'Cold Case': Vascular dysregulation in the chronic Complex Regional Pain Syndrome

The aim of this thesis was to study the nature of the vascular alterations in patients with cold chronic Complex Regional Pain Syndrome. CRPS usually develops as a disproportionate consequence of trauma and is characterised by spontaneous pain, movement disorders and abnormal regulation of blood flow and sweating. We hypothesised that endothelial dysfunction may in part be responsible for the diminished blood flow in cold chronic CRPS. An improvement on endothelial level would therefore lead to an increased blood flow and a subsequent improvement in pain and activity. In the second chapter we studied the characteristics of 195 patients with potential CRPS that visited our out-patients clinic. We found that a subgroup of patients with a lower temperature in the affected extremity had a longer disease duration and higher pain scores. The results of immunohistochemical staining on skin sections (chapter 3) and the measurement of blister fluids (chapter 4) indicate that endothelial dysfunction may play a role in chronic CRPS. Five female patients were treated with the nitric oxide donor isosorbide dinitrate (ISDN). In this pilot study, described in chapter five, topical application of ISDN improved temperature and pain in most patients. Two randomized placebo-controlled trials were initiated, both including 24 chronic cold CRPS patients. In the first study, which is described in chapter six, ISDN ointment was used by patients with CRPS in one hand. In the second study (chapter 7) the phosphodiesterase inhibitor tadalafil was used to induce vasodilation in patients with CPRS in one foot. Although neither studies produced a significant improvement in temperature asymmetry and blood flow there was a significant reduction of pain in the tadalafil group. We concluded that tadalafil may be a promising new treatment for patients with chronic cold CRPS due to endothelial dysfunction, which deserves further investigation. In chapter 8 we discuss the mechanisms responsible for ischemia and pain in chronic cold CPRS. The diminished blood flow may be caused by either sympathetic dysfunction, hypersensitivity to circulating catecholamines or endothelial dysfunction. Pain in CRPS may be of neuropathic, inflammatory, nociceptive, functional nature or of mixed origin. This origin of the pain should be the basis of the symptomatic therapy. Future research should focus on developing easily applied methods for clinical use to differentiate between central and peripheral blood flow regulation disorders in individual patients.

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