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

Abstract

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.

Microvascular Barrier Protection by microRNA-183 via FoxO1 Repression: A Pathway Disturbed in Neuropathy and Complex Regional Pain Syndrome

“…Behavioral testing in mice focused on mechanical sensitivity, as mechanoceptive pathologies are more robust in CRPS patients than thermoceptive pathologies. 18 Prior to the first injection and 6 h after each mimic injection, the paw withdrawal threshold as indicator of the mechanical sensitivity was measured using von Frey filaments. Thresholds were determined using Dixon"s Up-and-Down method.…”

“…6 While an entity of its own, CRPS exhibits features comparable to painful traumatic peripheral neuropathies including pain characteristics, gain in response to painful stimuli, and loss in response of nonpainful stimuli in quantitative sensory testing. 18 Several animal modelse.g., tibia fracture 24 , serum transfer with incision 26 , ischemia-reperfusion model 14 are available for CRPS each covering certain aspects of the disease. The neuropathic and neurogenic phenotype of CRPS can be modeled by chronic constriction injury (CCI).…”

“…12,31,54 They are found in the tissue but also circulating in the blood, including in exosomes. 18,40,64 MiR-183 is part of the miR-182/-183/-96 cluster: A sensory-neuron specific conditional knockout mouse of this whole cluster develops mechanic hypersensitivity 50 , while intrathecal miR-183 mimic application attenuates hyperalgesia. 38 Among validated targets of miR-183 is forkhead box protein O1 (FoxO1).…”

Komplexe regionale Schmerzsyndrome

“…Eine genetische Prädisposition [6][7][8][9][10][11][12][13][14] oder eine Störung im Heilungsprozess, die sich durch verschiedene Biomarker äußert (z. B. Bradykinin, löslicher IL-2-Rezeptor, Osteoprotegerin, IgG and IgM, microRNAs [15][16][17]), die längere Ruhigstellung der verletzten Extremität [18], psychologische Faktoren [19,20], ein autoantikörpervermittelter Autoimmunprozess [21][22][23][24][25][26][27][28][29][30][31] und epidemiologische Befunde wie eine Assoziation mit Migräne, Asthma oder Rheuma [32,33], wurden zwar diskutiert, treffen häufig jedoch nur auf einen Teil der Patienten zu.…”

The ceramide-S1P pathway as a druggable target to alleviate peripheral neuropathic pain

“…The pain is frequently located in muscles and bones and can increase upon experiencing orthostasis, anxiety, exercise or temperature changes. Mechanical hyperalgesia (increased sensation of pain) or allodynia (sensation of pain upon light touch) are common [196,197]. After an initial acute inflammatory phase CRPS transitions into a 'centralized' chronic phase, characterized by neuronal plasticity and reorganization with disturbed sensory-motor function, distorted body representation, and maladaptive non-use of the affected limb [198].…”