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 intramuscular 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 administered to 8 heroin-addicted patients. Arterial plasma concentrations of diacetylmorphine, monoacetylmorphine, morphine, morphine-3-glucuronide, morphine-6-glucuronide, and morphine-d3 were measured by liquid chromatography-mass spectrometry. Results: Intramuscularly administered diacetylmorphine (less than or equal to200-250 mg) exhibited linear diacetylmorphine, monoacetylmorphine, and morphine kinetics and resulted in sustained diacetylmorphine exposures (bioavailability, 380% plusminus 157% [mean plusminus SD]) and in lower and delayed peak monoacetylmorphine and morphine concentrations as compared with intravenous administration. Oral diacetylmorphine (less than or equal to600 mg) yielded negligible systemic diacetylmorphine and monoacetylmorphine exposures but was associated with linear kinetics and high bioavailabilities for morphine (67% plusminus 19%), morphine-3-glucuronide (205% plusminus 52%), and morphine-6-glucuronide (180% plusminus 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 diacetylmorphine, 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.