Methadone ( Symoron, Dolophine, Amidone, Methadose, Physeptone, Heptadon, Phy and many others) is a synthetic opioid, used medically as an analgesic, antitussive and a maintenance anti-addictive for use in patients on opioids. It was developed in Germany in 1937. Although chemically unlike morphine or heroin, methadone also acts on the opioid receptors and thus produces many of the same effects. Methadone is also used in managing chronic pain owing to its long duration of action and very low cost. In late 2004, the cost of a one-month supply of methadone was $120, as compared to an equivalent analgesic amount of meperidine (pethidine) at $240, up to $500 and more for hydromorphone, morphine, fentanyl, Vicodin (brand name of the generic hydrocodone with paracetamol/acetaminophen) and extended-release oxycodone.
Methadone is useful in the treatment of opioid dependence. It has cross-tolerance with other opioids including heroin and morphine and a long duration of effect: oral doses of methadone can stabilise patients by mitigating opioid withdrawal syndrome. Higher doses of methadone (60–80 mg+) can block the euphoric effects of heroin, morphine, and similar drugs. As a result, properly dosed methadone patients can reduce or stop altogether their use of these substances.
Methadone is approved for different indications in different countries. Common is approval as an analgesic and approval for the treatment of opioid dependence. It is not intended to reduce the use of non-narcotic drugs such as cocaine, methamphetamine, or alcohol.
Today a number of pharmaceutical companies produce and distribute methadone. The racemic hydrochloride is the only form available in most countries, such as the Netherlands, Belgium, France and in the United States as of March 2008. The tartrate and other salts of the laevorotary form (levomethadone (an NMDA-Antagonist with mild agonism at the Mu-receptor), with trade names like Polamidone, Heptadon etc.) are available in Europe and elsewhere. These are possibly more potent and lack the cardiac effects like lengthened QT interval caused by the dextrorotary form. The major producer remains Mallinckrodt, who sells bulk methadone to most of the producers of generic preparations, and also distributes its own brand name product in the form of tablets, dispersible tablets and oral concentrate under the name Methadose in the United States.
History
Methadone was developed in Germany (it is synthesised from 1,1-diphenylbutane-2-sulfonic acid and dimethylamino-2-chloropropane) in the late 1930s in anticipation of possible shortages of raw opium during the upcoming war and possible blockades by the enemy, which would result in shortages of morphine and other opiates for both the military and civilian populations. It was tested by medical professionals in the German military in 1939-40.
The drug was given the trade name Dolophine from the Latin dolor meaning pain (Cf. Dipidolor for piritramide, Dolantin for pethidine, and the "-dol" or "-phine" ending in so many trade and chemical names for analgesics of all types in German, English, French, and other languages) and was not named either in honour of or personally by Adolf Hitler as explored in greater detail below.
On September 11 , 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 no relation to morphine or the opiate alkaloids (Bockmühl and Ehrhart, 1949).
After the war, all German patents, trade names and research records were requisitioned and expropriated by the allied forces. The records on the research work of the I.G. Farbenkonzern at the Farbwerke Hoechst were confiscated by the U.S. Department of Commerce Intelligence, investigated by a Technical Industrial Committee of the U.S. Department of State and then brought to the US.
It was only in 1947 that Amidon was given the generic name “methadone” by the Council on Pharmacy and Chemistry of the American Medical Association (COUNCIL...1947). Since the patent rights of the I.G. Farbenkonzern and Farbwerke Hoechst were no longer protected each pharmaceutical company interested in the formula could purchase the rights for commercial production of methadone for just one dollar (MOLL 1990). Commercial production was first introduced in 1947 by the US company Eli-Lilly. Only then methadone was given the trade name Dolophine, derived from the Latin dolor (pain) and finis (end).
Methadone was introduced into the United States in 1947 by Eli Lilly and Company as an analgesic (they gave it the trade name Dolophine, which is now registered to Roxane Laboratories). Since then, it has been best known for its use in treating narcotic addiction. A great deal of anecdotal evidence was available "on the street" that methadone might prove effective in treating heroin withdrawal and it had even been used in some hospitals. It was not until studies performed at the Rockefeller University in New York City by Professor Vincent Dole, along with Marie Nyswander and Mary Jeanne Kreek, that methadone was systematically studied as a potential substitution therapy. Their studies introduced a sweeping change in the notion that drug addiction was not necessarily a simple character flaw, but rather a disorder to be treated in the same way as other diseases. To date, methadone maintenance therapy has been the most systematically studied and most successful, and most politically polarizing, of any pharmacotherapy for the treatment of drug addiction patients.
Methadone (as Dolophine) was first manufactured in the USA by Roxane Pharmacueticals, who first obtained FDA approval on August 14, 1947 for there Dolophine 5 mg and 10 mg Tablets. Mallinckrodt Pharmacueticals did not receive approval until December 15 1947 to manufacture their bulk compounding powder. Mallinckrodt received approval for there branded generic, Methadose, on April 15, 1993 for their 5 mg and 10 mg Methadose Tablets. Mallinckrodt who also makes 5 mg, 10 mg and 40 mg generic tablets in addition to their branded generic Methadose received approval for their plain generic tablets on April 27, 2004.
The results of the early major studies showed methadone could effectively interrupt illicit opioid use and reduce the associated costs to society, findings which have been consistent with later research and backed up by modern knowledge of the psychological, social and pharmacological mechanisms of illicit opioid addiction.
Origin of Dolophine name
A persistent but untrue urban legend claims that the trade name "Dolophine" was coined in tribute to Adolf Hitler by its German creators, and it is sometimes even claimed that the drug was originally named "adolphine" or "adolophine" or "Dolphamine". Typically, the claim is still presented as fact by Church of Scientology literature and was repeated by actor and vocal Scientologist Tom Cruise in a 2005 Entertainment Weekly interview. However, as the magazine pointed out, this is not true: the name "Dolophine" was in fact created after the war by the American branch of Eli Lilly, and the pejorative term "adolphine" (never an actual name of the drug) appeared in the United States in the early 1970s.
Pharmacology
Methadone acts by binding to the µ-opioid receptor, but also has some affinity for the NMDA ionotropic glutamate receptor. It is metabolized by the enzymes CYP3A4, CYP2B6 and CYP2D6, with great variability between individuals. Its main route of administration is oral. Adverse effects include hypoventilation, constipation and miosis, in addition to tolerance, dependence and withdrawal difficulties. The withdrawal can be much more prolonged than with other opiates, spanning anywhere from two weeks to six months.
Mode of action
Methadone is a full µ-opioid agonist. Methadone also binds to the glutamatergic NMDA (N-methyl-D-aspartate) receptor, and thus acts as a receptor antagonist against glutamate. Glutamate is the primary excitatory neurotransmitter in the CNS. NMDA receptors have a very important role in modulating long term excitation and memory formation. NMDA antagonists such as Dextromethorphan(DXM), Ketamine (A veterinary anaesthetic, also M.O.A+.), Tiletamine (also a veterinary anesthetic) and Ibogaine (from the African tree Tabernanthe iboga, also M.O.A+.) are being studied for their role in decreasing the development of tolerance to opioids and as possible for eliminating addiction/tolerance/withdrawal, possibly by disrupting memory circuitry. Acting as an NMDA antagonist may be one mechanism by which methadone decreases craving for opioids and tolerance, and has been proposed as a possible mechanism for its distinguished efficacy regarding the treatment of neuropathic pain.
Metabolism
Methadone has a slow metabolism and very high fat solubility, making it longer lasting than morphine-based drugs. Methadone has a typical elimination half-life of 15 to 60 hours with a mean of around 22. However, metabolism rates vary greatly between individuals, up to a factor of 100, ranging from as few as 4 hours to as many as 130 hours, or even 190 hours. This variability is apparently due to genetic variability in the production of the associated enzymes CYP3A4, CYP2B6 and CYP2D6. A longer half life frequently allows for administration only once a day in Opioid detoxification and maintenance programs. Pa
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