The purpose of this project is to elucidate the principles of treatment of acute and chronic pain syndromes, with particular attention to the drug treatment of pain caused by nerve injury. In an interim analysis of a double-blind, crossover study in 22 patients with painful diabetic neuropathy, 7 patients obtained significantly better pain relief with clonidine than placebo and had that response confirmed by two subsequent double-blind crossover comparisons of clonidine and placebo. Clonidine is ana2-adrenergic agonist commonly used as an antihypertensive. This confirms the result of a previous trial showing that a subset of patients were clonidine-responsive, and suggests that clonidine may be a useful advance in treatment for a subset of patients with neuropathic pain. Because of growing evidence from animal studies that neuropathic pain may be mediated by spinal cord neurons depolarized by NMDA channels, the NMDA antagonist ketamine is being studied in two conditions: chronic pain in patients with nerve damage or reflex sympathetic dystrophy, and normal volunteers with hyperalgesia of the skin briefly induced by intradermal injection of capsaicin.