Physostigmine antagonizes morphine-induced respiratory depression but not analgesia in dogs and rabbits

The ability of physostigmine to antagonize the respiratory depressant effect of morphine was studied in conscious rabbits and ketamine-anaesthetized dogs pretreated with atropine methyl nitrate. Morphine 4 mg kg^-1 increased Pa_co2 in the rabbit from 3.43 ±0.16 to 4.95 ±0.28 kPa, decreased arterial pH from 7.45±0.01 to 7.31 ±0.01 and decreased respiratory frequency by 36%. Physostigmine 0.1 mgkg^-1 reduced Pa_co2 to control values within 10 min and significantly increased arterial pH and respiratory frequency. There was no antagonism of the analgesic effect of morphine. Neostigmine 0.1 mg kg^-1 did not reverse the respiratory depressant effect of morphine. In dogs anaesthetized with ketamine, morphine 15 mg kg^-1 caused loss of consciousness and marked analgesia, decreased the respiratory frequency by 47%, and increased Pa_co2 by 47%. Physostigmine 0.1 mg kg^-1 antagonized the effect of morphine on respiration and restored consciousness in the dogs, but did not impair analgesia. It is concluded that physostigmine reverses morphine-induced respiratory depression by prolonging the effect of acetyl-cholinc released from brain-stem neurones. The possibility should be considered of replacing opiate antagonists by physostigmine to reverse postoperative respiratory depression and drowsiness induced by opiates.