TOXICOLOGICAL EVALUATION OF MU-AGONISTS .1. ASSESSMENT OF TOXICITY FOLLOWING 30 DAYS OF REPEATED ORAL DOSING OF MALE AND FEMALE RATS WITH LEVO-ALPHA-ACETYLMETHADOL HCL (LAAM)

This study evaluated levo-alpha-acetylmethadol hydrochloride (LAAM), a long-acting morphine-like (mu) agonist approved in 1993 to treat opia te dependence. Sprague-Dawley rate (20/sex/group) were gavaged with do ses of 3.0-33.5 mg kg(-1) for 30 days followed by a 14-day drug-free r ecovery period. Treatment-related effects included dose-dependent CNS depression, decreased food consumption and body weight gain, reddish u rine and abdominal staining. Tolerance developed by day 7. Mortality w as dose-dependent; deaths occurred predominantly during the first week . Increased alanine aminotransferase (SGOT, AST) and lactate dehydroge nase (LDH), observed only in high-dose males, were associated with fin dings in liver. Decreases in spleen/brain weight and increases in brai n/body weight ratios were seen in both sexes. Decreases in weights of heart, liver and kidney achieved statistical significance only for hig h-dose groups. Kidneys of mid- and high-dose groups displayed intertub ular mineral/crystal deposition, focal corticomedullary mineralization and focal regenerative tubular epithelium. Centrilobular hypertrophy was observed in livers of high-dose males and mid- and high-dose femal es. Following the recovery period, decreased body weights and increase d brain/body weight ratios occurred in mid-dose males and low-dose fem ales. Weights of liver and kidney and organ/brain weight ratios were d ecreased in mid-dose males. Histopathological findings observed in kid neys and livers had abated. In summary, acute and repeated administrat ion of LAAM produced a spectrum of activity consistent with its profil e as a long-acting pure mu-agonist which stimulates microsomal enzymes in rodents. Renal and hepatic effects seen in initially drug-naive ra ts treated with morphine-type agonists are not observed in tolerant in dividual stabilized on mu-agonists to treat opiate dependence.