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Brain imaging studies in complex regional pain syndrome (CRPS) have found mixed evidence for functional and structural changes in CRPS. In this cross-sectional study, we evaluated two patient cohorts from different centers and examined functional connectivity (rsFC) in 51 CRPS patients and 50 matched controls. rsFC was compared in predefined ROI pairs, but also in non-hypothesis driven analyses. Resting state (rs)fMRI changes in default mode network (DMN) and the degree rank order disruption index (k D ) were additionally evaluated. Finally, imaging parameters were correlated with clinical severity and somatosensory function. Among predefined pairs, we found only weakly to moderately lower functional connectivity between the right nucleus accumbens and bilateral ventromedial prefrontal cortex in the infra-slow oscillations (ISO) band. The unconstrained ROI-to-ROI analysis revealed lower rsFC between the periaqueductal gray matter (PAG) and left anterior insula, and higher rsFC between the right sensorimotor thalamus and nucleus accumbens. In the correlation analysis, pain was positively associated with insulo-prefrontal rsFC, whereas sensorimotor thalamo-cortical rsFC was positively associated with tactile spatial resolution of the affected side. In contrast to previous reports, we found no group differences for k D or rsFC in the DMN, but detected overall lower data quality in patients. In summary, while some of the previous results were not replicated despite the larger sample size, novel findings from two independent cohorts point to potential down-regulated antinociceptive modulation by the PAG and increased connectivity within the reward system as pathophysiological mechanisms in CRPS. However, in light of the detected systematic differences in data quality between patients and healthy subjects, validity of rsFC abnormalities in CRPS should be carefully scrutinized in future replication studies., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Complex regional pain syndrome (CRPS) is a rare pain disorder that usually occurs in a limb after trauma. The features of this disorder include severe pain and sensory, autonomic, motor, and trophic abnormalities. Research from the past decade has offered new insights into CRPS epidemiology, pathophysiology, diagnosis, and treatment. Early identification of individuals at high risk of CRPS is improving, with several risk factors established and some others identified in prospective studies during the past 5 years. Better understanding of the pathophysiological mechanisms of CRPS has led to its classification as a chronic primary pain disorder, and subtypes of CRPS have been updated. Procedures for diagnosis have also been clarified. Although effective treatment of CRPS remains a challenge, evidence-based integrated management approaches provide new opportunities to improve patient care. Further advances in diagnosis and treatment of CRPS will require coordinated, international multicentre initiatives., Competing Interests: Declaration of interests MCF is supported by an Australian Government Research Training Program scholarship and the Neuroscience Research Australia PhD Pearl supplementary scholarship; has received research grants from ERA-NET NEURON for research related to CRPS and neuropathic pain; and is a committee member of the IASP special interest group for CRPS. NEO has received funding from the National Health and Medical Research Council of Australia and ERA-NET NEURON for research related to CRPS. CS is funded by the German Research Foundation for the Clinical Research Group KFO5001 ResolvePAIN and has received funding from Deutsche Forschungsgemeinschaft and Bundesministerium für Bildung und Forschung. AG has received funding from the UK Medical Research Council, Pain Relief Foundation Liverpool, and Versus Arthritis; has been a consultant for UCB and Novartis; is Chair of the Scientific Committee of the British Pain Society, past Chair of the IASP special interest group for CRPS, and Chair of the European Pain Federation CRPS task force; and is a member of the scientific committee for the Pain Relief Foundation. JHB is co-Chair of the IASP special interest group for CRPS; has received fees for speaking about CRPS paid by Theoria Congresos, at a conference organised by Hospital Intermutual de Levante; and has received research funding from the Reflex Sympathetic Dystrophy Syndrome Association, the Netherlands Organisation for Scientific Research, and the Experimental Psychological Society. AGC, GLM, and JHM receive salary support from investigator grants from the National Health and Medical Research Council of Australia. GLM receives royalties for a book about a specific rehabilitation approach to CRPS that is mentioned in this Review; is an unpaid board member of the consumer advocacy body Pain Australia, and is an unpaid Chief Executive Officer of the non-profit community outreach initiative Pain Revolution. GLM and JHM have received funding from the National Health and Medical Research Council of Australia for research on CRPS., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Complex regional pain syndrome (CRPS) is a chronic pain condition that usually occurs in a limb following trauma or surgery. It is characterised by persisting pain that is disproportionate in magnitude or duration to the typical course of pain after similar injury. There is currently no consensus regarding the optimal management of CRPS, although a broad range of interventions have been described and are commonly used. This is the first update of the original Cochrane review published in Issue 4, 2013., Objectives: To summarise the evidence from Cochrane and non-Cochrane systematic reviews of the efficacy, effectiveness, and safety of any intervention used to reduce pain, disability, or both, in adults with CRPS., Methods: We identified Cochrane reviews and non-Cochrane reviews through a systematic search of Ovid MEDLINE, Ovid Embase, Cochrane Database of Systematic Reviews, CINAHL, PEDro, LILACS and Epistemonikos from inception to October 2022, with no language restrictions. We included systematic reviews of randomised controlled trials that included adults (≥18 years) diagnosed with CRPS, using any diagnostic criteria.  Two overview authors independently assessed eligibility, extracted data, and assessed the quality of the reviews and certainty of the evidence using the AMSTAR 2 and GRADE tools respectively. We extracted data for the primary outcomes pain, disability and adverse events, and the secondary outcomes quality of life, emotional well-being, and participants' ratings of satisfaction or improvement with treatment.  MAIN RESULTS: We included six Cochrane and 13 non-Cochrane systematic reviews in the previous version of this overview and five Cochrane and 12 non-Cochrane reviews in the current version. Using the AMSTAR 2 tool, we judged Cochrane reviews to have higher methodological quality than non-Cochrane reviews. The studies in the included reviews were typically small and mostly at high risk of bias or of low methodological quality. We found no high-certainty evidence for any comparison.  There was low-certainty evidence that bisphosphonates may reduce pain intensity post-intervention (standardised mean difference (SMD) -2.6, 95% confidence interval (CI) -1.8 to -3.4, P = 0.001; I 2 = 81%; 4 trials, n = 181) and moderate-certainty evidence that they are probably associated with increased adverse events of any nature (risk ratio (RR) 2.10, 95% CI 1.27 to 3.47; number needed to treat for an additional harmful outcome (NNTH) 4.6, 95% CI 2.4 to 168.0; 4 trials, n = 181).  There was moderate-certainty evidence that lidocaine local anaesthetic sympathetic blockade probably does not reduce pain intensity compared with placebo, and low-certainty evidence that it may not reduce pain intensity compared with ultrasound of the stellate ganglion. No effect size was reported for either comparison. There was low-certainty evidence that topical dimethyl sulfoxide may not reduce pain intensity compared with oral N-acetylcysteine, but no effect size was reported. There was low-certainty evidence that continuous bupivacaine brachial plexus block may reduce pain intensity compared with continuous bupivacaine stellate ganglion block, but no effect size was reported. For a wide range of other commonly used interventions, the certainty in the evidence was very low and provides insufficient evidence to either support or refute their use. Comparisons with low- and very low-certainty evidence should be treated with substantial caution. We did not identify any RCT evidence for routinely used pharmacological interventions for CRPS such as tricyclic antidepressants or opioids., Authors' Conclusions: Despite a considerable increase in included evidence compared with the previous version of this overview, we identified no high-certainty evidence for the effectiveness of any therapy for CRPS. Until larger, high-quality trials are undertaken, formulating an evidence-based approach to managing CRPS will remain difficult. Current non-Cochrane systematic reviews of interventions for CRPS are of low methodological quality and should not be relied upon to provide an accurate and comprehensive summary of the evidence., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Complex Regional Pain Syndrome (CRPS) is a disabling pain disorder that is most common after a distal limb fracture. While the acute systemic immune response to the injury is thought to play a role in the development of CRPS, this hypothesis has never been tested directly. Thus, we evaluated whether elevated levels of circulating pro-inflammatory cytokines early after a fracture were associated with the development of CRPS., Methods: We conducted a case-control study nested within a prospective cohort study. Individuals with wrist and/or hand fractures were recruited from specialist hand units. Baseline clinical data were obtained from participants within 28 days of fracture. CRPS status was determined 16 weeks after the fracture using a two-stage diagnostic process. Cytokine assays were obtained from all cases (defined using the Budapest criteria) and a random sample of those who did not have CRPS at 16 weeks. We calculated odds ratios with 95% confidence intervals to determine the risk of CRPS associated with the expression of each of 25 cytokines., Results: Baseline data were collected for 702 consenting participants, of whom 535 provided blood samples. Follow-up at 16 weeks was 97.2%. 15 (2.2% of the cohort) met the Budapest CRPS criteria and 69 (including those who met the Budapest criteria; 9.8%) met the International Association for the Study of Pain (IASP) CRPS criteria. In all of the primary analyses (using Budapest criteria) and 49/50 secondary analyses (using IASP criteria), 95% confidence intervals for the association between cytokine levels and the risk of subsequently developing CRPS included the null value (OR = 1). However, the confidence intervals were wide., Conclusion: There was no evidence that early post-injury expression of systemic cytokines was associated with a CRPS diagnosis 16 weeks after injury. This study does not provide support for the hypothesis that innate immune activation has a determinative role in the development of CRPS., (© 2022. The Author(s).)

Movement limitation is a common characteristic of chronic pain such that pain prevents the very movement and activity that is most likely to promote recovery. This is particularly the case for pathological pain states such as complex regional pain syndrome (CRPS). One clinical approach to CRPS that has growing evidence of efficacy involves progressive movement imagery training. Graded Motor Imagery (GMI) targets clinical and neurophysiological effects through a stepwise progression through implicit and explicit movement imagery training, mirror therapy and then functional tasks. Here we review experiences from over 20 years of clinical and research experience with GMI. We situate GMI in terms of its historical underpinnings, the benefits and outstanding challenges of its implementation, its potential application beyond CRPS. We then review the neuropathological targets of GMI and current thought on its effects on neurophysiological biomarkers. PERSPECTIVE: This article provides an overview of our experiences with graded motor imagery training over the last 20 years focussing on the treatment of CRPS. It does both cover the theoretical underpinnings for this treatment approach, biomarkers which indicate potential changes driven by GMI, and experiences for achieving optimal treatment results., (Copyright © 2022 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Complex Regional Pain Syndrome (CRPS) is a rare but disabling pain condition. Accurate and timely education about CRPS is key to promote optimal clinical outcomes, but it is unclear what the content of that education should be. We aimed to determine the content that both people with CRPS and expert health care professionals (HCPs) reported as important., Methods: An international three-round e-Delphi was conducted, recruiting adults diagnosed with CRPS and HCPs. In Round 1, participants were asked to list the most important information people with CRPS should know regarding the condition. Data were organized into concepts and allocated to themes. In Rounds 2 and 3, participants rated each concept on a 9-point Likert Scale, categorized as 'not important' (0-3), 'important' (4-6) and 'very important' (7-9). A concept attained consensus when ≥75% agreement was reached within a category., Results: Sixty-two participants (HCPs: n = 7; CRPS: n = 55) proposed 193 concepts in Round 1, resulting in 22 themes. Fifteen additional concepts were identified in Round 2, resulting in a total of 208 concepts. From that list, 48 concepts that emphasized understanding and evidence-based management of the disorder, the importance of self-management strategies, pacing and movement, reached joint consensus as 'very important'. One concept: 'Advise that movement does not help' reached joint consensus as 'not important'., Conclusion: Forty-eight concepts were jointly considered 'very important' for future CRPS-related educational content. Future research to better understand group differences and to canvas a broader HCP group is warranted., Significance: This e-Delphi study identified the 48 core concepts that those with the lived experience of CRPS, and advanced practitioner health care professionals jointly rated as 'very important' to include in fundamental and accessible educational material., (© 2022 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC®.)

Complex regional pain syndrome (CRPS) is a distressing and disabling pain condition. Many people with CRPS and the health professionals who treat them seek information about the condition via the Internet. The credibility, accuracy and comprehensiveness of online CRPS information remains unknown. The aim of this study was to determine the credibility, accuracy and comprehensiveness of information presented on freely accessible websites that aim to educate people about CRPS. Keyword searches were conducted on the Australian Google site, with 'trustworthy' websites included and critically appraised. Primary outcomes were recognised metrics of credibility (JAMA benchmark credibility criteria) and website accuracy (according to European CRPS guidelines). Comprehensiveness was assessed using the proportion of European CRPS guidelines covered by the websites. In all, 30 websites with 819 recommendations were critically appraised. Five (17%) websites met all credibility criteria; of the recommendations, 349 (43%) were accurate, 252 (31%) were inaccurate and 218 (26%) were unclear. For comprehensiveness, an average of 17% of general guidelines, 15% of therapeutic guidelines and 6% of medication/supplement guidelines were covered. Online information about CRPS available to Australians has low credibility, accuracy and comprehensiveness. Many website recommendations are inaccurate or unclear, and many websites endorse inappropriate treatments. There is an urgent need for accurate and comprehensive sources of CRPS information online.

Complex regional pain syndrome (CRPS) is a neuropathic pain condition that is difficult to treat. For behavioral interventions, graded motor imagery (GMI) showed relevant effects, but underlying neural substrates in patient groups have not been investigated yet. A previous study investigating differences in the representation of a left/right hand judgment task demonstrated less recruitment of subcortical structures, such as the putamen, in CRPS patients than in healthy controls. In healthy volunteers, the putamen activity increased after a hand judgment task training. In order to test for longitudinal effects of GMI training, we investigated 20 CRPS patients in a wait-list crossover design with 3 evaluation time points. Patients underwent a 6 week GMI treatment and a 6 week waiting period in a randomized group assignment and treatment groups were evaluated by a blinded rater. When compared to healthy matched controls at baseline, CRPS patients showed less functional activation in areas processing visual input, left sensorimotor cortex, and right putamen. Only GMI treatment, but not the waiting period showed an effect on movement pain and hand judgment task performance. Regression analyses revealed positive associations of movement pain with left anterior insula activation at baseline. Right intraparietal sulcus activation change during GMI was associated with a gain in performance of the hand judgment task. The design used here is reliable for investigating the functional representation of the hand judgment task in an intervention study. PERSPECTIVE: Twenty chronic CRPS patients underwent a 6 week GMI intervention in a randomized wait-list crossover design. functional MRI was tested pre and post for the hand lateralization task which improved over GMI but not over WAITING. Performance gain was positively related to right parietal functional MRI activation., (Copyright © 2021 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

It has long been thought that severe chronic pain conditions, such as complex regional pain syndrome (CRPS), are not only associated with, but even maintained by a reorganization of the somatotopic representation of the affected limb in primary somatosensory cortex (S1). This notion has driven treatments that aim to restore S1 representations in CRPS patients, such as sensory discrimination training and mirror therapy. However, this notion is based on both indirect and incomplete evidence obtained with imaging methods with low spatial resolution. Here, we used fMRI to characterize the S1 representation of the affected and unaffected hand in humans (of either sex) with unilateral CRPS. The cortical area, location, and geometry of the S1 representation of the CRPS hand were largely comparable with those of both the unaffected hand and healthy controls. We found no differential relation between affected versus unaffected hand map measures and clinical measures (pain severity, upper limb disability, disease duration). Thus, if any map reorganization occurs, it does not appear to be directly related to pain and disease severity. These findings compel us to reconsider the cortical mechanisms underlying CRPS and the rationale for interventions that aim to "restore" somatotopic representations to treat pain. SIGNIFICANCE STATEMENT This study shows that the spatial map of the fingers in somatosensory cortex is largely preserved in chronic complex regional pain syndrome (CRPS). These findings challenge the treatment rationale for restoring somatotopic representations in complex regional pain syndrome patients., (Copyright © 2019 Mancini, Wang et al.)

Background: Complex regional pain syndrome is a painful and disabling post-traumatic primary pain disorder. Acute and chronic complex regional pain syndrome (CRPS) are major clinical challenges. In Europe, progress is hampered by significant heterogeneity in clinical practice. We sought to establish standards for the diagnosis and management of CRPS., Methods: The European Pain Federation established a pan-European task force of experts in CRPS who followed a four-stage consensus challenge process to produce mandatory quality standards worded as grammatically imperative (must-do) statements., Results: We developed 17 standards in 8 areas of care. There are 2 standards in diagnosis, 1 in multidisciplinary care, 1 in assessment, 3 for care pathways, 1 in information and education, 4 in pain management, 3 in physical rehabilitation and 2 on distress management. The standards are presented and summarized, and their generation and consequences were discussed. Also presented are domains of practice for which no agreement on a standard could be reached. Areas of research needed to improve the validity and uptake of these standards are discussed., Conclusion: The European Pain Federation task force present 17 standards of the diagnosis and management of CRPS for use in Europe. These are considered achievable for most countries and aspirational for a minority of countries depending on their healthcare resource and structures., Significance: This position statement summarizes expert opinion on acceptable standards for CRPS care in Europe., (© 2019 European Pain Federation - EFIC®.)

Complex regional pain syndrome (CRPS) is associated with deficits in sensorimotor control. Herein we have used a novel finger illusion to investigate whether CRPS is associated with reduced weighting of bimanual hand representations. The illusion normally induces a compelling feeling that the hands are close together when in fact they are 12 cm apart. People with CRPS and age, gender, and dominant hand-matched controls tested the illusion in the midline then on either side of the midline. The illusion had 2 variants; the passive pincer-grip position, without contact (no grasp condition) and with contact (grasp condition) of the artificial finger. The primary outcome was the perceived vertical distance between the index fingers. Twenty people with CRPS and 20 controls participated (mean age 44.4 ± 11.7 years). During the no grasp condition, participants with CRPS perceived the vertical distance significantly closer to the actual 12 cm (mean 8.0 cm, 95% confidence interval 6.5-9.5 cm), than controls did (mean 6.4 cm, 95% confidence interval 5.5-7.2 cm]). That is, the illusion was weaker in people with CRPS than in controls during no grasp. There was no such difference during grasp; that is, both groups showed the predicted illusion response. There was no effect of hand placement relative to midline or relative to the opposite hand. We conclude that people with unilateral CRPS have lower weighting of bimanual hand representation than controls have, independent of hand location. However, adding additional cutaneous input returns those with CRPS to the expected performance. We suggest the results have clear clinical and research implications. PERSPECTIVE: An abnormal weighting of bilateral hand representation may reflect a vulnerability for chronic CRPS, an adaptation to the disease, and/or a potential therapeutic target. That addition of cutaneous input immediately normalizes the problem points to the possible role of bimanual tasks in prevention or rehabilitation., (Copyright © 2018. Published by Elsevier Inc.)

Objective: Spatially-defined disruption of autonomic and sensory function has been identified in Complex Regional Pain Syndrome (CRPS). This study aimed to determine whether motor performance is also disrupted in a spatially-defined manner in people with CRPS., Methods: Thirteen people with CRPS type 1 of the upper limb participated in two motor experiments. In Experiment 1 participants performed a circle drawing task that primarily tested motor accuracy. In Experiment 2 participants performed a button pressing task that tested motor co-ordination. In both experiments the motor tasks were performed with either hand (affected or healthy), and on either side of the body midline - that is, on the affected side of space or healthy side of space., Results: There was a main effect of both Limb and Side for the motor tasks. In Experiment 1, motor accuracy for the circle drawing task was poorer when participants used their affected hand than when they used their healthy one (p < .001), and when the task was performed on the affected side of their body midline than when it was performed on the healthy side (p < .001). In Experiment 2, motor co-ordination for the button pressing task was poorer when participants used their affected hand than when they used their healthy one (p < .001), and when the task was performed on the affected side of the midline (p < .001), as compared to the healthy side of the midline., Conclusions: Unilateral CRPS is associated with a spatially-defined disruption of motor performance. Participants perform worse when the task is performed on the affected side of the body midline, regardless of whether they use their affected or healthy hand., (Copyright © 2017. Published by Elsevier Ltd.)

Background and Aims: Recent evidence demonstrated that complex regional pain syndrome (CRPS) is associated with a larger than normal somatosensory (S1) representation of the healthy hand. The most intuitive mechanism for this apparent enlargement is increased, i.e. compensatory, use of the healthy hand. We investigated whether enlargement of the S1 representation of the healthy hand is associated with compensatory use in response to CRPS. Specifically, we were interested in whether the size of the S1 representation of the healthy hand is associated with the severity of functional impairment of the CRPS-affected hand. We were also interested in whether CRPS duration might be positively associated with the size of the representation of the healthy hand in S1., Methods: Using functional magnetic resonance imaging (fMRI) data from our previous investigation, the size of the S1 representation of the healthy hand in CRPS patients (n=12) was standardised to that of a healthy control sample (n=10), according to hand dominance. Responses to questionnaires on hand function, overall function and self-efficacy were used to gather information on hand use in participants. Multiple regression analyses investigated whether the S1 representation was associated with compensatory use. We inferred compensatory use with the interaction between reported use of the CRPS-affected hand and (a) reported overall function, and (b) self-efficacy. We tested the correlation between pain duration and the size of the S1 representation of the healthy hand with Spearman's rho., Results: The relationship between the size of the S1 representation of the healthy hand and the interaction between use of the affected hand and overall function was small and non-significant (β=-5.488×10 -5 , 95% C.I. -0.001, 0.001). The relationship between the size of the S1 representation of the healthy hand and the interaction between use of the affected hand and self-efficacy was also small and non-significant (β=-6.027×10 -6 , 95% C.I. -0.001, 0.001). The S1 enlargement of the healthy hand was not associated with pain duration (Spearman's rho=-0.14, p=0.67)., Conclusion: Our exploration did not yield evidence of any relationship between the size of the healthy hand representation in S1 and the severity of functional impairment of the CRPS-affected hand, relative to overall hand use or to self-efficacy. There was also no evidence of an association between the size of the healthy hand representation in S1 and pain duration. The enlarged S1 representation of the healthy hand does not relate to self-reported function and impairment in CRPS., Implications: While this study had a hypothesis-generating nature and the sample was small, there were no trends to suggest compensatory use as the mechanism underlying the apparent enlargement of the healthy hand in S1. Further studies are needed to investigate the possibility that inter-hemispheric differences seen in S1 in CRPS may be present prior to the development of the disorder., (Copyright © 2016 Scandinavian Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Orofacial pain disorders are relatively uncommon and pose a substantial diagnostic challenge. This case report documents the diagnosis and management of hemifacial pain in a patient who was referred to an interdisciplinary pain medicine unit. The purpose of this case report is twofold. First, it presents complex regional pain syndrome (CRPS) as a potential differential diagnosis in cases of facial pain. Second, it describes the successful adaption of contemporary management approaches for distal-extremity CRPS to treat people with CRPS of the facial region., Case Description: The patient had hemifacial pain and concomitant motor and autonomic symptoms after a small laceration of the eyelid. Extensive specialist medical evaluations were undertaken to exclude an underlying structural pathology. After detailed clinical assessments by a physical therapist, pain physician, and clinical psychologist, a diagnosis of CRPS involving the face was made., Outcomes: The patient's pain was largely unresponsive to pharmacological agents. A modified graded motor imagery program, together with desensitization and discrimination training, was commenced by the physical therapist and clinical psychologist. A positive clinical response was indicated by a decrease in allodynia, normalization of motor control, and regained function in activities of daily living., Discussion: Complex regional pain syndrome is an infrequently reported differential diagnosis that can be considered in patients with persistent facial pain. This case report highlights how careful examination and clinical decision making led to the use of an innovative therapeutic strategy to manage a challenging condition., (© 2016 American Physical Therapy Association.)

Pathological limb pain patients show decreased attention to some stimuli on the painful limb and increased attention to others, a paradox that has dogged the field for over a decade. We hypothesized that pathological pain involves a spatial inattention confined to bodily representations. Patients showed inattention to the painful side for visual processing of body parts but not letters, tactile processing but not auditory, and body-part bisection tasks but not line bisection tasks. We propose the new term "somatospatial inattention" to describe bodily-specific spatial inattention associated with pathological limb pain., (© 2016 American Neurological Association.)

It is widely accepted that complex regional pain syndrome (CRPS) is associated with shrinkage of the primary somatosensory cortex (S1) representation of the affected limb. However, supporting evidence is surprisingly limited and may be compromised by high risk of bias. This study compared the S1 spatial representation of the hand in 17 patients with upper-limb CRPS to 16 healthy controls, using functional MRI. Innocuous vibration was delivered to digits one (D1) and five (D5) in a block-design. Resultant activation maxima were located within a bilateral S1 mask, determined a priori. Distance between D1 and D5 activation maxima, calculated for both hands, was used as a measure of S1 representation. Analyses were blinded to group and hand. In patients, S1 representation was smaller for the affected hand than it was for the healthy hand (t(11) = 2.02, P = 0.03), as predicted. However, S1 representation of the affected hand was no different to that of either hand in controls. Critically, S1 representation of the healthy hand of patients was larger than that of controls' hands. CRPS seems to be associated with an enlarged representation of the healthy hand, not a smaller representation of the affected hand. These findings raise important questions about neuroplasticity in CRPS., (© 2014 Wiley Periodicals, Inc.)

Unlabelled: Dysfunction in the central nervous system is thought to underlie the movement disorders that commonly occur in complex regional pain syndrome (CRPS), with much of the literature focusing on reorganization of the primary motor cortex (M1). Presumed changes in the M1 representation of the CRPS-affected body part have contributed to new CRPS treatments, which are increasingly being integrated in the clinic. We systematically investigated the evidence for altered M1 function in CRPS. We adhered to rigorous systematic review procedure in our search strategy, risk-of-bias appraisal, and data extraction. Eighteen studies comprising 14 unique data sets were included. The included studies used several neuroimaging techniques, whose outcomes we grouped into M1 cortical excitability, spatial representation, reactivity, and glucose metabolism, and conducted meta-analyses where possible. Risk of bias across studies was high, mainly due to missing data and unblinded assessment of outcomes. No definitive conclusions can be drawn regarding M1 spatial representation, reactivity, or glucose metabolism in CRPS. There is limited evidence for bilateral M1 disinhibition in CRPS of the upper limb., Perspective: Despite widely held assumptions of primary motor cortex dysfunction in complex regional pain syndrome, there is only evidence to support bilateral disinhibition, and there is high risk of bias across the literature., (Copyright © 2013 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Unlabelled: That complex regional pain syndrome (CRPS) is associated with functional reorganization in the primary somatosensory cortex (S1) is widely accepted and seldom questioned. Despite more than a decade of research, there has been no systematic review of the CRPS literature concerning the changes in S1 function, and therefore the extent of these changes is unclear. Here we conduct a systematic review and meta-analysis to quantify the spatial and temporal aspects of S1 function in CRPS. A comprehensive search strategy identified functional neuroimaging studies of S1 in CRPS. We adhered to a rigorous systematic review protocol when extracting data and appraising risk of bias. Outcomes were grouped into spatial representation; activation levels, including disinhibition; peak latency of activation; and glucose metabolism. Meta-analysis was conducted where possible. Fifteen studies were included, all investigating upper-extremity CRPS. In patients with CRPS, the S1 spatial representation of the affected hand is smaller than that of the unaffected hand and that of non-CRPS controls; however, this evidence comes from only a few studies. There is no difference in activation, disinhibition, or latency of peripherally evoked S1 responses in CRPS. The risk of bias was high across studies, mainly from unclear sampling methods and unblinded analysis of outcomes., Perspective: The evidence for a difference in function of the primary somatosensory cortex in CRPS compared with controls is clouded by high risk of bias and conflicting results, but reduced representation size seems consistent., (Copyright © 2013 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Background: There is currently no strong consensus regarding the optimal management of complex regional pain syndrome although a multitude of interventions have been described and are commonly used., Objectives: To summarise the evidence from Cochrane and non-Cochrane systematic reviews of the effectiveness of any therapeutic intervention used to reduce pain, disability or both in adults with complex regional pain syndrome (CRPS)., Methods: We identified Cochrane reviews and non-Cochrane reviews through a systematic search of the following databases: Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects (DARE), Ovid MEDLINE, Ovid EMBASE, CINAHL, LILACS and PEDro. We included non-Cochrane systematic reviews where they contained evidence not covered by identified Cochrane reviews. The methodological quality of reviews was assessed using the AMSTAR tool.We extracted data for the primary outcomes pain, disability and adverse events, and the secondary outcomes of quality of life, emotional well being and participants' ratings of satisfaction or improvement. Only evidence arising from randomised controlled trials was considered. We used the GRADE system to assess the quality of evidence., Main Results: We included six Cochrane reviews and 13 non-Cochrane systematic reviews. Cochrane reviews demonstrated better methodological quality than non-Cochrane reviews. Trials were typically small and the quality variable.There is moderate quality evidence that intravenous regional blockade with guanethidine is not effective in CRPS and that the procedure appears to be associated with the risk of significant adverse events.There is low quality evidence that bisphosphonates, calcitonin or a daily course of intravenous ketamine may be effective for pain when compared with placebo; graded motor imagery may be effective for pain and function when compared with usual care; and that mirror therapy may be effective for pain in post-stroke CRPS compared with a 'covered mirror' control. This evidence should be interpreted with caution. There is low quality evidence that local anaesthetic sympathetic blockade is not effective. Low quality evidence suggests that physiotherapy or occupational therapy are associated with small positive effects that are unlikely to be clinically important at one year follow up when compared with a social work passive attention control.For a wide range of other interventions, there is either no evidence or very low quality evidence available from which no conclusions should be drawn., Authors' Conclusions: There is a critical lack of high quality evidence for the effectiveness of most therapies for CRPS. Until further larger trials are undertaken, formulating an evidence-based approach to managing CRPS will remain difficult.

Objectives: 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., Methods: 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., Results: 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., Conclusion: 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.

Numerous clinical conditions, including complex regional pain syndrome, are characterized by autonomic dysfunctions (e.g. altered thermoregulation, sometimes confined to a single limb), and disrupted cortical representation of the body and the surrounding space. The presence, in patients with complex regional pain syndrome, of a disruption in spatial perception, bodily ownership and thermoregulation led us to hypothesize that impaired spatial perception might result in a spatial-dependent modulation of thermoregulation and bodily ownership over the affected limb. In five experiments involving a total of 23 patients with complex regional pain syndrome of one arm and 10 healthy control subjects, we measured skin temperature of the hand with infrared thermal imaging, before and after experimental periods of either 9 or 10 min each, during which the hand was held on one or the other side of the body midline. Tactile processing was assessed by temporal order judgements of pairs of vibrotactile stimuli, delivered one to each hand. Pain and sense of ownership over the hand were assessed by self-report scales. Across experiments, when kept on its usual side of the body midline, the affected hand was 0.5 ± 0.3°C cooler than the healthy hand (P < 0.02 for all, a common finding in cold-type complex regional pain syndrome), and tactile stimuli delivered to the healthy hand were prioritized over those delivered to the affected hand. Simply crossing both hands over the midline resulted in (i) warming of the affected hand (the affected hand became 0.4 ± 0.3°C warmer than when it was in the uncrossed position; P = 0.01); (ii) cooling of the healthy hand (by 0.3 ± 0.3°C; P = 0.02); and (iii) reversal of the prioritization of tactile processing. When only the affected hand was crossed over the midline, it became warmer (by 0.5 ± 0.3°C; P = 0.01). When only the healthy hand was crossed over the midline, it became cooler (by 0.3 ± 0.3°C; P = 0.01). The temperature change of either hand was positively related to its distance from the body midline (pooled data: r = 0.76, P < 0.001). Crossing the affected hand over the body midline had small but significant effects on both spontaneous pain (which was reduced) and the sense of ownership over the hand (which was increased) (P < 0.04 for both). We conclude that impaired spatial perception modulated temperature of the limbs, tactile processing, spontaneous pain and the sense of ownership over the hands. These results show that complex regional pain syndrome involves more complex neurological dysfunction than has previously been considered.

Background: There is good evidence from studies conducted in a single-centre research setting for the efficacy of graded motor imagery (GMI) treatment, a complex physiotherapy intervention, to reduce pain in long-standing complex regional pain syndrome (CRPS). However, whether GMI is effective in clinical practice is not established., Aim: To establish whether GMI is effective in clinical practice., Methods: We undertook a prospective audit of GMI treatment at two UK centres with a special interest in the management of patients with CRPS. All patients received GMI, in conjunction with a range of other 'best practice' physical and psychological interventions., Results: The patients' average pain intensities did not improve with treatment [centre 1: n = 20, pre-post numeric rating scale (NRS) difference 0.6 [confidence interval (CI) -0.3 to 1.5]; centre 2: n = 12, pre-post NRS difference 0.2 (CI: -0.9 to 1.2)]. Patients at centre 1 reported significant functional improvement. Improved performance on left/right judgement replicated in both centres seen in the clinical trials., Conclusions: The failure of our real-world implementation of GMI suggests that better understanding of both the GMI methodology and its interaction with other treatment methods is required to ensure that GMI research results can be translated into clinical practice. Our results highlight challenges with the translation of complex interventions for chronic pain conditions into clinical practice., (© 2011 European Federation of International Association for the Study of Pain Chapters.)

Complex regional pain syndrome (CRPS) generally remains restricted to one limb but occasionally may spread to other limbs. Knowledge of the spreading pattern of CRPS may lead to hypotheses about underlying mechanisms but to date little is known about this process. The objective is to study patterns of spread of CRPS from a first to a second limb and the factors associated with this process. One hundred and eighty-five CRPS patients were retrospectively evaluated. Cox's proportional hazards model was used to evaluate factors that influenced spread of CRPS symptoms. Eighty-nine patients exhibited CRPS in multiple limbs. In 72 patients spread from a first to a second limb occurred showing a contralateral pattern in 49%, ipsilateral pattern in 30% and diagonal pattern in 14%. A trauma preceded the onset in the second limb in 37, 44 and 91%, respectively. The hazard of spread of CRPS increased with the number of limbs affected. Compared to patients with CRPS in one limb, patients with CRPS in multiple limbs were on average 7 years younger and more often had movement disorders. In patients with CRPS in multiple limbs, spontaneous spread of symptoms generally follows a contralateral or ipsilateral pattern whereas diagonal spread is rare and generally preceded by a new trauma. Spread is associated with a younger age at onset and a more severely affected phenotype. We argue that processes in the spinal cord as well as supraspinal changes are responsible for spontaneous spread in CRPS.

A complex regional pain syndrome (CRPS)--multiple system dysfunction, severe and often chronic pain, and disability--can be triggered by a minor injury, a fact that has fascinated scientists and perplexed clinicians for decades. However, substantial advances across several medical disciplines have recently improved our understanding of CRPS. Compelling evidence implicates biological pathways that underlie aberrant inflammation, vasomotor dysfunction, and maladaptive neuroplasticity in the clinical features of CRPS. Collectively, the evidence points to CRPS being a multifactorial disorder that is associated with an aberrant host response to tissue injury. Variation in susceptibility to perturbed regulation of any of the underlying biological pathways probably accounts for the clinical heterogeneity of CRPS., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Complex regional pain syndrome (CRPS) may occur after trauma, usually to one limb, and is characterized by pain and disturbed blood flow, temperature regulation and motor control. Approximately 25% of cases develop fixed dystonia. Involvement of dysfunctional GABAergic interneurons has been suggested, however the mechanisms that underpin fixed dystonia are still unknown. We hypothesized that dystonia could be the result of aberrant proprioceptive reflex strengths of position, velocity or force feedback., Methods: We systematically characterized the pattern of dystonia in 85 CRPS-patients with dystonia according to the posture held at each joint of the affected limb. We compared the patterns with a neuromuscular computer model simulating aberrations of proprioceptive reflexes. The computer model consists of an antagonistic muscle pair with explicit contributions of the musculotendinous system and reflex pathways originating from muscle spindles and Golgi tendon organs, with time delays reflective of neural latencies. Three scenarios were simulated with the model: (i) increased reflex sensitivity (increased sensitivity of the agonistic and antagonistic reflex loops); (ii) imbalanced reflex sensitivity (increased sensitivity of the agonistic reflex loop); (iii) imbalanced reflex offset (an offset to the reflex output of the agonistic proprioceptors)., Results: For the arm, fixed postures were present in 123 arms of 77 patients. The dominant pattern involved flexion of the fingers (116/123), the wrists (41/123) and elbows (38/123). For the leg, fixed postures were present in 114 legs of 77 patients. The dominant pattern was plantar flexion of the toes (55/114 legs), plantar flexion and inversion of the ankle (73/114) and flexion of the knee (55/114).Only the computer simulations of imbalanced reflex sensitivity to muscle force from Golgi tendon organs caused patterns that closely resembled the observed patient characteristics. In parallel experiments using robot manipulators we have shown that patients with dystonia were less able to adapt their force feedback strength., Conclusions: Findings derived from a neuromuscular model suggest that aberrant force feedback regulation from Golgi tendon organs involving an inhibitory interneuron may underpin the typical fixed flexion postures in CRPS patients with dystonia.

Complex regional pain syndrome (CRPS) occurs after stroke, but most cases develop after peripheral trauma and without evidence of brain trauma. However, CRPS is associated with symptoms that appear similar to those observed in patients suffering from hemispatial neglect. Ten participants (four males) with CRPS of one arm performed temporal order judgements of pairs of vibrotactile stimuli, one delivered to each hand, at one of 10 possible stimulus onset asynchronies, under two conditions: arms held each side of the midline and arms crossed over the midline. Participants released a foot switch to indicate which hand had been stimulated first. The order of conditions was randomized and the foot under which the switch was positioned was counterbalanced. There were two blocks of 150 trials in each condition. The stimulus onset asynchronicity at which the participants were equally likely to select either hand, the point of subjective simultaneity (PSS), was compared between conditions and between those with left or right-sided symptoms. When arms were not crossed, the participants prioritized stimuli from the unaffected limb over those from the affected limb (mean +/- SD PSS = 25 +/- 7.5 ms) and the magnitude of the PSS strongly related to the degree to which the affected hand was cooler than the unaffected hand (r = 0.942, P < 0.001). When the arms were crossed, the effect was reversed: the participants prioritized stimuli from the affected limb over those from the unaffected limb [PSS = -18 +/- 13 ms; main effect of condition F (1, 9) = 98.6, P < 0.001]. There was no effect of the side of symptoms. These results show that CRPS is associated with a deficit in tactile processing that is defined by the space in which the affected limb normally resides, not by the affected limb itself, and which relates to the relative cooling of the affected limb. This pattern is consistent with data from those with hemispatial neglect after stroke and raises the possibility that chronic CRPS involves a type of spatial neglect.

Objective: Chronic painful disease is associated with pain on movement, which is presumed to be caused by noxious stimulation. We investigated whether motor imagery, in the absence of movement, increases symptoms in patients with chronic arm pain., Methods: Thirty-seven subjects performed a motor imagery task. Pain and swelling were measured before, after, and 60 minutes after the task. Electromyography findings verified no muscle activity. Patients with complex regional pain syndrome (CRPS) were compared with those with non-CRPS pain. Secondary variables from clinical, psychophysical, and cognitive domains were related to change in symptoms using linear regression., Results: Motor imagery increased pain and swelling. For CRPS patients, pain (measured on a 100-mm visual analog scale) increased by a mean +/- SD of 5.3 +/- 3.9 mm and swelling by 8% +/- 5%. For non-CRPS patients, pain increased by 1.4 +/- 4.1 mm and swelling by 3% +/- 4%. There were no differences between groups (P > 0.19 for both). Increased pain and swelling related positively to duration of symptoms and performance on a left/right judgment task that interrogated the body schema, autonomic response, catastrophic thoughts about pain, and fear of movement (r > 0.42, P < 0.03 for all)., Conclusion: Motor imagery increased pain and swelling in patients with chronic painful disease of the arm. The effect increased in line with the duration of symptoms and seems to be modulated by autonomic arousal and beliefs about pain and movement. The results highlight the contribution of cortical mechanisms to pain on movement, which has implications for treatment.

In complex regional pain syndrome (CRPS1) initiated by wrist fracture, a motor imagery program (MIP), consisting of hand laterality recognition followed by imagined movements and then mirror movements, reduces pain and disability, but the mechanism of effect is unclear. Possibilities include sustained attention to the affected limb, in which case the order of MIP components would not alter the effect, and sequential activation of cortical motor networks, in which case it would. Twenty subjects with chronic CRPS1 initiated by wrist fracture and who satisfied stringent inclusion criteria, were randomly allocated to one of three groups: hand laterality recognition, imagined movements, mirror movements (RecImMir, MIP); imagined movements, recognition, imagined movements (ImRecIm); recognition, mirror movements, recognition (RecMirRec). At 6 and 18 weeks, reduced pain and disability were greater for the RecImMir group than for the other groups (P<0.05). Hand laterality recognition imparted a consistent reduction in pain and disability across groups, however, this effect was limited in magnitude. Imagined movements imparted a further reduction in pain and disability, but only if they followed hand laterality recognition. Mirror movements also imparted a reduction in pain and disability, but only when they followed imagined movements. The effect of the MIP seems to be dependent on the order of components, which suggests that it is not due to sustained attention to the affected limb, but is consistent with sequential activation of cortical motor networks.

Background: People with complex regional pain syndrome (CRPS) take longer to recognize the laterality of a pictured hand when it coincides with their affected hand. The author explored two aspects of this phenomenon: whether the duration of symptoms relates to the extent of the delay and whether guarding-type mechanisms are involved., Methods: Eighteen patients with CRPS type 1 of the wrist and 18 matched control subjects performed a hand laterality recognition task. McGill pain questionnaire, Neuropathic Pain Scale, and response time (RT) to recognize hand laterality were analyzed. Regressions related 1) mean RT for patients to the duration of symptoms and to pain intensity; and 2) mean RT for each picture to the predicted pain on executing that movement as judged by the patient, and to the awkwardness of the movement that would be required., Results: For patients, the duration of symptoms correlated with mean RT (Spearman rho = 0.44; p = 0.02). Predicted pain rating explained 45% of the variance in RT for each picture for each patient (p < 0.01)., Conclusions: The results suggest that in patients with complex regional pain syndrome type 1, delayed recognition of hand laterality is related to the duration of symptoms and to the pain that would be evoked by executing the movement. The former is consistent with chronic pain and disuse and may involve reorganization of the cortical correlate of body schema. The latter is consistent with a guarding-type response that probably occurs upstream of the motor cortex at a motor planning level.