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Pain. 2019 Oct;160(10):2278-2289. doi: 10.1097/j.pain.0000000000001617.

What is normal trauma healing and what is complex regional pain syndrome I? An analysis of clinical and experimental biomarkers.

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Department of Anesthesiology, University Hospital of Würzburg, Würzburg, Germany.
Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
Department of Neurology, University Hospital of Brno, Brno, Czech Republic.
Trauma-, Hand-, Plastic- and Reconstructive Surgery, University Hospital of Würzburg, Würzburg, Germany.
Department of Neurology, University Hospital of Würzburg, Würzburg, Germany.
Division of Physiology, Department of Physiology and Medical Physics, University of Innsbruck, Innsbruck, Austria.
Department of Neurology, University Hospital of Mainz, Mainz, Germany.


Complex regional pain syndrome (CRPS) typically develops after fracture or trauma. Many of the studies so far have analyzed clinical and molecular markers of CRPS in comparison with healthy or pain controls. This approach, however, neglects mechanisms occurring during physiological trauma recovery. Therefore, we compared the clinical phenotype, sensory profiles, patient-reported outcomes, and exosomal immunobarrier microRNAs (miRs) regulating barrier function and immune response between CRPS and fracture controls (FCs) not fulfilling the CRPS diagnostic criteria. We included upper-extremity FCs, acute CRPS I patients within 1 year after trauma, a second disease control group (painful diabetic polyneuropathy), and healthy controls. Fracture controls were not symptoms-free, but reported some pain, disability, anxiety, and cold pain hyperalgesia in quantitative sensory testing. Patients with CRPS had higher scores for pain, disability, and all patient-reported outcomes. In quantitative sensory testing, ipsilateral and contralateral sides differed significantly. However, on the affected side, patients with CRPS were more sensitive in only 3 parameters (pinprick pain and blunt pressure) when compared to FCs. Two principal components were identified in the cohort: pain and psychological parameters distinguishing FC and CPRS. Furthermore, the immunobarrier-protective hsa-miR-223-5p was increased in plasma exosomes in FCs with normal healing, but not in CRPS and healthy controls. Low hsa-miR-223-5p was particularly observed in subjects with edema pointing towards barrier breakdown. In summary, normal trauma healing includes some CRPS signs and symptoms. It is the combination of different factors that distinguish CRPS and FC. Fracture control as a control group can assist to discover resolution factors after trauma.

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