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Neuroimmune interactions may contribute to severe pain and regional inflammatory and autonomic signs in complex regional pain syndrome (CRPS), a posttraumatic pain disorder. Here, we investigated peripheral and central immune mechanisms in a translational passive transfer trauma mouse model of CRPS. Small plantar skin–muscle incision was performed in female C57BL/6 mice treated daily with purified serum immunoglobulin G (IgG) from patients with longstanding CRPS or healthy volunteers followed by assessment of paw edema, hyperalgesia, inflammation, and central glial activation. CRPS IgG significantly increased and prolonged swelling and induced stable hyperalgesia of the incised paw compared with IgG from healthy controls. After a short-lasting paw inflammatory response in all groups, CRPS IgG-injected mice displayed sustained, profound microglia and astrocyte activation in the dorsal horn of the spinal cord and pain-related brain regions, indicating central sensitization. Genetic deletion of interleukin-1 (IL-1) using IL-1αβ knockout (KO) mice and perioperative IL-1 receptor type 1 (IL-1R1) blockade with the drug anakinra, but not treatment with the glucocorticoid prednisolone, prevented these changes. Anakinra treatment also reversed the established sensitization phenotypewhen initiated 8 days after incision. Furthermore, with the generation of an IL-1β floxed(fl/fl) mouse line, we demonstrated that CRPS IgG-induced changes are in part mediated by microglia-derived IL-1β, suggesting that both peripheral and central inflammatory mechanisms contribute to the transferred disease phenotype. These results indicate that persistent CRPS is often contributed to by autoantibodies and highlight a potential therapeutic use for clinically licensed antagonists, such as anakinra, to prevent or treat CRPS via blocking IL-1 actions.

The cardinal clinical features of complex regional pain syndrome type I (CRPS-I) are pain, edema, autonomic changes, and limitation of motoric movement, which may indicate the role of inflammation and cytokines. We report the effect of prednisolone on the clinical severity and mRNA profiling of proinflammatory (tumor necrosis factor (TNF)-α and interleukin (IL)-2) and anti-inflammatory cytokines (IL-10 and transforming growth factor (TGF)-β) in the patient with CRPS-I. Thirty-nine patients with CRPS-I of shoulder joint were enrolled. Their CRPS, Visual Analog Scale (VAS) and Daily Sleep Interference Scale (DSIS) scores were recorded. TNF-α, IL-2, IL-10, and TGF-β gene expressions at mRNA of whole blood were measured by reverse transcriptase polymerase chain reaction. Patients were randomized to prednisolone 20 mg or 40 mg using 1: 1 randomization. The primary outcome was change in VAS score, and secondary outcomes were change in CRPS and DSIS scores at 1 month. Side effects were noted. The patients had increased expressions of TNF-α (p < 0.001) and IL-2 (p < 0.001) and reduced IL-10 (p < 0.01) mRNA compared to the healthy controls. The baseline characteristics were matched between the two treatment arms. At 1 month, CRPS, VAS, and DSIS scores improved significantly compared to baseline, which paralleled with improvement in IL-10 (p < 0.032) and reduction in TNF-α (p = 0.046). The improvement in clinical and biomarkers was similar in prednisolone 20 mg and 40 mg arms. None had to be withdrawn due to severe side effects. Future study in larger cohort may validate these findings.

The pathophysiology behind Complex Regional Pain Syndrome (CRPS) is not fully understood and associated factors and triggers for developing the condition are debated. We aimed to study such factors and long-term outcome in a descriptive cross-sectional study with a well-defined population with CRPS in the upper limb and related to sex and CRPS type. In retrospectively collected data from medical records, 149 subjects [women n = 104 (70%); type 1 CRPS, n = 108 (72%); type 2 CRPS, n = 41 (28%); follow-up time 21 [8-43] months] were identified and analysed (Chi-squared test, Mann-Whitney U-test, and multiple linear regression). A majority were manual workers, and a larger proportion of subjects were smokers and had less post-secondary education than a reference population (p < 0.001 and p < 0.008). Men were younger, more frequently smoked, had higher BMI, and had lower education levels than women (p = 0.044, p = 0.007, p < 0.001, and p = 0.016, respectively). Subjects with CRPS type 2 were younger and had a longer time from symptoms until diagnosis, longer follow-up time, and more follow-up visits, indicating worse outcome (p = 0.016, p = 0.0012, p = 0.003, and p = 0.004, respectively). Among CRPS, 32% had a prior pain disorder and 7% had previously visited a pain management clinic. While there was no significant difference in mental illness occurrence before CRPS diagnosis compared to a reference population, mental illness increased by 76% after diagnosis. Factors such as CRPS type 2, older age, and delayed diagnosis were associated with longer follow-up periods. Additionally, 45% were on sick leave for over 12 months, and 20% were permanently unable to work. Socioeconomic deprivation is an associated factor in developing CRPS, in which a variety of triggers exist. Subjects with CRPS, particularly type 2, are at high risk of severe remaining symptoms, including mental illness and risk of never returning to work.

Background Complex regional pain syndrome (CRPS) is a chronic pain condition of an extremity. While achieving pain relief in CRPS is challenging, esketamine infusions can accomplish pain relief for several weeks post-infusion in a subgroup of CRPS patients. Unfortunately, CRPS esketamine protocols are very heterogeneous in advice on dosage, administration and treatment setting. Currently, no trials are available that study differences between intermittent and continuous esketamine infusions for CRPS. With the current situation of bed shortages, it is difficult to admit patients for several consecutive days for inpatient esketamine treatments. In this study, we investigate whether 6 intermittent outpatient esketamine treatments are not inferior to a continuous 6-day inpatient esketamine treatment in establishing pain relief. In addition, several secondary study parameters will be assessed in order to investigate mechanisms responsible for pain relief by esketamine infusions. Furthermore, the cost-effectiveness will be analyzed. Methods In this RCT, the primary objective is to demonstrate that an intermittent esketamine dosing regimen is non-inferior to a continuous esketamine dosing regimen at 3 months follow-up. We will include 60 adult CRPS patients. The inpatient treatment group receives a continuous intravenous esketamine infusion for 6 consecutive days. The outpatient treatment group receives a 6-hour intravenous esketamine infusion every 2 weeks for 3 months. Esketamine dose will be individually tailored and is started at 0.05 mg/kg/h and can be increased to a maximum of 0.2 mg/kg/h. Each patient will be followed for 6 months. The primary study parameter is perceived pain intensity, measured by an 11-point Numerical Rating Scale. Secondary study parameters are conditioned pain modulation, quantitative sensory testing, adverse events, thermography, blood inflammatory parameter, questionnaires about functionality, quality of life and mood and costs per patient. Discussion If our study reveals non-inferiority between intermittent and continuous esketamine infusions, these findings can be beneficial to increase the availability and flexibility of esketamine infusions through outpatient treatments. Furthermore, the costs of outpatient esketamine infusions could be lower than inpatient esketamine infusions. In addition, secondary parameters may predict response to esketamine treatment. Trial registration ClinicalTrials.gov Identifier NCT05212571 , date of registration 01-28-2022. Protocol version: Version 3, February 2022.

There have been many articles highlighting differences and similarities between complex regional pain syndrome (CRPS) and functional neurological disorders (FND) but until now the discussions have often been adversarial with an erroneous focus on malingering and a view of FND as ‘all in the mind’. However, understanding of the nature, frequency and treatment of FND has changed dramatically in the last 10–15 years. FND is no longer assumed to be only the result of ‘conversion’ of psychological conflict but is understood as a complex interplay between physiological stimulus, expectation, learning and attention mediated through a Bayesian framework, with biopsychosocial predisposing, triggering and perpetuating inputs. Building on this new ‘whole brain’ perspective of FND, we reframe the debate about the ‘psychological versus physical’ basis of CRPS. We recognise how CRPS research may inform mechanistic understanding of FND and conversely, how advances in FND, especially treatment, have implications for improving understanding and management of CRPS.

Complex regional pain syndrome (CRPS) is a common complication following distal radius fractures that is difficult to diagnose and can lead to permanent disability. While various proposed prophylaxis and treatment modalities exist, high-quality evidence guiding practice is limited. This survey of Orthopaedic Trauma Association (OTA) and Canadian Orthopaedic Association (COA) members was conducted with the primary aim of assessing practice patterns in distal radius fractures complicated with CRPS. An electronic survey was distributed to practicing orthopaedic surgeons in the COA and OTA. Questions assessed practice setting, preference in management of distal radius fractures and CRPS, comfort level in managing CRPS, and identification of gaps in management. Responses were anonymized and collected over 8 months. Response data was analyzed using descriptive statistics; thematic analysis was used on free text response. 134 survey responses were completed. 84% of respondents felt the incidence of CRPS in distal radius fractures was 1-10%, while 15% felt it was closer to 11-20%. 24% of respondents utilized the \"Budapest Criteria\" to diagnose CRPS. 40% offered prophylaxis in patients felt to be at high risk of developing CRPS. 66% of surgeons felt neutral, uncomfortable, or very uncomfortable managing CRPS in distal radius fractures. When asked to consider adopting a prophylactic therapy, 38% of surgeons indicated that a therapy that reduced the absolute risk of CRPS by 6-10% would change their practice. Gaps in current practice included lack of evidence-based treatment and prevention strategies and diagnostic uncertainty. This study identified that amongst orthopaedic surgeons in the COA and OTA, diagnosis, treatment, and prophylaxis strategies for CRPS in distal radius fractures are heterogeneous. Surgeons are not confident in their treatment of CRPS. Future studies using rigorous research methods are warranted to improve management.

For patients who experience atypical neurogenic pain thought to be complex regional pain syndrome (CRPS) after Dupuytren’s fasciectomy early recognition has been reported to improve outcomes. Furthermore, given the progressive nature of Dupuytren’s, individuals with a history of CRPS have been “at risk” for further surgical intervention. To familiarize therapists with a Budapest criteria (BC) checklist for early diagnosis of CRPS, describe how tracking sudomotor/vasomotor signs alongside differences in skin temperature were used to monitor vasomotor instability and intervention effectiveness for a patient with atypical pain after fasciectomy and to detail management of the same patient with a CRPS history who had collagenase clostridium histolyticum (CCH) injection of her other hand without exacerbating CRPS. Case report. Medical record review was done by the author. Part 1- patient-reported symptoms and therapist-observed signs were mined and scored against the BC. Part 2- vasomotor/sudomotor signs and differences in skin temperatures (>1˚C) were used to interpret response to therapy and medical interventions. Part3- description and pictures of the process this patient underwent for CCH and manipulation. Part 1- therapist documentation failed to satisfy the BC. Part 2- vasomotor/sudomotor signs and skin temperature differences of >1˚C reflected the patient’s incomplete response to therapy and medication, thus strengthening need for percutaneous stellate ganglion sympathetic nerve blocks. Part 3- CRPS was not exacerbated with CCH procedure. Use of a BC checklist may guide documentation, speed recognition for an earlier diagnosis of CRPS in patients with Dupuytren’s and an atypical post-fasciectomy response. Once identified, observed signs and measures of skin temperature could be used to monitor response to therapy and medical interventions. The positive outcome for this woman with Dupuytren’s and CRPS-I after CCH injection are encouraging. •Therapists have tools to measure and monitor allodynia and vasomotor instability.•Measurement paired with Budapest criteria (BC) may improve neurogenic pain outcomes.•Monitor atypical fasciectomy recovery with BC checklist for earlier CRPS diagnosis.•Therapist usual method of documentation may change when using a BC checklist.•The BC qualifies skin temperature differences of >1°C as vasomotor instability.

Complex Regional Pain Syndrome (CRPS) is a debilitating pain disorder involving chronic inflammation, neural sensitization and autonomic dysfunction. Fascia, a highly innervated connective tissue, is increasingly recognized for its role in pain modulation, yet its contribution to CRPS remains underexplored. This narrative review synthesizes the current evidence on fascia’s involvement in CRPS pathophysiology and potential therapeutic strategies. A literature search was conducted in PubMed, Scopus and Web of Science, selecting studies on fascia, CRPS, inflammation, oxidative stress and autonomic dysfunction, with emphasis on recent experimental, anatomical and clinical research. Fascia contributes to CRPS through neuroinflammation, fibrosis and autonomic dysregulation. Its rich innervation facilitates peripheral and central sensitization, while inflammatory mediators drive fibrosis, reducing elasticity and exacerbating pain. Autonomic dysfunction worsens hypoxia and oxidative stress, fueling chronic dysfunction. Advances in sonoelastography provide new insights, while fascial manipulation and targeted therapies show promise in early studies. Fascia plays a key role in CRPS pathophysiology, yet its clinical relevance remains underexplored. Future research integrating imaging, molecular profiling and clinical trials is needed to develop evidence-based fascia-targeted interventions, potentially improving CRPS diagnosis and treatment.

IntroductionComplex Regional Pain Syndrome (CRPS) is a debilitating neuropathic condition often refractory to conventional treatments. N-methyl-D-aspartate (NMDA) receptor antagonists have a well-established role in the development and modulation of chronic neuropathic pain. Nitrous oxide is widely used and generally safe anesthetic gas with NMDA receptor antagonist activity. We therefore tested the hypothesis that brief periods of nitrous oxide exposure reduce pain in patients with CRPS.MethodsPatients with a diagnosis of CRPS were randomized to either 2 hours of nitrous oxide exposure on three alternating days (Nitrous Oxide) versus a placebo air/oxygen mixture (Air-Oxygen). Our primary outcome was patient-reported pain scores at 1 week and 1 month. Secondary and exploratory outcomes were physical and mental health (PRMOIS-29 v2 survey), specific neuropathic pain symptoms (McGill short-form questionnaire), and opioid consumption.Results44 patients participated in the study; 20 were randomized to Nitrous Oxide and 24 were assigned to Air-Oxygen. Pain scores did not differ significantly, with the estimated difference in means (Nitrous Oxide−Air-Oxygen) of −0.57 (95% CI: −1.42 to 0.28) points, p=0.19. There were also no differences detected in secondary outcomes, with the estimated difference in mean Z-scores for physical health (Nitrous Oxide−Air-Oxygen) of 0.13 (95% CI: −0.16 to 0.43), mental health 0.087 (95% CI: −0.31 to 0.48), and Patient Global Impression of Change score −0.7 (95% CI: −1.85 to 0.46).ConclusionsCompared with air/oxygen, 2 hours of nitrous oxide/oxygen exposure for three sessions did not provide meaningful therapeutic potential for patients with chronic CRPS. Our results do not support using nitrous oxide for the treatment of CRPS.

BACKGROUND: Complex regional pain syndrome (CRPS) is an extremely painful disorder driven primarily by inflammation. OBJECTIVES: We hypothesized that the immunomodulatory biologic, ExoFloTM, composed of bone marrow mesenchymal stem cell-derived extracellular vesicles, could be safely administered to CRPS patients and alleviate symptoms. STUDY DESIGN: Ten patients received 2 intravenous (IV) infusions, each containing 15 mL ExoFlo, on day one and day 4. A series of tests were performed at baseline (day 0, prior to infusion), week one, and months one, 3, and 6 after the second infusion. SETTING: All patients were treated in one of 2 outpatient pain management clinics in Orange County, CA. METHODS: Testing for clinical improvement included: visual analog scale of pain, brief pain inventory, 36-item short-form questionnaire, range of motion analysis, and jamar dynamometer testing. RESULTS: No serious adverse events related to ExoFlo treatment occurred. Statistically significant improvements in pain and motion assessments occurred across the patient pool. LIMITATIONS: This study was limited by its patient number enrolled (10), it lacked a control arm, and one patient who dropped out of the study. CONCLUSIONS: IV delivery of ExoFlo appears safe in patients with CRPS. In addition, ExoFlo exhibited efficacy in addressing CRPS symptoms. Given the lack of effective and safe treatments available to CRPS patients, these results suggest that further studies are warranted to explore and validate this potential treatment for CRPS. KEY WORDS: Complex regional pain syndrome (CRPS), mesenchymal stem cell, extracellular vesicle, ExoFlo