frequency of monthly migraine days from baseline; however, neither the onabotA 155 U group nor the 195 U group demonstrated a statistically significant improvement compared to the placebo group ( >0 .05). Similarly, secondary endpoints, including changes in monthly headache days, 50% responder rates and monthly acute medication use days, did not reach statistical significance. Adverse events in this trial were consistent with previous findings for onabotA in CM and were generally mild to moderate in severity.ConclusionsThe PRECLUDE trial demonstrated that onabotA was well tolerated but did not show significant efficacy compared to placebo for the endpoint reducing migraine days from baseline in patients with EM as defined by the trial protocol. While onabotA is effective for CM, these findings highlight the need for further research to better understand the pathophysiological differences between EM and CM and to understand whether there is a potential subset of EM patients which respond to onabotA.
Complementary, but not equivalent: Clarifying the role of RWE and RCT in migraine research.
Peres MFP, Yuan H, Tassorelli C
Cephalalgia · 2025 Oct · PMID 41068620 · Publisher ↗
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The importance of treating migraine attacks early - even in youth: A real-world argument for neuromodulation.
Peres MFP, Yuan H, Tassorelli C
Cephalalgia · 2025 Oct · PMID 41068608 · Publisher ↗
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It's not either-or: Why migraine care needs both real-world evidence studies and randomized controlled trials.
Lax DN, Stark-Inbar A, Ironi A … +1 more , Tomaschek I
Cephalalgia · 2025 Oct · PMID 41068582 · Publisher ↗
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Rimegepant for the acute treatment of migraine: A phase 3, multicenter, open-label, long-term safety and effectiveness study in adults from China.
Zhang M, Guo A, Wu J … +14 more , Wang H, Zhang Y, Dong H, Liu J, Zhang B, Guo H, Yu T, Lu Z, Ma L, Fountaine RJ, Pixton GC, Zhong Q, Han X, Yu S
Cephalalgia · 2025 Oct · PMID 41066271 · Publisher ↗
BackgroundThis study evaluated the long-term safety, tolerability and effectiveness of rimegepant, 75 mg orally disintegrating tablet, for the acute treatment of migraine in Chinese adults.MethodsThis phase 3, multicente...
BackgroundThis study evaluated the long-term safety, tolerability and effectiveness of rimegepant, 75 mg orally disintegrating tablet, for the acute treatment of migraine in Chinese adults.MethodsThis phase 3, multicenter, open-label, single-arm study enrolled Chinese adults with a ≥1 year history of migraine (with or without aura), 6-18 moderate-to-severe migraine attacks/month within three months before a screening visit and at least six migraine days during a 30-day observation phase (OP). After the OP, eligible participants took rimegepant as needed (maximum one tablet per day) at the onset of mild-to-severe migraine attack for a long-term treatment (LTT) of 52 weeks.ResultsOverall, 240 participants were treated and 208 (86.3%) completed the study. During LTT, 203 (84.6%) participants reported ≥1 treatment-emergent adverse event (TEAE) and 46 (19.2%) reported ≥1 TEAE considered to be rimegepant-related. There were no rimegepant-related serious AEs or rimegepant-related TEAEs that led to treatment interruption or discontinuation. Mean reduction from the OP in monthly migraine days was observed as early as the first four weeks (-1.7; 95% confidence interval = -2.2 to -1.2), with an overall mean reduction of -4.4 (95% confidence interval = -4.9 to -3.9) days across LTT.ConclusionsRimegepant had a favorable long-term safety profile, was well tolerated in Chinese participants, and a reduction in the number of monthly migraine days was observed during the LLT. ClinicalTrials.gov identifier: NCT05371652.
Research to improve headache classification: Results, methods, and future challenges.
Olesen J
Cephalalgia · 2025 Oct · PMID 41060967 · Publisher ↗
IntroductionThe international headache classification has been enormously important promoting research and clinical management of patients with headache. It is a living document that develops from edition to edition and...
IntroductionThe international headache classification has been enormously important promoting research and clinical management of patients with headache. It is a living document that develops from edition to edition and changes have been increasingly based on research, so called classification research. The aim of the present review is to present recent results of such research and to characterize the methods available for it.MethodsPublished research was identified by systematic search of PubMed. Lists of references of identified articles and the table of content of the last five years of were screened.ResultsThe major results of identified articles are summarized. Thereafter the different methodologies applied in these studies are described. Finally, some suggestions are made for the future consideration of the fourth classification committee.ConclusionClassification research is emerging as an important avenue of headache research. It has a multitude of different designs available and many of them do not need advanced equipment.
OnabotulinumtoxinA alters pro- and anti-inflammatory dural macrophage response to CSD in female mice.
Schain AJ, Delgado Fajardo D, Strassman AM … +6 more , Kulkarni S, Broide RS, Brideau-Andersen AD, Adams AM, Brin MF, Burstein R
Cephalalgia · 2025 Sep · PMID 41004644 · Publisher ↗
AimCortical spreading depression (CSD), the neural correlate of migraine aura, has been shown to cause activation of dural nociceptive neurons as well as immune cells, among which macrophages (MPs) are the most abundant...
AimCortical spreading depression (CSD), the neural correlate of migraine aura, has been shown to cause activation of dural nociceptive neurons as well as immune cells, among which macrophages (MPs) are the most abundant and reactive. OnabotulinumtoxinA (onbotA) is used to treat chronic migraine but the mechanism of action is not fully understood. Here we investigate the role of meningeal MPs in a model of migraine activation and evaluate whether onabotA has an effect on their response.MethodsWe use our previously developed method to determine meningeal MP activation based on shape changes using time-lapse in vivo multiphoton microscopy.ResultsWe found that a small subset (∼10%) of MPs contracted their processes in response to CSD induction, but only in female mice. A similar subset of MPs contracted with lipopolysaccharide injection, suggesting that this is an M1-like response. Together this may provide insight into the phenotypic differences of migraine across males and females. We also found a small subset of MPs (∼10%) that expanded their processes in response to IL-10 (presumably an M2-like response), but were not affected by CSD. In female mice, pre-treatment with onabotA (i) reduces overall MP number in the dura, (ii) reduces pro-inflammatory M1 MP response and (iii) increases anti-inflammatory M2 response post-CSD compared to pretreatment with saline.ConclusionThis suggests that the mechanism of action of onabotA may not be simply due to its effects on nociceptors, but also due to an additional anti-inflammatory effect on the environment of the dura.
Atogepant for the preventive treatment of episodic migraine in Japanese participants: A phase 2/3, randomized, double-blind, placebo-controlled trial with an active treatment extension (RELEASE).
Matsumori Y, Yamada H, Nagaseki Y … +8 more , Shimizu K, Nagy K, Matsuzawa R, Otani T, He MY, Guo H, Ahmadyar G, Takeshima T
Cephalalgia · 2025 Sep · PMID 41002192 · Publisher ↗
BackgroundAtogepant is an oral calcitonin gene-related peptide receptor antagonist approved in the US and EU for the preventive treatment of migraine in adults. We evaluated the efficacy, safety, and tolerability of atog...
BackgroundAtogepant is an oral calcitonin gene-related peptide receptor antagonist approved in the US and EU for the preventive treatment of migraine in adults. We evaluated the efficacy, safety, and tolerability of atogepant for the preventive treatment of episodic migraine (EM) in Japanese participants.MethodsRELEASE was a phase 2/3, multicenter, randomized, double-blind, placebo-controlled study enrolling adult participants with a ≥1-year history of migraine, <50 years of age at time of migraine onset, history of 4-14 monthly migraine days (MMDs), and <15 monthly headache days in the three months prior to screening and during the screening/baseline period. The study included a four-week screening/baseline period, 12-week double-blind treatment period (DBTP), 12-week active treatment extension period, and 30-day safety follow-up. Participants were randomized 1:1:1:1 to placebo, atogepant 10 mg once daily (QD), 30 mg QD, or 60 mg QD for the 12-week DBTP. Completers of the DBTP could continue to the 12-week active treatment extension period where the placebo group was rerandomized 1:1:1 to atogepant 10 mg, 30 mg, or 60 mg; atogepant groups continued the same dose. The primary endpoint was the change from baseline in mean MMDs across the 12-week DBTP.ResultsOf 807 participants screened, 523 were treated in the 12-week DBTP (Safety Population 1 [placebo, N = 134; atogepant 10 mg, N = 126; 30 mg, N = 131; 60 mg, N = 132]; modified intent-to-treat population [placebo, N = 133; atogepant 10 mg, N = 127; 30 mg, N = 130; 60 mg, N = 131]). The least square mean difference (95% confidence interval) from placebo in mean MMDs across 12 weeks was -1.57 (-2.24, -0.89) for atogepant 10 mg, -1.90 (-2.57, -1.22) for 30 mg, and -2.10 (-2.78, -1.43) for 60 mg (all < 0.0001). Treatment-emergent adverse events (TEAEs) in the DBTP occurred in 46.3%, 45.2%, 38.9%, and 43.2% of participants receiving placebo, atogepant 10 mg, 30 mg and 60 mg, respectively. During the DBTP, TEAEs occurring ≥5% were constipation and nasopharyngitis, and there was one serious TEAE in the atogepant 10 mg group considered not related to treatment. TEAEs resulting in treatment discontinuation were infrequent in all treatment groups in the DBTP. Safety was consistent in the 12-week active treatment extension period.ConclusionsAtogepant treatment demonstrated statistically significant and clinically meaningful reductions in mean MMDs compared with placebo across the 12-week DBTP in Japanese participants with EM. The safety profile of atogepant in Japanese participants was consistent with the known safety profile in the global population. No new safety signals were identified.Trial registrationClinicalTrials.gov NCT05861427; https://clinicaltrials.gov/study/NCT05861427.
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