A-Acetylmethadol

LAAM (L-a-acetylmethadol or levomethadyl acetate) is a full agonist at the i opioid receptor with pharmacologic properties similar to those of methadone. A number of studies have demonstrated that treatment with LAAM results in reduction of opioid use and beneficial effects comparable to those achieved with methadone (Ling et al. 1978 Tennant et al. 1986 Zangwell et al. 1986). However, retention rates are higher in patients who take methadone doses of 80—100 mg/day. 

Note. LAAM = L-a-acetylmethadol (no longer available in the United States). 

Oral rifampin dose and AUC changes abstracted from alfentanil (205), buspirone (208), gefitinib (209), L-a-acetylmethadol (210), midazolam (77) nifedipine (62), simvastatin (211), tamoxifen (212), toremifene (212), triazolam (213), and verapamil (60). 

Resolution of a cheap racemate at the start of a synthesis is economically advantageous if it can be demonstrated that chirality is not lost in the subsequent stages. Moreover, optical purity can be enhanced by purification of intermediates during the total synthesis. This strategy of resolution at the beginning has been applied to a new synthesis of optically active methadones and levo-a-acetylmethadol (LAAM) (16). 

There has been revived interest in a-acetylmethadol as a result of its use in the maintenance of addicts (p. 304) and several pharmacokinetic(19) and pharmacological studies of the ester have been made. The acetate is characterized by a slow onset of action, a feature attributed to its conversion to an active metabolite,(40) and this proposal is supported by the isolation of two metabolic products from rats(41) and opioid addicts(42) that are effective analgesics. The compounds are the secondary and primary amines corresponding to a-acetylmethadol formed by successive N-demethylation and were detected by GCMS after conversion to trichloroacetamide derivatives. Authentic primary amine 15 was initially prepared by oxidizing a-(-)-acetylmethadol... 

Nelson AC, Huang W, Moody DE. Human liver microsome preparation impact on the kinetics of L-a-acetylmethadol (LAAM) N-demethylation and dextromethorphan O-demethylation. Drug Metab Disp. 2001 29 319-325. 

The relative binding affinities of the optical isomers of methadone, a-methadol, a-acetylmethadol and their N-demethylated derivatives to the opiate receptors of rat brain confirmed the agonistic nature of this series of drugs.144... 

The a- and /3- racemic dZ-methadols are less effective than dZ-methadone the acetyl esters have toxicities similar to the parent compound, but produce more pronounced analgesia than does dZ-methadone (7). d-a-Afethadol and Z- -methadol were less effective than the parent compound Z-methadone. However, Z-a-methadol, Z-a-acetylmethadol, and d-/3 ac-etylmethadol exhibited analgesic activity when administered orally or subcutaneously these compounds are derived from d-methadone which has only slight analgesic activity (7). 

The racemic a-acetylmethadol (dZ-6-dimethylamino-4,4-diphenyl-3-acetyoxyheptane) has been studied clinically by David and Sender (93). When the racemic dZ-a-acetylmethadol was administered oraUy or subcutaneously to hospitalized patients, the average daily dose required to control pain adequately was 20-30 mg. given either in 5 mg. doses four or five times daily or 10 mg. two or three times daily. Some cumulative action... 

Five to 20 mg. of d- -acetylmethadol subcutaneously led within 15 min. to effects which were subjectively pleasing to the patients. The effects had disappeared mthin 24 hr. Fifteen to 20 mg. of d-a-acetylmethadol orally yielded no evidence of morphine-like effects and no subjective reports of pleasurable sensations were obtained. 

Cumulative toxic effects such as motor depression, incipient coma, respiratory depression, severe nausea, vomiting, and mental confusion were observed following the subcutaneous administration of 30 mg. of dZ-a-acetyl-methadol twice daily for 2 days, and after 15 mg. of i-a-acetylmethadol twice daily for 3 days. Due to the long duration of action cumulative effects are obtained with multiple daily doses. 

Single doses of 30 mg. of f-a-acetylmethadol had inconsistent effects when administered subcutaneously at the 28th and 36th hr. of abstinence to patients previously stabilized on 240 mg. of morphine. With single doses of 30-60 mg. of i-a-acetylmethadol orally, all signs of abstinence were completely abolished from patients stabilized on 400 mg. of morphine and then deprived of morphine for 28 hr. 

Abrupt substitution of i- -acetylmethadol for morphine in patients stabilized on 160-400 mg. of morphine daily Avas completely adequate when 1 mg. of Z-a-acetylmethadol replaced 6-8 mg. of morphine. Following abrupt discontinuance of the Fa-acetylmethadol, a mild but definite abstinence syndrome quite similar in intensity and course to that from methadone appeared. 

Levo-a-acetylmethadol (LAAM, levomethadyl acetate) is longer acting than methadone. Its slow... 

Opioid Treatment Program Substance Abuse and Mental Health Services Administration (SAMHSA) certified program, usually comprising a facility, staff, administration, patients, and services that engages in supervised assessment and treatment, using methadone, buprenorphine, L-a-acetylmethadol (LAAM), or naltrexone, of individuals who are addicted to opioids. 

---