¹Department of Anaesthesia and Pain Management, University of Sydney at Royal North Shore Hospital, Sydney, Australia; and Aradigm Corporation, Hayward, Calif.

Correspondence: Laurence E. Mather, PhD, Department of Anaesthesia and Pain Management, University of Sydney at Royal North Shore Hospital, St. Leonards, NSW 2065, Australia. E-mail: lmather@med.usyd.edu.au

^*Supported by Aradigm Corporation, Hayward, Calif.

Presented in part at the Eleventh World Congress of Anaesthesiologists, Sydney, Australia, April 1996, and at the Eighth World Congress on Pain, Vancouver, Canada, August 1996.

Received 21 March 1997; Accepted 24 July 1997.

Abstract

Background: Successful pharmacotherapy of pain often depends on the mode of drug delivery. A novel, unit dose, aqueous aerosol delivery system (AERx Pulmonary Drug Delivery System) was used to examine the feasibility of the pulmonary route for the noninvasive systemic administration 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 subjects with 4.4 mg (nominal) aerosolized morphine sulfate administered over 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 years old. Arterial blood was sampled for a total of 6 hours and plasma morphine concentrations were measured by gas chromatography-mass spectrometry.

Results: In part 1, plasma morphine concentrations were proportional to dose. In part 2, the mean SD peak plasma concentration (C_max) 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 bioavailability [AUC(0–360 min)] of aerosol-delivered morphine was approximately 100% relative to intravenous infusion, with similar intersubject variability in AUC for both routes (coefficient of variation <30%).

Conclusion: The time courses of plasma morphine concentrations after pulmonary 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 administration of morphine if an appropriate aerosol drug delivery system is used.