Journal of Headache and Pain最新文献

Background: Orally administered second-generation gepants are effective for the treatment of migraine. The intranasal administration of the third-generation gepant zavegepant might have additional benefits including a rapid onset of action, but it is not clear yet to which extent this has clinical relevance.

Methods: We examined the effect of zavegepant on the relaxations induced by calcitonin gene-related peptide (CGRP) in human isolated middle meningeal arteries. Furthermore, we connected the pharmacodynamics and pharmacokinetics of gepants by combining data from clinical and basic research.

Results: We showed that 10 nM zavegepant potently antagonized the functional response to CGRP. We also showed that all gepants are effective at inhibiting functional responses to CGRP at their therapeutic plasma concentrations.

Conclusions: The relatively low predicted potency of zavegepant to inhibit CGRP-induced relaxation at therapeutic systemic plasma concentrations may point to the relevance of local delivery to the trigeminovascular system through intranasal administration. This approach may have additional benefits for various groups of patients, including overweight patients.

Background: miR-155 is involved in the generation and maintenance of inflammation and pain, endothelial function and immune system homeostasis, all functions that are relevant for migraine. The present study aims to assess the levels of miR-155 in migraine subtypes (episodic and chronic) in comparison to age- and sex-matched healthy controls.

Methods: This is a cross-sectional, controlled, study involving three study groups: I) episodic migraine (n = 52, EM), II) chronic migraine with medication overuse (n = 44, CM-MO), and III) healthy controls (n = 32, HCs). We assessed the interictal gene expression levels of miR-155, IL-1β, TNF-α, and IL-10 in peripheral blood monocytes using rtPCR. The monocytic differentiation toward the M1 (pro-inflammatory) or M2 (anti-inflammatory) phenotypes was assessed in circulating monocytes with flow cytometry analysis and cell sorting.

Results: miR-155 gene expression was higher in CM-MO group (2.68 ± 2.47 Relative Quantification - RQ) when compared to EM group (1.46 ± 0.85 RQ, p = 0.006) and HCs (0.44 ± 0.18 RQ, p = 0.001). In addition, miR-155 gene expression was higher in EM group when compared to HCs (p = 0.001). A multivariate analysis confirmed the difference between EM and CM-MO groups after correction for age, sex, smoking habit, preventive treatment, aura, presence of psychiatric or other pain conditions. We found higher gene expression of IL-1β, TNF-α, and lower gene expression of IL-10 in migraine participants when compared to HCs (p = 0.001 for all comparisons). TNF-α and IL-10 genes alterations were more prominent in CM-MO when compared to EM participants (p = 0.001). miR-155 positively correlated with IL-1β (p = 0.001) and TNF-α (p = 0.001) expression levels. Finally, in people with CM-MO, we described an up-regulated percentage of events in both M1 and M2 monocytic profiles.

Conclusions: Our study shows for the first time a specific profile of activation of miR-155 gene expression levels in monocytes of selected migraine subpopulations, more pronounced in subjects with CM-MO. Interestingly, mir-155 expression correlated with markers of activation of the inflammatory and immune systems. The CM-MO subpopulation showed a peculiar increase of both pro-inflammatory and anti-inflammatory monocytes which worths further investigation.

Trial registration: www.

Clinicaltrials: gov . (NCT05891808).

Background: Widespread neuropathic pain usually affects a wide range of body areas and inflicts huge suffering on patients. However, little is known about how it happens and effective therapeutic interventions are lacking.

Methods: Widespread neuropathic pain was induced by partial infraorbital nerve transection (p-IONX) and evaluated by measuring nociceptive thresholds. In vivo/vitro electrophysiology were used to evaluate neuronal activity. Virus tracing strategies, combined with optogenetics and chemogenetics, were used to clarify the role of remodeling circuit in widespread neuropathic pain.

Results: We found that in mice receiving p-IONX, along with pain sensitization spreading from the orofacial area to distal body parts, glutamatergic neurons in the ventral posteromedial nucleus of the thalamus (VPM^Glu) were hyperactive and more responsive to stimulations applied to the hind paw or tail. Tracing experiments revealed that a remodeling was induced by p-IONX in the afferent circuitry of VPM^Glu, notably evidenced by more projections from glutamatergic neurons in the dorsal column nuclei (DCN^Glu). Moreover, VPM^Glu receiving afferents from the DCN extended projections further to glutamatergic neurons in the posterior insular cortex (pIC). Selective inhibition of the terminals of DCN^Glu in the VPM, the soma of VPM^Glu or the terminals of VPM^Glu in the pIC all alleviated trigeminal and widespread neuropathic pain.

Conclusion: These results demonstrate that hyperactive VPM^Glu recruit new afferents from the DCN and relay the extra-cephalic input to the pIC after p-IONX, thus hold a key position in trigeminal neuropathic pain and its spreading. This study provides novel insights into the circuit mechanism and preclinical evidence for potential therapeutic targets of widespread neuropathic pain.

Background: Cluster headache (CH) is a significant health concern due to its major socioeconomic consequences and most patients being refractory to conventional strategies. For treatment resistant CH, occipital nerve stimulation (ONS) is considered an effective treatment option. Whereas most patients do not adjust the amplitude of the ONS system, a subset changes the amplitude on a regular basis using their remote control, and are therefore referred to as 'voltage tuners'. Anxiety and self-control are thought to be central themes to this behavior. Research on this voltage tuning behavior could provide new insights in the use of ONS as acute attack treatment. To date, voltage tuning has not been assessed for CH. Hence this is a unique study aiming to investigate the occurrence and efficacy of voltage tuning in patients with CH and ONS.

Methods: For this analysis, patients with CH who received ONS from 2020-2024, at our university medical center, were included. All patients underwent bilateral ONS implantation. Data on attack frequency, intensity and duration were collected retrospectively. Outcomes on the response, frequency, moment during the day, duration, rationale, sensation, average increase in amplitude, and efficacy of voltage tuning were collected with prospective interviews.

Results: Thirty-three patients (M = 20) (42 ± 12.7 years) were included in the current analysis. At 1y follow-up, an overall response rate of 70% (23/33) was found for ONS. In total, 48% (18/33) of patients were defined as voltage tuners. Voltage tuning was performed with an average increase in amplitude of 92 (20-360)%, a frequency of 1-20 times/month and duration of 20 minutes-48 hours. Sensations of voltage tuning were described as "tingling" and/or "pinching". The rationale for voltage tuning in patients varied from prevention and ceasing to lowering the intensity and enhance control of CH attack.

Conclusions: Outcomes show that voltage tuning may cease and/or terminate CH attacks and therefore raise interests in the use of ONS as acute attack treatment for patients with resistant CH treated with ONS. Future research on the occurrence and potential of voltage tuning will provide valuable insights for achieving optimal efficacy of ONS and quality of life in patients with CH.

Background: A global schools-based programme within the Global Campaign against Headache is estimating the burden of headache in children (6-11 years) and adolescents (12-17 years), cluster-sampling the world by conducting national studies in all world regions. Its purpose is to complement population-based studies in adults, adding to knowledge of the burden of headache and informing educational and health policies. This study in Benin was the third in the programme from sub-Saharan Africa (SSA).

Methods: We followed the generic protocol for the global study. In a cross-sectional survey, the child and adolescent versions of the Headache-Attributed Restriction, Disability, Social Handicap and Impaired Participation (HARDSHIP) structured questionnaire were administered to pupils within their classes in 16 schools selected from across the country to be representative of its diversities. Headache diagnostic questions were based on ICHD-3 criteria but for the inclusion of undifferentiated headache (UdH).

Results: Very large proportions of pupils were absent on the survey days. The sampled population defined by class registers totalled 11,802 pupils, of whom only 2,488 were present. A further 193 pupils (or their parents) declined the survey. The surveyed sampled (N = 2,295; males 1,156 [50.4%], females 1,139 [49.6%]) included 1,081 children (47.1%) and 1,214 adolescents (52.9%), with a non-participating proportion (193/2,488) of 7.8%. Headache ever was reported by 97.3% of the sample. Age- and gender-adjusted 1-year prevalences, according to responses given, were 53.4% for migraine (almost three quarters of this being probable migraine), 21.3% for tension-type headache, 8.2% for UdH, 1.0% for probable medication-overuse headache (pMOH) and 2.6% for other headache on ≥ 15 days/month (H15+). Both pMOH and other H15 + were substantially more prevalent among adolescents.

Conclusion: The finding for migraine is anomalous, but, within this series of studies, the same was found in Zambia and similar in Ethiopia, both in SSA. While many cases identified as probable migraine, especially among children, might better have been diagnosed as UdH, the true prevalence of migraine almost certainly exceeds 21%. Regardless of diagnosis, headache is very common among children and adolescents in Benin. The study sounds an alarm with regard to pMOH as a developing problem pre-adulthood.

This commentary addresses the use of rimegepant for situational prevention in migraine management. While the approach of using prophylactic treatments during high-risk periods is not new, its application with rimegepant described by Lipton et al. raises ethical and clinical concerns. These include the challenge of defining high-risk periods, the potential for overmedication, and the risk of medication overuse headache (MOH). The current evidence on MOH with gepants is inconclusive, and recommendations on dosing may be insufficient. Additionally, the long-term safety of calcitonin gene-related peptide (CGRP) antagonists remains uncertain, especially regarding cardiovascular and other systemic effects. The commentary emphasizes the need for caution and thorough investigation into the long-term risks and benefits of situational prevention with rimegepant before widespread adoption.

Background: Migraine is a neurological disorder characterized by complex, widespread, and sudden attacks with an unclear pathogenesis, particularly in chronic migraine (CM). Specific brain regions, including the insula, amygdala, thalamus, and cingulate, medial prefrontal, and anterior cingulate cortex, are commonly activated by pain stimuli in patients with CM and animal models. This study employs fluorescence microscopy optical sectioning tomography (fMOST) technology and AAV-PHP.eB whole-brain expression to map activation patterns of brain regions in CM mice, thus enhancing the understanding of CM pathogenesis and suggesting potential treatment targets.

Methods: By repeatedly administering nitroglycerin (NTG) to induce migraine-like pain in mice, a chronic migraine model (CMM) was established. Olcegepant (OLC) was then used as treatment and its effects on mechanical pain hypersensitivity and brain region activation were observed. All mice underwent mechanical withdrawal threshold, light-aversive, and elevated plus maze tests. Viral injections were administered to the mice one month prior to modelling, and brain samples were collected 2 h after the final NTG/vehicle control injection for whole-brain imaging using fMOST.

Results: In the NTG-induced CMM, mechanical pain threshold decreased, photophobia, and anxiety-like behavior were observed, and OLC was found to improve these manifestations. fMOST whole-brain imaging results suggest that the isocortex-cerebral cortex plate region, including somatomotor areas (MO), somatosensory areas (SS), and main olfactory bulb (MOB), appears to be the most sensitive area of activation in CM (P < 0.05). Other brain regions such as the inferior colliculus (IC) and intermediate reticular nucleus (IRN) were also exhibited significant activation (P < 0.05). The improvement in migraine-like symptoms observed with OLC treatment may be related to its effects on these brain regions, particularly SS, MO, ansiform lobule (AN), IC, spinal nucleus of the trigeminal, caudal part (Sp5c), IRN, and parvicellular reticular nucleus (PARN) (P < 0.05).

Conclusions: fMOST whole-brain imaging reveals c-Fos + cells in numerous brain regions. OLC improves migraine-like symptoms by modulating brain activity in some brain regions. This study demonstrates the activation of the specific brain areas in NTG-induced CMM and suggests some regions as a potential treatment mechanism according to OLC.

Objective: To assess rates of traversing barriers to care to access optimal clinical outcomes in people with migraine internationally.

Background: People in need of medical care for migraine should consult a health care professional knowledgeable in migraine management, obtain an accurate diagnosis, and receive an individualized treatment plan, which includes scientific society guideline-recommended treatments where appropriate.

Methods: The Chronic Migraine Epidemiology and Outcomes-International (CaMEO-I) Study was a cross-sectional, web-based survey conducted from July 2021 through March 2022 in Canada, France, Germany, Japan, the United Kingdom, and the United States (US). Respondents who met modified International Classification of Headache Disorders, 3rd edition, criteria for migraine and had Migraine Disability Assessment Scale (MIDAS) scores of ≥ 6 (i.e., mild, moderate, or severe disability) were deemed to need medical care and were included in this analysis. Minimally effective treatment required that participants were currently consulting a health care professional for headache (barrier 1), reported an accurate diagnosis (barrier 2), and reported use of minimally appropriate pharmacologic treatment (barrier 3; based on American Headache Society 2021 Consensus Statement recommendations). Proportions of respondents who successfully traversed each barrier were calculated, and chi-square tests were used to assess overall difference among countries.

Results: Among 14,492 respondents with migraine, 8,330 had MIDAS scores of ≥ 6, were deemed in need of medical care, and were included in this analysis. Current headache consultation was reported by 35.1% (2926/8330) of respondents. Compared with the US, consultation rates and diagnosis rates were statistically significantly lower in all other countries except France where they were statistically significantly higher. Total appropriate treatment rates were also statistically significantly lower in all other countries compared with the US except France, which did not differ from the US. All 3 barriers were traversed by only 11.5% (955/8330) of respondents, with differences among countries (P < 0.001).

Conclusions: Of people with migraine in need of medical care for migraine, less than 15% traverse all 3 barriers to care. Although rates of consultation, diagnosis, and treatment differed among countries, improvements are needed in all countries studied to reduce the global burden of migraine.

Trial registration: NA.

Background: We have previously shown headache to be highly prevalent in Cameroon. Here we present the attributed burden. We also perform a headache-care needs assessment.

Methods: This was a cross-sectional survey among adults (18-65 years) in the general population. Multistage cluster-sampling in four regions (Centre, Littoral, West and Adamawa), home to almost half the country's population, generated a representative sample. We used the standardised methodology of the Global Campaign against Headache, including the HARDSHIP questionnaire, with diagnostic questions based on ICHD-3 and enquiries into symptom burden, impaired participation (lost productivity and disengagement from social activity), quality of life (QoL) using WHOQoL-8, and willingness to pay (WTP) for effective care. We defined headache care "need" in terms of likelihood of benefit, counting all those with probable medication-overuse headache (pMOH) or other headache on ≥ 15 days/month (H15 +), with migraine on ≥ 3 days/month, or with migraine or tension-type headache (TTH) and meeting either of two criteria: a) proportion of time in ictal state (pTIS) > 3.3% and intensity ≥ 2 (moderate-to-severe); or b) ≥ 3 lost days from paid and/or household work in the preceding 3 months.

Results: Among 3,100 participants, mean frequency of any headache was 6.7 days/month, mean duration 13.0 h and mean intensity 2.3 (moderate). Mean pTIS was 9.8%, which (with prevalence factored in) diluted to 6.1-7.4% of all time in the population. Most time was spent with H15 + (5.3% of all time), followed by TTH (1.0%) and migraine (0.8%). For all headache, mean lost days/3 months were 3.4 from paid work, 3.0 from household work and 0.6 from social/leisure activities, diluting to 2.5, 2.2 and 0.6 days/3 months in the population. QoL (no headache: 27.9/40) was adversely impacted by pMOH (25.0) and other H15 + (26.0) but not by migraine (28.0) or TTH (28.0). WTP (maximally XAF 4,462.40 [USD 7.65] per month) was not significantly different between headache types. An estimated 37.0% of adult Cameroonians need headache care.

Conclusion: Headache disorders in Cameroon are not only prevalent but also associated with high attributed burden, with heavily impaired participation. Headache-care needs are very high, but so are the economic costs of not providing care.

Background: While growing evidence suggests a relationship between migraine and cardiovascular disease, the genetic evidence for a causal relationship between migraine and cardiovascular disease is still scarce. Investigating the causal association between migraine and cardiovascular disease is vital.

Methods: We carried out a bidirectional Mendelian randomization (MR) study including discovery samples and replication samples using publicly available genome-wide association study (GWAS) summary datasets and stringent screening instrumental variables. Four different MR techniques-Inverse variance weighted (IVW), MR ‒Egger, weighted median, and weighted mode-as well as various sensitivity analyses-Cochran's Q, IVW radial, leave-one-out (LOO), and MR-PRESSO-were utilized to investigate the causal relationship between cardiovascular disease and migraine.

Results: The protective causal effects of genetically predicted migraine on coronary artery disease (OR, 0.881; 95% CI 0.790-0.982; p = 0.023) and ischemic stroke (OR, 0.912; 95% CI 0.854-0.974; p = 0.006) were detected in forward MR analysis but not in any other cardiovascular disease. Consistently, we also discovered protective causal effects of coronary atherosclerosis (OR, 0.865; 95% CI 0.797-0.940; p = 0.001) and myocardial infarction (OR, 0.798; 95% CI 0.668-0.952; p = 0.012) on migraine in reverse MR analysis.

Conclusion: We found a potential protective effect of migraine on coronary artery disease and ischemic stroke and a potential protective effect of coronary atherosclerosis and myocardial infarction on migraine. We emphasised epidemiological and genetic differences and the need for long-term safety monitoring of migraine medications and future research to improve cardiovascular outcomes in migraine patients.