Report of a preliminary discontinued double-blind, randomized, placebo-controlled trial of the anti-TNF-α chimeric monoclonal antibody infliximab in complex regional pain syndrome.

OBJECTIVE: Inflammation appears to play a role in CRPS as, for example, cytokines (like TNF-α) are involved in the affected limb. The ongoing inflammation is probably responsible for the central sensitization that sometimes occurs in CRPS. Thus, early start of a TNF-α antagonist may counteract inflammation, thereby preventing rest damage and leading to recovery of the disease. DESIGN: Patients (n = 13) were randomly assigned to infliximab 5 mg/kg or placebo, both administered at week 0, 2, and 6. OUTCOME MEASURES: The aim was to confirm a reduction in clinical signs of regional inflammation (based on total impairment level sumscore: ISS) after systemic administration of infliximab. Also, levels of mediators in the fluid of induced blisters were examined in relation to normalization and improvement in quality of life. RESULTS: Six patients received infliximab and 7, placebo. There was no significant change in total ISS score between the two groups. Similarly, no significant difference in change in cytokine levels was found between infliximab compared with placebo. However, there was a trend toward a greater reduction of TNF-α in the intervention group compared with the placebo group. A subscale of the EuroQol (ie EuroQol VAS) revealed significant decrease in health status in the intervention group compared with the placebo group. CONCLUSIONS: This study was terminated before the required number of participants had been reached for sufficient statistical power. Nevertheless, a trend was found toward an effect of infliximab on the initially high TNF-α concentration.

Complex regional pain syndrome type 1 may be associated with menstrual cycle disorders: a case-control study.

BACKGROUND: Complex regional pain syndrome type 1 (CRPS1) can develop after severe trauma or surgery in the limbs, and presents with chronic, changes in temperature, edema and dysfunction. Seventy-five percent of CRPS1 patients are female. While neurological and inflammatory components have been proposed, the etiology remains unclear. No consensus on optimal management of CRPS1 exists. In traditional Chinese medicine, menstrual disorders are related to the state of women's constitution and therefore identify their pain patterns. A classification by constitution might improve the pain management in CRPS1 patients. It is unknown whether associations exist between menstrual-cycle-conditions and CRPS1. AIM: To investigate whether a specified menstrual condition is associated with the risk of developing CRPS1. METHODS: A population-based case-control study of CRPS1 was conducted among Dutch women aged 18-82; i.e. 34 women with CRPS1 and 147 controls. A standard questionnaire consisting of 59 menstrual-cycle-symptom-based questions was administered. From this questionnaire, 15 CRPS1-related questions (DRQ 15) were analyzed. We used multivariate logistic regression to obtain odds ratios and 95% confidence intervals (CI) for specified menstrual disorders adjusting for age, oral contraceptives, hysterectomy and age at menarche < or = 12 and > or = 17 years. RESULTS: On the basis of the DRQ 15, women with CRPS1 were 5.3 (95%CI 2.1, 12.9) times more likely to have menstrual disorders than comparable controls. CONCLUSION: Our results suggest that selected menstrual conditions are associated with the risk of developing CRPS1.

No recovery of cold complex regional pain syndrome after transdermal isosorbide dinitrate: a small controlled trial.

The microcirculation appears to be impaired in cold chronic complex regional pain syndrome (CRPS). This double-blind, placebo-controlled, randomized trial investigated the effect of the nitric oxide (NO) donor isosorbide dinitrate (ISDN) on the peripheral blood flow in patients with chronic CRPS. Twenty-four patients received 1% ISDN in Vaseline or a placebo ointment applied to the dorsum of the affected hand four times daily for 10 weeks. The patients participated in a physical therapy program to improve activity. The primary outcome measure was blood distribution in the affected extremity, which was determined by measuring the skin temperature using videothermography. We also measured NO and endothelin-1 concentrations in blister fluid, pain using the visual analog scale, and activity limitations using an upper limb activity monitor and the Disabilities of Arm Shoulder and Hand Questionnaire. ISDN failed to produce a significant improvement in temperature asymmetry in chronic cold CRPS patients, and it did not result in the expected reduction in pain and increase in activity compared with placebo either. There may be other central or peripheral factors contributing to the disturbed vasodynamics in cold chronic CRPS that are not influenced by NO substitution. This study does not show an improvement of the regional blood distribution by ISDN in the involved extremity of patients with cold-type CRPS.

IgE-mediated hypersensitivity: patients with complex regional pain syndrome type 1 (CRPS1) vs the Dutch population. A retrospective study.

OBJECTIVE: To investigate whether hypersensitivity is more common in Complex Regional Pain Syndrome type 1 (CRPS1) patients than in the general population. In a recent study, the level of tryptase, a specific marker for mast cells, was significantly higher in blister fluid from the involved extremity of CRPS1 patients. This suggested that mast cells may play a role in the pathophysiology of CRPS1. Mast cells are major effectors in allergic reactions, and are also involved in a variety of noninfectious inflammatory diseases. Patients. Sixty-six Dutch patients with CRPS1 in one extremity were included. OUTCOME MEASURES: Allergy information was obtained from the medical history and a modified questionnaire based on the Europees Luchtweg Onderzoek Nederland 1 study. Total IgE and allergen-specific IgE were measured from blood samples. Also tryptase, as a marker for mast cells, was measured. The data from the questionnaire were compared with that of the general Dutch population, and the plasma levels were compared with reference values and data in the literature. RESULTS: The medical history did not differ from information provided in the questionnaire by the CRPS1 group. There was no significant difference between the answers to the questionnaire between the CRPS1 patients and the general population. The total IgE levels were elevated in 30% of the CRPS1 patients compared with 15-24% of the general population, and allergen-specific IgE and tryptase levels were comparable with the reference values. CONCLUSIONS: Based on the medical history, an allergy questionnaire, and objective laboratory findings we conclude that IgE-mediated hypersensitivity is not more common in CRPS1 patients than in the general population.

Effect of tadalafil on blood flow, pain, and function in chronic cold complex regional pain syndrome: a randomized controlled trial.

BACKGROUND: This double-blind, randomized, controlled trial investigated the effect of the phosphodiesterase-5 inhibitor tadalafil on the microcirculation in patients with cold Complex Regional Pain Syndrome (CRPS) in one lower extremity. METHODS: Twenty-four patients received 20 mg tadalafil or placebo daily for 12 weeks. The patients also participated in a physical therapy program. The primary outcome measure was temperature difference between the CRPS side and the contralateral side, determined by measuring the skin temperature with videothermography. Secondary outcomes were: pain measured on a Visual Analogue Scale, muscle force measured with a MicroFet 2 dynamometer, and level of activity measured with an Activity Monitor (AM) and walking tests. RESULTS: At the end of the study period, the temperature asymmetry was not significantly reduced in the tadalafil group compared with the placebo group, but there was a significant and clinically relevant reduction of pain in the tadalafil group. Muscle force improved in both treatment groups and the AM revealed small, non-significant improvements in time spent standing, walking, and the number of short walking periods. CONCLUSION: Tadalafil may be a promising new treatment for patients that have chronic cold CRPS due to endothelial dysfunction, and deserves further investigation. TRIAL REGISTRATION: The registration number in the Dutch Trial Register is ISRCTN60226869.

Six years follow-up of the levels of TNF-alpha and IL-6 in patients with complex regional pain syndrome type 1.

In an earlier study, levels of the proinflammatory cytokines TNF-alpha and IL-6 are higher in blisters fluid from the complex regional pain syndrome type 1 (CRPS1) side obtained at 6 and 30 months (median) after the initial event. The aim of this follow-up study is to determine the involvement of these cytokines in long lasting CRPS1. Twelve CRPS1 patients, with median disease duration of 72 months, participated. The levels of TNF-alpha and IL-6 were measured in blister fluid; disease activity was reevaluated by measuring pain and differences in temperature, volume, and mobility between both extremities. Differences in levels of IL-6 and TNF-alpha and mobility between both sides were significantly decreased. Pain and differences in temperature and volume were not significantly altered. No correlation was found between the cytokines and the disease characteristics. These results indicate that IL-6 and TNF-alpha are only partially responsible for the signs and symptoms of CRPS1.

Increased plasma serotonin in complex regional pain syndrome type 1.

BACKGROUND: In patients with complex regional pain syndrome type 1 (CRPS1), some improvement can be achieved by the administration of ketanserin, a 5-HT(2A) receptor antagonist. We measured plasma levels of serotonin (5-HT) during CRPS1 and correlated these levels with disease characteristics. METHODS: Plasma 5-HT was measured in 35 patients who had CRPS1 for 3 yr and compared with 35 age-matched healthy controls. RESULTS: The plasma 5-HT levels were 411 +/- 263 nmol/L and 29 +/- 18 nmol/L, respectively (P < 0.001). No correlations with disease characteristics were observed. CONCLUSIONS: The markedly elevated levels of plasma 5-HT in CRPS1 patients suggest a role for 5-HT during the course of this disease. However, because of the lack of correlations with distinct disease characteristics, 5-HT is probably one of a number of mediators in CRPS1.

Vasodilative effect of isosorbide dinitrate ointment in complex regional pain syndrome type 1.

BACKGROUND: In complex regional pain syndrome type 1 (CRPS1) vascular changes occur from the initial, inflammatory event onto the trophic signs during chronicity of the disease, resulting in blood flow disturbances and marked temperature changes. Pharmacotherapeutic treatment is generally inadequate. AIM: To determine whether local application of the nitric oxide donor isosorbide dinitrate (ISDN) could cause vasodilation and thereby improve tissue blood distribution in the affected extremity. METHODS: In a pilot study, 5 female patients with CRPS1 in one hand were treated with ISDN ointment 4 times daily during 10 weeks. As a primary objective videothermography was used to monitor changes in blood distribution in both the involved and contralateral extremities. RESULTS: Patients treated with ISDN showed an increase of 4 degrees C to 6 degrees C in mean skin temperature of the cold CRPS1 hands, reaching values similar to that of the contralateral extremities within 2 to 4 weeks time, suggesting normalization of blood distribution. This was confirmed by an improvement in skin color. In 3 patients the Visual Analog Scale pain declined, whereas in the other 2 patients the Visual Analog Scale pain was unchanged over time. CONCLUSIONS: In this pilot study, topical application of ISDN seems to be beneficial to improve symptoms for patients with cold type CRPS1, but further study is needed.

Tumor necrosis factor-alpha and interleukin-6 are not correlated with the characteristics of Complex Regional Pain Syndrome type 1 in 66 patients.

It was previously shown in a group of 9 patients with complex regional pain syndrome type 1 (CRPS1) that levels of the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) are higher in blister fluid from the involved side. We hypothesize that local inflammation is responsible for the characteristics of CRPS1. The aim of this study was to confirm the previous observation in a large group of CRPS1 patients, repeating the measurement of TNF-alpha and IL-6 in blister fluid. Furthermore, we sought to determine whether these cytokines are responsible for the characteristics of CRPS1 and characterize the relationship between cytokine levels and duration of the disease. Sixty-six patients with CRPS1 participated. Skin blisters were artificially induced for measurement of cytokines in both extremities. The following disease characteristics were assessed: pain and differences in temperature, volume, and mobility between the extremities. TNF-alpha and IL-6 levels were significantly higher in blister fluid from the involved side. However, cytokine levels did not correlate with the characteristics or duration of the disease. Our findings confirm the presence of local inflammation in a population of 66 patients in the first 2 years of CRPS1. Proinflammatory cytokines seem to be only partly involved in the pathophysiology of CRPS1, as indicated by the lack of coherence between TNF-alpha and IL-6 levels and the signs and symptoms of inflammation and disease duration. Other inflammatory mediators and mechanisms, such as central sensitization, are probably involved in the early stages of CRPS1.

Suction blister fluid as potential body fluid for biomarker proteins.

Early diagnosis is important for effective disease management. Measurement of biomarkers present at the local level of the skin could be advantageous in facilitating the diagnostic process. The analysis of the proteome of suction blister fluid, representative for the interstitial fluid of the skin, is therefore a desirable first step in the search for potential biomarkers involved in biological pathways of particular diseases. Here, we describe a global analysis of the suction blister fluid proteome as potential body fluid for biomarker proteins. The suction blister fluid proteome was compared with a serum proteome analyzed using identical protocols. By using stringent criteria allowing less than 1% false positive identifications, we were able to detect, using identical experimental conditions and amount of starting material, 401 proteins in suction blister fluid and 240 proteins in serum. As a major result of our analysis we construct a prejudiced list of 34 proteins, relatively highly and uniquely detected in suction blister fluid as compared to serum, with established and putative characteristics as biomarkers. We conclude that suction blister fluid might potentially serve as a good alternative biomarker body fluid for diseases that involve the skin.

Multiplex bead array assay for detection of 25 soluble cytokines in blister fluid of patients with complex regional pain syndrome type 1.

Inflammatory processes are known to be involved at least in the early phase of complex regional pain syndrome type 1 (CRPS1). Blister fluid obtained from the involved extremities displayed increased amounts of proinflammatory cytokines IL-6 and TNFalpha compared with the noninvolved extremities. The aim of this paper is to investigate the involvement of mediators by measurement of several other cytokines using new detection techniques that enable multiple cytokine measurement in small samples. The use of a multiplex-25 bead array cytokine assay and Luminex technology enabled simultaneous measurement of representative (1) proinflammatory cytokines such as GM-CSF, IL-1beta, IL-1RA, IL-6, IL-8, and TNF-alpha; (2) Th1/Th2 distinguishing cytokines IFN-gamma, IL-2, IL-2R, IL-4, IL-5, and IL-10; (3) nonspecific acting cytokines IFN-alpha, IL-7, IL-12p40/p70, IL-13, IL-15, and IL-17; and (4) chemokines eotaxin, IP-10, MCP-1, MIP-1alpha, MIP-1beta, MIG, and RANTES. Although minimal detection levels are significantly higher in the bead array system than those in common ELISA assays, in blister fluid, IL-1RA, IL-6, IL-8, TNF-alpha, IL-12p40/p70, MCP-1, and MIP-1beta were detectable and increased in CRPS1 affected extremities. Levels of IL-6 and TNF-alpha simultaneously measured by ELISA (Sanquin Compact kit) and by multiplex-25 bead array assay (Biosource) were highly correlated (r = 0.85, P < .001 for IL-6 and r = 0.88, P < .001 for TNF-alpha). Furthermore, IP-10 and eotaxin were detectable but diminished in CRPS1, whereas detectable amounts of IL-10 were similar in involved and noninvolved extremities. Multiplex bead array assays are useful systems to establish the involvement of cytokines in inflammatory processes by measurements in blister fluids of CRPS1. Ten representative cytokines were detectable. However, detection levels and amounts measured are at least 3 times higher in the multiplex-25 array assay than in the ELISA assays used simultaneously for the measurement of cytokines.