Methadone-naloxone mixtures for use in methadone maintenance programs. I. An evaluation in man of their pharmacological feasibility II. Demonstration of acute physical dependence

It has been proposed that mixtures of methadone and the narcotic antagonist, naloxone, be substituted for the methadone dispensed in methadone maintenance programs to reduce methadone diversion. By the oral route in nondependent subjects methadone-naloxone mixtures are indistinguishable from methadone alone. By the parenteral route, the mixtures have significantly less miotic, behavioral, and subjective effects than methadone alone. Administration of methadone with naloxone to morphine-dependent subjects ameliorates but does not abolish the abstinence precipitated by the naloxone. Ten milligrams of naloxone administered orally does not precipitate abstinence in morphine-dependent subjects, and doses of 15 and 30 mg produce only mild signs o f abstinence. It is concluded that methadone-naloxone mixtures could be compounded that would be interchangeable with methadone intended for oral consumption, but have less parenteral abuse liability than methadone. The observation that 4 mg of parenterally administered naloxone precipitated signs of abstinence 1 week after a single dose of methadone indicated the development of acute physical dependence on methadone.