Sex-related differences in the influence of morphine on ventilatory control in humans

Background: Opiate agonists have different analgesic effects in male and female patients. The authors describe the influence of sex on the respiratory pharmacology of the mu-receptor agonist morphine. Methods: The study was placebo-controlled, double-blind, and randomized. Steady-state ventilatory responses to carbon dioxide and responses to a step into hypoxia (duration, 3 min; oxygen saturation, similar to 82%; end-tidal carbon dioxide tension, 45 mmHg) were obtained before and during intravenous morphine or placebo administration (bolus dose of 100 mu g/kg, followed by a continuous infusion of 30 mu g.kg(-1).h(-1)) in 12 men and 12 women. Results: In women, morphine reduced the slope of the ventilatory response to carbon dioxide from 1.8 +/- 0.9 to 1.3 +/- 0.7 l.min(-1).mmHg(-1) (mean +/- SD; P < 0.05), whereas in men there was no significant effect (control = 2.0 +/- 0.4 vs. morphine = 1.8 +/- 0.4 l.min(-1).mmHg(-1)). Morphine had no effect on the apneic threshold in women (control = 33.8 +/- 3.8 vs. morphine = 35.3 +/- 5.3 mmHg), but caused an increase in men from 34.5 +/- 2.3 to 38.3 +/- 3 mmHg, P < 0.05). Morphine decreased hypoxic sensitivity in women from 1.0 +/- 0.5 l.min(-1).%(-1) to 0.5 +/- 0.4 l.min(-1).%(-1) (P < 0.05) but did not cause a decrease in men (control = 1.0 +/- 0.5 l.min(-1).%(-1) vs. morphine = 0.9 +/- 0.5 l.min(-1).%(-1)). Weight, lean body mass, body surface area, and calculated fat mass differed between the sexes, but their inclusion in the analysis as a covariate revealed no influence on the differences between men and women in morphine-induced changes. Conclusions: In both sexes, morphine affects ventilatory control. However, we observed quantitative and qualitative differences between men and women in the way-morphine affected the ventilatory responses to carbon dioxide and oxygen. Possible mechanisms for the observed sex differences in the respiratory pharmacology of morphine are discussed.