Physostigmine antagonizes morphine-induced respiratory depression in human subjects

The effect of physostigmine on the respiratory depression induced by morphine was studied in human subjects who received morphine as part of their preanesthetic medication. After pretreatment with droperidol (2.5-5 mg, iv) to prevent nausea, the change in minute ventilation was measured in 16 patients in response to increasing concentrations of inspired CO₂ (CO₂-response curve) by the rebreathing method. This was repeated 30 min after morphine (0.166 mg/kg, iv) in nine subjects and in seven controls who did not receive morphine and again 5-10 min after physostigmine (13-33 μg/kg, iv) in all subjects. All subjects were given N-butylhyoscine hydrobromide (5 mg, iv) to antagonize any peripheral cholinergic effects of physostigmine. Morphine decreased the mean slope of the CO₂-response curve from 1.78 ± 0.18 to 1.12 ± 0.14 l.min^-1.mmHg^-1 (P < 0.01) and increased the alveolar P(CO₂) for a fixed minute ventilation (position of curve) from 45.0 ± 1.3 to 51.9 ± 1.5 mmHg (P < 0.001). Physostigmine restored the mean slope after morphine to control value, i.e., 1.79 ± 0.231.min^-1.mmHg^-1, and position to 46.2 ± 1.2 mmHg (P < 0.001). Physostigmine did not increase the slope or alter the position of the CO₂-response curves of subjects given droperidol alone. The authors conclude that physostigmine can reverse the respiratory depressant effect of morphine and restore the sensitivity of the respiratory center of CO₂, presumably by raising acetylcholine levels in the brain after these have been reduced by morphine.