l-alpha-Acetylmethadol, l-alpha-acetyl-N-normethadol and l-alpha-acetyl-N,N-dinormethadol: comparisons with morphine and methadone in suppression of the opioid withdrawal syndrome in the dog.
l-alpha-Acetyl-N-normethadol (nor-LAAM) and l-alpha-acetyl-N, N-dinormethadol (dinor-LAAM) are active metabolites of the opiate l-alpha-acetylmethadol (LAAM), and they contribute to the prolonged actions of the parent compound. Single doses of nor-LAAM, dinor-LAAM, LAAM, methadone and morphine were given intravenously to the chronic spinal dog to determine acute, single-dose effects and their ability to suppress withdrawal in morphine-dependent dogs. These opioids produced dose-dependent antinociception, decreases in body temperature and pupillary constriction. For these measures, dinor-LAAM was 1.5 to 3 times and nor-LAAM 6 to 12 times as potent as LAAM. Five hours after the acute administration of LAAM or either of the metabolites, a 1-mg/kg dose of naltrexone given intravenously produced withdrawal, indicating the presence of acute physical dependence. In dogs physically dependent on a daily dose of 125 mg of morphine, nor-LAAM was 9 times as potent as either LAAM or dinor-LAAM in suppressing spontaneous withdrawal 40 hr after the last dose of morphine. The efficacies of LAAM and its demethylated metabolites in the dog for producing acute opiate effects were comparable with those of morphine and methadone. There was a trend, however, for LAAM to suppress the expression of abstinence more fully than either metabolite. The usefulness of LAAM as a treatment for opiate addiction is likely due in part to the equivalent efficacies and higher potencies of its nor and dinor metabolites.
Vaupel
D B
DB
Brain Imaging Section, Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland 21224, USA. bvaupel@nida.gov
Jasinski
D R
DR
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D008691:Methadone / Q000494:pharmacology*; D008692:Methadyl Acetate / Q000031:analogs & derivatives* / Q000494:pharmacology*; D009020:Morphine / Q000494:pharmacology*; D009293:Opioid-Related Disorders / Q000188:drug therapy*; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy*
D000701:Analgesics, Opioid; C020783:paracymethadol; C020700:1 alpha-acetyldinormethadol; D009020:Morphine; D008692:Methadyl Acetate; D008691:Methadone