Methadone is a synthetic opioid first developed in Germany in the late 1930’s and approved for production in the US in 1947, when it was given the generic name methadone by the Council on Pharmacy and Chemistry of the American Medical Association. It is used clinically to treat chronic pain and as a maintenance therapy for opioid use disorder. Methadone is a regulated as a Schedule II controlled substance in the United States and Schedule I internationally under the United Nations Single Convention on Narcotic Drugs of 1961.
As with all opioid medications, tolerance and dependence can develop with repeated doses.Primarily found as a racemic mixture, methadone acts as both a µ-opioid agonist via its l-isomer and as a NMDA antagonist via its d-isomer. This dual function may make methadone more effective against neuropathic pain such as that experienced during opioid withdrawal and may account for more gradual tolerance-development than other opioids, as well as disrupting memory circuitry to reduce cravings for more addictive opiates.
According to the CDC, in the United States, methadone-related deaths rose from 3 people per million in 1999 to 18 per million in 2007. Since then, and while natural and other synthetic opioid deaths have dramatically increased, methadone deaths have been steadily declining to 9 per million in 2017. These methadone-related deaths have primarily been from combinations of methadone and other drugs and methadone acquired by means other than opioid treatment programs. Of particular risk is combining methadone with other compounds that depress the central nervous system such as alcohol or benzodiazepine. Naloxone has been used to prevent overdose deaths, which may also be helping in the reduction in death rates. However, because naloxone is quickly cleared from the opioid receptor complex while methadone has a much longer half-life, repeated uses of naloxone may be required if a methadone overdose was recent or large enough to re-bind after the initial dose of naloxone wears off.
Research has shown that methadone maintenance therapy significantly reduces the frequency of intravenous drug use, which has also reduced rates of HIV and hepatitis transmissions. In developing an individualized program for treatment of opioid use disorder, methadone can be measured in urine or blood samples, and usage history is an important element to consider as chronic users can develop tolerance to doses that would be more dangerous to opioid-naïve individuals.
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