Pharmacokinetics of high doses of intramuscular and oral heroin in narcotic addicts Background: In several countries medical prescription of diacetylmorphine is currently being evaluated as a treatment option for heavily dependent narcotic addicts. Because of damaged veins, many patients administer diacetylmorphine intramuscularly or orally. Therefore we characterized the pharmacokinetics of intramus- cular and oral diacetylmorphine in the high dose range usually required in narcotic addicts. Methods: Three intramuscular doses, 3 oral doses, and 1 intravenous dose of diacetylmorphine and oral and intravenous test doses of deuterium-labeled morphine (morphine-N-methyl-d3 [morphine-d3]) were admin- istered to 8 heroin-addicted patients. Arterial plasma concentrations of diacetylmorphine, monoacetylmor- phine, morphine, morphine-3-glucuronide, morphine-6-glucuronide, and morphine-d3 were measured by liquid chromatography–mass spectrometry. Results: Intramuscularly administered diacetylmorphine (<200-250 mg) exhibited linear diacetylmorphine, monoacetylmorphine, and morphine kinetics and resulted in sustained diacetylmorphine exposures (bioavail- ability, 380%  157% [mean  SD]) and in lower and delayed peak monoacetylmorphine and morphine concentrations as compared with intravenous administration. Oral diacetylmorphine (<600 mg) yielded negligible systemic diacetylmorphine and monoacetylmorphine exposures but was associated with linear kinetics and high bioavailabilities for morphine (67%  19%), morphine-3-glucuronide (205%  52%), and morphine-6-glucuronide (180%  61%). In addition, oral diacetylmorphine was absorbed more rapidly and to a greater extent than a concomitant test dose of morphine-d3. Conclusions: On the basis of the linear pharmacokinetics, the high bioavailability of intramuscular diacetyl- morphine, and the rapid and extended morphine absorption from oral diacetylmorphine, the intramuscular and oral routes can be recommended as safe and feasible alternatives to the intravenous route for medical prescription of diacetylmorphine. (Clin Pharmacol Ther 2003;74:341-52.) Franc ¸ois Girardin, MD, Katharina M. Rentsch, PhD, Marc-Andre ´ Schwab, MD, Marco Maggiorini, MD, Christiane Pauli-Magnus, MD, Gerd A. Kullak-Ublick, MD, Peter J. Meier, MD, and Karin Fattinger, MD Zu ¨rich, Switzerland In Switzerland and several other countries including the Netherlands, Germany, Spain, and Canada, 1,2 med- ical prescription of diacetylmorphine is currently being considered or evaluated as a treatment option for heavily dependent narcotic addicts. Safe diacetylmor- phine dosing in these patients requires adequate phar- macokinetic data. We have demonstrated previously that after intravenous administration the kinetics of diacetylmorphine and its predominant metabolites (ie, the pharmacologically active monoacetylmorphine, morphine, and morphine-6-glucuronide and the inac- tive morphine-3-glucuronide) are linear even up to the excessively high doses required by narcotic addicts. 3 Furthermore, substantial differences between arterial and venous diacetylmorphine, monoacetylmorphine, and morphine concentrations were detected, indicating From the Division of Clinical Pharmacology and Toxicology, Depart- ment of Medicine, Institute of Clinical Chemistry, and Division of Intensive Care, Department of Medicine, University Hospital. This study was supported by the Swiss Federal Office of Public Health. Dr Fattinger is a recipient of a SCORE Career Develop- ment Award (grant 32-052190.97 and 32-065173.01) from the Swiss National Science Foundation. Received for publication April 10, 2003; accepted June 24, 2003. Reprint requests: Karin Fattinger, MD, Division of Clinical Pharma- cology and Toxicology, Department of Medicine, University Hos- pital, CH-8091 Zu ¨rich, Switzerland. E-mail: fattinge@kpt.unizh.ch Copyright © 2003 by the American Society for Clinical Pharmacol- ogy & Therapeutics. 0009-9236/2003/$30.00 + 0 doi:10.1067/S0009-9236(03)00199-1 341