Journal of Headache and Pain最新文献

{"title":"Increased infection risk in patients on preventive CGRP-targeting therapies- a meta-analysis and clinical effect assessment.","authors":"Marcin Straburzyński, Daria Kopyt, Karol Marschollek, Bartłomiej Błaszczyk, Ewa Kuca-Warnawin, Weronika Kurowska, Błażej Misiak, Kuan-Po Peng, Marta Waliszewska-Prosół, Arne May","doi":"10.1186/s10194-025-02040-0","DOIUrl":"https://doi.org/10.1186/s10194-025-02040-0","url":null,"abstract":"<p><strong>Background: </strong>Calcitonin gene related peptide (CGRP) pathway targeting therapies have proven efficacy, safety and tolerability. However, CGRP is also involved in immune responses, and reports of an increased risk of infection have emerged. This meta-analysis aims to verify whether CGRP-targeting therapies show evidence of increasing infection risk.</p><p><strong>Methods: </strong>A systematic review was conducted according to PRISMA-Harms guidelines. A PubMed and Embase search result selection and extraction was performed. Risk of bias, sensitivity analysis, and fixed/random effects network meta-analyses were conducted for incidence of infectious adverse events in the studied populations with subsequent effect size assessment. An additional infectious serious adverse event search was performed in double-blind and open-label studies.</p><p><strong>Results: </strong>The search and selection process yielded 37 randomized placebo-controlled trials. 22,518 patients (77.3% women) treated with erenumab, fremanezumab, galcanezumab, eptinezumab, atogepant and rimegepant participated in these studies. Preventive CGRP-targeting therapies appear to increase the infection relative risk (RR = 1.08 [1.01; 1.14], p = 0.016, Number Needed to Harm [NNH] = 287). However, in individual analyses only galcanezumab and eptinezumab showed an increase in risk of infections: galcanezumab at clinically used doses (RR 1.13 [1.02; 1.25], p = 0.024, NNH = 77); eptinezumab at higher doses (RR 1.23 [1.04; 1.45], p = 0.015, NNH = 24). Fremanezumab was associated with fewest infectious SAEs (n = 3 in 3 studies), while erenumab showed the highest incidence of these events (n = 36 in 11 studies).</p><p><strong>Conclusions: </strong>CGRP has multiple and often potentially opposing effects on the immune system. In effect, preventive CGRP pathway antagonists (especially eptinezumab and galcanezumab) possibly only mildly increase the risk of infections. However, it is unlikely to affect most migraine patients considering relatively high NNH, low effect size and few infectious SAEs reported so far. The result of CGRP-targeting therapies potentially depends on the type of pathogen and patient's immune status. Consequently, in immunocompromised patients or at public health levels the increased infection risk may have more pronounced effect.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"88"},"PeriodicalIF":7.3,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12023699/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144021958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transient focal neurological symptoms and headache: is it TIA or migraine with aura?","authors":"Elena R Lebedeva, Jes Olesen","doi":"10.1186/s10194-025-02038-8","DOIUrl":"https://doi.org/10.1186/s10194-025-02038-8","url":null,"abstract":"","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"87"},"PeriodicalIF":7.3,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12023349/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144022446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma SuPAR and therapeutic response to erenumab in migraine: a REFORM study.","authors":"William K Karlsson, Rune H Christensen, Haidar M Al-Khazali, Thomas Kallemose, Baker N Jawad, Ove Andersen, Messoud Ashina, Håkan Ashina","doi":"10.1186/s10194-025-02037-9","DOIUrl":"https://doi.org/10.1186/s10194-025-02037-9","url":null,"abstract":"<p><strong>Background: </strong>Soluble urokinase-plasminogen activator receptor (suPAR) is a biomarker of systemic inflammation and elevated in plasma of individuals with migraine with aura. As inflammatory cytokines can upregulate calcitonin gene-related peptide (CGRP), suPAR levels might be linked to response to CGRP-targeting therapies. Therefore, we investigated whether plasma suPAR levels are associated with response to the CGRP-receptor antagonist erenumab.</p><p><strong>Methods: </strong>In this single-center, prospective study, adults with ≥ 4 monthly migraine days received 140 mg erenumab subcutaneously every 4 weeks for 24 weeks. Blood samples were collected at baseline, Week 24 (end of treatment), and Week 48 (24 weeks post-treatment). Responders were defined as achieving a ≥ 50% reduction in monthly migraine days from baseline to weeks 13-24. Associations between baseline suPAR and treatment response were analyzed using logistic and linear regression. Longitudinal changes in suPAR were assessed using linear mixed models.</p><p><strong>Results: </strong>The study included 623 participants with migraine (mean age 44.1 ± 12.3 years; 90.4% female) and 154 healthy controls. Among participants, 183 (29.4%) had migraine with aura, and 406 (65.2%) had chronic migraine. Baseline plasma suPAR levels were not associated with response to erenumab in the total migraine population (odds ratio [OR] 0.83, 95% confidence interval [CI] 0.64 to 1.07; p = 0.14) or in the aura subgroup (OR 0.73, 95% CI 0.48 to 1.10; p = 0.14). Plasma suPAR levels were significantly higher in non-responders compared to responders at Week 48 (7.5% higher, 95% CI 3.3 to 11.5%; p = 0.005). Non-responders with aura had higher suPAR concentrations than controls at baseline (difference 10.1%; 95% CI 3.0 to 17.8%; p = 0.023) and Week 24 (8.7%; 95% CI 1.6 to 16.2%; p = 0.047). These differences persisted at Week 48 (12.4%; 95% CI 4.6 to 20.7%; p = 0.013). No longitudinal changes in suPAR concentrations were observed.</p><p><strong>Conclusions: </strong>We did not find an association between baseline plasma suPAR levels and response to erenumab. Plasma suPAR concentrations remained stable, even among participants with aura. These findings suggest that systemic low-grade inflammation, as measured by suPAR, does not influence treatment efficacy.</p><p><strong>Trial registration: </strong>Pre-registered on ClinicalTrials.gov (NCT04603976 and NCT04674020).</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"86"},"PeriodicalIF":7.3,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12020035/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143969979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of endocannabinoid hydrolases MAGL, FAAH and ABHD6 by AKU-005 reduces ex vivo cortical spreading depression.","authors":"Flavia Brugia, Konstantin Ivanov, Auni Aroviita, Raisa Giniatullina, Marko Lehtonen, Tarja Malm, Juha Savinainen, Rashid Giniatullin, Adriana Della Pietra","doi":"10.1186/s10194-025-02030-2","DOIUrl":"https://doi.org/10.1186/s10194-025-02030-2","url":null,"abstract":"<p><strong>Background: </strong>Migraine is a common neurovascular disorder that remains currently untreated in half of the patients. One third of migraine patients experience aura, which is associated with the development of cortical spreading depolarization (CSD), a wave of depolarization involving neurons and glial cells. Cannabinoids have proven to be a promising class of compounds for the treatment of migraine pain. In this study, we are proposing a new strategy to counteract development of CSD and downstream events via multicomponent enhancement of the endocannabinoid system (ECS) by using a AKU-005, to simultaneously target several key endocannabinoids hydrolases. To this end, we profiled the activity of selective endocannabinoid hydrolases and their inhibition by AKU-005 and analyzed the effect of AKU-005 on the development of CSD in an ex vivo cortical slice model.</p><p><strong>Methods: </strong>The inhibitory profile of AKU-005 was evaluated by a glycerol assay of lysates from HEK293 cells expressing mouse and human MAGL and ABHD6. After ex vivo treatment of cortex slices of Wistar rats and C57 BL/6 J-OlaHsd mice, endocannabinoids were quantified by mass spectrometry (LC-MS/MS), and activity of the hydrolases MAGL, FAAH, and ABHD6 were measured by activity-based protein profiling (ABPP). The effect of AKU-005 on ex vivo CSD wave in cortical slices was studied by live calcium imaging.</p><p><strong>Results: </strong>Ex vivo, AKU-005 inhibited MAGL, FAAH, and ABHD6, increasing 2-arachidonoylglycerol (2-AG) and anandamide (AEA) levels in rat cortex under both basal and CSD conditions. In mice, AKU-005 showed a milder effect, inhibiting MAGL only under CSD conditions and increasing 2-AG levels in both basal and CSD states. In vitro analyses confirmed the ex vivo findings for rats and revealed basal MAGL inhibition in mice cortex. AKU-005, previously reported as a double MAGL/FAAH-inhibitor, also inhibited overexpressed mouse and human ABHD6, a little studied 2-AG-hydrolyzing enzyme in brain. In line with these results, AKU-005 reduced CSD events in cortical slices from both rodent species, with higher efficacy in rats.</p><p><strong>Conclusions: </strong>Given the distinct profile of endocannabinoids hydrolases activities between rats and mice in the brain areas associated with migraine, AKU-005 may target multiple endocannabinoid hydrolases to serve as an efficient treatment option for migraine with aura.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"85"},"PeriodicalIF":7.3,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12016430/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143971661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adoption of rimegepant in Denmark: a register-based study on uptake, prescribing patterns and initiator characteristics.","authors":"Lanfranco Pellesi, Thien Phu Do, Martin Thomsen Ernst, Jesper Hallas, Anton Pottegård","doi":"10.1186/s10194-025-02028-w","DOIUrl":"https://doi.org/10.1186/s10194-025-02028-w","url":null,"abstract":"<p><strong>Background: </strong>Rimegepant, an oral calcitonin gene-related peptide (CGRP) receptor antagonist, is the first drug within its class approved for both acute and preventive treatment of migraine. This study examines its uptake in Denmark.</p><p><strong>Methods: </strong>Using nationwide healthcare registry data, we analyze trends in rimegepant prescriptions from its introduction in October 2022 to December 2024. Parameters assessed include demographic and clinical characteristics of users, temporal trends in drug use, treatment adherence, and concomitant use of other migraine therapies.</p><p><strong>Results: </strong>By December 2024, over 140,000 defined daily doses (DDDs) of rimegepant had been dispensed in Denmark, primarily among females (88%), with a users' median age of 45 years. Most initiators had prior experience with triptans (79%) or NSAIDs (38%) for migraine treatment and 69% met criteria for medication overuse before initiation. Concomitant use of triptans (63%) and NSAIDs (17%) remained common, but a substantial decline in the overuse of acute headache medications was observed after rimegepant initiation. Early discontinuation was very common, with 45% of initiators filling only one prescription. Among the 55% who continued treatment, the most substantial drop occurred within the first 90 days, followed by a more gradual decrease over time.</p><p><strong>Conclusions: </strong>The study highlights the rapid uptake of rimegepant in Denmark, especially among middle-aged females with a history of triptan use and medication overuse. While rimegepant was associated with a reduction in acute medication overuse, early discontinuation rates suggest barriers to sustained use, potentially influenced by cost, efficacy, or patient preferences. There is a need for strategies to optimize long-term adherence and access to rimegepant in clinical practice.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"83"},"PeriodicalIF":7.3,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12007292/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144029082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancement of the endocannabinoid system through monoacylglycerol lipase inhibition relieves migraine-associated pain in mice.","authors":"Elizaveta Mangutov, Yaseen Awad-Igbaria, Kendra Siegersma, Francois Gastambide, Ayodeji A Asuni, Amynah A A Pradhan","doi":"10.1186/s10194-025-02029-9","DOIUrl":"https://doi.org/10.1186/s10194-025-02029-9","url":null,"abstract":"<p><strong>Background: </strong>Migraine affects over 1 billion people worldwide and is a leading cause of disability. Targeting the cannabinoid system offers a promising approach for pain and migraine relief. This study evaluated a novel monoacylglycerol lipase (MAGL) inhibitor to prolong endocannabinoid action in acute and chronic mouse models of migraine. It also examined MAGL and cannabinoid receptor 1 (CB₁) mRNA expression in key head pain-processing regions.</p><p><strong>Methods: </strong>C57BL6/J male and female mice received the human migraine trigger nitroglycerin (NTG) acutely or every other day for 9 days. Allodynia was assessed by von Frey hair stimulation of the periorbital area. A single dose of MAGL inhibitor (ABD-1970) was tested in acute and chronic NTG models. Additionally, ABD-1970 was given daily for 5 days to assess tolerance. In situ hybridization measured transcript expression of MAGL, CB₁, and neuronal marker Rbfox3 in trigeminal ganglia (TG) and trigeminal nucleus caudalis (TNC).</p><p><strong>Results: </strong>A single injection of ABD-1970 blocked cephalic allodynia induced by acute NTG. ABD-1970 also blocked chronic allodynia established by chronic intermittent NTG. Repeated administration did not induce tolerance, and ABD-1970 continued to block NTG-induced allodynia after 5 days of administration. There was high expression of MAGL and CB₁ in the TG and TNC, present in Rbfox3 positive and negative cells.</p><p><strong>Conclusion: </strong>MAGL inhibitor effectively blocked acute and chronic migraine-associated pain, likely through prolonged endocannabinoid action. This effect may be mediated through action at peripheral or central sites considering the high MAGL and CB₁ expression in the TG and TNC, respectively. The endocannabinoid system appears to modulate migraine mechanisms, and MAGL may be a promising target for this disorder.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"84"},"PeriodicalIF":7.3,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12007319/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144025522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The association between endometriosis and migraine: a systematic review and meta-analysis of observational studies.","authors":"Giorgia Elisabeth Colombo, Sofia Makieva, Edgardo Somigliana, Georgios Schoretsanitis, Brigitte Leeners, Christian Polli, Noemi Salmeri, Dimitrios Rafail Kalaitzopoulos, Paola Vigano'","doi":"10.1186/s10194-025-02020-4","DOIUrl":"https://doi.org/10.1186/s10194-025-02020-4","url":null,"abstract":"<p><strong>Background: </strong>Endometriosis affects women of reproductive age. Increasing attention is being given to the characterization of comorbidities in endometriosis to enhance clinical phenotyping. Among these comorbidities, migraine has been reported to be significantly more common in individuals with endometriosis compared to the general population. However, the true epidemiological burden remains uncertain, and no conclusive evidence links specific subtypes of endometriosis to migraine.</p><p><strong>Main body: </strong>Seven electronic databases were searched from inception until July 22nd, 2024, using combinations of relevant keywords. PROSPERO Registration CRD42023449492. Two independent reviewers screened the records according to inclusion/exclusion criteria and abstracted data. The risk of bias assessment was undertaken using the ROBINS-E tool. Random effects models were implemented to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between endometriosis and migraine. Fourteen studies were included in the qualitative synthesis, and 13 in the meta-analysis, accounting for a total of 331,655 individuals (32,489 with endometriosis vs. 299,166 controls). There was a serious risk of bias in the majority of the included studies, with 50% being at very high risk of bias. The risk of migraine was higher in individuals with endometriosis compared to those without (OR 2.25, 95%CI = 1.85-2.72; n = 13 studies; I² = 81%). This association remained significant in the sensitivity analyses: (i) when excluding studies at very high or high risk of bias (OR 2.64; 95%CI = 1.62-4.31; n = 4 studies; I² = 77%), (ii) when including only risk estimates adjusted for clinically relevant confounders (OR 2.35; 95%CI = 1.77-3.13; n = 6 studies; I² = 88%), and (iii) when including only risk estimates adjusted for hormonal therapy (OR 1.95; 95%CI = 1.42-2.66; n = 3; I² = 92%). Endometriosis was significantly associated with migraine without aura (OR 2.64, 95%CI 1.89-3.69; n = 3 studies; I² = 0%), but not migraine with aura (OR 3.47, 95%CI = 0.53-22.89; n = 3, I² = 73%).</p><p><strong>Conclusion: </strong>This meta-analysis highlights the high prevalence of migraine in patients with endometriosis. However, due to observed high heterogeneity and risk of bias, caution is advised when interpreting and applying these findings in clinical practice. Future research should address these issues by limiting variations in diagnostic criteria, stratifying study populations, accounting for key confounders, and investigating potential underlying pathophysiological mechanisms to enhance understanding of the endometriosis-migraine relationship.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"82"},"PeriodicalIF":7.3,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12007130/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144028555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy and safety of ultrasound-guided peripheral nerve blocks in management of chronic resistant migraine.","authors":"Nourhan Abdelmohsen Taha, Mai Fathy, Ahmed Elsadek, Tamer Hussein Emara, Sherien Mohamed Farag, Ramez Reda Moustafa, Mohamad Osama Abdulghani","doi":"10.1186/s10194-025-02013-3","DOIUrl":"https://doi.org/10.1186/s10194-025-02013-3","url":null,"abstract":"<p><strong>Background: </strong>Migraine is a common primary headache disorder with different treatment modalities emerging as ultrasound guided peripheral nerve blocks. We compared the efficacy and safety of ultrasound guided bilateral sphenopalatine ganglion (SPG) block versus bilateral greater occipital nerve (GON) block, in chronic resistant migraine patients and controls.</p><p><strong>Methods: </strong>This study was an interventional randomized controlled trial, including 53 patients, 22 in sphenopalatine ganglion arm, 21 greater occipital nerve arm and 10 in sham group. All patients were assessed initially by headache diary (for 3 months), HIT-6 and MIDAS scales. The patients (blindly allocated) underwent nerve block ultrasound guided, then followed up after one month by headache diary and HIT- 6 scale and three months by MIDAS. Results were analysed on SPSS, using mixed AVOVA and Tukey's Post-Hoc analysis, Fisher's exact and paired t-test.</p><p><strong>Results: </strong>The two groups were matched as regards the gender, age, type of migraine, frequency and years lived with headache. The study revealed that GON and SPG block, were equally effective (p < 0.05) as regards reducing the headache diary parameters, as well as the total pain index and the functional impact on HIT-6 and MIDAS scale. SPG block was more effective in patients with autonomic manifestations and temporal location of pain.</p><p><strong>Conclusion: </strong>Ultrasound guided SPG is as effective as GON as a treatment modality for chronic resistant migraine and may be more useful in the presence of autonomic manifestations and temporal location of pain.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"80"},"PeriodicalIF":7.3,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12004780/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143969778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Network meta‑analysis comparing efficacy of different strategies on medication‑overuse headache.","authors":"Prut Koonalintip, Suppakorn Yamutai, Suwanna Setthawatcharawanich, Therdpong Thongseiratch, Ply Chichareon, Benjamin R Wakerley","doi":"10.1186/s10194-025-02031-1","DOIUrl":"https://doi.org/10.1186/s10194-025-02031-1","url":null,"abstract":"","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"81"},"PeriodicalIF":7.3,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12004853/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143996242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PACAP38-induced migraine attacks are independent of CGRP signaling: a randomized controlled trial.","authors":"Mohammad Al-Mahdi Al-Karagholi, Zixuan Alice Zhuang, Signe Beich, Håkan Ashina, Messoud Ashina","doi":"10.1186/s10194-025-02022-2","DOIUrl":"https://doi.org/10.1186/s10194-025-02022-2","url":null,"abstract":"<p><strong>Background: </strong>Calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) are key pathogenic drivers of migraine. While CGRP has become the target of several mechanism-based therapies, less is known about PACAP38 signaling in migraine pathogenesis. Previous studies suggest that PACAP38 can modulate CGRP release, but it might also induce migraine attacks via CGRP-independent mechanisms. Whether PACAP38 signaling is independent of and parallel to CGRP signaling has implications for future therapeutic strategies. Here, we aimed to ascertain whether PACAP-38 can mediate migraine attacks independently of CGRP signaling by assessing the ability of eptinezumab to prevent PACAP38-induced migraine attacks.</p><p><strong>Methods: </strong>In a double-blind, placebo-controlled, parallel-group study, we randomly allocated adults with migraine without aura to receive either an intravenous infusion of 300-mg eptinezumab or matching placebo (isotonic saline) over 30 min. Two hours post-infusion, all participants were administered PACAP38 intravenously at 10 pmol/kg/min for 20 min. The primary endpoint was the incidence of migraine attacks during the 24-hour observational period post-infusion of eptinezumab or placebo. Key secondary endpoints included between-group differences in incidence of headache, and area under the curve (AUC) for headache intensity scores, diameter of the superficial temporal artery (STA) and facial skin blood flow.</p><p><strong>Results: </strong>A total of 38 participants were enrolled and completed the study. No difference was observed in the incidence of PACAP38-induced migraine attacks between the eptinezumab (10 [53%] of 19) and placebo (12 [63%] of 19) groups (Fisher's exact test: P = 0.74). Headache of any intensity was reported by 15 (79%) participants in the eptinezumab group, compared with 16 (84%) participants in the placebo group (Fisher's exact test: P > 0.99). The AUC for headache intensity scores did not differ between the two groups during the first 12 h post-infusion of PACAP38 (Mann-Whitney U-test: P = 0.96). No differences were observed in AUC between the eptinezumab and placebo groups with respect to changes in STA diameter and facial skin blood flow (P > 0.05). No serious adverse events occurred.</p><p><strong>Conclusions: </strong>Our results suggest that PACAP38 may mediate its signaling independently of CGRP in migraine pathogenesis. Therapies targeting PACAP signaling are thus a promising new avenue for treating migraine.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov, NCT05635604. Registered on November 15 2022.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"79"},"PeriodicalIF":7.3,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11998216/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144016760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}