Complex Regional Pain Syndrome Type I Patients Research Articles

Electroacupuncture Alleviates Mechanical Allodynia of a Rat Model of CRPS-I and Modulates Gene Expression Profiles in Dorsal Root Ganglia.

Complex regional pain syndrome type-I (CRPS-I) is chronic neurological disorder accompanied with devastating pain. Most conventional medical treatments lack effectiveness, making CRPS-I a challenging clinical condition. Electroacupuncture (EA) showed effectiveness in alleviating the pain symptoms of CRPS-I patients. However, the molecular mechanisms underlying EA's therapeutic effect are still not well-understood. Here, we established the rat chronic post-ischemic pain (CPIP) model to mimic CRPS-I and performed repetitive EA on bilateral hind limbs of the CPIP model rats. We then performed RNA-sequencing (RNA-Seq) to study the differences in gene expression, gene networks, and molecular pathways in ipsilateral DRGs innervating the hind limb of the CPIP model rats with and without repetitive EA treatment. Our results found that repetitive EA treatment significantly alleviated mechanical allodynia in bilateral hind limbs of CPIP model rats. RNA-Seq analysis indicated that EA modulated the expression of multiple genes and gene networks in the DRGs of CPIP model rats. Further bioinformatics analysis identified the up-regulation of an array of genes involved in biological process such as neutrophil chemotaxis and immune response in the DRGs of CPIP model rats after EA treatment. Thus, these results suggest that EA may alleviate pain response in CPIP model rats via regulating multiple genes. Our work may help to further advance the understandings of the molecular mechanisms underlying EA's therapeutic effects on CRPS-I and help to identify novel targets for CRPS-I treatment.

Bilaterally Reduced Intraepidermal Nerve Fiber Density in Unilateral CRPS-I.

Findings regarding small nerve fiber damage in complex regional pain syndrome type I (CRPS-I) are not uniform, and studies have not included a matched healthy control group. The aim was to assess intraepidermal nerve fiber density (IENFD) in relation to thermal sensitivity of the same skin areas in CRPS-I patients and a gender- and age-matched healthy control group. IENFD was investigated in skin biopsies from the CRPS-affected and contralateral limbs of eight CRPS-I patients and from an equivalent site in eight gender- and age-matched healthy controls (HCs). Thermal thresholds (cold/warm detection, cold- and heat-pain detection) were assessed on the affected limb, the matching contralateral limb, and on the equivalent limbs of HCs, and participants rated the intensity of cold/heat and pain to static thermal stimuli (5 °C and 40 °C). IENFD was significantly lower in both the affected and contralateral limbs of CRPS-I patients than HCs, but IENFD did not differ between the affected and contralateral limbs of patients. The heat pain threshold was lower in the affected CRPS-I limb than in HCs, but all other thermal thresholds were similar in both groups. CRPS-I patients rated the cold stimulus as colder and more painful in the affected limb, and the warm stimulus as hotter, bilaterally, than the HCs. CRPS-I may be associated with bilateral small fiber damage, and perhaps small fiber neuropathy and bilateral disturbances in thermo-sensory perception. These disturbances could stem from a systemic response to injury or might increase the risk of developing CRPS-I after physical trauma.

Expose or protect? A randomized controlled trial of exposure in vivo vs pain-contingent treatment as usual in patients with complex regional pain syndrome type 1.

Complex regional pain syndrome type I (CRPS-I) highly affects patients' ability to perform daily life activities. Pain-related fear might be a key target to reduce disability in chronic pain. Current treatments aiming at reducing pain show little improvements on pain and disability, whereas novel exposure-based treatments targeting pain-related fears have shown to be promising. We conducted a randomized controlled trial (N = 46) comparing exposure in vivo (EXP) with pain-contingent treatment as usual (TAU), for CRPS-I patients with at least moderate levels of pain-related fear. Primary outcome is self-reported disability, for upper and lower extremity, respectively. Secondary outcomes are self-reported pain-intensity, pain-catastrophizing, perceived harmfulness of physical activity, and health-related quality of life. Pretreatment to posttreatment and pretreatment to 6-month follow-up change scores were tested using randomization-based inference. EXP was superior to TAU in reducing upper extremity disability from pretreatment to posttreatment (between-group difference, 1.082; 95% confidence interval [CI], 0.563-1.601; P < 0.001) and from pretreatment to 6-month follow-up (1.303; 95% CI, 0.917-1.690; P < 0.001). EXP was superior in reducing lower extremity disability from pretreatment to 6-month follow-up (3.624; 95% CI, 0.467-6.781; P = 0.02), but not from pretreatment to posttreatment (3.055; 95% CI, -0.018 to 6.128; P = 0.054). All secondary outcomes significantly favored EXP pretreatment to posttreatment, as well as pretreatment to 6-month follow-up. Exposure to daily activities shows to be more effective than a protective pain-contingent TAU in reducing self-reported disability in daily life of CRPS-I patients with at least moderate levels of pain-related fear.

Sensitization of the Nociceptive System in Complex Regional Pain Syndrome.

BackgroundComplex regional pain syndrome type I (CRPS-I) is characterized by sensory, motor and autonomic abnormalities without electrophysiological evidence of a nerve lesion.ObjectiveAims were to investigate how sensory, autonomic and motor function change in the course of the disease.Methods19 CRPS-I patients (17 with acute, 2 with chronic CRPS, mean duration of disease 5.7±8.3, range 1–33 months) were examined with questionnaires (LANSS, NPS, MPI, Quick DASH, multiple choice list of descriptors for sensory, motor, autonomic symptoms), motor and autonomic tests as well as quantitative sensory testing according to the German Research Network on Neuropathic Pain at two visits (baseline and 36±10.6, range 16–53 months later).ResultsCRPS-I patients had an improvement of sudomotor and vasomotor function, but still a great impairment of sensory and motor function upon follow-up. Although pain and mechanical detection improved upon follow-up, thermal and mechanical pain sensitivity increased, including the contralateral side. Increase in mechanical pain sensitivity and loss of mechanical detection were associated with presence of ongoing pain.ConclusionsThe results demonstrate that patients with CRPS-I show a sensitization of the nociceptive system in the course of the disease, for which ongoing pain seems to be the most important trigger. They further suggest that measured loss of function in CRPS-I is due to pain-induced hypoesthesia rather than a minimal nerve lesion. In conclusion, this article gives evidence for a pronociceptive pain modulation profile developing in the course of CRPS and thus helps to assess underlying mechanisms of CRPS that contribute to the maintenance of patients’ pain and disability.

Intact 2D-form recognition despite impaired tactile spatial acuity in complex regional pain syndrome type I

Tactile acuity measured by 2-point discrimination performance is impaired in patients with complex regional pain syndrome type I (CRPS-I). This is mirrored by pain-associated shrinkage of the cortical representation of the affected limb. We investigated whether, also, more complex tactile performance assessed by a dynamic 2D-form perception task is disturbed in CRPS-I patients. Therefore, we developed a Braille-like recognition task (BT) for geometrical dot pattern identification by dynamic touch. We studied 47 healthy volunteers (Study I) and compared them to 16 CRPS-I patients (Study II). Besides recognition time and error quote of the BT, we assessed static 2-point discrimination thresholds (TPDT). In healthy subjects, the performance in the BT correlated significantly with age and TPDT. In CRPS patients, TPDT was significantly increased on the affected side compared to sex- and age-matched controls from study I (2.98±0.84mm vs 2.05±0.82mm, P<0.01). The performance in the BT was not impaired in CRPS-I patients (compared to sex- and age-matched controls from study I) and was not correlated to the TPDT. The intact 2D-form recognition ability in CRPS-I patients might be explained by intact dynamic tactile and proprioceptive functions, which appear to be uncompromised by the impaired static tactile perception, provided that the spacing of the dot pattern is above the individual tactile acuity. These intact 2D-form perception capacities may also be related to higher sensory integration functions like the visual system and intact semantic understanding, which may be spared by the cortical reorganization phenomena in CRPS-I.

Diagnosis of complex regional pain syndrome type I of the upper extremity: Role of dual energy X-ray absorptiometry and three-phase bone scintigraphy

Objective: The aim of the present study was to evaluate and compare the role of dual energy X-ray absorptiometry and three-phase bone scintigraphy in the diagnosis of complex regional pain syndrome type I of upper extremity. Methods: Five male and nineteen female patients diagnosed with complex regional pain syndrome type I (CRPSI) were included in this study. Three-phase bone scintigraphy (TPBS), bone mineral density (BMD) and bone mineral content (BMC) of wrist, metacarpophalangeal joint (MCP) and proximal interphalangeal (PIP) area in the affected and unaffected hands of patients were measured simultaneously using dual energy X-ray absorptiometry (DEXA). The time passed between the precipitating event and clinical onset of CRPSI was also recorded. Results: TPBS findings were in agreement with CRPSI diagnosis in 96% of the patients (23 of 24 patients). Periarticular BMD and BMC values in wrist, MCP, and PIP joints were statistically lower in affected hands than in unaffected hands for all three regions. Moreover, we found no correlation between BMD or BMC values with the sex, age, dominant hand, and the duration between the clinical onset of CRPSI and its precipitating event. Conclusion: The present study suggests that beside TPBS, a valuable tool in the early diagnosis of CRPSI, DEXA can also be used in the determination of early demineralization of bones in CRPSI patients. DEXA is an accurate, noninvasive, rapid, and safe device for quantitative assessment of unilateral bone loss caused by upper limb CRPSI.

Serum and salivary oxidative analysis in Complex Regional Pain Syndrome

Although both inflammatory and neural mechanisms have been suggested as potential contributors to Complex Regional Pain Syndrome type I (CRPS-I), the pathogenesis of the syndrome is still unclear. Clinical trials have shown that free radical scavengers can reduce signs and symptoms of CRPS-I, indirectly suggesting that free radicals and increased oxidative stress are involved in the pathogenesis of CRPS-I. This study investigated this premise by determining the levels of antioxidants in the serum and saliva of 31 patients with CRPS-I and in a control group of 21 healthy volunteers. Serum lipid peroxidation products (MDA) and all antioxidative parameters analyzed were significantly elevated in CRPS-I patients: median salivary peroxidase and superoxide dismutase (SOD) activity values, uric acid (UA) concentration and total antioxidant status (TAS) values were higher in CRPS-I patients by 150% ( p = 0.01), 280% ( p = 0.04), 60% ( p = 0.0001), and 200% ( p = 0.0003), respectively, as compared with controls. Similar although not as extensive pattern of oxidative changes were found in the serum: mean serum UA and MDA concentrations and TAS value in the CRPS-I patients were higher by 16% ( p = 0.04), 25% ( p = 0.02), and 22% ( p = 0.05), respectively, than in the controls. Additionally, median salivary albumin concentration and median salivary LDH activities in the patients were 2.5 times ( p = 0.001) and 3.1 ( p = 0.004) times higher than in the controls. The accumulated data show that free radicals are involved in the pathophysiology of CRPS-I, which is reflected both in serum and salivary analyses. These data could be used for both diagnostic and therapeutic purposes in CRPS-I patients.

Development of a Symptoms Questionnaire for Complex Regional Pain Syndrome and Potentially Related Illnesses: The Trauma Related Neuronal Dysfunction Symptoms Inventory

Collins S, van Hilten JJ, Marinus J, Zuurmond WW, de Lange JJ, Perez RS. Development of a symptoms questionnaire for complex regional pain syndrome and potentially related illnesses: the Trauma Related Neuronal Dysfunction Symptoms Inventory. Objective To develop a questionnaire to evaluate symptoms of complex regional pain syndrome type I (CRPS-I), fibromyalgia, and repetitive strain injury to determine the test-retest reliability and investigate concurrence in the clinical manifestations of CRPS-I and fibromyalgia. Design The Trauma Related Neuronal Dysfunction Symptoms Inventory (TSI) was developed by determining the content validity and the practical use of the questionnaire. Furthermore, the test-retest reliability was assessed on 2 identical questionnaires filled out within a 7-day interval by CRPS-I and fibromyalgia patients. Setting Outpatient pain clinic of a Dutch medical center. Participants CRPS-I (n=26; mean age, 54y) and fibromyalgia patients (n=42; mean age, 45.4y). Interventions Not applicable. Main Outcome Measure Test-retest reliability calculated with intraclass correlation (ICC). Results Reliability scores were good for the whole questionnaire, its categories, and domains (ICC>.75) for both CRPS-I and fibromyalgia patients. Sensory complaints (except for change in cold perception), motor complaints, and visceral complaints (diarrhea and incontinence) were reported by both CRPS-I and fibromyalgia patients. A change in cold perception, discoloration, change in skin temperature, change in sweating behavior, change in the severity of edema during exercise, and trophic changes of skin were reported significantly more often by CRPS-I patients, whereas complaints of the (upper and lower) back, constipation, urine retention, and experiencing a dry mouth were reported significantly more often by fibromyalgia patients. Conclusions The TSI is a reliable instrument with good content validity, which can be used in the evaluation of similarities and differences between CRPS-I and fibromyalgia. The systematic evaluation of symptoms of CRPS-I and potentially related illnesses may provide a better basis for future research into the underlying mechanism(s).

Reduction of pain-related fear in complex regional pain syndrome type I: The application of graded exposure in vivo

Fear of (re)injury/movement has been identified as a potential predictor of chronic disability in complex regional pain syndrome type I (CRPS-I). In order to reduce pain-related fears and pain disability, graded exposure in vivo (GEXP) is likely to be an appropriate treatment. Indeed, there is evidence that in chronic pain patients reporting substantial fear of (re)injury/movement, GEXP is successful in reducing pain disability. However, the efficacy of exposure-based protocols in the treatment of CRPS-I patients for reducing pain disability has not been tested. The main research question of this study was whether the reduction of pain-related fear through GEXP also resulted in a decrease of disability in a subgroup of patients with CRPS-I who report substantial pain-related fear. A single-case experimental ABCD-design was used with random determination of the start of the intervention. Eight patients with CRPS-I were included in the study. To assess daily changes in pain intensity, pain-related fear, pain catastrophizing, and activity goal achievement, a diary was used. Standardized questionnaires of pain-related fear, pain disability, and self-reported signs and symptoms of CRPS-I were administered before and after each intervention, and at 6-month follow-up. The current study supports a GEXP approach to chronic CRPS-I. The GEXP was successful in decreasing levels of self-reported pain-related fear, pain intensity, disability, and physiological signs and symptoms. These results support the hypothesis that the meaning people attach to a noxious stimulus influences its experienced painfulness, and that GEXP activates cortical networks and reconciles motor output and sensory feedback.

Assessment of the Peripheral Microcirculation Using Computer-Assisted Venous Congestion Plethysmography in Post-Traumatic Complex Regional Pain Syndrome Type I

In complex regional pain syndrome type I (CRPS-I), edema of the affected limb is a common finding. Therefore, the changes in macro- and microcirculatory parameters were investigated to elucidate the underlying pathophysiology. Twenty-four patients with post-traumatic CRPS-I and 25 gender- and age-matched healthy subjects were examined by means of an advanced computer-assisted venous congestion strain-gauge plethysmograph. The recording of the volume response of the forearm to a stepwise inflation of an occlusion cuff placed at the upper arm enabled the calculation of the arterial blood flow into the arm (Q_a), the vascular compliance (C), the peripheral venous pressure (P_v), the isovolumetric venous pressure (P_vi; = hydrostatic pressure needed to achieve net fluid filtration) and the capillary filtration capacity (CFC) – an index of microvascular permeability. The study revealed no difference in any of the parameters between the right and left hand of healthy subjects. In CRPS-I patients, however Q_a, P_v, P_vi and CFC were significantly (p < 0.01/0.001) elevated in the affected arm (Q_a 11.2 ± 7.0 ml min^–1 100 ml^–1, P_v 20.2 ± 8.1 mm Hg, P_vi 24.7 ± 4.2 mm Hg, CFC 0.0058 ± 0.0015 ml min^–1 100 ml^–1 mm Hg^–1) compared to the unaffected arm (Q_a 4.2 ± 2.4 ml min^–1 100 ml^–1, P_v 10.0 ± 5.1 mm Hg, P_vi 13.2 ± 3.7 mm Hg, CFC 0.0038 ± 0.0005 ml min^–1 100 ml^–1 mm Hg^–1) and the values obtained in healthy controls (Q_a 5.1 ± 1.3 ml min^–1 100 ml^–1, P_v 10.4 ± 4.3 mm Hg, P_vi 15.7 ± 3.3 mm Hg, CFC 0.0048 ± 0.0012 ml min^–1 100 ml^–1 mm Hg^–1). Whereas the values in the unaffected arm of CRPS-I patients revealed no difference in Q_a, P_v and P_vi but a lower CFC (p < 0.01) compared to those from healthy controls. These results suggest profound changes in both macro- and microvascular perfusion in the affected arm of CRPS-I patients. The high CFC contributes to the edema formation, and combined with the elevated P_vi, they are in agreement with the hypothesis of an inflammatory origin of CRPS.