Project description:Sex differences have been increasingly highlighted in complex regional pain syndrome (CRPS) in clinical practice. In CRPS type I (CRPS-I), although inflammation and oxidative stress have been implicated in its pathogenesis, whether pain behavior and the underlying mechanism are sex-specific is unclear. In the present study, we sought to explore whether sex differences have an impact on inflammation, oxidative stress, and pain sensitivity in CRPS-I.Chronic post-ischemia pain (CPIP) was established in both male and female mice as an animal model of CRPS-I. Edema and mechanical allodynia of bilateral hind paws were assessed after reperfusion. Blood samples were analyzed for serum levels of oxidative stress markers and inflammatory cytokines.Both male and female mice developed edema. Male mice developed CPIP at day 3 after reperfusion; female mice developed CPIP at day 2 after reperfusion. Female mice displayed significantly earlier and higher mechanical allodynia in the ischemic hind paw, which was associated with higher serum levels of IL-2, TNF-α, isoprostanes, 8 OhdG, and malondialdehyde at day 2 after reperfusion. Moreover, female mice showed significantly lower SOD and IL-4 compared to male mice at day 2 after reperfusion.Our results indicate that sex differences in inflammatory and oxidative stress states may play a central role in the sex-specific nociceptive hypersensitivity in CRPS-I, and offer a new insight into pharmacology treatments to improve pain management with CRPS.
Project description:BACKGROUND:Complex Regional Pain Syndrome (CRPS) presents as chronic, continuous pain and sensory, autonomic, and motor abnormalities affecting one or more extremities. People with CRPS can also show changes in their perception of and attention to the affected body part and sensory information in the affected side of space. Prism Adaptation (PA) is a behavioural intervention targeted at reducing attention deficits in post-stroke hemispatial neglect. PA also appears to reduce pain and other CRPS symptoms; however, these therapeutic effects have been demonstrated only in small unblinded studies. This paper describes the protocol for an ongoing double-blind, randomized, sham-controlled clinical trial that will evaluate the efficacy of PA treatment for CRPS. The secondary aims of the study are to examine the relationships between neuropsychological changes (such as spatial attention, space and body representation, and motor spatial performance) and clinical manifestations of CRPS, as well as symptom improvement. METHODS:Forty-two participants with upper-limb CRPS type I will undergo 2 weeks of twice-daily PA treatment or sham treatment. The primary outcome measures are current pain intensity and CRPS severity score, measured immediately before and after the treatment period. Secondary outcome measures include the results of self-report questionnaires about pain, movement, symptoms interference, and body representation; clinical assessments of sensory, motor, and autonomic functions; and computer-based psychophysical tests of neuropsychological functions. Data are collected in four research visits: 4 weeks and 1 day before treatment, and 1 day and 4 weeks after the end of treatment. Additional follow-up through postal questionnaires is conducted 3 and 6 months post-treatment. DISCUSSION:It is hypothesised that participants undergoing PA treatment, compared to those receiving sham treatment, will show greater reduction in pain and CRPS severity score, and improvements on other clinical and neuropsychological measures. Also, more pronounced neuropsychological symptoms are predicted to correlate with more severe clinical CRPS symptoms. This study will provide the first randomized double-blind evaluation of the therapeutic effects of PA that could be implemented as a rehabilitation method for CRPS, and will contribute to the understanding of how neuropsychological changes in body representation and attention pertain to the manifestation and treatment of CRPS. TRIAL REGISTRATION:(27/03/2017): ISRCTN46828292 (ISRCTN - ISRCTN46828292: Treatment of complex regional pain syndrome (CRPS) with sensory-motor adaptation).
Project description:we successfully identified pain-related genes through genome-wide expression profiling in 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 12 genes selected from the microarray were confirmed in 24 CRPS patients and 18 controls by quantitative reverse transcription-polymerase chain reaction. We focused on matrix metalloproteinase 9 (MMP9) that showed statistically significant difference from controls and the highest relative fold change in CRPS II patients to controls by qPCR validation (6.4 ± 2.47 times and p = 0.001). Identification of pain-related genes in peripheral blood of complex regional pain syndrome (CRPS) using cDNA microarray. Comparative gene expression profiles in peripheral blood of 5 healthy controls and 4 CRPS patients.
Project description:we successfully identified pain-related genes through genome-wide expression profiling in 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 12 genes selected from the microarray were confirmed in 24 CRPS patients and 18 controls by quantitative reverse transcription-polymerase chain reaction. We focused on matrix metalloproteinase 9 (MMP9) that showed statistically significant difference from controls and the highest relative fold change in CRPS II patients to controls by qPCR validation (6.4 ± 2.47 times and p = 0.001).
Project description:Complex Regional Pain Syndrome (CRPS) is a multifactorial and disabling disorder with complex etiology and pathogenesis. Goals of therapy in CRPS should be pain relief, functional restoration, and psychological stabilization, but early interventions are needed in order to achieve these objectives. Several drugs have been used to reduce pain and to improve functional status in CRPS, despite the lack of scientific evidence supporting their use in this scenario. They include anti-inflammatory drugs, analgesics, anesthetics, anticonvulsants, antidepressants, oral muscle relaxants, corticosteroids, calcitonin, bisphosphonates, calcium channel blockers and topical agents. NSAIDs showed no value in treating CRPS. Glucocorticoids are the only anti-inflammatory drugs for which there is direct clinical trial evidence in early stage of CRPS. Opioids are a reasonable second or third-line treatment option, but tolerance and long term toxicity are unresolved issues. The use of anticonvulsants and tricyclic antidepressants has not been well investigated for pain management in CRPS. During the last years, bisphosphonates have been the mostly studied pharmacologic agents in CRPS treatment and there are good evidence to support their use in this condition. Recently, the efficacy of intravenous (IV) administration of neridronate has been reported in a randomized controlled trial. Significant improvements in VAS score and other indices of pain and quality of life in patients who received four 100 mg IV doses of neridronate versus placebo were reported. These findings were confirmed in the open-extension phase of the study, when patients formerly enrolled in the placebo group received neridronate at the same dosage, and these results were maintained at 1 year follow-up. The current literature concerning sympathetic blocks and sympathectomy techniques lacks evidence of efficacy. Low evidence was recorded for a free radical scavenger, dimethylsulphoxide (DMSO) cream (50%). The same level of efficacy was noted for vitamin C (500 mg per day for 50 days) in prevention of CRPS in patients affected by wrist fracture. In conclusion, the best available therapeutic approach to CRPS is multimodal and is based on the use of several classes of drugs, associated to early physiotherapy. Neridronate at appropriate doses is associated with clinically relevant and persistent benefits in CRPS patients.
Project description:BackgroundComplex regional pain syndrome (CRPS) is much more prevalent in women than men but potential differences in clinical phenotype have not been thoroughly explored to date. Differences in the clinical presentation between sexes may point at new avenues for a more tailored management approach of CRPS. We therefore explored if in CRPS, the patient's sex is associated with differences in clinical and psychological characteristics.MethodsIn this cross-sectional study of 698 CRPS patients (599 females) fulfilling the Budapest clinical or research criteria, CRPS signs and symptoms, CRPS severity, pain (average pain intensity in the previous week and McGill pain rating index), pain coping (Pain Coping Inventory), physical limitations (Radboud Skills Questionnaire (upper limb), Walking and Rising questionnaire (lower limb)), anxiety and depression (Hospital Anxiety and Depression scale) and kinesiophobia (Tampa scale for kinesiophobia) were evaluated.ResultsMale CRPS patients used more often extreme words to describe the affective qualities of pain, used more passive pain coping strategies, and were more likely to suffer from depression and kinesiophobia.ConclusionSex-related differences are present in CRPS, but the effect is generally small and mainly concerns psychological functioning. A greater awareness of sex-specific factors in the management of CRPS may contribute to achieving better outcomes.SignificanceWhat is known? Nonsex-specific clinical data of CRPS patients. What is new? Male CRPS patients used more often extreme words to describe the affective qualities of pain, used more passive pain coping strategies, and were more likely to suffer from depression and kinesiophobia.
Project description:BackgroundAberrant expression of small noncoding RNAs called microRNAs (miRNAs) is a common feature of several human diseases. The objective of the study was to identify miRNA modulation in patients with complex regional pain syndrome (CRPS) a chronic pain condition resulting from dysfunction in the central and/or peripheral nervous systems. Due to a multitude of inciting pathologies, symptoms and treatment conditions, the CRPS patient population is very heterogeneous. Our goal was to identify differentially expressed miRNAs in blood and explore their utility in patient stratification.MethodsWe profiled miRNAs in whole blood from 41 patients with CRPS and 20 controls using TaqMan low density array cards. Since neurogenic inflammation is known to play a significant role in CRPS we measured inflammatory markers including chemokines, cytokines, and their soluble receptors in blood from the same individuals. Correlation analyses were performed for miRNAs, inflammatory markers and other parameters including disease symptoms, medication, and comorbid conditions.ResultsThree different groups emerged from miRNA profiling. One group was comprised of 60% of CRPS patients and contained no control subjects. miRNA profiles from the remaining patients were interspersed among control samples in the other two groups. We identified differential expression of 18 miRNAs in CRPS patients. Analysis of inflammatory markers showed that vascular endothelial growth factor (VEGF), interleukin1 receptor antagonist (IL1Ra) and monocyte chemotactic protein-1 (MCP1) were significantly elevated in CRPS patients. VEGF and IL1Ra showed significant correlation with the patients reported pain levels. Analysis of the patients who were clustered according to their miRNA profile revealed correlations that were not significant in the total patient population. Correlation analysis of miRNAs detected in blood with additional parameters identified miRNAs associated with comorbidities such as headache, thyroid disorder and use of narcotics and antiepileptic drugs.ConclusionsmiRNA profiles can be useful in patient stratification and have utility as potential biomarkers for pain. Differentially expressed miRNAs can provide molecular insights into gene regulation and could lead to new therapeutic intervention strategies for CRPS.
Project description:Complex regional pain syndrome (CRPS) is a chronic pain condition associating sensory, motor, trophic and autonomic symptoms in one limb. Cognitive difficulties have also been reported, affecting the patients' ability to mentally represent, perceive and use their affected limb. However, the nature of these deficits is still a matter of debate. Recent studies suggest that cognitive deficits are limited to body-related information and body perception, while not extending to external space. Here we challenge that statement, by using temporal order judgment (TOJ) tasks with tactile (i.e. body) or visual (i.e. extra-body) stimuli in patients with upper-limb CRPS. TOJ tasks allow characterizing cognitive biases to the advantage of one of the two sides of space. While the tactile TOJ tasks did not show any significant results, significant cognitive biases were observed in the visual TOJ tasks, affecting mostly the perception of visual stimuli occurring in the immediate vicinity of the affected limb. Our results clearly demonstrate the presence of visuospatial deficits in CRPS, corroborating the cortical contribution to the CRPS pathophysiology, and supporting the utility of developing rehabilitation techniques modifying visuospatial abilities to treat chronic pain.
Project description:The choroid plexus, located in brain ventricles, has received surprisingly little attention in clinical neuroscience. In morphometric brain analysis, we serendipitously found a 21% increase in choroid plexus volume in 12 patients suffering from complex regional pain syndrome (CRPS) compared with age- and gender-matched healthy subjects. No enlargement was observed in a group of 8 patients suffering from chronic pain of other etiologies. Our findings suggest involvement of the choroid plexus in the pathogenesis of CRPS. Since the choroid plexus can mediate interaction between peripheral and brain inflammation, our findings pinpoint the choroid plexus as an important target for future research of central pain mechanisms.
Project description:ObjectiveTo investigate whether pain-related fears are mediators for reducing disability and pain in patients with Complex Regional Pain Syndrome type 1 when treating with Pain Exposure Physical Therapy.DesignAn explorative secondary analysis of a randomised controlled trial.ParticipantsFifty-six patients with Complex Regional Pain Syndrome type 1.InterventionsThe experimental group received Pain Exposure Physical Therapy in a maximum of five treatment sessions; the control group received conventional treatment following the Dutch multidisciplinary guideline.Outcome measuresLevels of disability, pain, and pain-related fears (fear-avoidance beliefs, pain catastrophizing, and kinesiophobia) were measured at baseline and after 3, 6, and 9 months follow-up.ResultsThe experimental group had a significantly larger decrease in disability of 7.77 points (95% CI 1.09 to 14.45) and in pain of 1.83 points (95% CI 0.44 to 3.23) over nine months than the control group. The potential mediators pain-related fears decreased significantly in both groups, but there were no significant differences between groups, which indicated that there was no mediation.ConclusionThe reduction of pain-related fears was comparable in both groups. We found no indication that pain-related fears mediate the larger reduction of disability and pain in patients with Complex Regional Pain Syndrome type 1 treated with Pain Exposure Physical Therapy compared to conventional treatment.Trial registrationInternational Clinical Trials Registry NCT00817128.