LAAM is a synthetic opioid agonist with actions qualitatively similar to morphine (a prototypic mu agonist) and affecting the central nervous system (CNS) and smooth muscle. Principal actions include analgesia and sedation. Tolerance to these effects develops with repeated use. An abstinence syndrome generally occurs upon cessation of chronic administration similar to that observed with other opiates, but with slower onset, more prolonged course, and less severe symptoms.

LAAM exerts its clinical effects in the treatment of opiate abuse through two mechanisms. First, LAAM cross-substitutes for opiates of the morphine-type, suppressing symptoms of withdrawal in opiate-dependent individuals. Second, chronic oral administration of LAAM can produce sufficient tolerance to block the subjective "high" of usual doses of parenterally administered opiates.

LAAM is metabolized by N-demethylation to nor-LAAM and dinor-LAAM, which are also opioid agonists. These metabolites are more potent than the parent drug. The opioid effect which occurs when LAAM is administered is slower in onset and longer in duration (72 hours) than that of methadone (24 hours). This extended duration of action allows three-times-weekly administration (see CLINICAL TRIALS ).

PHARMACODYNAMICS

The duration of action of a single dose of LAAM is due to the sum of the opioid activity of the parent drug and its metabolites. A single dose of orally administered LAAM has an onset of opioid effects averaging 2 to 4 hours after ingestion and a duration of action of 48 to 72 hours (as measured by pupillary constriction and suppression of abstinence signs). LAAM cross-substitutes for opiates like morphine in opiate-dependent individuals, suppressing symptoms of withdrawal from these compounds. Single oral doses of 30 to 60 mg of LAAM eliminate signs of abstinence for 24 to 48 hours in individuals maintained on high doses of morphine who are abruptly withdrawn. At higher doses (80 mg and above), suppression of withdrawal can increase to 48 to 72 hours in most individuals.

Repeated oral administration of LAAM can produce sufficient tolerance to block the effects of parenterally administered opiates. Chronic oral administration of 70 to 100 mg of LAAM three times weekly produces tolerance which blocks the "high" of a 25 mg dose of intravenously administered heroin for up to 72 hours; maintenance on lower doses (50 mg) of LAAM produces only partial blockage for the same period.

PHARMACOKINETICS

Absorption

LAAM is rapidly absorbed from an oral solution. Plasma levels are detectable within 15 to 30 minutes after ingestion and reach their peak within 1.5 to 2 hours at steady-state. LAAM undergoes first-pass metabolism to its demethylated metabolite nor-LAAM, which is sequentially N-demethylated to dinor-LAAM. Both metabolites are active and contribute to the extent and duration of ORLAAM's clinical activity (see PHARMACODYNAMICS ).

Pharmacokinetic Model

The steady-state pharmacokinetics of LAAM were modeled from a study in 25 healthy adult addicts using three-times-a-week dosing over a 15-day observation period. LAAM and its metabolites were found to follow a multi-compartment model with extensive tissue distribution (Vd ~ 20 L/kg). LAAM had a clearance of about 0.22 L/kg/hr, mostly by conversion to nor-LAAM. Kinetic studies of the pure metabolites in man have not yet provided accurate estimates of their clearance in the absence of the precursor, but the half-lives observed in this study were 2.6 days for LAAM, approximately 2 days for nor-LAAM, and approximately 4 days for dinor-LAAM.

The pharmacokinetic model used to estimate steady-state plasma levels for each subject in this study assumed a common 3 mg/kg/wk dosage regimen (0.94 mg/kg on Mon. and Wed., 1.125 mg/kg on Fri.). The estimates (which fit the observed data with a correlation of better than 0.95) revealed a large inter-patient variability. There was at least a 5-fold range in peak plasma concentrations for LAAM and its metabolites across the 25 subjects over the 72-hour interval from Friday to Monday on a 3-times-a-week dosage regimen. Table 1 contains these estimates of peak and trough plasma concentrations of LAAM, nor-LAAM, and dinor-LAAM.

Bookmark this page: