SPINAL DELIVERY OF SUFENTANIL, ALFENTANIL AND MORPHINE IN DOGS - PHYSIOLOGICAL AND TOXICOLOGIC INVESTIGATIONS

Background: This study examines the behavioral effects and potential n eurotoxicity of sufentanil, alfentanil, and morphine after chronic dai ly epidural (15-day) and intrathecal (28-day) administration in dogs. Methods: Dogs were chronically implanted with a lumbar intrathecal or epidural catheter and received daily injections for 28 or 15 days, res pectively, of saline or one of three mu agonists: sufentanil (intrathe cal 5, 25, or 50 mu g/0.5 ml; epidural 10, 50, or 100 mu g/2.0 ml), al fentanil (intrathecal 40 or 400 mu g/0.5 ml; epidural 80 or 800 mu g/2 .0 ml), or morphine (intrathecal 0.5 or 5 mg/0.5 ml; epidural 1 or 10 mg/2.0 ml). Dogs were examined for antinociception (skin twitch) and n eurobehavioral changes. When the animals were killed, cisternal cerebr ospinal fluid was taken for clinical chemistry, and after perfusion fi xation, spinal cord tissue was taken for histologic analysis. Results: Bolus intrathecal and epidural injections of sufentanil, alfentanil a nd morphine produced dose dependent antinociception, bradycardia, an i nitial tachypnea followed by a decrease in respiratory rate, hypotherm ia and somnolence. The order of potency was sufentanil > alfentanil > morphine on all measures. Over the extended period of drug delivery, a loss of response (tolerance) was observed on all measures. No abnorma l morphologic or histologic effects were found when comparing the drug and dose groups. An inflammatory reaction secondary to the catheter w as found in all animals. Intrathecal, but not epidural, catheters resu lted in significant increases in cerebrospinal fluid protein and cell counts in vehicle animals. Values in drug treated animals did not diff er significantly from the respective vehicle controls. A rapid systemi c redistribution of all three drugs was observed. No differences were found in the pharmacokinetic parameters measured at day 1 and at the d ay of killing for any route. Conclusions: This large-animal model demo nstrates the expected pharmacologic potency of these three agents and tolerance development. Based on cerebrospinal fluid and systematic his topathologic analyses, these three spinally administered agents showed no evidence of neurotoxicity over the range of doses/concentrations e mployed when given by the intrathecal or epidural route as compared to vehicle controls. Consideration of the toxicokinetics in this canine model suggests that it provides an appropriate test of the safety of t hese agents in concentrations which exceed those employed for daily in termittent epidural and intrathecal drug delivery in humans.