Intravenous and Oral l-␣-Acetylmethadol: Pharmacodynamics and Pharmacokinetics in Humans 1

Abstract

ABSTRACT Levo-␣-acetylmethadol (LAAM) is a long-acting opioid agonist approved for use as a maintenance treatment for opioid dependence. Previous clinical studies report that the onset of the effects of LAAM is slower after parenteral administration than oral administration; however, preclinical studies suggest otherwise. This study examined the pharmacodynamic and pharmacokinetic profile of LAAM when given orally and intravenously to humans. Opioid-experienced volunteers (n ϭ 6), who were not physically dependent on opioids, received LAAM (20 and 40 mg/70 kg i.v. and p.o.) and placebo under double-blind, double-dummy conditions during five weekly experimental sessions. Behavioral, physiological, subjective and pharmacokinetic measures were collected before and for 96 hr after drug administration. Intravenous LAAM produced significant subjective and physiological effects that appeared within 5 min, whereas the effects of oral LAAM appeared more slowly within 1 to 2 hr after drug administration. Pharmacokinetic data indicate that the immediate effects of intravenous LAAM are largely attributable to the parent drug rather than the active metabolites, nor-LAAM and dinor-LAAM. LAAM produced prototypic opioid agonist effects (i.e., miosis, subjective ratings of high, nodding) that were of equal magnitude across routes, doserelated and of long duration (up to 60 hr). These data are in contrast to previous clinical reports and indicate that LAAM produces effects of immediate onset when administered parenterally, which suggests that intravenous LAAM possesses greater abuse potential than previously believed. Levo-␣-acetylmethadol is a synthetic opioid that was approved for use as a treatment for opioid dependence by the Food and Drug Administration in 1993. A congener of methadone, LAAM produces opioid effects typical of mu agonists, including analgesia, euphoria, miosis and respiratory depression The persistent action of LAAM has been attributed primarily to its sequential N-demethylation to two primary active metabolites, nor-LAAM and dinor-LAA