Methadone Maintenance and TestingMethadone is a synthetic narcotic analgesic developed in Germany during the Second World War. The first pharmacological studies of methadone were performed by 1946 at which time the compound was found to be a potent narcotic analgesic. Methadone was approved for use in controlling severe pain. In 1963 methadone was introduced as an experimental drug for the treatment of heroin dependence. Methadone dosage can be maintained or gradually decreased in order to overcome physical dependence. This detoxification process is generally conducted over a period during which counseling and other therapy are also employed. Methadone itself has considerable abuse potential and is classified as a DEA Schedule II controlled substance. Since methadone use in drug treatment situations requires strict monitoring, routine urine drug screening is often employed to verify the use of methadone and the absence of signs of heroin use. Proper interpretation of urine drug testing results for methadone require some understanding of the metabolism and excretion of methadone, as well as knowledge of the strengths and weaknesses of the testing methodologies. Methadone is usually administered orally and as such is rapidly absorbed. Methadone is metabolized primarily in the liver by demethylation and subsequent cyclization to form 2-Ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP). This cyclization process yields a primary metabolite molecule quite distinct from the parent molecule. The elimination half-life of a 15mg dose is approximately 14 hours. Methadone and metabolites are primarily excreted in the feces. Unmetabolized methadone excretion in the urine accounts for less than 11% of the administered dose. Following a single dose, the metabolite concentration in urine is approximately one half the unchanged concentration. Chronic administration in situations such as drug treatment causes the relative metabolite concentration to increase to up to two times the unchanged form. The excretion of methadone is markedly enhanced by the acidification of the urine. Several different methods are used to test for methadone maintenance compliance. The three most widely used testing technologies are Enzyme Multiplied Immunoassay (EMIT), Fluorescence Polarization Immunoassay (FPIA) and Thin Layer Chromatography (TLC). There are advantages and disadvantages to each of these technologies. Both EMIT and FPIA are based on the immunoassay principle of competitive binding of antibodies with labeled and unlabeled antigen in urine specimens. There is no extraction involved and the analysis is performed on an automated instrument. Test times range from one to fifteen minutes. This makes both methods very useful in situations where rapid turn around is necessary. Because of the rather radical chemical differences between methadone and its primary metabolite, 2-Ethylidine-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), the antibodies in these immunoassays are specific to free methadone and only slightly cross-reactive to its metabolites. Thin Layer Chromatography (rLC) testing is performed by extracting drugs from the urine and chromatographing the extract on a glass plate coated with a thin-layer of absorbent silica. TLC testing is much more time consuming than immunoassay testing but potentially yields more information. Since TLC extraction, development and visualization are based on several different chemical principles, TLC can simultaneously detect several different compounds. In the case of methadone testing, TLC can detect the presence of both the parent drug and its metabolite. Since less than 11% of methadone is excreted unchanged in the urine, the ability to detect methadone metabolite will usually result in a lower incidence of false negatives than immunoassay testing. Because TLC can detect the presence of methadone metabolite, it can also detect the absence of methadone metabolite. In cases where the administration of methadone in not controlled or is itself administered, it is possible for it patient to falsify his or her urine sample by adding a small amount of their methadone dose to a urine sample and selling or otherwise distributing the rest of the dose. In cases where urine specimen collections are not adequately controlled and methadone is self administered, urine falsification can often be detected by Thin Layer Chromatography. In a survey of results for methadone maintenance patients tested by Friends Medical Laboratory from January to October 1992, 32 cases were discovered where only free, unmetabolized, methadone was found in the urine specimen. Of these samples, eight were identified as being from the same three patients. This would indicate that the methadone in these urines was non-metabolic. The primary testing methodologies for methadone, immunoassay and TLC, each have distinct advantages and disadvantages. A proper knowledge of each method's strengths and weaknesses will allow for better interpretation of methadone testing results. The speed and convenience of immunoassay testing is sometimes offset by the myopia of the results compared to TLC testing. Immunoassay tests are often more sensitive to interferences than TLC testing. Fluctuations in specimen pH or very turbid samples are often untestable by EMIT. TLC can overcome many of these difficulties. Reliance on one immunoassay testing alone for the monitoring of methadone maintenance patients may not provide the best information about methadone use. Ref: Periodic Newsletter, Fall, 1992 Content copyright ©1992-1999 Friends
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