However, it does represent the initial trajectory of attack of an amine on a carbonyl group and was an important piece of experimental evidence for the proposal of the Bürgi–Dunitz angle for carbonyl addition reactions. History
Methadone was developed in 1937 in Germany by scientists working for I.G. Farbenindustrie AG at the Farbwerke Hoechst who were looking for a synthetic opioid that could be created with readily available precursors, to solve Germanys opium and morphine shortage problem. On 11 September 1941 Bockmühl and Ehrhart filed an application for a patent for a synthetic substance they called Hoechst 10820 or Polamidon (a name still in regular use in Germany) and whose structure had little relation to morphine or other "true opiates” such as diamorphine (HeroinTM), desomorphine (PermonidTM), nicomorphine (VilanTM), codeine, dihydrocodeine, oxymorphone (OpanaTM), hydromorphone (DilaudidTM), oxycodone (OxyContinTM), hydrocodone (DicodidTM), and other closely related opium alkaloid derivatives and analogues. It was brought to market in 1943 and was widely used by the German army during WWII as a substitute for morphine.In the 1930s, pethidine (meperidine) went into production in Germany; however, production of methadone, then being developed under the designation Hoechst 10820, was not carried forward because of side effects discovered in the early research. After the war, all German patents, trade names and research records were requisitioned and expropriated by the Allies. The records on the research work of the I.G.
"In 2006, the U.S. Food and Drug Administration issued a caution about methadone, titled "Methadone Use for Pain Control May Result in Death." The FDA also revised the drugs package insert. The change deleted previous information about the usual adult dosage. The Charleston Gazette reported, "The old language about the usual adult dose was potentially deadly, according to pain specialists." Pharmacology
Methadone acts by binding to the µ-opioid receptor, but also has some affinity for the NMDA receptor, an ionotropic glutamate receptor. Methadone is metabolized by CYP3A4, CYP2B6, CYP2D6, and is a substrate, or in this case target, for the P-glycoprotein efflux protein, a protein which helps pump foreign substances out of cells, in the intestines and brain. The bioavailability and elimination half-life of methadone are subject to substantial interindividual variability. Its main route of administration is oral. Adverse effects include sedation, hypoventilation, constipation and miosis, in addition to tolerance, dependence and withdrawal difficulties. The withdrawal period can be much more prolonged than with other opioids, spanning anywhere from two weeks to several months. The metabolic half-life of methadone differs from its duration of action. The metabolic half-life is 8 to 59 hours (approximately 24 hours for opioid-tolerant people, and 55 hours in opioid-naive people), as opposed to a half-life of 1 to 5 hours for morphine. The length of the half-life of methadone allows for exhibition of respiratory depressant effects for an extended duration of time in opioid-naive people.