CRPS Briefing | January 2013

Happy New Year! I hope that everyone has had a good Christmas period.

Welcome to the first CRPS briefing for 2013. I am particularly interested in Luke Parkitny’s review on inflammation in CRPS as this is an area we must think about and address, as well as some interesting work looking at gut bacteria and CRPS.

The gut is supplied by its own nervous system (the enteric nervous system), often called the second brain. This system is autonomic (sympathetic and parasympathetic branches) and certainly responds to how we feel and think; e.g. think about lunch and your tummy rumbles and think about giving a speech to a large group and feel your palms moisten. There is well known communication between the gut and the brain and it seems that this plays a role in our mood. Many people whom I see with persisting pain and sensitivity will complain of abdominal pain and bloating (IBS-type presentation). This study has found some differences between the gut bacteria of CRPS patients, opening an interesting line of thought and enquiry.


Neurology. 2013 Jan 1;80(1):106-17. doi: 10.1212/WNL.0b013e31827b1aa1.

Inflammation in complex regional pain syndrome: A systematic review and meta-analysis.

Parkitny L, McAuley JH, Di Pietro F, Stanton TR, O’Connell NE, Marinus J, van Hilten JJ, Moseley GL.


From Neuroscience Research Australia (L.P., J.H.M., F.D.P., T.R.S.) and Prince of Wales Clinical School (L.P., F.D.P.), University of New South Wales, Sydney; Sansom Institute for Health Research (T.R.S., G.L.M.), University of South Australia, Adelaide, Australia; Centre for Research in Rehabilitation (N.E.O), Brunel University, Uxbridge, UK; Department of Neurology (J.M., J.J.v.H.), Leiden University Medical Center, Leiden, the Netherlands.



We conducted a systematic review of the literature with meta-analysis to determine whether complex regional pain syndrome (CRPS) is associated with a specific inflammatory profile and whether this is dependent on the duration of the condition.


Comprehensive searches of the literature using MEDLINE, Embase, Scopus, Web of Science, and reference lists from published reviews identified articles that measured inflammatory factors in CRPS. Two independent investigators screened titles and abstracts, and performed data extraction and risk of bias assessments. Studies were subgrouped by medium (blood, blister fluid, and CSF) and duration (acute and chronic CRPS). Where possible, meta-analyses of inflammatory factor concentrations were performed and pooled effect sizes were calculated using random-effects models.


Twenty-two studies were included in the systematic review and 15 in the meta-analysis. In acute CRPS, the concentrations of interleukin (IL)-8 and soluble tumor necrosis factor receptors I (sTNF-RI) and II (sTNF-RII) were significantly increased in blood. In chronic CRPS, significant increases were found in 1) TNFα, bradykinin, sIL-1RI, IL-1Ra, IL-2, sIL-2Ra, IL-4, IL-7, interferon-γ, monocyte chemoattractant protein-1 (MCP-1), and sRAGE (soluble receptor for advanced glycation end products) in blood; 2) IL-1Ra, MCP-1, MIP-1β, and IL-6 in blister fluid; and 3) IL-1β and IL-6 in CSF. Chronic CRPS was also associated with significantly decreased 1) substance P, sE-selectin, sL-selectin, sP-selectin, and sGP130 in blood; and 2) soluble intercellular adhesion molecule-1 (sICAM-1) in CSF. Most studies failed to meet 3 or more of our quality criteria.


CRPS is associated with the presence of a proinflammatory state in the blood, blister fluid, and CSF. Different inflammatory profiles were found for acute and chronic cases.


J Pain. 2013 Jan;14(1):66-78. doi: 10.1016/j.jpain.2012.10.004. – click here

Topical Combinations Aimed at Treating Microvascular Dysfunction Reduce Allodynia in Rat Models of CRPS-I and Neuropathic Pain.

Ragavendran JV, Laferrière A, Xiao WH, Bennett GJ, Padi SS, Zhang J, Coderre TJ.


Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada; Department of Anesthesia, McGill University, Montreal, QC, Canada.


Growing evidence indicates that various chronic pain syndromes exhibit tissue abnormalities caused by microvasculature dysfunction in the blood vessels of skin, muscle, or nerve. We tested whether topical combinations aimed at improving microvascular function would relieve allodynia in animal models of complex regional pain syndrome type I (CRPS-I) and neuropathic pain. We hypothesized that topical administration of either α(2)-adrenergic (α(2)A) receptor agonists or nitric oxide (NO) donors combined with either phosphodiesterase (PDE) or phosphatidic acid (PA) inhibitors would effectively reduce allodynia in these animal models of chronic pain. Single topical agents produced significant dose-dependent antiallodynic effects in rats with chronic postischemia pain, and the antiallodynic dose-response curves of PDE and PA inhibitors were shifted 2.5- to 10-fold leftward when combined with nonanalgesic doses of α(2)A receptor agonists or NO donors. Topical combinations also produced significant antiallodynic effects in rats with sciatic nerve injury, painful diabetic neuropathy, and chemotherapy-induced painful neuropathy. These effects were shown to be produced by a local action, lasted up to 6 hours after acute treatment, and did not produce tolerance over 15 days of chronic daily dosing. The present results support the hypothesis that allodynia in animal models of CRPS-I and neuropathic pain is effectively relieved by topical combinations of α(2)A or NO donors with PDE or PA inhibitors. This suggests that topical treatments aimed at improving microvascular function may reduce allodynia in patients with CRPS-I and neuropathic pain. PERSPECTIVE: This article presents the synergistic antiallodynic effects of combinations of α(2)A or NO donors with PDE or PA inhibitors in animal models of CRPS-I and neuropathic pain. The data suggest that effective clinical treatment of chronic neuropathic pain may be achieved by therapies that alleviate microvascular dysfunction in affected areas.


Brain Behav Immun. 2012 Dec 18. pii: S0889-1591(12)00535-1. doi: 10.1016/j.bbi.2012.12.005. [Epub ahead of print]

Establishing a Relationship between Bacteria in the Human Gut and Complex Regional Pain Syndrome.

Reichenberger ER, Alexander GM, Perreault MJ, Russell JA, Schwartzman RJ, Hershberg U, Rosen G.


Department of Biomedical Engineering, Drexel University.


Complex Regional Pain Syndrome (CRPS) is a serious and painful condition involving the peripheral and central nervous systems. Full comprehension of the disorder’s pathophysiology remains incomplete, but research implicates the immune system as a contributor to chronic pain. Because of the impact gastrointestinal bacteria have in the development and behavior of the immune system, this study compares the GI microbial communities of 16 participants with CRPS (5 of whom have intestinal discomforts) and 16 healthy controls using 454 sequencing technology. CRPS subjects were found to have significantly less diversity than their healthy counterparts. Statistical analysis of the phylogenetic classifications revealed significantly increased levels of Proteobacteria and decreased levels of Firmicutes in CRPS subjects. Clustering analysis showed significant separation between healthy controls and CRPS subjects. These results support the hypothesis that the GI microbial communities of CRPS participants differ from those of their healthy counterparts. These variations may hold the key to understanding how CRPS develops and provide information that could yield a potential treatment.


Pain Res Manag. 2012 Nov-Dec;17(6):386-90. – click here

Complex regional pain syndrome in children: Asking the right questions.

Goldschneider KR.



Complex regional pain syndrome (CRPS) is a painful disorder without a known unifying mechanism. There are little data on which to base evaluation and treatment decisions, and what data are available come from studies involving adults; however, even that literature is relatively sparse. Developing robust research for CRPS in children is essential for the progress toward optimal treatment.


To determine potential avenues of research in pediatric CRPS based on a review of the literature. Areas of concern include diagnostic criteria, peripheral mechanisms, central nervous system mechanisms, the role of the autonomic nervous system, possible risk factors, options for prevention and potential avenues of treatment.


A literature review was performed and the results applied to form the hypotheses posited in the form of research questions


CRPS is a complicated entity that is more than a painful sensory condition. There is evidence for peripheral inflammatory and neurological changes, and reorganization in both sensory and motor cortexes. In addition, a significant motor component is frequently observed and there appear to be tangible risk factors. Many of these pieces of evidence suggest options for prevention, treatment and monitoring progress and outcome. Most of the data are derived from adult studies and need to be replicated in children. Furthermore, there may be factors unique to pediatrics due to developmental changes in neuroplasticity as well as somatic, endocrinological and emotional growth. Some of these developmental factors may shed light on the adult condition.


Autoimmun Rev. 2012 Dec 6. pii: S1568-9972(12)00273-X. doi: 10.1016/j.autrev.2012.10.015. [Epub ahead of print] – click here

Complex regional pain syndrome, prototype of a novel kind of autoimmune disease.

Goebel A, Blaes F.


Pain Research Institute, Department of Translational Medicine, Liverpool University, Liverpool, UK; The Walton Centre NHS Foundation Trust, Liverpool, UK. Electronic address:


Complex regional pain syndrome (CRPS) is a painful condition, which arises in a limb after trauma. CRPS can profoundly affect patients’ quality of life, and there is no cure. CRPS is associated with limb-confined sensory, motor, skin, bone and autonomic abnormalities. Recent research has shown that some patients respond to treatment with immunoglobulins, and that a majority have IgG serum-autoantibodies directed against, and activating autonomic receptors. CRPS serum-IgG, when transferred to mice elicits abnormal behaviour. These results suggest that CRPS is associated with an autoantibody-mediated autoimmune process in some cases. CRPS has unusual features, including a non-destructive, and regionally-confined course. We propose that CRPS constitutes a prototype of a new kind of autoimmunity, which we term ‘IRAM’ (injury-triggered, regionally-restricted autoantibody-mediated autoimmune disorder with minimally-destructive course). Understanding autoimmune contribution to CRPS should allow the exploration of novel treatment modalities in the future. Additional ‘functional’ disorders, painful or painless may be autoimmune in nature.


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