Journal of Headache and Pain最新文献

Background: Rimegepant is a small-molecule calcitonin gene-related peptide receptor antagonist approved in adults for acute treatment of migraine (with or without aura) and preventive treatment of episodic migraine (EM). Rimegepant is well tolerated at approved doses; 75 mg as needed up to once per day for acute treatment and 75 mg every other day for preventive treatment. This study evaluated long-term safety and tolerability of once-daily (QD) rimegepant 75 mg for EM prevention.

Methods: Adults with 4-14 migraine attacks per month received open-label oral rimegepant 75 mg QD for up to 24 weeks. Standard-of-care medications for acute treatment of migraine and stable dosing of preventive migraine medications were permitted. Endpoints included on-treatment adverse events (AEs) occurring in ≥5% of participants, on-treatment serious AEs, on-treatment AEs leading to rimegepant discontinuation, and on-treatment grade 3-4 laboratory test abnormalities. Efficacy was not assessed in this study.

Results: Overall, 250 participants (female = 82.4%, White = 86.4%, mean age = 42.6 years) received ≥1 dose of rimegepant and 74.8% completed open-label treatment. Mean (SD) time on rimegepant was 19.3 (8.7) weeks. Overall, 53.6% of participants had ≥1 on-treatment AE, none had a serious AE, 1.6% had a severe AE, and 2.8% had an AE leading to rimegepant discontinuation. On-treatment AEs occurring in ≥5% of participants included nasopharyngitis (9.2%), COVID-19 (6.4%), and nausea (6.0%). On-treatment grade 3-4 laboratory test abnormalities included low lymphocytes (0.4%), high creatine kinase (3.8%), low glucose (0.4%), high low-density lipoprotein cholesterol (LDL-C; 9.8%), high fasting LDL-C (9.3%), high non-fasting LDL-C (10.2%), high potassium (1.3%), high triglycerides (0.9%), high fasting triglycerides (1.3%), and urine glucose (0.5%). No on-treatment elevations in liver transaminases (alanine aminotransferase [ALT] or aspartate aminotransferase [AST]) > 5× the upper limit of normal (ULN) or potential Hy's law cases (ALT or AST > 3× the ULN concurrent with total bilirubin levels > 2× the ULN) were observed.

Conclusion: Rimegepant 75 mg QD for up to 24 weeks had a favorable safety profile for preventive treatment of EM.

Trial registration: ClinicalTrials.gov NCT05207865 (registered January 12, 2022).

Background: Primary headache disorders such as migraine and cluster headache exhibit circadian and circannual variations in attack onset. Melatonin plays a central role in regulating biological rhythms and likely influences the timing of headache attacks. Recent evidence suggests melatonin may be a promising treatment for migraine and cluster headache; however, underlying mechanisms need to be elucidated. Because of the importance of the trigeminovascular system (TVS) and trigeminal-parasympathetic ganglia in these disorders, we proposed that melatonin receptors (MT1 and MT2) are expressed in these pathways.

Methods: The trigeminal ganglion (TG), sphenopalatine ganglion (SPG), dorsal root ganglion (DRG), basilar artery, dura mater and hypothalamus were dissected from adult male and female rats. RT-qPCR and immunohistochemistry were used to assess the expression of mRNA and protein, respectively, for melatonin MT1 and MT2 receptors.

Results: Immunohistochemical analysis showed MT1 and MT2 were differentially expressed in the TG, SPG and DRG. MT1 was widely distributed in the cytoplasm and nuclei of neurons and satellite glial cells (SGCs) in the TG, while MT2 localized mainly in the cytoplasm of neurons and Aδ-fibers. Both MT1 and MT2 co-localized with CGRP and the CGRP receptor component RAMP1. MT2 immunoreactivity was also found in Aδ-fibers throughout the dura mater and was co-expressed with Contactin-associated protein 1(CASPR) at the paranodal regions of Aδ-fibers. No significant sex differences were found in receptor expression in the TG, although mRNA levels of MT1 were approximately twice as high as those for MT2. In SPG, both receptors co-localized with the neuropeptides VIP and PACAP. In cerebral arteries, only MT1 was detected, and it was localized mainly in endothelial and smooth muscle cells.

Conclusions: This study demonstrates that MT1 and MT2 receptors are expressed in the TVS and SPG, key components involved in migraine and cluster headache. Melatonin receptor co-localization with neuropeptides involved in autonomic and sensory neuronal regulation supports a potential mechanism by which melatonin influences headache onset and progression. Together, these findings support a role for melatonin influences in primary headache pathophysiology and point to its potential for novel headache treatment.

Background: Migraine is a common, disabling neurological disorder. Genome-wide association studies have mapped numerous migraine risk loci, but the causal genes and their cell-type context remain unclear. Prior work linked migraine GWAS to bulk brain eQTLs; however, tissue-average signals obscure cell-specific regulation.

Methods: We extended these findings to single-cell resolution. Cis-eQTL instruments from 183 human donors across eight brain cell types were filtered by genome-wide significance, LD pruning, and instrument strength, yielding 1,746 independent eGenes. Two-sample Mendelian randomization (MR) tested effects on migraine risk in FinnGen R12 (discovery) with replication in UK Biobank (GCST90473326). To control for multiple testing, we applied within-cell-type Bonferroni correction and global false discovery rate (FDR) adjustment. Bayesian colocalization was performed in both discovery and replication cohorts to evaluate shared causal variants. We also performed a phenome-wide association screen (PheWAS) and profiled regional brain RNA.

Results: Eleven eGenes were significant in FinnGen. Protective associations were observed for BTBD16 in excitatory and inhibitory neurons, RRP15 in excitatory neurons, CCDC146 and GSTM3 in oligodendrocytes, and PDE4B in microglia. Risk-increasing associations were found for GSTM2 (excitatory neurons), RIMS1 and DPH1 (astrocytes), AADAC (microglia), and RBM20 (endothelium). Replication supported signals for inhibitory-neuronal BTBD16 and astrocytic RIMS1. Colocalization analyses indicated shared causal variants at both loci in the discovery cohort (PP.H4 > 0.80). PheWAS showed no genome-wide liabilities for either gene. Regional expression suggested white-matter enrichment for BTBD16 and a cerebellar peak for RIMS1.

Conclusions: Cell-type-specific MR sharpens migraine mechanisms beyond bulk tissue and prioritizes inhibitory-neuronal BTBD16 (protective) and astrocytic RIMS1 (risk-increasing) for mechanistic validation and therapeutic exploration.

Background: Suicide is considered as common in patients with cluster headache (CH) and is defined as 'suicidal headache'. However, the exact level of suicidality is not known and is intuitively assumed to be correlated with the CH severity.

Methods: This work is a systematic review of data accessible through PubMed and published up to July 25, focusing on the suicidality of CH according to the rates of suicidal ideation and suicide attempts. This meta-analysis was carried out with all selected studies then by considering studies with specialized recruitment and studies with non-specialized recruitment. A qualitative analysis was performed to identify determinants of CH suicidality.

Results: Among the 53 publications identified, 12 were selected corresponding to 10 studies. These selected studies included a total of 34180 subjects (range 75-24131). Eight were performed in a specialized field (headache tertiary center, neurology clinic or via CH patients' association) and 2 in a non-specialized field (via heath registry). The overall rate of suicidal ideation in CH was estimated at 8.0% (95%CI [7.7; 8.3] and overall rate of suicide attempts in CH was estimated at 1.2% (95%CI [1.1; 1.3]). In a non-specialized field, these rates were estimated at 5.2% (95%CI [4.9; 5.4]) and 1.1% (95%CI [1.0; 1.2]) respectively. In specialized field, these rates were estimated at 44.6% (95%CI [42.7; 46.6]) and 5.1% (95%CI [3.9; 6.7]) respectively. The qualitative analysis showed that few determinants have been considered but it appears that the risk is greater during CH attacks, and it involves psychological determinants such as demoralization.

Conclusion: The overall suicidal risk in CH does not appear to be higher than that of the general population, but there is a suicidal risk increase among CH patients followed up in specialized field. This higher risk is indeed probably related to the severity of CH in terms of pain, but it is also probably related to other factors such as impulsive aggressiveness during CH attacks and psychological factors such as demoralization.

Registration: The systematic review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) on 07/22/2025 (number: CRD420251110095).

Background: The Global Campaign against Headache is undertaking a worldwide programme of cross-sectional schools-based studies of headache prevalence and attributed burden among children (6-11 years) and adolescents (12-17). The purpose is to expand the still sparse knowledge of headache among these age groups, using a data-acquisition technique that cluster-samples the world. This survey in Georgia was the fourth in the European Region, following similar studies in Turkey, Austria and Lithuania, and others in African, Eastern Mediterranean, South-East Asia and Western Pacific Regions.

Methods: We used the Global Campaign's standardized protocol, selecting schools representative of the country. The child and adolescent versions of the structured HARDSHIP questionnaire, translated into Georgian language, were completed by pupils under supervision in class. Headache diagnoses followed ICHD-3, with the exception of undifferentiated headache (UdH), which we defined initially as mild and subsequently as mild-to-moderate headache lasting < 1 h. Enquiry timeframes were 1 year, 4 weeks and 1 day (headache yesterday [HY]).

Results: Of 2,790 participants, two thirds (68.5%) reported headache in the preceding year (age- and gender-adjusted 1-year prevalence: 66.3%). HY was reported by 20.4%, a proportion that might be expected to have headache on any day. Headache on ≥ 15 days/month (H15+) was common (4.1%), with probable medication-overuse headache (pMOH) accounting for 0.5% (0.2% among children, 0.7% among adolescents; p = 0.06). UdH took diagnostic precedence over migraine and tension-type headache (TTH), so all other estimates were influenced by the definition of UdH. By the conventional (initial) definition, 1-year prevalence of UdH was 18.2%; by the modified definition, it was 30.2%. Estimates for migraine and TTH, 29.1% and 13.1% respectively with UdH defined conventionally, were reduced to 22.2% and 9.5% with the modified definition.

Conclusions: Headache is very common among children and adolescents in Georgia. The findings raise particular concern about the prevalence of H15 + in young people, with a strong trend of increasing pMOH with age. They also highlight the diagnostic uncertainties inherent in epidemiological studies in these age groups. With the definition of UdH a dominating issue, the findings support the view that it needs to be modified, without offering a definitive solution.