CRPS Bugle | Nov 2013

CRPS Bugle

Welcome to November’s CRPS Bugle for updates on Complex Regional Pain Syndrome.


Intense Pain Soon After Wrist Fracture Strongly Predicts Who Will Develop Complex Regional Pain Syndrome: Prospective Cohort Study.

Moseley GL, Herbert RD, Parsons T, Lucas S, Van Hilten JJ, Marinus J.


Complex regional pain syndrome (CRPS) is a distressing and difficult-to-treat complication of wrist fracture. Estimates of the incidence of CRPS after wrist fracture vary greatly. It is not currently possible to identify who will go on to develop CRPS after wrist fracture. In this prospective cohort study, a nearly consecutive sample of 1,549 patients presenting with wrist fracture to 1 of 3 hospital-based fracture clinics and managed nonsurgically was assessed within 1 week of fracture and followed up 4 months later. Established criteria were used to diagnose CRPS. The incidence of CRPS in the 4 months after wrist fracture was 3.8% (95% confidence interval = 2.9-4.8%). A prediction model based on 4 clinical assessments (pain, reaction time, dysynchiria, and swelling) discriminated well between patients who would and would not subsequently develop CRPS (c index .99). A simple assessment of pain intensity (0-10 numerical rating scale) provided nearly the same level of discrimination (c index .98). One in 26 patients develops CRPS within 4 months of nonsurgically managed wrist fracture. A pain score of ≥5 in the first week after fracture should be considered a “red flag” for CRPS.

This study shows that excessive baseline pain in the week after wrist fracture greatly elevates the risk of developing CRPS. Clinicians can consider a rating of greater than 5/10 to the question “What is your average pain over the last 2 days?” to be a “red flag” for CRPS.

RS: We know that high levels of early pain can impact on the trajectory of a condition. The posed question becomes an essential part of the enquiry.


Genome-wide expression profiling of complex regional pain syndrome.

Jin EH, Zhang E, Ko Y, Sim WS, Moon DE, Yoon KJ, Hong JH, Lee WH.

PLoS One. 2013 Nov 14;8(11):e79435. doi: 10.1371/journal.pone.0079435. – full article here

Complex regional pain syndrome (CRPS) is a chronic, progressive, and devastating pain syndrome characterized by spontaneous pain, hyperalgesia, allodynia, altered skin temperature, and motor dysfunction. Although previous gene expression profiling studies have been conducted in animal pain models, there genome-wide expression profiling in the whole blood of CRPS patients has not been reported yet. Here, we successfully identified certain pain-related genes through genome-wide expression profiling in the blood from CRPS patients. We found that 80 genes were differentially expressed between 4 CRPS patients (2 CRPS I and 2 CRPS II) and 5 controls (cut-off value: 1.5-fold change and p<0.05). Most of those genes were associated with signal transduction, developmental processes, cell structure and motility, and immunity and defense. The expression levels of major histocompatibility complex class I A subtype (HLA-A29.1), matrix metalloproteinase 9 (MMP9), alanine aminopeptidase N (ANPEP), l-histidine decarboxylase (HDC), granulocyte colony-stimulating factor 3 receptor (G-CSF3R), and signal transducer and activator of transcription 3 (STAT3) genes selected from the microarray were confirmed in 24 CRPS patients and 18 controls by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). We focused on the MMP9 gene that, by qRT-PCR, showed a statistically significant difference in expression in CRPS patients compared to controls with the highest relative fold change (4.0±1.23 times and p = 1.4×10(-4)). The up-regulation of MMP9 gene in the blood may be related to the pain progression in CRPS patients. Our findings, which offer a valuable contribution to the understanding of the differential gene expression in CRPS may help in the understanding of the pathophysiology of CRPS pain progression.


Anesth Pain Med. 2012 Fall;2(2):54-59. Epub 2012 Sep 13. – full article here
Rethinking the Psychogenic Model of Complex Regional Pain Syndrome: Somatoform Disorders and Complex Regional Pain Syndrome.

Hill RJ, Chopra P, Richardi T.


Explaining the etiology of Complex Regional Pain Syndrome (CRPS) from the psychogenic model is exceedingly unsophisticated, because neurocognitive deficits, neuroanatomical abnormalities, and distortions in cognitive mapping are features of CRPS pathology. More importantly, many people who have developed CRPS have no history of mental illness. The psychogenic model offers comfort to physicians and mental health practitioners (MHPs) who have difficulty understanding pain maintained by newly uncovered neuro inflammatory processes. With increased education about CRPS through a biopsychosocial perspective, both physicians and MHPs can better diagnose, treat, and manage CRPS symptomatology.


J Pain. 2013 Nov 7. pii: S1526-5900(13)01352-7. doi: 10.1016/j.jpain.2013.10.011.

Complex Regional Pain Syndrome is associated with structural abnormalities in pain-related regions of the human brain.
Barad MJ, Ueno T, Younger J, Chatterjee N, Mackey S.

Complex regional pain syndrome (CRPS) is a chronic condition that involves significant hyperalgesia of the affected limb, typically accompanied by localized autonomic abnormalities, and frequently motor dysfunction. Although central brain systems are thought to play a role in the development and maintenance of CRPS, these systems have not been well characterized. In this study, we used structural magnetic resonance imaging (sMRI) to characterize differences in gray matter volume between patients with right upper extremity CRPS and matched controls . Analyses were carried out using a whole brain voxel-based morphometry (VBM) approach. The CRPS group showed decreased gray matter volume in several pain-affect regions, including the dorsal insula, left orbitofrontal cortex, and several aspects of the cingulate cortex. Greater gray matter volume in CRPS patients was seen in the bilateral dorsal putamen and right hypothalamus. Correlation analyses with self-reported pain were then performed on the CRPS group. Pain duration was associated with decreased gray matter in the left dorsolateral prefrontal cortex. Pain intensity was positively correlated with volume in the left posterior hippocampus and left amygdala, and negatively correlated with the bilateral dorsolateral prefrontal cortex. Our findings demonstrate that CRPS is associated with abnormal brain system morphology, particularly pain-related sensory, affect, motor, and autonomic systems.

This paper presents structural changes in the brains of patients with Complex Regional Pain Syndrome helping us differentiate CRPS from other chronic pain syndromes and furthering our understanding of this challenging disease.


Autoimmun Rev. 2013 Oct 23. pii: S1568-9972(13)00181-X. doi: 10.1016/j.autrev.2013.10.006.
Complex regional pain syndrome: A comprehensive and critical review.

Borchers AT, Gershwin ME.

Complex regional pain syndrome (CRPS) is a term used to describe a variety of disorders characterized by spontaneous or stimulus-induced pain that is disproportional to the inciting event and accompanied by a myriad of autonomic and motor disturbances in highly variable combinations. There are no standards which can be applied to the diagnosis and would fulfill definitions of evidence-based medicine. Indeed, there are almost as many diagnostic criteria as there are names to this disorder. The umbrella term CRPS has been subdivided into type I and type II. CRPS I is intended to encompass reflex sympathetic dystrophy and similar disorders without a nerve injury; while CRPS II occurs after damage to a peripheral nerve. There are numerous etiological pathophysiological events that have been incriminated in development of CRPS, including inflammation, autoimmune responses, abnormal cytokine production, sympathetic-sensory disorders, altered blood flow and central cortical reorganization. However, the number of studies that have included appropriate controls and have sufficient numbers of patients to allow statistical analysis with appropriate power calculations is vanishingly small. This has led to over-diagnosis and often excessive pharmacotherapy and even unnecessary surgical interventions. In this review we provide a detailed critical overview of not only the history of CRPS, but also the epidemiology, the clinical features, the pathophysiological studies, the proposed criteria, the therapy and, in particular, an emphasis that future research should apply more rigorous standards to allow a better understanding of CRPS, i.e. what it is, if it is, and when it is.


Pain. 2013 Oct 18. pii: S0304-3959(13)00555-1. doi: 10.1016/j.pain.2013.10.011. [Epub ahead of print]
A CRPS-IgG-transfer-trauma model reproducing inflammatory and positive sensory signs associated with complex regional pain syndrome.
Tékus V, Hajna Z, Borbély E, Markovics A, Bagoly T, Szolcsányi J, Thompson V, Kemény A, Helyes Z, Goebel A.

The aetiology of complex regional pain syndrome (CRPS), a highly painful, usually post-traumatic condition affecting the limbs, is unknown, but recent results have suggested an autoimmune contribution. To confirm a role for pathogenic autoantibodies, we established a passive-transfer trauma model. Prior to undergoing incision of hind limb plantar skin and muscle, mice were injected either with serum IgG obtained from chronic CRPS patients or matched healthy volunteers, or with saline. Unilateral hind limb plantar skin and muscle incision was performed to induce typical, mild tissue injury. Mechanical hyperalgesia, paw swelling, heat and cold sensitivity, weight-bearing ability, locomotor activity, motor coordination, paw temperature, and body weight were investigated for 8days. After sacrifice, proinflammatory sensory neuropeptides and cytokines were measured in paw tissues. CRPS patient IgG treatment significantly increased hind limb mechanical hyperalgesia and oedema in the incised paw compared with IgG from healthy subjects or saline. Plantar incision induced a remarkable elevation of substance P immunoreactivity on day 8, which was significantly increased by CRPS-IgG. In this IgG-transfer-trauma model for CRPS, serum IgG from chronic CRPS patients induced clinical and laboratory features resembling the human disease. These results support the hypothesis that autoantibodies may contribute to the pathophysiology of CRPS, and that autoantibody-removing therapies may be effective treatments for long-standing CRPS.


Clin J Pain. 2013 Oct 16. 
Relationships Between Psychological Factors, Pain and Disability in Complex Regional Pain Syndrome and Low Back Pain.
Bean DJ, Johnson MH, Kydd RR.

Cognitive and emotional factors are known to influence patients’ pain experiences in many conditions, including low back pain. However in complex regional pain syndrome (CRPS), their role is unclear. This study aimed to assess the relationships between psychological factors, pain and disability in CRPS, compared to low back pain. This could help to identify target variables for psychological treatment.
88 CRPS patients and 88 low back pain patients completed measures of pain, disability, depression, anxiety, and kinesiophobia. Mean scores between the two groups were compared, and correlations between psychological factors, pain and disability were compared between the two groups. Predictors of pain and disability were assessed using multiple regression analyses.
The two groups had remarkably similar scores on measures of pain, disability, depression, anxiety, and kinesiophobia. In both groups, those who were more depressed, anxious and kinesiophobic were more disabled. For the CRPS group (but not the low back pain group), pain intensity significantly correlated with distress. Multivariate analyses showed that the unique predictors of disability for the two groups were pain and depression, and that depression had a stronger relationship with disability for the CRPS group. For both groups, pain intensity was predicted by kinesiophobia, and anxiety was a unique predictor in the CRPS group only.
In CRPS, disability and pain severity were more strongly associated with psychological factors than they were in low back pain. Cause and effect relationships could not be established by this cross-sectional study.

For further information about Complex Regional Pain Syndrome (CRPS) and treatment please contact us on 07932 689081 or visit the clinic website here.


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