Intravenous and Oral l-α-Acetylmethadol: Pharmacodynamics and Pharmacokinetics in Humans1
- Behavioral Pharmacology Research Unit, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland
Abstract
Levo-α-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 = 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, dose-related 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.
Footnotes
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Send reprint requests to: Sharon L. Walsh, Ph.D., BPRU, Behavioral Biology Research Center, Johns Hopkins Bayview Campus, 5510 Nathan Shock Drive, Baltimore, MD 21224-6823.
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↵1 This research was supported by U.S. Public Health Service Research Grants P50 DA 05273 and KO5 DA00050 from the National Institute on Drug Abuse.
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↵2 With the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD.
- Abbreviations:
- AUC
- area under the curve
- LAAM
- l-α-acetylmethadol
- ARCI
- Addiction Research Center Inventory
- ANOVA
- analysis of variance
- BENZ
- benzedrine scale
- DSM-III-R
- Diagnostic and Statistical Manual of Mental Disorders (3rd edition, revised)
- LSD
- lysergic acid diethylamide (“dysphoria” scale)
- MBG
- morphine-benzedrine group (“euphoria” scale)
- PCAG
- pentobarbital-chlorpromazine-alcohol group (“sedation” scale)
- S.E.M.
- standard error of the mean
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- Received July 11, 1997.
- Accepted December 22, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
