Intraspinally administered alpha 2-adrenergic agonists may relieve pain in sympathetically maintained pain (SMP) syndromes, such as reflex sympathetically dystrophy (RSD), by spinal, peripheral, and central nervous system actions. This study examined analgesic efficacy and side effects of epidurally administered clonidine in patients with severe, refractory RSD. Twenty-six patients with severe chronic pain consistent with RSD were studied in a randomized, blinded, placebo-controlled design. Cervical or lumbar epidural catheters were inserted for patients with upper or lower extremity RSD, respectively, and patients received, in random order on three consecutive days, epidural injection of clonidine, 300 or 700 micrograms, or placebo. Pain (by visual analog score (VAS) and McGill Pain Questionnaire), sedation, blood pressure, and heart rate were monitored at specified intervals for 6 h after injection. Patients who responded to clonidine, but not placebo, then entered a trial of open-label, continuous epidural infusion of clonidine (10-50 micrograms/h). Clonidine, but not placebo, caused pain relief, sedation, and decreased blood pressure and heart rate after bolus epidural injection. The smaller clonidine dose (300 micrograms), produced pain relief and decreases in blood pressure and heart rate similar to those of the 700 micrograms dose, but with less sedation. Epidural clonidine was infused for a mean of 43 days in 19 patients at a mean rate of 32 micrograms/h for sustained analgesia. Transdermal clonidine has been demonstrated to produce analgesia in the area surrounding its application site in patients with SMP. The current study indicates that extensive analgesia may be obtained by epidural administration. Sedation and hypotension may limit bolus epidural clonidine administration for RSD. The role for chronic epidural infusion of clonidine has not yet been established.