MORPHINE PHARMACOKINETICS AFTER PULMONARY ADMINISTRATION FROM A NOVELAEROSOL DELIVERY SYSTEM

Background: Successful pharmacotherapy of pain often depends on the mo de of drug delivery. A novel, unit dose, aqueous aerosol delivery syst em (AERx Pulmonary Drug Delivery System) was used to examine the feasi bility of the pulmonary route for the noninvasive systemic administrat ion of morphine. Methods: The study had two parts: (1) a dose-ranging study in four subjects with three consecutive aerosolized doses of 2.2 , 4.4, and 8.8 mg (nominal) morphine sulfate pentahydrate at 40-minute intervals, and (2) a crossover study, on separate days, in six subjec ts with 4.4 mg (nominal) aerosolized morphine sulfate administered ove r 2.1 minutes on three occasions and intravenous infusions of 2 and 4 mg over 3 minutes. Subjects were healthy volunteers from 19 to 34 year s old. Arterial blood was sampled for a total of 6 hours and plasma mo rphine concentrations were measured by gas chromatography-mass spectro metry. Results: In part 1, plasma morphine concentrations were proport ional to dose. In part 2, the mean I SD peak plasma concentration (C-m ax) occurred at 2.7 +/- 0.8 minutes after the aerosol dose, with mean values for C-max of 109 +/- 85, 165 +/- 22, and 273 +/- 114 ng/ml for the aerosol and 2 and 4 mg intravenous doses, respectively. The bioava ilability [AUC(0-360 min)] of aerosol-delivered morphine was approxima tely 100% relative to intravenous infusion, with similar intersubject variability in AUC for both routes (coefficient of variation < 30%). C onclusion: The time courses of plasma morphine concentrations after pu lmonary delivery by the AERx system and by intravenous infusions were similar. This shows the utility of the pulmonary route in providing a noninvasive method for the rapid and reproducible systemic administrat ion of morphine if an appropriate aerosol drug delivery system is used .