PHARMACOLOGY AND TOXICOLOGY OF CHRONICALLY INFUSED EPIDURAL CLONIDINEHCL IN DOGS

To evaluate the physiological effects and toxicity of epidural clonidi ne.HCl, male Beagle dogs were prepared with chronic lumbar epidural ca theters and administered constant infusions of either saline (N = 10), or 80 mu g/hr (N = 6), 200 mu g/hr (N = 6), or 320 mu g/hr (N = 12) c lonidine.HCl at a rate of 4 ml/24 hr for 28 days. Saline infusion had no effect upon any behavioral measure. Epidural clonidine produced a d ose-dependent increase in thermal skin-twitch response latency (antino ciception), lowering of respiration rate, heart rate, and blood pressu re, and increased sedation. The effects were maximum from approximatel y Day 1 to Day 3 when, with the exception of respiration which remaine d depressed, a progressive adaptation was observed over the course of the study. There were no negative effects on body weight, body tempera ture, motor function, bowel or bladder function, or clinical pathology values. After 28 days of continuous infusion, the dogs were deeply an esthetized and terminated. Cisternal cerebrospinal fluid taken at term ination displayed no clinically significant differences in protein of glucose concentration. All groups, including control, had dogs which h ad a chronic inflammatory response in the epidural space, as represent ed by fibrosis, foreign body giant cells, and lymphocytes, but no spin al cord pathology. Both the steady-state plasma and CSF concentrations of clonidine were proportional to the dose; the ratio of CSF to plasm a concentration was approximately 0.5. The failure to see any change i n CSF composition, significant spinal cord pathology, or signs of tiss ue or organ toxicity emphasizes the safety of epidurally administered clonidine at infusion rates up to 320 mu g/hr and at infusate concentr ations up to 2 mg/ml. (C) 1994 Society of Toxicology.