Journal of Headache and Pain最新文献

Background: Physical activity (PA) has emerged as a promising non-pharmacological intervention for pain management, the relationship between objectively measured PA patterns and multi-site pain remains poorly understood. This exploratory study investigated associations between accelerometer-derived PA patterns and pain across various anatomical sites in older adults, and evaluated the predictive utility of machine learning model for pain outcomes.

Methods: This study utilized data from the National Health and Aging Trends Study in 2021-2022. Wrist-worn accelerometers measured PA, derived total activity, sedentary time, and activity/sedentary fragmentation) and time-frequency domain features. Cross-sectional and longitudinal analyses examined associations between PA patterns and site-specific pain using multivariable logistic regression with false discovery rate correction, while restricted cubic splines explored non-linear dose-response relationships. Random forest models with recursive feature elimination were developed to predict current pain status and pain relief.

Results: Cross-sectional analysis indicated that moderate sedentary time was associated with back pain (OR = 2.24, 95%CI: 1.12-4.47) and neck pain (OR = 2.12, 95%CI: 1.07-4.20), while moderate-to-vigorous activity fragmentation was associated with lower leg pain prevalence (OR = 0.34, 95%CI: 0.15-0.78), and moderate sedentary fragmentation with foot pain (OR = 1.89, 95%CI: 1.07-3.33). Longitudinal analysis revealed that moderate-to-vigorous activity fragmentation was associated with pain persistence in head (OR = 0.21, 95%CI: 0.05-0.90), though associations did not survive FDR correction. Machine learning prediction models achieved performance for pain status (AUC: back = 0.56, wrist = 0.54) and pain relief prediction (AUC: wrist = 0.85, back = 0.72).

Conclusion: Site-specific tailoring of PA intensity and fragmentation is warranted for effective chronic pain management in older adults based on associations between PA and anatomical pain distribution.

Background: Central sensitization is a crucial pathophysiological mechanism of chronic migraine (CM), and neuroinflammation mediated by activated microglia contributes significantly to the development of central sensitization. The P2Y13 receptor (P2Y13R), belonging to the G protein-coupled receptor family, is expressed in microglia and actively participates in the intricate pathophysiological process underlying chronic neuropathic pain. However, the precise relationship between the P2Y13R and CM remains largely unclear.

Methods: The CM mouse model was established by repeatedly injecting nitroglycerin (NTG) intraperitoneally at intermittent intervals, and the pain threshold was assessed using von Frey fiber and hot plate tests. Specific interventions were conducted on the P2Y13R and p38 MAPK signaling pathways in the Trigeminal Nucleus Caudalis (TNC) of mice through stereotactic injection. Western blotting and immunofluorescence were employed to assess the expression and localization of P2Y13R, c-Fos, calcitonin gene-related peptide (CGRP), components of the p38 MAPK signaling pathway, and inflammatory factors.

Results: The expression of P2Y13R was significantly upregulated upon NTG administration and exhibited a predominant distribution within the microglia in the TNC in mice with CM. Pharmacological inhibition of P2Y13R effectively reduced hyperalgesia in CM mice, lowered CGRP and c-fos levels, thereby improving central sensitization. Furthermore, inhibiting P2Y13R suppressed microglial activation and pro-inflammatory cytokine production. Additionally, activation of the p38MAPK pathway was observed in the TNC of CM mice, with P2Y13R inhibition significantly reducing p38MAPK pathway activity. Pharmacological inhibition of p38MAPK significantly ameliorates central sensitization in CM mice, while suppressing microglial activation and pro-inflammatory cytokine levels.

Conclusions: This research emphasizes the significance of P2Y13R in mediating central sensitization in CM mice through the p38MAPK pathway, thereby suggesting that targeting P2Y13R holds promise as a potential therapeutic strategy for effectively managing CM.

Background: Migraine is a prevalent and disabling condition affecting one billion people worldwide. calcitonin gene-related peptide (CGRP) inhibitors have transformed migraine management. We describe real-world trends in CGRP inhibitor treatment, switching, discontinuation, and migraine-related health care use (including emergency department, ED, and ambulatory care visits).

Methods: We used the Merative™ MarketScan^® Research data, providing data on inpatient and outpatient healthcare use and drug dispensation from a large sample of individuals with employer-sponsored health insurance in the United States. We identified adults using CGRP inhibitors (comprising both monoclonal antibodies, mAbs, and small-molecule CGRP receptor antagonists, gepants) as preventive treatment for migraine between May 2018 and December 2022. We evaluated treatment patterns, including switching between CGRP agents or other prophylactic migraine treatments, and therapy discontinuation. Healthcare and migraine-related medication use were compared one year pre- and post-CGRP inhibitor initiation. Migraine-related medications included preventive migraine-specific treatments (e.g., onabotulinumtoxinA), non-specific preventives (e.g., antidepressants), and acute treatments-both migraine-specific (e.g., triptans) and non-specific (e.g., opioids).

Results: We studied 148,100 adults with at least one CGRP inhibitor dispensation. CGRP inhibitor use increased over time, with newer agents being more commonly dispensed in recent years. Within the first year, 10.3% of individuals switched between CGRP inhibitors, and an additional 13.5% discontinued their first CGRP inhibitor without switching to another. Post-initiation, there was a 4.5% reduction in migraine-related medication use (95% confidence interval, CI: -4.9% to -4.0%, and 12.8% reduction in healthcare use (95% CI: -13.2% to -12.3%).

Conclusions: CGRP inhibitors are increasingly used over time. About 10% switch between CGRP agents within the first year of initiation. There was reduction in other migraine-related medications and healthcare visits following CGRP initiation.

Trial registration: N/A.

Background: Chronic neuropathic pain, particularly in the orofacial region, markedly reduces quality of life. Peripheral trigeminal nerve injury activates satellite glial cells (SGCs) in the trigeminal ganglion (TG), which contributes to orofacial neuropathic pain. However, the upstream signal responsible for SGC activation remains unclear. This study investigated the role and cellular sources of interferon gamma (IFN-γ) signaling in the TG following infraorbital nerve injury (IONI) in rats.

Methods: Mechanical sensitivity of the whisker pad skin was assessed after IONI. Changes in IFN-γ levels, IFN-γ receptor expression, and glial fibrillary acidic protein (GFAP; a marker of SGC activation) were examined in the TG by immunohistochemistry. The effects of intra-TG administration of IFN-γ, an IFN-γ receptor antagonist, and isolated CD8⁺ T cells on mechanical hypersensitivity were evaluated. GFAP expression after intra-TG administration of IFN-γ or the receptor antagonist was also quantified. Flow cytometry and immunohistochemistry were used to identify IFN-γ-producing cells. In primary SGC cultures, IFN-γ-induced interleukin-1β (IL-1β) release was measured, and the impact of IL-1 receptor (IL-1R1) antagonism on mechanical hypersensitivity was tested. IL-1R1 localization and expression in TG neurons was further evaluated after IONI.

Results: IONI induced persistent mechanical hypersensitivity and upregulated IFN-γ, IFN-γ receptor, and GFAP expression in the TG. CD8⁺ T cells were the primary source of IFN-γ after IONI, and intra-TG transfer of isolated CD8⁺ T cells transiently induced mechanical hypersensitivity. IFN-γ receptors were localized to SGCs, with expression levels increasing after IONI. Intra-TG IFN-γ administration triggered mechanical hypersensitivity and SGC activation, and its receptor antagonism attenuated the hypersensitivity. IFN-γ stimulation of cultured SGCs enhanced IL-1β release. Co-administration of an IL-1R1 antagonist prevented IFN-γ-induced mechanical hypersensitivity. IL-1R1 was localized on TG neurons and were upregulated following IONI.

Conclusions: CD8⁺ T cell-derived IFN-γ activates SGCs in the TG, leading to IL-1β release that promotes neuronal hyperactivity and orofacial neuropathic pain following IONI. Targeting the IFN-γ-SGC-IL-1β signaling axis may represent a novel therapeutic strategy for orofacial neuropathic pain.

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.