German scientists synthesised methadone during World War II because of a shortage of morphine. Although chemically unlike morphine or heroin, methadone produces many of the same effects. Introduced into the United States in 1947 as an analgesic (Dolophine), it is best known for its use in treating narcotic addiction, although it is also used in managing chronic pain, due to its long duration of action and very low cost. The old name "Dolophine" comes from the German "Dolphium", which comes from the Latin word for pain, "dolor".
Because of its slow metabolism and very high lipid solubility, methadone is longer lasting than morphine-based drugs. Methadone has a typical half life of 24 hours or more, permitting administration only once a day in heroin detoxification and maintenance programmes. Methadone is almost as effective when administered orally as by injection. Tolerance and dependence may develop, and withdrawal symptoms, although they develop more slowly and are less acutely severe than those of morphine and heroin, are more prolonged. Some heroin addicts feel that it is actually harder to quit methadone than heroin itself. Methadone is encountered on the illicit market and has been associated with a number of overdose deaths, although the illicit demand comes primarily from opioid addicts unable to get into a legal methadone programme; addicts seeking a "high" strongly prefer shorter-acting opioids.
Closely related to methadone, the synthetic compound levo-alphacetylmethadol, or LAAM (ORLAAM), has an even longer duration of action (from 48 to 72 hours), permitting a reduction in its frequency of use. In 1994, it was approved as a treatment of narcotic addiction. Like methadone, LAAM is in Schedule II of the United States Controlled Substances Act.
Buprenorphine has also been used in the treatment of narcotic addiction. In October, 2002, the FDA approved two compounds containing buprenorphine (Subutex® and Suboxone®) for the treatment of narcotic addiction.
Another close relative of methadone is dextropropoxyphene, first marketed in 1957 under the trade name of Darvon. Oral analgesic potency is one-half to one-third that of codeine, with 65 mg approximately equivalent to about 600 mg of aspirin. Dextropropoxyphene is prescribed for the relief of mild to moderate pain. Bulk dextropropoxyphene is in Schedule II of the United States Controlled Substances Act, while preparations containing it are in Schedule IV. More than 100 tons of dextropropoxyphene are produced in the United States annually, and more than 25 million prescriptions are written for the products. This narcotic is associated with a number of toxic side-effects and is among the top 10 drugs reported by medical examiners in drug abuse deaths.
During the past few decades, the use of methadone has been increased as a result of the interest in optimising its therapeutics in opioid addicts, one of the groups with a higher risk for AIDS infection. However, standard doses of methadone are far from being appropriate for the relief of pain or prevention of withdrawal signs in maintenance programmes in many patients. To achieve an optimal dose regimen for an individual, knowledge of the relationship between the pharmacokinetic/pharmacodynamic (pk/pd) drug properties and the demographic and physiopathological characteristics of the subject is required.
Methadone maintenance treatment (MMT) for opioid addiction is safe and effective but is under-utilised because of inaccessibility, under-financing and the stigma generally attached to maintenance therapies. In addition, cumbersome regulation of methadone prescription and treatment impedes the delivery of care and retards expansion of methadone maintenance into office practice settings. Exaggeration of the problem of methadone diversion further hinders the development of MMT. Despite such obstacles, methadone maintenance has been successfully expanded and extended into primary care settings abroad. Initial trials in the United States have shown that methadone maintenance in physician office-based settings yields positive results with some advantages over care in large methadone clinics.
When administered orally, methadone is approximately one-half as potent as when given parenterally. Oral administration results in a delay in onset, a lowering of the peak and an increase in the duration of analgesic effect.
Methadone for treatment of chronic pain
Methadone is a safe and effective long-acting opioid analgesic that is useful in managing chronic pain. Although it has unique pharmacokinetic and pharmacodynamic properties, the general principles of dosing methadone are similar to those of other opioids. In general, as with other opioids, methadone should be used as one aspect of a comprehensive pain management plan, as agreed upon by the practitioner and the patient. Methadone is most easily titrated by using small initial doses or adjusting the initial dose according to the previous opioid dose. A number of methods are available for titrating methadone using conversion ratios. However, titration should be based on patient response and not solely based on equianalgesic dosing tables. Methadone should be initiated by, or in consultation with, a practitioner who has the relevant knowledge. If a practitioner or consultant with experience in using methadone for chronic pain is not available, then another long-duration opioid may be used until such consultation can be obtained.