“Inflammatory Soup” Mediators of inflammation in CRPS

Complex Regional Pain Syndrome type 1 (CRPS1) is a disease of the extremity that usually occurs as a complication after surgery or trauma, although spontaneous occurrence has also been described. The clinical features include pain/sensory abnormalities, vasomotor dysfunction, edema/sudomotor dysfunction, and motor/trophic changes. The diagnosis of CRPS is based on findings during the history and physical examination. Several diagnostic criteria sets have been developed, and the most used are the Veldman criteria, the IASP criteria (the International Association for the Study of Pain), and the Bruehl criteria. There is a distinction between CRPS types 1 and 2. Type 1 occurs without any peripheral nerve lesion, whereas in type 2 there is definite peripheral nerve damage. In the Netherlands, the incidence of CRPS is estimated to be approximately 26.2 per 100,000 person years, with a median age of onset of 52.7 years. CRPS occurs more often in females than in males, with a ratio of approximately 3.4:1. The upper extremity is more often affected than the lower extremity, and the right and the left sides of the body are affected with the same frequency. A fracture is the most common precipitating event (44%) for CRPS, followed by a contusion/sprain in 17% of the population

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

In an earlier study, levels of the proinflammatory cytokines TNF-α 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-α 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-α 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-α are only partially responsible for the signs and symptoms of CRPS1.</p

Six Years Follow-up of the Levels of TNF-α and IL-6 in Patients with Complex Regional Pain Syndrome Type 1

In an earlier study, levels of the proinflammatory cytokines TNF-α 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-α 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-α 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-α are only partially responsible for the signs and symptoms of CRPS1

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

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 TNFα 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-1β, IL-1RA, IL-6, IL-8, and TNF-α; (2) Th1/Th2 distinguishing cytokines IFN-γ, IL-2, IL-2R, IL-4, IL-5, and IL-10; (3) nonspecific acting cytokines IFN-α, IL-7, IL-12p40/p70, IL-13, IL-15, and IL-17; and (4) chemokines eotaxin, IP-10, MCP-1, MIP-1α, MIP-1β, 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-α, IL-12p40/p70, MCP-1, and MIP-1β were detectable and increased in CRPS1 affected extremities. Levels of IL-6 and TNF-α 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-α). 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

Report of a Preliminary Discontinued Double-Blind, Randomized, Placebo-Controlled Trial of the Anti-TNF-alpha Chimeric Monoclonal Antibody Infliximab in Complex Regional Pain Syndrome

Objective: Inflammation appears to play a role in CRPS as, for example, cytokines (like TNF-alpha) 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-alpha 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-alpha 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 compare 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-alpha concentration

Increased plasma glutamate, glycine, and arginine levels in complex regional pain syndrome type 1

Background: Various inflammatory mediators have been identified as potential contributors to complex regional pain syndrome type 1 (CRPS1), but these mediators do not entirely explain certain manifestations of the syndrome, such as pain. The objective of this study was to investigate the role of amino acids in the pathogenesis of CRPS1. Methods: We used HPLC to determine plasma concentrations of 16 amino acids, especially those related to the NMDA receptor (e.g., glutamate and glycine) and nitric oxide (NO) synthesis (e.g., arginine and citrulline) in patients with CRPS1 (n=64) and age- and sex-matched healthy controls (n=51). Patients rated pain intensity (visual analog scale) and the subjective experience of pain intensity (McGill Pain Questionnaire). Psychological dysfunction was assessed using the SCL-90. Results: Relative to controls, in CRPS1 patients, plasma levels of glutamate, arginine, taurine, and glycine were increased, and plasma levels of glutamine and the ratio of citrulline to arginine were decreased. Remarkably, in CRPS1 patients there was a highly significant inverse correlation between glutamine and glutamate, although the sum of molar concentrations of glutamate and glutamine remains unchanged. Subjective measures of pain and indicators of psychoneuroticism and emotional instability did not correlate with amino acid levels. Conclusion: This study shows for the first time a pronounced increase in amino acid levels in this chronic pain syndrome. The marked differences in glutamate, glutamine, glycine, taurine and arginine levels between patients and controls suggest the involvement of both the NDMA receptor and the endothelium-dependent arginine-NO system in CRPS1