CRPS Update July 20th

Can J Anaesth. 2012 Jul 14. [Epub ahead of print]

Update on the pathogenesis of complex regional pain syndrome: Role of oxidative stress.

Multinnova Medical Centre, Université de Montréal, Montreal, QC, Canada.



Complex regional pain syndrome (CRPS) is a chronic inflammatory pain syndrome that affects one or more extremities of the body. It is characterized by burning pain and abnormalities in the sensory, motor, and autonomic nervous systems. This review illustrates how oxidative stress and nuclear factor erythroid 2-related factor (Nrf2) activation might contribute to understanding the etiopathogenesis of CRPS.


The precise cause of CRPS remains unclear, and current treatments are not effective in many patients. The mechanism underlying CRPS may differ across patients and even within a single patient over time. Inflammatory and neuronal mechanisms have been suggested as key contributors to CRPS. Recent evidence demonstrates that oxidative stress is associated with clinical symptoms in patients with CRPS-I. Oxidative stress plays a key role in CRPS pathogenesis. The Nrf2 factor is a master regulator of the transcription of multiple antioxidants, which protects against oxidative stress and inflammation by inducing antioxidant and detoxifying genes through binding with an antioxidant response element. It has antinociceptive effects against inflammatory pain in an animal model.


This review summarises the effect of oxidative stress and mitochondrial dysfunction in the pathogenesis of CRPS. It also addresses the question of whether there is a potential role for Nrf2 (activated by pharmacological or nutritional activators) in alleviating the clinical features of CRPS or preventing its progression.


Med Hypotheses. 2010 Sep;75(3):319-23. Epub 2010 Apr 7.

Complex regional pain syndrome: a vitamin K dependent entity?

Yuzuncu Yil University Medical Faculty, Physical Medicine and Rehabilitation Department, 65100 Van, Turkey.

Complex regional pain syndrome (CRPS) is the complication of some injuries, such as a fracture, which affects the distal end of the injured extremity characterized by pain, allodynia, hyperalgesia, edema, abnormal vasomotor and sudomotor activity, movement disorders, joint stiffness, regional osteoporosis, and dystrophic changes in soft tissue. Exact pathogenic mechanism of CRPS is still unclear. Suggested pathogenic mechanisms of CRPS are evaluated in four major groups consist of classic inflammation, hypoxic changes and chronic ischemia, neurogenic inflammation and sympathetic dysregulation. All of these suggested pathogenic mechanisms produced by inflammatory cytokines mediated by nuclear factor kappaB. Vitamin K is a family of structurally similar, fat-soluble, 2-methyl-1,4-naphthoquinones. Vitamin K exerts a powerful influence on bone formation, especially in osteoporosis. Fat in bone stores some vitamin K. Gamma-carboxylation of the glutamic acid in osteocalcin is vitamin K dependent. Osteocalcin plays a role in calcium uptake and bone mineralization. Osteocalcin, the most abundant non-collagenous protein in bone, is produced by osteoblasts during bone matrix formation. Because osteocalcin is not carboxylated in case of vitamin K deficiency at the distal site of fracture or injury, it cannot bind to hydroxyapatite causing osteoporosis. Fracture starts a local inflammatory process in the fracture site and adjacent tissues as seen in CRPS. Vitamin K was shown to suppress the inflammatory cytokines and NF-kappaB and prevent oxidative, hypoxic, ischemic injury (which have key role in both initiation and progression of CRPS) to oligodendrocytes and neurons. We hypothesized that vitamin K has a key role and modulatory effect in CRPS pathogenesis. Vitamin K deficiency at the distal site of fracture occurs because of diminished and slowed circulation, local immobilization after extremity fracture or injury and use of vitamin K store at the distal site of the injured extremity and in the circulation for fracture healing and bone remodelling. In case of vitamin K deficiency at the distal site of fracture, classic inflammation starts with fracture at the distal tissues could not be restricted and classic inflammation, hypoxic changes, chronic ischemia, neurogenic inflammation, sympathetic dysregulation, which are the pathogenic mechanisms of CRPS, and patchy osteoporosis which occur due to high level of under-carboxylated osteocalcin could not be prevented. Briefly vitamin K level decreases in the distal site of the injured extremity consequently resulting in patchy osteoporosis due to high level of under-carboxylated osteocalcin and unrestricted inflammation which are the cause for both initiation and progression of CRPS.


Anesthesiology. 2010 Sep;113(3):713-25.

An update on the pathophysiology of complex regional pain syndrome.

Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, Tennessee 37212, USA.

Complex regional pain syndrome (CRPS) is a neuropathic pain disorder with significant autonomic features. Few treatments have proven effective, in part, because of a historically poor understanding of the mechanisms underlying the disorder. CRPS research largely conducted during the past decade has substantially increased knowledge regarding its pathophysiologic mechanisms, indicating that they are multifactorial. Both peripheral and central nervous system mechanisms are involved. These include peripheral and central sensitization, inflammation, altered sympathetic and catecholaminergic function, altered somatosensory representation in the brain, genetic factors, and psychophysiologic interactions. Relative contributions of the mechanisms underlying CRPS may differ across patients and even within a patient over time, particularly in the transition from “warm CRPS” (acute) to “cold CRPS” (chronic). Enhanced knowledge regarding the pathophysiology of CRPS increases the possibility of eventually achieving the goal of mechanism-based CRPS diagnosis and treatment.


Ann Nucl Med. 2012 Jul 14. [Epub ahead of print]

Is there a correlation between symptoms and bone scintigraphic findings in patients with complex regional pain syndrome?

Nuclear Medicine Section, Radiology and Nuclear Medicine Department, Faculty of Medicine, Jordan University Hospital, University of Jordan, Queen Rania Street, Al-Jubeiha, P.O.Box 13046, 11942, Amman, Jordan,


Complex regional pain syndrome (CRPS) is characterized by pain in combination with sensory, vasomotor, sudomotor, trophic and motor abnormalities. The diagnosis of CRPS is based primarily on clinical criteria and the presence of distinct signs and symptoms. The role of bone scintigraphy in the diagnosis of these patients has been limited by its variable sensitivity. In this study, we aim to look if the presence of specific symptoms or symptom subgroups in patients with clinically diagnosed CRPS correlates with scintigraphic findings in bone scan.


We retrospectively reviewed clinical records of patients referred for bone scintigraphy with the clinical diagnosis of CRPS during the period December 2006 until February 2011. Patients were classified into 4 distinct subgroups according to the presence of specific symptoms namely sensory subgroup, sudomotor and/or edema subgroup, vasomotor subgroup and finally motor and/or trophic changes subgroup. We looked specifically for the correlation between these specific symptoms and scintigraphic bone findings.


37 patients were referred for bone scintigraphy with the clinical diagnosis of CRPS and were enrolled in the study. The presence of vasomotor symptoms and (motor and/or trophic changes) was significantly higher in patients with positive bone scintigraphy (P value 0.0133, 0.018 respectively). There was no other statistically significant correlation between the presence of specific symptoms or symptom subgroups on one hand and the result of bone scintigraphy on the other hand.


The probability of positive bone scintigraphy increased significantly in patients with vasomotor symptoms and in patients with motor and/or trophic changes. This may contribute to the reported variability of the diagnostic performance of bone scintigraphy in CRPS patients.


J Pain. 2012 Jul 11. [Epub ahead of print]

Genetic HLA Associations in Complex Regional Pain Syndrome With and Without Dystonia.


Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.

We previously showed evidence for a genetic association of the human leukocyte antigen (HLA) system and complex regional pain syndrome (CRPS) with dystonia. Involvement of the HLA system suggests that CRPS has a genetic component with perturbed regulation of inflammation and neuroplasticity as possible disease mechanisms. However, it is at present unclear whether the observed association with HLA-B62 and HLA-DQ8 in CRPS patients with dystonia also holds true for patients without dystonia. Therefore, we tested the possible association with HLA-B62 and HLA-DQ8 in a clinically homogeneous group of 131 CRPS patients without dystonia. In addition, we investigated the possible association with other alleles of the HLA-A, HLA-B, HLA-C, HLA-DR, and HLA-DQ loci. We showed an increased prevalence of HLA-DQ8 (molecularly typed as HLA-DQB1*03:02; OR = 1.65 [95% CI 1.12-2.42], P = .014) in CRPS without dystonia, whereas no association was observed for HLA-B62 (molecularly typed as HLA-B*15:01; OR = 1.22 [95% CI .78-1.92], P = .458). Our data suggest that CRPS with and CRPS without dystonia may be genetically different, but overlapping, disease entities because only HLA-DQ8 is associated with both. The findings also indicate that distinct biological pathways may play a role in both CRPS subtypes. PERSPECTIVE: This study is the first to replicate a specific HLA region conferring genetic risk for the development of CRPS. Moreover, associations of HLA-DQ8 with both CRPS with and CRPS without dystonia, and HLA-B62 only with CRPS with dystonia, suggest that these disease entities may be genetically different, but overlapping.


Pain. 2009 Sep;145(1-2):82-5. Epub 2009 Jun 11.

HLA-B62 and HLA-DQ8 are associated with Complex Regional Pain Syndrome with fixed dystonia.

Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.

Complex Regional Pain Syndrome (CRPS) is clinically characterized by pain in combination with sensory, autonomic, and motor symptoms that may include weakness, tremor, myoclonus and dystonia of the affected limb(s). The syndrome is multifactorial in origin and mostly attributed to tissue injury. There is some evidence that the human leukocyte antigen (HLA) system plays a role in the pathophysiology of CRPS, but previous studies lacked power. Here we performed the most extensive study investigating the contribution of HLA alleles (i.e. HLA-A, HLA-B, HLA-DRB1, and HLA-DQB1) in 150 CRPS patients who also had fixed dystonia. HLA-B62 (OR=2.05 [95% CI 1.41-2.99], P=0.0005) and HLA-DQ8 (OR=1.75 [95% CI 1.20-2.57], P=0.005) were found significantly associated with CRPS and dystonia. The association remained significant after correction (HLA-B62 P(corrected) [P(c)] = 0.02 and HLA-DQ8 P(c)=0.04). The involvement of HLA-B62 and HLA-DQ8 in CRPS with dystonia may indicate that these HLA loci are implicated in the susceptibility or expression of the disease.



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