Buprenorphine and methoclocinnamox: agonist and antagonist effects on respiratory function in rhesus monkeys.

Buprenorphine and methoclocinnamox are partial micro-opioid receptor agonists with potential use in the treatment of opioid abuse. The ability of these drugs to suppress respiration as well as their ability to antagonize the respiratory suppressant effects of morphine and heroin were tested in rhesus monkeys. Frequency (f), minute volume (V(e)) tidal volume (V(t)) in monkeys breathing air or 5% CO(2) in air were recorded using a pressure-displacement plethysmograph. Buprenorphine (0.001-10 mg/kg) produced a dose-dependent decrease in respiratory parameters that plateaued at a dose of 1 mg/kg in both air and 5% CO(2). Methoclocinnamox (0. 032-1 mg/kg) also produced dose-dependent respiratory depression that plateaued at a dose of 0.3 mg/kg in air, and was directly related to dose in 5% CO(2). Respiratory suppression produced by buprenorphine 1 and 10 mg/kg lasted for 3 and 7 days, respectively, whereas the suppression produced by the largest dose of methoclocinnamox (1 mg/kg, the solubility limit) lasted less than 24 h. Buprenorphine and methoclocinnamox antagonized morphine- and heroin-induced respiratory depression, and this antagonist effect was observed concomitantly with, as well as following, the mu-opioid receptor agonist effects of buprenorphine and methoclocinnamox. The mu-opioid receptor antagonist effects of buprenorphine (10 mg/kg) and methoclocinnamox (1 mg/kg) lasted for 2 weeks. These results suggest that buprenorphine and methoclocinnamox have a wide margin of safety in clinical use and that these two compounds have a prolonged, insurmountable, mu-opioid receptor antagonist effect after the disappearance of their agonist effects.