Daniel X Freedman R N Pechnick

METHADONE Methadone (Dolophine) is a synthesized molecule with pharmacological actions very similar to those of the OPIOD drug, MORPHINE. Methadone serves an important place in the history of opioid ANALGESICS, since it is one of the first synthesized agents (1939). The ability to synthesize opioid analgesics from simple chemicals diminishes our reliance on natural products (such as morphine, CODEINE, and thebaine) to provide the base for many of the currently used opioid analgesics. Structurally, the drug does not look like morphine. Unlike the rigid fused ring structures of morphine, the structure of methadone is extremely flexible. It bends so that the key portions of the molecule can assume positions similar to those of morphine. The structure of methadone is very similar to that of propoxyphene (Darvon), a weaker opiate widely used to treat mild to moderate pain. It has two stereoisomers, but the ( —)isomer is far more active than the ( + )isomer.

Methadone can be administered orally, intramuscularly, or intravenously. It is well absorbed from the gastrointestinal track making it very useful orally. Its oral/parenteral ratio of potency is approximately two. Methadone is threefold more potent than morphine orally, but about equipotent when given by injection. It is metabolized by the liver to a variety of inactive compounds, which then are eliminated by the kidneys.

Pharmacologically, methadone is used in the form of its hydrochloride salt. It has actions quite similar to morphine and works predominantly through mu opiate RECEPTORS. As an analgesic, methadone is similar in actions and in potency to morphine. It produces analgesia, as well as many of the side effects associated with morphine use, including respiratory depression and constipation. A major difference between methadone and morphine is methadone's long duration of action. Typically, the drug is given to patients every six to eight hours. This long duration of action can be very advantageous, particularly in patients who require the drug for long periods of time, such as cancer patients. However, there are some disadvantages. With a half-life ranging from twenty to thirty hours, it may take many days of continued dosing to reach constant (or steady-state) levels of the drug in the body. Thus, the full effect of a change in drug dose may not be seen for three or four days. This may make it difficult to adjust the dose for an individual patient. Increasing the dose too rapidly may even lead to delayed increases in its concentration in the body, far beyond those anticipated and, in some situations, may actually lead to an overdose. Continued administration of methadone will produce TOLERANCE AND PHYSICAL DEPENDENCE. The actions of methadone, like those of morphine, are readily reversed by ANTAGONISTS such as Naloxone or Naltrexone; however, these antagonists will also produce an immediate WITHDRAWAL syndrome in physically dependent people.

Despite its clear utility in the control of PAIN, the major use of methadone in the United States is in the treatment of HEROIN addicts. Although metha-

done must be administered approximately every six to eight hours to maintain analgesia, its slow rate of elimination prevents the appearance of withdrawal symptoms for over twenty-four hours. This slow appearance of withdrawal signs has made this agent very useful in maintenance programs, since it permits once-a-day dosing. With chronic administration of high doses of methadone, addicts become very tolerant, markedly limiting the euphoria an addict might obtain from illicit use of other opiates such as heroin. Thus, methadone minimizes occasional opiate use, is readily tolerated by the addicts, and can be administered once a day, which makes it easily dispensed. Methadone has been used clinically in maintenance programs and is one of the most effective treatment modalities available for opiate addicts.

(SEE ALSO: Addiction: Concepts and Definitions; Methadone Maintenance Programs; Pain, Drugs Used in Treatment of; Treatment Types: Pharmacotherapy)


O'BRIEN, C. P. (1996). Drug addiction and drug abuse. In J. G. Hardman et al. (Eds.), The Pharmacological basis of therapeutics, 9th ed. (557-577). New York: McGraw-Hill.

Reisine, T., & Pasternak, G. (1996) Opioid analgesics and antagonists. In J. G. Hardman et al. (Eds.), The pharmacological basis of therapeutics, 9th ed. (521555). New York: McGraw-Hill.

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