Sex-related Differences in the Influence of Morphine on Ventilatory Control in Humans

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Abstract
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, approximately 82%; end-tidal carbon dioxide tension, 45 mmHg) were obtained before and during intravenous morphine or placebo administration (bolus dose of 100 microg/kg, followed by a continuous infusion of 30 microg x kg(-1) x 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 x min(-1) x 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 x min(-1) x 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 x min(-1) x %(-1) to 0.5 +/- 0.4 l x min(-1) x %(-1) (P < 0.05) but did not cause a decrease in men (control = 1.0 +/- 0.5 l x min(-1) x %(-1) vs. morphine = 0.9 +/- 0.5 l x min(-1) x %(-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.