Clonidine is approved for intraspinal administration in the treatment of neuropathic cancer pain. Some studies have suggested an analgesic effect after systemic clonidine administration. The purpose of this study was to compare the analgesic effects of intrathecal and IV clonidine with acute noxious stimulation and with hyperalgesia from intradermal capsaicin injection in volunteers. Sixteen healthy volunteers received intradermal injections of capsaicin (100 [micro sign] g) before and after the IV or intrathecal injection of clonidine 50 or 150 [micro sign] g in a randomized, double-blind manner. Pain and areas of mechanical hyperalgesia and allodynia were determined at specified intervals. In addition, pain to noxious heat stimulation was determined. The capsaicin injection produced pain, followed by hyperalgesia and allodynia. The intrathecal, but not IV, injection of 150 [micro sign] g of clonidine reduced capsaicin-induced pain and area of hyperalgesia. Intrathecal clonidine (150 [micro sign] g) reduced pain to heat stimulation, whereas IV clonidine did not. The groups did not differ in hemodynamic or sedative effects from clonidine. These data support the value of intraspinal administration of clonidine for the treatment of acute pain and of pain states associated with hyperalgesia. Similarly, they suggest that analgesia from the systemic administration of this [alpha] 2-adrenergic agonist, if any, is weak in doses that produce sedation and reduce blood pressure. Implications: To the extent that the experimental pain conditions used in this study reflect those in patients with acute and chronic pain, these data support the spinal rather than IV injection of clonidine for analgesia.