Methadone, Serum
 NAME OF DRUG: METHADONE (DOLOPHINE) |
| PHYSICAL CHARACTERISTICS: The drug is available as a hydrochloride salt of the racemic mixture in tablets of 5-10 mg, diskets of 40 mg for oral usage, and a 10 mg/mL solution for parenteral injection. |
| DOSAGE/OCCURRENCE/USAGE: Methadone was first synthesized as a morphine substitute in Germany during World War II. It was made clinically available in the United States in 1947. It has many of the same pharmacologic properties of morphine. When administered parenterally, it is approximately equipotent as an analgesic. Unlike morphine, methadone produces marked sedative effects with repeated administration as a result of drug accumulation. Because of this, methadone had restricted clinical usage until 1965 when Doyle and Nyswander began narcotic maintenance treatments of former heroin addicts using large daily oral doses of dl-methadone. Maintenance patients may receive as much as 180 mg of the drug daily. Doses of 50 mg or less have been known to prove fatal to nontolerant adults. |
| BLOOD CONCENTRATIONS VS. DOSAGE: Plasma concentrations of methadone reached a peak at 4 hours of 75 ng/mL following a single 15 mg dose. Concentration levels declined slowly (plasma half-life of 15 hours) until 24 hours after administration when the concentration was still 30 ng/mL. In tolerant users with chronic administration of 100-200 mg daily oral doses, the plasma concentration again peaked at 4 hours, with and average value of 830 ng/mL (range 570-1060), and declined to 460 ng/mL (range 280-790) 24 hours after the last dose. |
| URINE EXCRETION RATE: Methadone and EDDP each accounted for 5% of the dose in the 24 hour urine following a single 15 mg oral dose. Less than 1% appeared as EMDP. Excretion rates of the unchanged methadone increased to 22% of the dose and only 2% as EDDP in acidic urine. In maintenance subjects, 24 hour urinary methadone may account for 5-50% of the dose and EDDP for 3-25%, with large individual variations due to urine pH, urine volume, dose, and rate of metabolism. Concentrations of methadone and EDDP in these subjects ranging from 1000-50000 ng/mL are commonly encountered. |
| METABOLITES: 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenylpyrroline (EMDP). |
| TOXICITY: Overdosage with methadone is characterized by stupor,
muscle flaccidity, respiratory depression, cold and clammy skin, pupillary constriction, hypotension, coma, and
circulatory collapse. Naloxone is considered a specific antidote. The deaths of 4 children were reported
following accidental ingestion of methadone; postmortem blood methadone concentrations ranged from 60-1100 ng/mL. Fatalities in adults from methadone overdosage have increased significantly in many urban areas as a result of widespread availability of the drug, both from licit and illicit sources. In a recent study most of the deaths were found to have occurred following oral administration of the drug, and lack of opiate tolerance was considered to play a major role. The span of blood concentrations of victims of methadone overdosage overlaps that of methadone maintenance subjects and it is difficult, if not impossible, to distinguish between the two on this basis alone. |
| REFERENCES: Abbott Laboratories TDx package insert for FPIA. Baselt RC. Disposition of Toxic Drugs and Chemicals in Man, Second Edition. Davis, Calif: Biomedical Publications, 1982. Clarke EGC. Isolation and Identification of Drugs. London: The Pharmaceutical Press, 1969. |