The Outcome of Complex Regional Pain Syndrome Type 1: A Systematic Review

The purpose of this systematic review was to examine the outcome of complex regional pain syndrome (CRPS) type 1. We searched MEDLINE, Embase, and PsycINFO for relevant studies and included 18 studies, with 3,991 participants, in this review. The following data were extracted: study details, measurement tools used, and rates or severity scores for the symptoms/signs of CRPS at baseline and follow-up, or in groups of patients with different disease durations. A quality assessment revealed significant limitations in the literature, with many studies using different diagnostic criteria. The 3 prospective studies demonstrated that for many patients, symptoms improve markedly within 6 to 13 months of onset. The 12 retrospective studies had highly heterogeneous findings, documenting lasting impairments in many patients. The 3 cross-sectional studies showed that rates of pain and sensory symptoms were highest among those with the longest duration of CRPS. Additionally, most studies showed that motor symptoms (stiffness and weakness) were the most likely to persist whereas sudomotor and vasomotor symptoms were the most likely to improve. Overall, this suggests that some CRPS patients make a good early recovery whereas others develop lasting pain and disability. As yet little is known about the prognostic factors that might differentiate between these groups.PerspectiveWe found evidence that many CRPS patients recover within 6 to 13 months, but a significant number experience some lasting symptoms, and some experience chronic pain and disability. The quality of the evidence was poor. Future research should examine the factors associated with recovery and identify those at risk of poor outcomes.     

氯胺酮在复杂的局部痛综合症治疗中的应用

目的：观察氯胺酮用于复杂的局部痛综合症(CRPS)的临床治疗效果。方法：5例外伤引起的CRPS病人接受腰硬膜外阻滞治疗，每日治疗一次，两周为一个疗程，所用阻滞液为0．125％布匹卡因20mL复合1．5mg／kg氯胺酮。结果：所有病人在接受3-5次的治疗后都明显好转，经过一个疗程的治疗后，症状都基本完全缓解，半年后随访未见复发。结论：氯胺酮作为N-甲基-D-天门冬氨酸(NMDA)受体阻断剂可能在CRPS治疗中发挥重要作用．1．5mg／kg的剂量可安全、有效地应用于临床疼痛治疗。     

Stellate Ganglion Block: A Pediatric Case of Complex Regional Pain Syndrome

Complex regional pain syndrome (CRPS) affects both children and adults. The pathophysiology may be complicated. This article outlines the criteria for CRPS and the treatment available. It includes a case discussion on the use of an interventional fluoroscopic procedure for medically refractory CRPS. This is performed to facilitate physical therapy and return of normal function.     

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.     

Primary Somatosensory Cortex Function in Complex Regional Pain Syndrome: A Systematic Review and Meta-Analysis

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.     

Primary Motor Cortex Function in Complex Regional Pain Syndrome: A Systematic Review and Meta-Analysis

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.     

Muscle Hyperalgesia Correlates With Motor Function in Complex Regional Pain Syndrome Type 1

At present it is unclear if disturbed sensory processing plays a role in the development of the commonly observed motor impairments in patients with complex regional pain syndrome (CRPS). This study aims to investigate the relation between sensory and motor functioning in CRPS patients with and without dystonia. Patients with CRPS of the arm and controls underwent comprehensive quantitative sensory testing and kinematic analysis of repetitive finger movements. Both CRPS groups showed thermal hypoesthesia to cold and warm stimuli and hyperalgesia to cold stimuli. A decreased pressure pain threshold reflecting muscle hyperalgesia emerged as the most prominent sensory abnormality in both patient groups and was most pronounced in CRPS patients with dystonia. Moreover, the decreased pressure pain threshold was the only nociceptive parameter that related to measures of motor function in both patients and controls. CRPS patients with dystonia had an increased 2-point discrimination as compared to controls and CRPS patients without dystonia. This finding was also reported in other types of dystonia and has been associated to cortical reorganization in response to impaired motor function. We hypothesize that increased sensitivity of the circuitry mediating muscle nociception may play a crucial role in impaired motor control in CRPS.PerspectiveThis is the first study linking a sensory dysfunction, ie, muscle hyperalgesia, to motor impairment in CRPS. Circuitries mediating muscle nociception may therefore play an important role in impaired motor control in CRPS.     

Sensorimotor integration in Complex Regional Pain Syndrome: a transcranial magnetic stimulation study

There is evidence that patients with Complex Regional Pain Syndrome (CRPS) have altered central sensorimotor processing. Sensory input can influence motor output either through indirect pathways or through direct connections from the sensory to motor cortex. The purpose of this study was to investigate sensorimotor interaction via direct connections in patients with CRPS and to compare the results with normal subjects'. Direct short-latency sensory-motor interaction was evaluated in eight patients with CRPS1 affecting a hand. Modulation of EMG responses to transcranial magnetic stimulation (TMS) induced by concomitant median nerve stimulation was measured, the so-called, short-latency afferent inhibition (SAI). Results were compared with eight normal subjects who were age and sex matched with the patients. As expected, all the normal subjects' EMG responses to TMS with median nerve stimulation were smaller than responses to TMS alone. In seven of the eight CRPS patients EMG responses to TMS were suppressed when paired with median nerve stimulation. Only one CRPS patient's results showed no suppression of EMG responses. These results suggest that the disease mechanisms of CRPS1 do not typically affect the direct neural circuit between sensory and motor cortex and that normal sensorimotor interaction is occurring via this route.     

Genetic HLA Associations in Complex Regional Pain Syndrome With and Without Dystonia

We previously showed evidence for a genetic association of the human leukocyte antigen (HLA) system and complex regional pain syndrome (CRPS) with dystonia. Involvement of the HLA system suggests that CRPS has a genetic component with perturbed regulation of inflammation and neuroplasticity as possible disease mechanisms. However, it is at present unclear whether the observed association with HLA-B62 and HLA-DQ8 in CRPS patients with dystonia also holds true for patients without dystonia. Therefore, we tested the possible association with HLA-B62 and HLA-DQ8 in a clinically homogeneous group of 131 CRPS patients without dystonia. In addition, we investigated the possible association with other alleles of the HLA-A, HLA-B, HLA-C, HLA-DR, and HLA-DQ loci. We showed an increased prevalence of HLA-DQ8 (molecularly typed as HLA-DQB1*03:02; OR = 1.65 [95% CI 1.12–2.42], P = .014) in CRPS without dystonia, whereas no association was observed for HLA-B62 (molecularly typed as HLA-B*15:01; OR = 1.22 [95% CI .78–1.92], P = .458). Our data suggest that CRPS with and CRPS without dystonia may be genetically different, but overlapping, disease entities because only HLA-DQ8 is associated with both. The findings also indicate that distinct biological pathways may play a role in both CRPS subtypes.PerspectiveThis study is the first to replicate a specific HLA region conferring genetic risk for the development of CRPS. Moreover, associations of HLA-DQ8 with both CRPS with and CRPS without dystonia, and HLA-B62 only with CRPS with dystonia, suggest that these disease entities may be genetically different, but overlapping.     

The Use of Transdermal Buprenorphine in Complex Regional Pain Syndrome: A Report of Two Cases

Management of complex regional pain syndrome (CRPS) can be challenging. Various pharmacological approaches have produced mixed results. Buprenorphine activates mu-opioid receptors and antagonizes kappa and delta receptors, acts at N-methyl-d-aspartate (NMDA) receptor, and is an orphan-related ligand-1 receptor agonist. It is available in transdermal patches that last for up to 7 days. This report describes two patients with refractory CRPS who were treated with transdermal buprenorphine. The patients experienced approximately 50% reduction in pain intensity scores. Application site rash that occurred was managed with topical steroid spray used before applying the patch.     

Prevalence and Related Factors for Poststroke Complex Regional Pain Syndrome: A Retrospective Cross-Sectional Cohort Study

ObjectiveThe objective of this study was to evaluate the prevalence of poststroke complex regional pain syndrome (CRPS) to estimate related factors for poststroke CRPS in patients with first-ever stroke.DesignThis was a retrospective cross-sectional cohort study of adult patients (age >18y) with stroke who were admitted to rehabilitation unit from December 2014 to May 2018 in Korea.SettingSingle acute rehabilitation unit of university hospital.ParticipantsParticipants (N=313) diagnosed with first-ever stroke were identified from the stroke rehabilitation registry of our institute.InterventionsNot applicable.Main Outcome MeasuresPrevalence of poststroke CRPS based on clinical features and 3-phase bone scintigraphy and the related factors of poststroke CRPS.ResultsA total of 313 records were analyzed, including demographic, clinical characteristics, and functional variables. Poststroke CRPS was found in 8.94% (28 of 313) patients with first-ever stroke. Logistic regression analysis showed that Fugl Meyer Assessment of Upper Extremity (FMA-UE) score was a significant associated factor for the presence of CRPS (odds ratio, 0.96; 95% confidence interval, 0.94-0.98; P=.003). The cutoff value of 76 points for FMA-UE score yielded moderate accuracy in identifying of poststroke CRPS (92.6% sensitivity, 65.8% specificity, and 0.85 area under the curve).ConclusionsThe prevalence of poststroke CRPS was 8.94% in patients with first-ever stroke. The FMA-UE score was associated with the poststroke CRPS. Therefore, in patients with low FMA-UE score, prevention and high suspicion of post-stroke CRPS is necessary.     

Ketamine produces effective and long-term pain relief in patients with Complex Regional Pain Syndrome Type 1

Complex Regional Pain Syndrome Type 1 (CRPS-1) responds poorly to standard pain treatment. We evaluated if the N-methyl-d-aspartate receptor antagonist S(+)-ketamine improves pain in CRPS-1 patients. Sixty CRPS-1 patients (48 females) with severe pain participated in a double-blind randomized placebo-controlled parallel-group trial. Patients were given a 4.2-day intravenous infusion of low-dose ketamine (n = 30) or placebo (n = 30) using an individualized stepwise tailoring of dosage based on effect (pain relief) and side effects (nausea/vomiting/psychomimetic effects). The primary outcome of the study was the pain score (numerical rating score: 0–10) during the 12-week study period. The median (range) disease duration of the patients was 7.4 (0.1–31.9) years. At the end of infusion, the ketamine dose was 22.2 ± 2.0 mg/h/70 kg. Pain scores over the 12-week study period in patients receiving ketamine were significantly lower than those in patients receiving placebo (P < 0.001). The lowest pain score was at the end of week 1: ketamine 2.68 ± 0.51, placebo 5.45 ± 0.48. In week 12, significance in pain relief between groups was lost (P = 0.07). Treatment did not cause functional improvement. Patients receiving ketamine more often experienced mild to moderate psychomimetic side effects during drug infusion (76% versus 18%, P < 0.001). In conclusion, in a population of mostly chronic CRPS-1 patients with severe pain at baseline, a multiple day ketamine infusion resulted in significant pain relief without functional improvement. Treatment with ketamine was safe with psychomimetic side effects that were acceptable to most patients.     

Pathophysiological Mechanisms Involved in Vasomotor Disturbances in Complex Regional Pain Syndrome and Implications for Therapy: A Review

Complex regional pain syndrome (CRPS) is characterized by continuous pain, disproportional to the initial trauma. It usually spreads to the distal parts of the affected limb. Besides continuing pain, a mix of sensory, sudo‐ and vasomotor disturbances, motor dysfunction, and trophic changes is responsible for physical complaints. Vasomotor disturbance is characterized by changes in skin temperature and color. In CRPS patients with a cold extremity, a decrease in blood flow can cause decreased tissue saturation and tissue acidosis, resulting in ischemic pain. The pathophysiology of vasomotor disturbances is not completely understood. Temperature asymmetry is generally assumed as a result of disturbance in the sympathetic nervous system. Vasodilating drugs and sympathetic blockade have been cornerstones of therapy in cold CRPS for years. However, only a limited part of these patients improve on this kind of therapies. Research has shown a pivotal role for inflammation in the pathophysiology of CRPS. Inflammation can result in endothelial dysfunction. Endothelial function plays an important role in the local regulation of vascular tone. Endothelial dysfunction could be another mechanism responsible for the vasomotor disturbances in cold CRPS. An important goal in the treatment of cold‐type CRPS is the restoration of a normal blood flow. Consequently it is important to distinguish the underlying pathophysiological mechanisms of vasomotor disturbances. A disturbance of the sympathetic nervous system may require another type of treatment than inflammation‐induced endothelial dysfunction. Diagnostic tools to distinguish these underlying pathophysiological mechanisms of vasomotor disturbances would enable a mechanism‐based treatment and improve clinical outcome.     

Interactions between Pain and the Motor Cortex: Insights from Research on Phantom Limb Pain and Complex Regional Pain Syndrome

Purpose: Pain is a significantly disabling problem that often interacts with other deficits during the rehabilitation process. The aim of this paper is to review evidence of interactions between pain and the motor cortex in order to attempt to answer the following questions: (1) Does acute pain interfere with motor-cortex activity? (2) Does chronic pain interfere with motor-cortex activity, and, conversely, does motor-cortex plasticity contribute to chronic pain? (3) Can the induction of motor plasticity by means of motor-cortex stimulation decrease pain? (4) Can motor training result in both motor-cortex reorganization and pain relief?Summary of Key Points: Acute experimental pain has been clearly shown to exert an inhibitory influence over the motor cortex, which can interfere with motor learning capacities. Current evidence also suggests a relationship between chronic pain and motor-cortex reorganization, but it is still unclear whether one causes the other. However, there is growing evidence that interventions aimed at normalizing motor-cortex organization can lead to pain relief.Conclusions: Interactions between pain and the motor cortex are complex, and more studies are needed to understand these interactions in our patients, as well as to develop optimal rehabilitative strategies.