Regional Anesthesia and Pain Medicine

Ren, Renee; Chen, Tina; Illescas, Alex; Yin, Claire; Chan, William; Candan, Burcu; Poeran, Jashvant; Malhotra, Anuj; Memtsoudis, Stavros G; Sideris, Alexandra; Gungor, Semih

doi: 10.1136/rapm-2026-107817pmid: 42398975

BackgroundEhlers-Danlos syndrome (EDS) is a genetic connective tissue disorder characterized by joint instability and recurrent injuries, which has been linked to chronic pain syndromes, including complex regional pain syndrome (CRPS). This study examines the co-occurrence of EDS and CRPS and evaluates demographic differences using a large national claims database, with findings interpreted as population-level signal detection based on diagnostic coding.MethodsThis retrospective cohort study used 2017–2022 Merative MarketScan data (IRB# 2017-0169), including commercially insured US patients. Individuals with and without EDS (ICD-10-CM: Q79.6x) were assessed for CRPS diagnoses (ICD-10-CM: G90.5x, G56.4x, G57.7x). Sensitivity analysis was conducted with all patients to investigate associations between CRPS and EDS.ResultsOf 54,235,476 patients, 26,053 (0.05%) had EDS, and 51,424 (0.09%) had CRPS. There were 273 patients with a CRPS diagnosis after an EDS diagnosis, 217 with a CRPS diagnosis before an EDS diagnosis, and 490 with co-occurrence of EDS and CRPS, regardless of the order of diagnosis. The proportion of recorded CRPS diagnoses was higher among patients with recorded EDS diagnoses (1.05%; 273/26,053) compared with patients without EDS (0.09%; 51,151/54,158,272), corresponding to an approximately 11-fold higher proportion of recorded CRPS diagnoses among patients with EDS (95% CI 9.89 to 12.51). Among patients with EDS, those with recorded CRPS diagnoses and those without recorded CRPS diagnoses were predominantly female (96.7% vs 81.3%), with a median age of 27 years. Among CRPS cases, 76.8% had type 1 disease, and lower-limb involvement was most frequent (49.0%).ConclusionsPatients with EDS had a substantially higher proportion of recorded CRPS diagnoses than patients without EDS in this national claims dataset. These findings support further investigation into the observed association between EDS and CRPS diagnostic coding.

Neville, Mariana Fontes Lima; Oliveira, Bruno Luiz Araujo; Orfali, Guilherme di Camillo; Machado, Henrique Louzan; Ferreira, Antonio Gilberto; Luiz, Jaine Honorata Hortolan

doi: 10.1136/rapm-2026-108074pmid: 42425700

Çelik, Gözde

doi: 10.1136/rapm-2026-107943pmid: 42457312

Zhang, Lingyi; Yu, Jessica; Yu, Xiaobing; Guan, Zhonghui; Su, Po-Yi Paul

doi: 10.1136/rapm-2026-107844pmid: 42419790

Background/importanceNeuropathic pain affects up to 10% of the population and is often refractory to current treatments. Growing evidence implicates neuroimmune interactions, particularly microglia, in the pathophysiology, but their role is underappreciated in clinical practice.ObjectiveTo summarize current evidence for microglial contributions to neuropathic pain, emphasizing microglia–neuron interactions and translational implications for clinicians.Evidence reviewThis narrative review synthesizes preclinical and emerging human data (postmortem histopathology, glial-signal positron emission tomography (PET) imaging, dorsal root ganglion transcriptomics) to examine microglial contributions to pain initiation, maintenance and resolution, sex differences and therapeutic implications.FindingsPreclinical evidence demonstrates that microglia are necessary and sufficient for pain initiation. Nerve injury engages central sensitization through colony-stimulating factor 1 (CSF1)–CSF1 receptor (CSF1R), purinergic receptors, damage-associated molecular pattern/Toll-like receptor signaling, cytokine cascades (TNFα, IL-1β, IL-6), prostaglandin E₂, extracellular matrix and synaptic remodeling and brain-derived neurotrophic factor–tropomyosin receptor kinase B-mediated disinhibition. Microglia also contribute to pain resolution via pro-resolving mediators and stimulator of interferon genes (STING)/interferon signaling. Sex differences are prominent: microglial mechanisms predominate in males, whereas T-cell-mediated pathways prevail in females. Human postmortem and glial-signal imaging studies support glial involvement in chronic pain but lack direct validation of specific microglial targets.ConclusionsMicroglia coordinate pain initiation and resolution via conserved, drug-addressable pathways. Three translational implications emerge: (1) neuroimmune interventions are most effective early, given that microglia drive initiation more than maintenance; (2) sex-stratified trial designs are warranted given divergent microglial versus T-cell mechanisms by sex and (3) CSF1R-PET imaging may enable mechanism-based patient selection. These implications require prospective clinical validation.