Disposition of nasal, intravenous, and oral methadone in healthy volunteers

Objective Nasal administration of many opioids demonstrates rapid uptake and fast onset of action. Nasal administration may be an alternative to intravenous and oral administration of methadone and was therefore studied in human volunteers. Methods The study was approved by the Institutional Review Board of the University of Washington, Seattle. Eight healthy volunteers (6 men and 2 women) aged 19 to 33 years were enrolled after informed written consent was obtained. Subjects received 10 mg methadone hydrochloride nasally, orally, or intravenously on 3 separate occasions in a crossover design. Nasal methadone (50 mg/mL in aqueous solution) was given as a 100‐μL spray in each nostril (Pfeiffer BiDose sprayer). Blood samples for liquid chromatography‐mass spectrometry analyses of methadone and the metabolite 2‐ethyl‐1,5‐dimethyl‐3,3‐diphenylpyrrolinium were drawn for up to 96 hours. The methadone effect was measured by noninvasive infrared pupilometry coincident with blood sampling. Results Nasal uptake of methadone was rapid, with maximum plasma concentrations occurring within 7 minutes. The maximum effects of intravenous, nasal, and oral methadone, on the basis of dark‐adapted pupil diameter, were reached in about 15 minutes, 30 minutes, and 2 hours, respectively. The respective durations were 24, 10, and 8 hours. Both nasal and oral bioavailabilities were 0.85. Subjects reported that nasal methadone caused a burning sensation. Conclusions Nasal administration of methadone results in rapid absorption and onset of effect and high bioavailability, which was greater than that reported for other nasal opioids, with a similar duration of effect. Nasal administration may be an alternative route of methadone administration; however, improved formulations are desirable to reduce nasal irritation. Clinical Pharmacology & Therapeutics (2002) 72, 536–545; doi: 10.1067/mcp.2002.128386