IntroductionTypical migraine aura is characterized by transient focal neurologic symptoms, visual, sensory, dysphasic or other higher cortical dysfunctions. Their manifestations are multi-faceted, with inter and intra-va...IntroductionTypical migraine aura is characterized by transient focal neurologic symptoms, visual, sensory, dysphasic or other higher cortical dysfunctions. Their manifestations are multi-faceted, with inter and intra-variability.ObjectiveTo provide a narrative review describing contributions that assist in achieving a precise phenotypic classification of migraine aura.MethodsWe conducted a comprehensive review of the literature to identify and analyze the full spectrum of migraine aura variables. Based on the findings, we proposed a prospective diary model for systematically recording these elements in clinical or research settings.ResultsVisual symptoms are the most multifaceted with many peculiarities such as quality (26 elementary visual symptoms have been described), colour, intermittence, localization and laterality in visual field and direction of spreading. Sensory and dysphasic symptoms have lower level of complexity. The combinations of symptoms, such as their time relationships or duration, are also extremely variable. Furthermore, headache can have five different patterns of presentation with respect to aura onset/end. Higher cortical dysfunctions need to be further investigated in wider populations. After collecting the full spectrum of migraine aura features, we created a diary which we propose can prospectively record those variables.ConclusionThe findings of this review show that migraine auras present a wide and multi-faceted spectrum of symptoms, generating hundreds of possible scenarios. Therefore, a detailed aura diary to complete during attacks will be of utmost importance to move toward a precise phenotypic classification.
AimTo evaluate the effectiveness and tolerability of non-invasive vagus nerve stimulation (nVNS) as acute or preventive treatment, or both, in a cohort of trigeminal autonomic cephalalgia (TAC) patients.MethodsA service...AimTo evaluate the effectiveness and tolerability of non-invasive vagus nerve stimulation (nVNS) as acute or preventive treatment, or both, in a cohort of trigeminal autonomic cephalalgia (TAC) patients.MethodsA service evaluation retrospectively included patients with TACs between January 2014 and February 2025 who had used, or currently use, nVNS. Data were collected from clinical letters. Data are presented as descriptive statistics analysis and non-parametric tests were performed.ResultsIn total, 108 patients were included, 74 patients with cluster headache (CH), 10 with paroxysmal hemicrania, 15 with hemicrania continua, four with short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), three with short-lasting unilateral neuralgiform with cranial autonomic symptoms (SUNA) and two with an undifferentiated TAC. Overall, 70 patients considered nVNS useful over a median time using nVNS of 47 (interquartile range = 18-66) months. The median time of use in patients who did not find nVNS useful was 7 (interquartile range = 4-12) months. Twenty-three patients reported an adverse event (AE), while no serious treatment-related AEs occurred. Fifty-nine patients withdrew from using the device, including 11 patients that initially reported nVNS as useful. All groups considered nVNS more useful as preventive, while cluster headache and SUNCT/SUNA patients also considered it useful as acute treatment.ConclusionsOur findings complement previous evidence of the effectiveness and tolerability of nVNS in CH in addition to other forms of TACs. Interestingly, nVNS seems to be more effective as preventive rather than as acute treatment in our cohort.
Lund N, Søborg MK, Carlsen LN
… +2 more, Jensen RH, Petersen AS
Cephalalgia
· 2025 Aug · PMID 40879338
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BackgroundIt is not well established to what extent medication-overuse occurs in cluster headache (CH), if medication-overuse headache exists in CH and whether the existing criteria for medication-overuse headache are a...BackgroundIt is not well established to what extent medication-overuse occurs in cluster headache (CH), if medication-overuse headache exists in CH and whether the existing criteria for medication-overuse headache are a suitable diagnostic tool in CH. We aimed to examine the prevalence of medication-overuse and probable medication-overuse headache in a well characterized cohort of people with CH and describe associated factors and clinical impact.MethodsParticipants diagnosed with CH according to International Classification of Headache Disorders, 3rd edition (ICHD-3) beta and ICHD-3 were invited to participate in a semi-structured interview investigating medication-overuse and probable medication-overuse headache according to ICHD-3. To add nuance to the debate, we also included a more conservative definition, applying the ICHD-3 criteria for the medication-overuse but specified the headache phenotype to a daily bilateral headache.ResultsIn total, 21% of 433 participants with CH had a medication-overuse according to ICHD-3. Of these, 16% fulfilled the criteria for probable medication-overuse headache according to the ICHD-3, and 12% if excluding isolated triptan overuse. The overused analgesics constituted simple analgesics (52.2%), triptans (37.3%), opioids (29.9%) and combination therapies (20.9%). Associated factors were having chronic CH (odds ratio = 11.4, < 0.00001) and comorbid migraine (odds ratio = 2.35, < 0.05). Participants with probable medication-overuse headache had longer attack duration (30.0 vs. 20.0 minutes, < 0.01) and less effect of acute and preventive medication than those without (20.0 vs. 55.9%, < 0.05 and 13.3 vs. 37.3%, < 0.01, respectively). If applying the conservative definition with a daily bilateral headache along with a medication-overuse, the prevalence was reduced to 4%.ConclusionsProbable medication-overuse headache was present in every sixth participant with CH in this large cross-sectional cohort study. Interestingly, only a smaller proportion was the result of isolated triptan overuse. In CH, where patients often suffer from daily attacks and may suffer from a daily bilateral inter-ictal pain, our very conservative definition noted a prevalence of 4%. While the existing ICHD-3 criteria for medication-overuse headache may not be directly applicable in CH, the applicability and validity of the very conservative definition warrant further investigation. Still, as in other cross-sectional populations with medication-overuse, we noted an association that acute and preventive treatments were less effective in participants with probable medication-overuse headache compared to those without. Altogether, future prospective studies are necessary to establish the exact extent and presentation of medication-overuse headache in CH and determine whether it is an aggravating factor for the disease. We do not recommend discontinuing triptans if suspecting MOH due to ethical concerns.
Russo A, Silvestro M, Finkelstein I
… +7 more, Seabi D, Ahlden A, Aamodt AH, Caronna E, Pozo-Rosich P, Tronvik E, Sundal C
Cephalalgia
· 2025 Aug · PMID 40874574
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BackgroundThe discovery of calcitonin gene-related peptide (CGRP) as a key player in migraine pathophysiology has revolutionized the approach to preventive treatment. Atogepant, an oral small-molecule CGRP receptor antag...BackgroundThe discovery of calcitonin gene-related peptide (CGRP) as a key player in migraine pathophysiology has revolutionized the approach to preventive treatment. Atogepant, an oral small-molecule CGRP receptor antagonist, has shown promising efficacy in randomized controlled trials (RCTs) for both episodic and chronic migraine. However, real-world evidence, particularly in individuals with chronic migraine and multiple preventive treatment failures, remains limited. This study is aimed to evaluate the effectiveness, safety, and tolerability of daily atogepant 60 mg in a homogeneous cohort of resistant individuals with chronic migraine over a 24-week period to extend the short-term observation assessed in previous real-world studies.MethodsIn the present real-world, prospective, monocentric study, a total of 100 participants (93% female; mean ± SD, age 43 ± 11 years) with chronic migraine with at least three previous treatment failures without medication overuse headache were consecutively recruited and received atogepant 60 mg daily for six months. All participants had failed a median of six previous preventive treatments, including CGRP-monoclonal antibodies (mAbs) (68%) and onabotulinumtoxin-A (BoNT-A) (14%). Primary outcomes included change in monthly migraine days (MMDs) and greater than 50% responder rate at 12 and 24 weeks. Secondary outcomes included changes in monthly headache days (MHDs), acute medication intake (MAMI), headache impact (Headache Impact Test (HIT-6)), anxiety and depression (Hospital Anxiety and Depression Scale (HADS)) and patient satisfaction (Patient's Global Impression of Change (PGIC)), change in MMDs, demographic and clinical features associated with greater than 50% responder rate, as well as effectiveness in individuals with previous CGRP-mAbs failure. Treatment-emergent adverse events (TEAEs) were also recorded.ResultsAt weeks 12 and 24, MMDs were reduced by 5.6 and 7.1 days from baseline, respectively ( < 0.001), while 45% and 53% of participants achieved a ≥ 50% reduction in MMDs. Significant improvements were also seen in MHDs (-8.1 days), MAMI (-5.1 days) and HIT-6 scores (-6.2 points). Conversion from chronic to episodic migraine occurred in 60% of participants. PGIC results showed that 69% of participants reported feeling "much" or "very much" better. Logistic regression identified higher socioeconomic status (odds ratio = 2.87) as a positive predictor and previous CGRP-mAb failure (odds ratio = 0.38) as a negative predictor of treatment response. Nevertheless, among individuals with more than one CGRP-mAb failure, 47% achieved a ≥50% reduction in MMDs. TEAEs were reported by 53% of participants, with constipation (28%) and fatigue (16%) being the most common.ConclusionsAtogepant 60 mg daily demonstrated meaningful clinical benefit and good tolerability in real-world individuals with treatment-resistant chronic migraine over a 24-week period. These findings extend data from RCTs and real-world studies limited to 12-week period of observation, supporting atogepant as an effective option even in individuals with prior CGRP-mAb failure.
Christensen RH, Al-Khazali HM, Ashina M
… +4 more, Vashchenko N, Dominguez-Moreno R, Tolnai D, Ashina H
Cephalalgia
· 2025 Aug · PMID 40853152
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BackgroundPersistent post-traumatic headache (PTH) is a prevalent and disabling neurological disorder, often attributed to mild traumatic brain injury and resembling migraine in clinical features. The underlying cortical...BackgroundPersistent post-traumatic headache (PTH) is a prevalent and disabling neurological disorder, often attributed to mild traumatic brain injury and resembling migraine in clinical features. The underlying cortical morphometric changes and their relevance to persistent PTH remain unclear.MethodsThis cross-sectional magnetic resonance imaging (MRI) investigation enrolled 103 adults with persistent PTH, 296 with migraine and 155 healthy controls (HC), to undergo structural MRI at 3T. Cortical surface area, thickness and volume were evaluated in FreeSurfer. The analyses applied cluster-determining thresholds of < 0.001 and cluster-wise thresholds of < 0.05, adjusted for age, sex and total intracranial volume.ResultsParticipants with persistent PTH exhibited larger surface area in the right anterior and posterior cingulate cortex ( = 0.003), as well as the right superior parietal cortex/postcentral gyrus, compared to HC ( < 0.035). No morphometric differences were observed between participants with persistent PTH and migraine (including subgroups: episodic, chronic, with aura without aura).ConclusionsThese findings reveal morphometric alterations in persistent PTH, specifically within pain processing regions of the mid-cingulate and somatosensory cortex. Similar changes have been reported in migraine, suggesting a shared neurobiological substrate. These enlargements might reflect adaptations to recurrent nociceptive stimuli that sustain persistent PTH.
Johnson MP, Krikke-Workel J, Patel CN
… +10 more, Morin SM, Turner PK, Clark KA, Donley D, Jin Y, Johnson KW, Vincent M, Stille JR, Broad LM, Patel A
Cephalalgia
· 2025 Aug · PMID 40836866
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AimLY3451838 is a monoclonal antibody against pituitary adenylate cyclase-activating peptide (PACAP), a target in migraine research. The present study aimed to evaluate LY3451838 as a preventive treatment for participant...AimLY3451838 is a monoclonal antibody against pituitary adenylate cyclase-activating peptide (PACAP), a target in migraine research. The present study aimed to evaluate LY3451838 as a preventive treatment for participants with treatment-resistant migraine.MethodsFollowing preclinical assessment of LY3451838, including pharmacokinetic and pharmacodynamic studies, safety was evaluated in a phase 1 study of LY3451838 (n = 33) versus placebo (n = 13) in healthy participants. A phase 2 trial was carried out in treatment-resistant participants with chronic migraine (CM) (n = 16) or episodic migraine (EM) (n = 22). In phase 2, participants received a single intravenous (IV) dose of 1500 mg LY3451838 (n = 19) or placebo (n = 19) and completed ePRO daily diaries. Participants were followed for safety for 140 days.ResultsIn phase 2, at one-month post-dose, patients who had received a single IV dose of LY3451838 exhibited greater changes from baseline than placebo in mean monthly migraine headache days in both the CM and EM subgroups (CM: -4.7 days vs. -3.0 days; EM: -1.7 days vs. -1.2 days), but the treatment contrast was not statistically significant in either subgroup. Similar non-significant results were seen at the three-month time point. The percentage of participants reporting treatment-emergent adverse events was similar for LY3451838 and placebo, with one serious adverse event of B-cell lymphoma in an LY3451838-treated participant that led to study discontinuation.ConclusionsLY3451838 did not demonstrate superior efficacy over placebo in patients with treatment-resistant CM or EM. However, the difference observed between LY3451838 and placebo among CM patients is similar to the statistically significant difference reported in the recent HOPE trial, which primarily consisted of CM patients. Further clinical research with larger sample sizes is needed to inform on the utility of blocking PACAP in various migraine populations.Trial RegistrationClinicalTrials.gov: NCT03692949 (phase 1); NCT04498910 (phase 2).
Yuan H, Hoffmann J, Ruiz de la Torre E
… +2 more, Marmura MJ, Peres MFP
Cephalalgia
· 2025 Aug · PMID 40836704
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Cluster headache (CH) is a rare and painful primary headache disorder characterized by severe unilateral pain and cranial autonomic symptoms. This perspective examines the epidemiological evidence supporting the classifi...Cluster headache (CH) is a rare and painful primary headache disorder characterized by severe unilateral pain and cranial autonomic symptoms. This perspective examines the epidemiological evidence supporting the classification of chronic cluster headache (CCH) as a rare disease, noting a prevalence of CH of approximately 124 per 100,000 individuals, with only 3.5-13.7% manifesting CCH. This prevalence meets criteria established by both the US Food and Drug Administration and European Medicines Agency for rare disease designation. The rarity of CCH creates substantial clinical and research challenges, including prolonged diagnostic delays, limited research funding and a dearth of approved treatments. The economic burden is particularly notable, with annual costs exceeding €20,000 per patient. Addressing these challenges requires a coordinated approach focusing on increased research funding, enhanced policy advocacy, improved diagnostic training and the development of comprehensive disease registries to advance both patient care and scientific understanding of this devastating neurological condition.
Ashina S, Ashina M, Holle-Lee D
… +8 more, Tassorelli C, Cho SJ, He MY, De Abreu Ferreira R, Gandhi P, Smith JH, Pfleeger K, Trugman JM
Cephalalgia
· 2025 Aug · PMID 40831083
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AimLong-term data for oral calcitonin gene-related peptide receptor antagonist, atogepant, in episodic migraine (EM) has been reported. This is the first report on one-year outcomes in participants with chronic migraine...AimLong-term data for oral calcitonin gene-related peptide receptor antagonist, atogepant, in episodic migraine (EM) has been reported. This is the first report on one-year outcomes in participants with chronic migraine (CM) and in the EM population with prior preventive treatment failures. Here, we report the long-term safety, tolerability, efficacy and functional outcomes of one-year preventive treatment of EM or CM with atogepant.MethodsThis is an interim analysis of an ongoing, open-label, multicenter, 156-week, safety extension study that enrolled completers from phase 3 PROGRESS and ELEVATE trials. The participants completing week 52 or early termination were evaluated. Eligible adults with at least a one-year history of migraine, with either CM (PROGRESS) or EM who previously had inadequate response to two to four classes of conventional oral preventive treatments (ELEVATE). All participants received atogepant 60 mg once daily. The primary outcome was safety and tolerability of atogepant. Efficacy and functional outcomes were prespecified exploratory analyses.ResultsOf 596 participants, 595 (PROGRESS, n = 325; ELEVATE, n = 270) were treated and included in the safety population and 524 (PROGRESS, n = 284; ELEVATE, n = 240) were included in the modified intent-to-treat population. In this interim analysis, mean duration of atogepant exposure was 496.5 days. Treatment-emergent adverse events (TEAEs) occurred in 79.0% of participants; most were mild/moderate and not related to atogepant. Common TEAEs (≥5%) included COVID-19 (28.7%), nasopharyngitis (10.9%) and constipation (8.2%). TEAEs leading to discontinuation occurred in 5.9% of participants. One death attributed to asphyxia by housefire was observed. Other serious TEAEs occurred in 5.5% of participants and none were related to atogepant. Alanine aminotransferase and/or aspartate aminotransferase ≥3× upper limit of normal occurred in two participants; neither met Hy's law criteria. Improvements in efficacy and functional outcomes from lead-in study baseline were observed at weeks 13-16 in this open-label study and were consistent through 48 and 52 weeks, respectively.ConclusionsOverall safety results were consistent with the known safety profile of atogepant and the drug was well-tolerated over the course of the study. No new safety signals were identified. Improvements in efficacy and functional outcomes were consistent during the study.Trial RegistrationClinicalTrials.gov identifier: NCT04686136.
Peles I, Sharvit S, Steen YM
… +4 more, Gordon M, Novack V, Waismel-Manor R, Ifergane G
Cephalalgia
· 2025 Aug · PMID 40820314
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BackgroundMigraine, a neurovascular disorder that affects quality of life, with peak prevalence during individuals' most productive working years. Work-family conflict (WFC), a well-documented source of stress, occurs wh...BackgroundMigraine, a neurovascular disorder that affects quality of life, with peak prevalence during individuals' most productive working years. Work-family conflict (WFC), a well-documented source of stress, occurs when work and family responsibilities interfere with each other. While migraine has been associated with occupational impairment, its association with WFC remains underexplored. The present study examines the association between migraine diagnosis, severity and WFC, stratified by gender.MethodsThis study analyzed data from the SMILE cohort, a subset of the Negev Migraine Cohort. Participants with and without migraine were recruited and completed a structured questionnaire assessing WFC. The main exposures were migraine diagnosis and severity, measured using the Migraine Disability Assessment (MIDAS) score. The primary outcome was WFC. Covariates included sociodemographic characteristics, employment factors, and psychological distress (Depression, Anxiety and Stress Scale - 21 Items (DASS-21)). Statistical analyses involved multivariable gamma generalized linear mode regression models and quantile regression to examine associations, adjust for potential confounders and effect modification by gender.ResultsIn total, 675 migraine patients and 232 non-migraine participants were included in the study; 80.6% of migraine patients were female. Severe disability (MIDAS score ≥21) was reported by 65.0% of migraine patients, with employment rates of 89.2% for females and 93.1% for males. Migraine patients worked longer hours per week (median 40.0 vs. 36.0 hours for females, and 48.0 vs. 42.0 hours for males), and were more likely to work over 42 hours per week (18.2% vs. 7.0% for females and 32.8% vs. 8.7% for males, standardized mean difference = 0.487). Migraine diagnosis was associated with higher Work To Family and Family To Work strain-based conflict scores among males (β = 0.43, 95% confidence interval = 0.06-0.78, = 0.03 and β = 0.35, 95% 95% confidence interval = 0.03-0.66, = 0.04, respectively); however, no statistically significant associations were observed among female. Higher migraine severity (MIDAS) was correlated with greater WFC, with the effect more pronounced at higher levels of migraine disability and more strongly associated with men ( < 0.01 for all).ConclusionsMigraine is associated with higher WFC, especially in strain-based domains, with a stronger effect in men. Greater migraine severity further amplifies this conflict. These findings emphasize the need for workplace and clinical strategies to support migraine patients in managing work-life balance.
Burish M, Kim SA, Ran C
… +3 more, Yoo SH, Lee MJ, Belin AC
Cephalalgia
· 2025 Aug · PMID 40808422
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Cluster headache attacks display uniquely rhythmic patterns in their manifestations. Multiple international studies have shown circadian and even circannual timing of attacks, although we do not yet fully understand the...Cluster headache attacks display uniquely rhythmic patterns in their manifestations. Multiple international studies have shown circadian and even circannual timing of attacks, although we do not yet fully understand the effects of culture, sleep, chronotype, seasonal changes, temperature or inter-individual changes over time. Multiple cluster headache treatments alter the core circadian oscillator, although they affect the oscillator differently and are not well understood. Multiple small genetic studies have shown core circadian gene variants to be cluster headache susceptibility genes, whereas larger genetic studies have not shown core circadian gene variants but have also not documented the presence or absence of circadian rhythmicity. In this narrative review, we describe the multi-level circadian features of cluster headache and propose future circadian directions, including a clinical definition of circadian attacks, a potential animal model of circadian headache and study design changes to incorporate circadian features into larger genetic studies.
Christensen RH, Strassman AM, Ashina M
… +2 more, Ashina H, Burstein R
Cephalalgia
· 2025 Aug · PMID 40785517
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AimMeningeal nociceptors within the trigeminal ganglion are important contributors to migraine pathogenesis because they transmit pain signals from the dura mater to the central nervous system. As such, pharmacological i...AimMeningeal nociceptors within the trigeminal ganglion are important contributors to migraine pathogenesis because they transmit pain signals from the dura mater to the central nervous system. As such, pharmacological interventions that target these peripheral neurons might offer new avenues for migraine treatment. In this context, ATP-sensitive potassium (K) channels have garnered increasing attention as potential modulators of meningeal nociception. Human experimental studies support this hypothesis, showing that intravenous infusion of levcromakalim, a K channel opener, induces migraine attacks in people with migraine and mild, transient headache in healthy adults. However, the precise anatomical site and mechanism of action remain incompletely understood.MethodsTo address these gaps, we conducted single-unit electrophysiological recordings of 36 meningeal nociceptors (23 Aδ- and 13 C-fibers) in the trigeminal ganglion of anesthetized male and female rats. We measured spontaneous firing rates before and up to four hours after a 20-minute continuous intracarotid infusion of levcromakalim (1.43 mg/kg or 0.14 mg/kg) or vehicle (71.4% ethanol).ResultsLevcromakalim at 1.43 mg/kg activated nine (69%) of 13 nociceptors, compared with one (11%) of nine in the vehicle group ( = 0.012). Activation rates did not differ between Aδ-fibers (6 of 8, 69%) and C-fibers (3 of 6; 50%; = 1.00), or between male (6 of 8; 75%) and female animals (3 of 5; 60%; = 0.61). Moreover, levcromakalim at 0.14 mg/kg activated only three (21%) of 14 nociceptors.ConclusionsTaken together, our findings demonstrate that K channel opening mediates activation of meningeal nociceptors, providing a mechanistic basis for previous observations in humans. The development of K channel blockers might therefore hold therapeutic promise for migraine by inhibiting meningeal nociceptors.
Cephalalgia
· 2025 Aug · PMID 40785294
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ObjectiveTo compare plasma adrenomedullin (AM) levels between adults with migraine and healthy controls (HCs), assessing subgroup differences and clinical associations.MethodsThis cross-sectional, observational single-ce...ObjectiveTo compare plasma adrenomedullin (AM) levels between adults with migraine and healthy controls (HCs), assessing subgroup differences and clinical associations.MethodsThis cross-sectional, observational single-center study was carried out from September 2020 to June 2022. Adults with migraine and HCs were enrolled and underwent blood sampling. Migraine subgroups included episodic migraine, chronic migraine, migraine without aura and migraine with aura. Plasma AM concentrations were quantified using a validated immunoluminometric assay by trained personnel who were blinded to group status.ResultsIn total, 667 participants with migraine and 147 HCs provided data eligible for analysis. Plasma AM concentrations did not differ significantly between the migraine and HC group (18.2 ± 9.1 pg/ml vs. 18.5 ± 8.4 pg/ml; = 0.08). However, participants with episodic migraine exhibited lower AM levels than HCs (16.9 ± 7.7 pg/ml vs. 18.5 ± 8.4 pg/ml; = 0.04). Multivariate regression models showed that plasma AM concentrations are positively associated with body mass index (4.2% increase in AM per kg/m; 3.6 to 4.8%; < 0.001) and monthly migraine days (0.6% increase in AM per MMD; 0.2 to 1.0%; = 0.006).ConclusionsPlasma AM concentrations were comparable between participants with migraine and HCs; however, those with episodic migraine exhibited slightly lower levels. Future studies should investigate other candidate blood-based biomarkers for migraine.
Vaghi G, Corrado M, Pocora MM
… +17 more, Bighiani F, Cammarota F, Antoniazzi A, Costantino L, Martinelli D, Allena M, Ghiotto N, Guaschino E, Bottiroli S, Iannone LF, De Cesaris F, Montisano DA, Grazzi L, Sances G, Montomoli C, Tassorelli C, De Icco R
Cephalalgia
· 2025 Aug · PMID 40770917
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BackgroundThe present prospective, real-world study aims to assess anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) effectiveness across three consecutive one-year treatment cycles by means of a c...BackgroundThe present prospective, real-world study aims to assess anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) effectiveness across three consecutive one-year treatment cycles by means of a conservative intention-to-treat (ITT) analysis.MethodsWe enrolled 179 subjects (75.4% females, 51.3 years 95% confidence interval [49.2-53.4] years), 87.2% with chronic migraine and medication overuse) who started mAbs between 2018 and 2020. We recorded clinical data supported by a prospectively filled headache diary up to three one-year treatment cycles. The ITT analysis was performed with a multivariate linear mixed model considering the entire population.ResultsWe observed a marked and consistent reduction in monthly migraine days (MMDs) across the three one-year cycles of treatment: -12.7 )[-11.4 - -14.1] at end of the first year of treatment (C1), -12.4 [-11.0 - -13.8] at the end of the second year (C2) and -12.9 [-11.4 - -14.3] at the end of the third year (C3). Baseline and residual MMDs progressively decreased across the three cycles ( 0.008): from 21.1 [19.8-22.4] to 9.6 [8.3-11.0] in C1, from 19.0 [17.4-20.5] to 9.6 [8.1-11.1] in C2, and from 15.9 [14.3-17.5] to 8.5 [6.9-10.1] in C3. At the end of C3, the 50% response rate was 38.5% (69/179)ConclusionsIn our cohort, mAbs induced a meaningful and sustained reduction in MMDs across three consecutive one-year cycles of treatment. The ITT analysis revealed a remaining high burden of disease. While confirming mAbs effectiveness in migraine prevention, these findings underscore the need for more treatment approaches and for exploring other non-CGRP dependent pathways.
Cephalalgia
· 2025 Aug · PMID 40767099
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The neuropeptides pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) play roles in vasodilation, the immune response and neuronal signaling, with recent links to headache d...The neuropeptides pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) play roles in vasodilation, the immune response and neuronal signaling, with recent links to headache disorders. This association has resulted in considerable interest in targeting this family of peptides and their receptors for drug development, and, notably, an anti-PACAP antibody has reported clinical efficacy in reducing migraine frequency. The PACAP/VIP ligands act at G protein-coupled receptors (GPCRs). PAC, VPAC and VPAC are the officially-recognized canonical receptors. Each of these has the potential to generate receptor variants through exon splicing. These variants may exhibit altered function, significantly increasing the diversity of PACAP-responsive receptors. In addition to these canonical receptors, PACAP is proposed to activate other unrelated receptors, GPR55 and MRGPRX2. Altogether, any of these canonical and proposed receptors may mediate the biological actions of PACAP, including migraine-relevant behaviors. However, we have a limited understanding of how these receptors function, such as their capacity to activate downstream signaling, the cellular and subcellular location of that signaling, and whether accessory protein interactions may alter these responses, especially in migraine-relevant contexts. The complex nature of the PACAP/VIP system therefore provides not only numerous considerations for target design and validation, but also unique opportunities for "designer" drugs. This narrative review provides an overview of the complex PACAP/VIP system, exploring peptide, receptor and downstream signaling behaviors that may be potential targets for the treatment of headache disorders and beyond.