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Unlabelled: Complex regional pain syndrome (CRPS) is a potentially debilitating chronic pain syndrome with a poorly understood but likely neuroimmune/multifactorial pathophysiology associated with axonal injury. Based on the potential contribution of proinflammatory cytokines to CRPS pathogenesis and prior research with thalidomide, we investigated lenalidomide, a thalidomide derivative, for CRPS treatment. We conducted a phase II, randomized, double-blind, placebo-controlled study to evaluate the efficacy of oral lenalidomide 10 mg once daily in consenting patients with unilateral or bilateral CRPS type 1. The study comprised 12 weeks of treatment followed by a long-term extension. The primary efficacy outcome was reduced pain in the index limb, defined as ≥30% improvement from baseline using an 11-point numeric rating scale. One hundred eighty-four subjects enrolled. The primary endpoint was not met because equal proportions of treated (16.1%) and control (16.1%) subjects achieved the outcome; however, lenalidomide was well tolerated, with no evidence of neuropathy or major adverse effects. This study is the largest controlled, blinded clinical trial in subjects with chronic CRPS using the Budapest research criteria. It demonstrates the feasibility of conducting high-quality clinical trials in CRPS type 1 and provides considerations for designing future trials., Perspective: This article reports an adequately powered, controlled clinical trial in subjects with CRPS. Treatment and placebo were equally effective, but the study demonstrated that lenalidomide treatment is feasible in this population. The study provides examples to consider in designing future CRPS trials., (Copyright © 2014 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Unlabelled: There are indications of motor circuit changes in patients with complex regional pain syndrome (CRPS). Nevertheless, although several studies have analyzed motor behavior in CRPS, a relation with pain could not be detected. This might be explained by the use of cross-sectional designs in these studies, in which pain is considered as a trait- rather than a state-dependent variable. We therefore studied the time-dependent relation between pain and motor function in affected arms of 29 CRPS patients during their participation in a placebo-controlled ketamine study. Movement parameters (velocity, frequency, amplitude, and number of arrests) were assessed during a finger tapping task. Linear mixed model analysis of the effects of pain (numerical rating scale score), treatment (ketamine/placebo), and week (1, 3, 6, and 12 weeks after treatment) on the movement parameters revealed that pain intensity was significantly (inversely) related to motor function, irrespective of whether patients had received ketamine or placebo. Movement parameters changed 3-12% per point numerical rating scale change. Because patients were unaware of possible effects of ketamine on motor function, these findings suggest that motor function changes were mediated by, or occurred simultaneously with, changes in pain intensity. By improving motor function, pain relief may offer a window of opportunity for rehabilitation programs in CRPS., Perspective: This article provides evidence for a direct relation between pain and motor function in CRPS, which indicates that pain relief may be an important factor in the treatment of motor disturbances in this condition. These findings may help to advance our understanding of the pathways underlying motor disturbances in CRPS., (Copyright © 2013 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Growing evidence indicates that various chronic pain syndromes exhibit tissue abnormalities caused by microvasculature dysfunction in the blood vessels of skin, muscle, or nerve. We tested whether topical combinations aimed at improving microvascular function would relieve allodynia in animal models of complex regional pain syndrome type I (CRPS-I) and neuropathic pain. We hypothesized that topical administration of either α(2)-adrenergic (α(2)A) receptor agonists or nitric oxide (NO) donors combined with either phosphodiesterase (PDE) or phosphatidic acid (PA) inhibitors would effectively reduce allodynia in these animal models of chronic pain. Single topical agents produced significant dose-dependent antiallodynic effects in rats with chronic postischemia pain, and the antiallodynic dose-response curves of PDE and PA inhibitors were shifted 2.5- to 10-fold leftward when combined with nonanalgesic doses of α(2)A receptor agonists or NO donors. Topical combinations also produced significant antiallodynic effects in rats with sciatic nerve injury, painful diabetic neuropathy, and chemotherapy-induced painful neuropathy. These effects were shown to be produced by a local action, lasted up to 6 hours after acute treatment, and did not produce tolerance over 15 days of chronic daily dosing. The present results support the hypothesis that allodynia in animal models of CRPS-I and neuropathic pain is effectively relieved by topical combinations of α(2)A or NO donors with PDE or PA inhibitors. This suggests that topical treatments aimed at improving microvascular function may reduce allodynia in patients with CRPS-I and neuropathic pain., Perspective: This article presents the synergistic antiallodynic effects of combinations of α(2)A or NO donors with PDE or PA inhibitors in animal models of CRPS-I and neuropathic pain. The data suggest that effective clinical treatment of chronic neuropathic pain may be achieved by therapies that alleviate microvascular dysfunction in affected areas., (Copyright © 2013 American Pain Society. Published by Elsevier Inc. All rights reserved.)

The effects of short-term dependency and immobility on skin temperature were assessed in two experiments. In the first study, ten volunteers hung their left arm dependent and motionless while using their right hand for light office work. After 30 minutes, the dependent left hands were cooler (mean=0.9 degrees C: 95% CI=0.7-1.1) than the active right hands and exhibited a deeper colour with significantly increased green intensity (P=0.03) as assessed on digital images. In the second study, seven volunteers submerged both their hands in water at 15 degrees C for 15 minutes. The left arm was then left dependent and motionless while the right hand was placed on the table and its fingers were flexed and extended every 10 seconds. The left hands remained cooler than the right and were a median of 3.6 (range 2.9-4.5) degrees C cooler after 60 minutes. These studies demonstrate that skin temperature and colour differences between the hands, which are sometimes used to support the diagnosis of CRPS-1, can be produced and maintained by short-term immobility and dependency of the hand.

Unlabelled: We describe a 12-year-old patient with severe, protracted complex regional pain syndrome type I. His pain did not respond to gabapentin, amitriptyline, physical therapy, opioids, or nonsteroidal drugs. Sympathetic or regional block was not attempted because of persistent bacteremia and severe local sepsis. His pain responded dramatically to the addition of oxcarbazepine, with rapid improvement in his symptoms and functional status. We suggest that oxcarbazepine might be a useful adjunct in the treatment of gabapentin-resistant complex regional pain syndrome type I in children and should be considered., Perspective: Oxcarbazepine's antinociceptive effect is mediated via sodium channel inhibition in neuropathic models and by inhibition of substance P and prostaglandins in anti-inflammatory models. The efficacy of oxcarbazepine in this patient might be attributable to these mechanisms or possibly to synergism with either gabapentin or the anti-inflammatory effects produced by amitriptyline.

A scoring system for the clinical severity of reflex sympathetic dystrophy (RSD) is proposed. The following signs and symptoms were considered to be significant: pain, reduction of finger flexion, swelling, temperature changes, discolouration, sensory disturbances, shoulder pain and loss of movement, increased sweating, and hair/nail growth changes. One point was assigned for strong expression of most of these features, half a point for moderate expression and no point if the feature was absent. A total score of 4 points was assumed, empirically, to indicate a mild degree of RSD, and the maximum score of 10 to indicate the most severe form of RSD. One hundred and forty-six patients with RSD of the hand were classified according to this system. Seventy-four patients (51%) had a score of 4-6, 51 patients (35%) a score of 6.5-8, and 21 patients (14%) a score of 8.5-10. Use of this system will allow more precise analysis of RSD patients and facilitate comparisons between studies.

This paper presents the results of a retrospective analysis of 94 patients who were assessed at a mean of 11 months after successful treatment of reflex sympathetic dystrophy (RSD) of the hand. Fifty-four percent still complained of pain related to the weather, and many complained of cold intolerance (44%), slight pain after use (34%), nail and hair growth changes (34%), sensory disturbances (34%) and stiffness of fingers in the morning (28%). There were also complaints of reduced finger extension, pain and loss of movement in the shoulder joint and hand swelling after use, and 78% of patients had significantly reduced grip strength. These results suggest that, in spite of resolution of the acute RSD problem, significant long term sequelae of RSD continue to impair function of the hand in a proportion of patients.

The paper presents the results of a prospective trial to examine the natural history of early reflex sympathetic dystrophy (RSD). Thirty patients with post-traumatic RSD of the hand were observed without treatment. They were reassessed 1, 2 and 6 months after diagnosis with a final assessment at 10 to 18 months (average 13 months). Twenty-seven patients completed the study. Three were withdrawn during the study because of persistence of signs and symptoms of RSD and were given further treatment. Of the 27 patients who completed the study, only one showed sufficient features of the condition to warrant the diagnosis of mild RSD. In the remaining 26, most features of RSD had resolved spontaneously. Pain and swelling disappeared more quickly than other features of RSD. Although the signs and symptoms of RSD had largely gone at 13 months, the hands were still functionally impaired because of weaker grip strength.

The sympathetic nervous system function in 20 patients with reflex sympathetic dystrophy (RSD) of one upper extremity was examined by a non-invasive laser Doppler method to assess fingertip blood flow and vasoconstrictor response to deep inspiration. We observed an increased blood flow but an unchanged vasoconstrictor response in the affected hand in stage 1 of the disorder, but in stage 2 there was a decreased blood flow and a stronger vasoconstriction following an inspiratory gasp. Skin blood flow and vasoconstrictor response returned to normal following successful treatment of the condition. These results suggest that in RSD patients the sympathetic nervous system function is altered and is different in the various stages. The objective method used in our study may be of value in the diagnosis and management of RSD.

17 patients with established algodystrophy following trauma were treated with serial intravenous regional guanethidine blockade. Subjective improvement occurred in all cases. This improvement could be confirmed quantitatively using objective assessment criteria. The subjective and objective improvements demonstrated in each of the features of algodystrophy correlate closely (p < 0.001). There appears to be no difference in the effectiveness of one block compared to another in the same patient.