Journal of Headache and Pain最新文献

Background: There is a lack of up-to-date information on the prevalence and burden of headache in Norway. Here we describe the methods and validation of the diagnostic tool of the PopHEAD study, a study designed to determine the prevalence and burden of migraine, tension-type headache, and medication-overuse headache.

Method: PopHEAD is a Norwegian population-based cross-sectional study conducted in Vestfold and Telemark County in 2023. A random sample of 28,753 individuals aged 18 to 70 was invited to participate. The study used a digital version of the Headache-Attributed Restriction, Disability, Social Handicap and Impaired Participation (HARDSHIP) questionnaire, translated into Norwegian using the Lifting The Burden translation protocol. A subsample of participants was contacted by telephone within four weeks for an interview with a headache neurologist blinded to the questionnaire responses. Headache disorders were diagnosed according to the criteria of the International Classification of Headache Disorders version 3. Validity was expressed by sensitivity, specificity and Cohen's kappa (κ).

Results: In total, 8,265 (3,344 men and 4,921 women) responded. Most men (75.0%) and women (89.7%) reported having had a headache in the past year. Of 667 participants contacted for a telephone interview, 505 responded. The sensitivity and specificity of the questionnaire-based diagnoses were 97% and 72% for self-reported headache in the previous year (Cohen's kappa κ = 0.72), 77% and 85% for migraine (κ = 0.61), 77% and 74% for tension-type headache (κ = 0.51), and 58% and 99% for medication-overuse headache (κ = 0.63), respectively.

Conclusion: The PopHEAD questionnaire is a valid tool for identifying individuals with lifetime headache, migraine, tension-type headache, and medication overuse headache.

Background: Headache is a pain disorder present in populations world-wide with a higher incidence in females. Specifically, the incidences of medication overuse headache (MOH) have increased worldwide. Comorbidities of MOH include photosensitivity, anxiety, "brain fog", and decreased physical activity. The FDA-approved long-lasting selective β₂-adrenergic receptor agonist, formoterol, is currently approved for use in severe asthma and chronic obstructive pulmonary disease. Recently, interest in repurposing formoterol for use in other disorders including Alzheimer's disease, and neuropathic pain after spinal cord injury and traumatic brain injury has gained traction. Thus, revisiting known side-effects of formoterol, like headache and anxiety, could inform treatment paradigms. The endocannabinoid (eCB) system is implicated in the etiology of preclinical headache, with observed decreases in the circulating levels of endogenous cannabinoids, referred to as Clinical Endocannabinoid Deficiency. As cross-talk between the eCB system and adrenergic receptors has been reported, this study investigated the role of the eCB system and ability of formoterol to induce headache-like periorbital allodynic behavior.

Methods: Female 8-week-old C57Bl/6J mice were treated daily with formoterol (0.3 mg/kg, i.p.) for up to 42-days, during which they were assessed for periorbital allodynia, open field/novel object recognition, and photosensitivity. At the end of the study, the periaqueductal grey (PAG), a brain region known to contribute to both headache induction and maintenance, was collected and subjected to LC-MS to quantify endocannabinoid levels.

Results: Mice exhibited periorbital allodynia at nearly all time points tested and photosensitivity from 28-days onward. Levels of endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), along with cannabinoid receptor 1 (CB₁R) expression were altered by both age and upon treatment with formoterol. Administration of FAAH/MAGL inhibitors, to target the eCB system, and a non-selective cannabinoid receptor agonist, WIN 55,212 reversed the formoterol-induced periorbital allodynia.

Conclusions: These results suggest that formoterol is dysregulates eCB tone to drive headache-like periorbital allodynic behaviors. These results could help inform preventative treatment options for individuals receiving formoterol, as well as provide information on the interaction between the eCB and adrenergic system.

Background: Headache disorders are among the leading causes of disability worldwide, especially in young adults. However, no data on the burden of these disorders in Vietnam have been published to date. This study is the first to assess the prevalence of headache disorders among Vietnamese medical students.

Methods: This study was conducted in accordance with the recommended methodology of the Global Campaign. Data were collected through interviews using the HARDSHIP structured questionnaire, translated into Vietnamese, with diagnostic assessments based on ICHD-3 criteria. Participants were recruited from two medical universities in Vietnam. The 1-year prevalence rates of headache disorders of public health significance (migraine, tension-type headache [TTH], and probable medication-overuse headache [pMOH]) were estimated. Logistic regression analyses were performed to evaluate the associations between headache disorders and sociodemographic/anthropometric variables.

Results: A total of 1,362 participants (42.7% males and 57.3% females) with a mean age of 21.1 ± 1.6 years were included. The overall 1-year prevalence of any headache was 82.6% [95% CI: 80.5-84.6], with a prevalence of 74.7% [71.0-78.2] among males and 88.5% [86.0-90.6] among females. The 1-year prevalences for specific headache types were as follows: migraine 21.8% [19.6-24.1], TTH 54.0% [51.3-56.7], pMOH 0.4% [0.2-1.0], and other headaches on ≥ 15 days/month 3.7% [2.7-4.8]. The one-day prevalence of any headache was 12.1%. Female gender (adjusted OR = 1.77 [1.32-2.36]; p < 0.001) was independently associated with a higher prevalence of migraine, while older age (aOR = 0.84 [0.77-0.91] per year increase) was associated with a lower prevalence. In contrast, TTH was more common among older participants (aOR = 1.07 [1.005-1.15] per year increase).

Conclusions: This study highlights the high prevalence of headache disorders, particularly migraine and TTH, among medical students in Vietnam. These findings underscore the critical need for public health initiatives to improve early diagnosis and effective management of headache disorders within this population.

Background: In recent years, miRNAs found in biological fluids have gained interest as biomarkers of numerous conditions, including migraine. This study aimed to identify differences in the levels of circulating miRNAs in the serum of migraineurs as compared to healthy controls, as well as between patients with different types of migraine and during the ictal and nonictal phases of the condition.

Methods: The screening phase of the study included serum from 13 migraine patients and 13 sex and age matched controls. A panel of 179 miRNAs was analysed using locked nucleic acid SYBR based qPCR. Based on statistical analysis (U Mann-Whitney test) and data from existing literature, nine miRNAs were selected for validation by TaqMan qPCR in an independent cohort of 26 migraineurs and eleven healthy controls. For comparison between the study and control group, U Mann-Whitney test was performed. The differences between patients with chronic and episodic migraine, migraine with and without aura and in ictal and nonictal phases were analysed with Kruskal-Wallis test. The results were corrected for multiple comparisons using Benjamini-Hochberg method. In all analysis p value ≤ 0,05 was considered as significant.

Results: Two miRNAs, miR-145-5p and miR-26a-5p were significantly upregulated in serum of migraineurs compared to healthy controls. MiRNA-19a-3p was downregulated in patients currently experiencing migraine headache compared to those in the interictal period. No differences were found between patients with different migraine types.

Conclusion: The results of our study add to the growing body of evidence for dysregulation of the circulating miRNA profile by migraine. They are further supported by previous reports on differential expression of miR-145-5p, miR-26a-5p and miR-19a-3p in migraineurs. However, more research on larger populations is needed to validate these findings, as well as elucidate the role of circulating miRNAs in the condition. Moreover, to wholly explore the biomarker potential of miRNAs, migraine patients should not only be compared to healthy controls but also to populations with different headache disorders.

Background: Medication overuse headache (MOH) is the most common secondary headache disorder, resulting from chronic and excessive use of medication to treat headaches, for example, sumatriptan. In a recent study, we have shown that the peripheral C-C motif ligand 2 (CCL2), C-C motif chemokine receptor 2 (CCR2) and calcitonin-gene-related peptide (CGRP) signaling pathways interact with each other and play critical roles in the development of chronic migraine-related behavioral and cellular sensitization. In the present study, we investigated whether CCL2-CCR2 and CGRP signaling pathways play a role in the development of sumatriptan overuse-induced sensitization, and whether they are involved in its resolution by the low-dose interleukin-2 (LD-IL-2) treatment.

Methods: Mice received daily sumatriptan administration for 12 days. MOH-related behavioral sensitization was assessed by measuring changes of periorbital mechanical thresholds for 3 weeks. CCL2-CCR2 and CGRP signaling pathways were inhibited by targeted gene deletion or with an anti-CCL2 antibody. Ca²⁺-imaging was used to examine whether repetitive sumatriptan treatment enhances CGRP and pituitary adenylate cyclase-activating polypeptide (PACAP) signaling in trigeminal ganglion (TG) neurons. LD-IL-2 treatment was initiated after the establishment of sumatriptan-induced sensitization. Immunohistochemistry and flow cytometry analyses were used to examine whether CCL2-CCR2 signaling controls regulatory T (Treg) cell proliferation and/or trafficking.

Results: CCL2, CCR2 and CGRPα global KO mice exhibited robust sumatriptan-induced behavioral sensitization comparable to wild-type controls. Antibody neutralization of peripheral CCL2 did not affect sumatriptan-induced behaviors either. Repeated sumatriptan administration did not enhance the strength of CGRP or PACAP signaling in TG neurons. Nevertheless, LD-IL-2 treatment, which facilitated the resolution of sumatriptan-induced sensitization in wild-type and CGRPα KO mice, was completely ineffective in mice with compromised CCL2-CCR2 signaling. In CCL2 KO mice, we observed normal LD-IL-2-induced Treg expansion in peripheral blood, but the increase of Treg cells in dura and TG tissues was significantly reduced in LD-IL-2-treated CCL2 KO mice relative to wild-type controls.

Conclusions: These results indicate that the endogenous CCL2-CCR2 and CGRP signaling pathways are not involved in sumatriptan-induced behavioral sensitization, suggesting that distinct molecular mechanisms underlie chronic migraine and MOH. On the other hand, peripheral CCL2-CCR2 signaling is required for LD-IL-2 to reverse chronic headache-related sensitization.

Background: Patients with migraine often experience not only headache pain but also cognitive dysfunction, particularly in attention, which is frequently overlooked in both diagnosis and treatment. The influence of these attentional deficits on the pain-related clinical characteristics of migraine remains poorly understood, and clarifying this relationship could improve care strategies.

Methods: This study included 52 patients with migraine and 34 healthy controls. We employed the Attentional Network Test for Interactions and Vigilance-Executive and Arousal Components paradigm, combined with electroencephalography, to assess attentional deficits in patients with migraine, with an emphasis on phasic alerting, orienting, executive control, executive vigilance, and arousal vigilance. An extreme gradient boosting binary classifier was trained on features showing group differences to distinguish patients with migraine from healthy controls. Moreover, an extreme gradient boosting regression model was developed to predict clinical characteristics of patients with migraine using their attentional deficit features.

Results: For general performance, patients with migraine presented a larger inverse efficiency score, a higher prestimulus beta-band power spectral density and a lower gamma-band event-related synchronization at Cz electrode, and stronger high alpha-band activity at the primary visual cortex, compared to healthy controls. Although no behavior differences in three basic attentional networks were found, patients showed magnified N1 amplitude and prolonged latency of P2 for phasic alerting-trials as well as an increased orienting evoked-P1 amplitude. For vigilance function, improvements in the hit rate of executive vigilance-trials were exhibited in controls but not in patients. Besides, patients with migraine exhibited longer reaction time as well as larger variability in arousal vigilance-trials than controls. The binary classifier developed by such attentional deficit features achieved an F1 score of 0.762 and an accuracy of 0.779 in distinguishing patients with migraine from healthy controls. Crucially, the predicted value available from the regression model involving attentional deficit features significantly correlated with the real value for the frequency of headache.

Conclusions: Patients with migraine demonstrated significant attentional deficits, which can be used to differentiate migraine patients from healthy populations and to predict clinical characteristics. These findings highlight the need to address cognitive dysfunction, particularly attentional deficits, in the clinical management of migraine.

Background: The gut microbiota may be involved in neuropathic pain. However, the causal association between gut microbiota and neuropathic pain remains unclear. Whether immune cells and inflammatory factors mediate the pathway from gut microbiota to neuropathic pain has not been elucidated.

Methods: We obtained the summary data of 412 gut microbiota, 731 immune cells, 91 inflammatory factors, and five types of neuropathic pain (drug-induced neuropathy, postherpetic neuralgia, sciatica, trigeminal neuralgia, and unspecified neuralgia) from large-scale genome-wide association study (GWAS) datasets and the FinnGen database. We used bidirectional Mendelian randomization (MR) analysis to explore the causal association between gut microbiota and neuropathic pain. Additionally, we conducted a mediation analysis to identify whether immune cells and inflammatory factors act as mediators within these causal relationships.

Results: Our study revealed 30 causal relationships between 26 gut bacterial taxa and five types of neuropathic pain, including four associated with drug-induced neuropathy, six with postherpetic neuralgia, five with sciatica, eight with trigeminal neuralgia, and seven with unspecified neuralgia. Moreover, we identified 35 gut bacterial pathway abundances causally involved in neuropathic pain. The reverse MR analysis showed no evidence of reverse causality from gut microbiota to neuropathic pain. Mediation analysis demonstrated that the immune cell phenotype "HLA-DR⁺⁺ monocyte % leukocyte" mediated the causal relationship between p_Proteobacteria and sciatica with a mediation proportion of 36.15% (P = 0.038), whereas "CD11c on CD62L⁺ myeloid dendritic cell" mediated the causal pathway from assimilatory sulfate reduction to trigeminal neuralgia with a mediation proportion of 27.90% (P = 0.041).

Conclusion: This study identified the causal relationships between several specific gut microbiota and various neuropathic pain subtypes. Additionally, two immune cells may act as potential mediators in the pathways from gut microbiota to neuropathic pain.

Background: Calcitonin gene-related peptide (CGRP) is part of the calcitonin peptide family, which includes calcitonin (CT), amylin (AMY), and adrenomedullin (ADM). CGRP and its receptor are highly present in the trigeminovascular system (TVS). Recent research suggests that other members of the calcitonin family could be feasible therapeutic targets in the treatment of migraine. The present study aims to elucidate the distribution of ADM, AMY, CT, and their receptors in the rat TVS, and to explore potential sex differences in their expression.

Methods: Trigeminal ganglia (TG) were dissected from male and female adult rats. Protein and gene expression were assessed through immunohistochemistry and RT-qPCR. Additionally, the dura mater was isolated for further investigation of protein expression and fiber localization using immunohistochemistry.

Results: Quantitative gene expression analysis revealed the presence of all genes in male and female TGs, except for calcitonin receptor (CTR). Notably, CGRP mRNA levels in TG were several folds higher than those of other genes. The receptor activity-modifying protein-1 (RAMP1) mRNA levels were significantly higher in female compared to male. No AMY or CT immunoreactivity was observed in the TVS. In contrast, immunoreactivity for ADM, CGRP, RAMP1, CTR, and calcitonin-like receptor (CLR) were observed in the cytoplasm of TG neurons. Immunoreactive Aδ-fibers storing RAMP1, ADM and CLR were also identified. RAMP2 and RAMP3 were expressed in nucleus of TG neurons and in satellite glial cells. Furthermore, RAMP1 and CLR were co-localized with CASPR in the nodes of Ranvier located in Aδ-fibers.

Conclusions: This study provides valuable insights into the distribution of the CGRP family of peptides and their receptors in the TVS. CGRP mRNA levels in the TG were markedly higher than those of other genes, demonstrating the key role of CGRP. The co-localization of CLR and RAMP1 on Aδ-fibers with CASPR suggests a potential role for this receptor in modulating trigeminal nerve function and neuronal excitability, with implications for migraine pathophysiology. Additionally, RAMP1 mRNA levels were significantly higher in female TG compared to males, indicating sex-specific differences in gene expression. These findings underscore the need for further research into the functional significance of gender-related variations.

Background: Novel abortive treatments for migraine, ditans and gepants, have promising implications in triptan-insufficient responders with minimal existing comparative data. Our study aims to synthesize evidence through a systematic review and network meta-analysis to assess the comparative efficacy of lasmiditan, rimegepant and ubrogepant in triptan-insufficient responders.

Method: We searched PubMed, Embase, CENTRAL, and EBSCO Open Dissertations up to May 2024. We included randomized controlled trials (RCTs) that compared novel abortive treatments, including lasmiditan, rimegepant, and ubrogepant, in migraine patients who self-reported insufficient response to triptans. Outcomes are represented using relative risks with corresponding 95% confidence intervals (CI). The surface under the cumulative ranking curve (SUCRA) was used to rank each medication.

Results: A total of five phase 3 RCTs involving 3,004 patients were included in the analysis. All three agents were significantly superior to placebo for two-hour pain freedom (RR = 1.93, 95% CI [1.52, 2.46]), freedom from the most bothersome symptoms at two hours (RR = 1.55, 95% CI [1.37, 1.75]), and pain relief at two hours (RR = 1.46, 95% CI [1.35, 1.58]). No statistically significant differences in efficacy outcomes were observed among the three agents. However, lasmiditan 200 mg had the highest cumulative probability for two-hour pain freedom and relief (SUCRA 0.9, 0.8, respective), while rimegepant led in relieving the most bothersome symptoms (SUCRA 0.7).

Conclusion: Lasmiditan, rimegepant, and ubrogepant are effective for acute treatment of migraine in triptan-insufficient responders, with high-dose lasmiditan showing the highest efficacy for pain control.

Objective: Chronic migraine (CM) patients with medication overuse headache (MOH) were recently shown to be associated with leaky gut and inflammation. We aimed to investigate gut microbiota profiles of CM patients with MOH, and their correlations with inflammatory serum parameters, migraine food triggers, and comorbid anxiety and depression.

Materials and methods: The study included women participants (32 CM patients with NSAID overuse headache, and 16 healthy non-headache sufferers). Migraine duration, monthly migraine headache days, presence of irritable bowel syndrome symptoms, and HADS-D and HADS-A scores were recorded. Serum samples were collected to measure circulating LPS, HMGB1, HIF-1α, and IL-6. The gut microbiota profiles of the patients were evaluated using fecal samples.

Results: Serum LPS, HMGB1, HIF-1α, and IL-6 levels were significantly higher in the CM + MOH group compared to the healthy controls. HADS-A and HADS-D scores were considerably higher in the CM + MOH group compared to the healthy controls. In the microbiota analysis, alpha and beta diversities were similar between the two groups. The class Clostridia, the order Eubacteriales, and the genus Ruminococcus were less abundant in the CM + NSAID overuse headache group compared to the control group. At the genus level Desulfovibrio, Gemmiger, and Dialister and at the species level, Clostridium fessum, Blautia luti, Dorea longicatena, Eubacterium coprostanoligenes, and Gemmiger formicilis were more abundant in the CM + NSAID overuse headache group compared to the control group. Desulfovibrio, Gemmiger, Dialister, Ethanoligenens harbinense, Eubacterium coprostanoligenes, Dorea longicatena, and Thermoclostridium stercorarium showed positive correlations and Clostridia bacteria showed negative correlations with migraine food triggers. Positive correlations were found between LPS and Hapalosiphonaceae, HMGB1 and Melghirimyces, HIF1-α and Rouxeilla and Blautia luti, IL-6 and Melghirimyces and Ruminococcus.

Conclusion: In CM patients with MOH, we have revealed the presence of dysbiosis towards an inflammatory state, and positive correlations were shown between altered gut microbiota and inflammatory serum parameters and migraine food triggers.