Pharmacodynamic effect of morphine-6-glucuronide versus morphine on hypoxic and hypercapnic breathing in healthy volunteers

Background: Morphine-6-glucuronide (M6G) is an active metabolite of morphine that is generally associated with less respiratory depression than morphine. Because M6G will be on the market in the near future, the authors assessed the time profile and relative potency of M6G's effect versus morphine's effect on carbon dioxide-driven and hypoxic breathing. Methods: In nine healthy female volunteers, the effects of 0.2 mg/kg intravenous M6G, 0.13 mg/kg intravenous morphine, and intravenous placebo were tested on ventilation at a fixed end-tidal pressure of carbon dioxide (PETCO2) of 45 mmHg (V,45) and on the acute hypoxic ventilatory response (AHR). All subjects participated in all three arms of the study. Respiratory studies were performed at 1-h intervals for 7 h after drug infusion. The data were analyzed using a population dose-driven approach, which uses a dose rate in function of time as input function driving the pharmacodynamics, and a population pharmacokinetic-pharmacodynamic (PK/PD) approach in which fixed pharmacokinetic parameter values from the literature were used as input function to the respiratory model. From the latter analysis, the authors obtained the blood effect-site equilibration half-life (t(1/2)k(c0)) and the effect-site concentration producing 25% depression of V,45 and AHR (C-25). Values reported are mean +/- SE. Results. Placebo had no effect on V(i)45 or AHR over time. Both analysis approaches yielded good descriptions of the data with comparable model parameters. M6G PK/PD model parameters for V(i)45 were t(1/2)k(e0) 2.1 +/- 0.2 h and C-25 528 +/- 88 nm and for AHR were t(1/2)k(e0) 1.0 +/- 0.1 h and C-25 873 +/- 81 nm. Morphine PK/PD model parameters for V(i)45 were t(1/2)k(e0) 3.8 +/- 0.9 h and C-25 28 +/- 6 nm and for AHR were t(1/2)k(e0) 4.3 +/- 0.6 h and C-25 16 +/- 2 nm. Conclusions. Morphine is more potent in affecting hypoxic ventilatory control than M6G, with a potency ratio ranging from 1:19 for V(i)45 to 1:50 for AHR. At drug concentrations causing 25% depression of V(i)45, M6G caused only 15% depression of AHR, whereas morphine caused greater than 50% depression of AHR. Furthermore, the speed of onset/offset of M6G is faster than morphine by a factor of approximately 2. The authors discuss some of the possible mechanisms for the observed differences in opioid behavior.