sert net nmdar m:d:k sert:net racemic methadone 1.74354051,4002592,500–8,3001:256:2381:5 dextromethadone 19.79601,37099212,7002,600–7,4001:49:701:13 levomethadone 0.9453711,86014.17022,800–3,4001:393:19681:50 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. mechanism of action levomethadone (the l enantiomer) is a μ-opioid receptor agonist with higher intrinsic activity than morphine, but lower affinity. dextromethadone (the s enantiomer) has lower affinity to the μ-opioid receptor than levomethadone. both enantiomers bind to the glutamatergic nmda (n-methyl-d-aspartate) receptor, acting as noncompetitive antagonists. methadone has been shown to reduce neuropathic pain in rat models, primarily through nmda receptor antagonism. nmda antagonists such as dextromethorphan, ketamine, tiletamine and ibogaine 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. methadone also acted as a potent, noncompetitive α3β4 neuronal nicotinic acetylcholine receptor antagonist in rat receptors, expressed in human embryonic kidney cell lines. 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 cytochrome enzymes cyp3a4, cyp2b6 and cyp2d6. many substances can also induce, inhibit or compete with these enzymes further affecting (sometimes dangerously) methadone half-life. a longer half-life frequently allows for administration only once a day in opioid detoxification and maintenance programs. people who metabolize methadone rapidly, on the other hand, may require twice daily dosing to obtain sufficient symptom alleviation while avoiding excessive peaks and troughs in their blood concentrations and associated effects. this can also allow lower total doses in some such people. the analgesic activity is shorter than the pharmacological half-life; dosing for pain control usually requires multiple doses per day normally dividing daily dosage for administration at 8 hour intervals. the main metabolic pathway involves n-demethylation by cyp3a4 in the liver and intestine to give 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (eddp). this inactive product, as well as the inactive 2-ethyl-5-methyl-3,3- diphenyl-1-pyrroline (emdp), produced by a second n-demethylation, are detectable in the urine of those taking methadone. methadone and its two main metabolites methadone eddp edmp route of administration the most common route of administration at a methadone clinic is in a racemic oral solution, though in germany, only the r enantiomer (the l optical isomer) has traditionally been used, as it is responsible for most of the desired opioid effects. the single-isomer form is becoming less common due to the higher production costs. methadone is available in traditional pill, sublingual tablet, and two different formulations designed for the person to drink. drinkable forms include ready-to-dispense liquid (sold in the united states as methadose), and diskets (known on the street as "wafers" or "biscuits") tablets which are dispersible in water for oral administration, used in a similar fashion to alka-seltzer. the liquid form is the most common as it allows for smaller dose changes. methadone is almost as effective when administered orally as by injection. oral medication is usually preferable because it offers safety, simplicity and represents a step away from injection-based drug abuse in those recovering from addiction. u.s. federal regulations require the oral form in addiction treatment programs. injecting methadone pills can cause collapsed veins, bruising, swelling, and possibly other harmful effects. methadone pills often contain talc that, when injected, produces a swarm of tiny solid particles in the blood, causing numerous minor blood clots. these particles cannot be filtered out before injection, and will accumulate in the body over time, especially in the lungs and eyes, producing various complications such as pulmonary hypertension, an irreversible and progressive disease. the formulation sold under the brand name methadose (flavored liquid suspension for oral dosing, commonly used for maintenance purposes) should not be injected either. information leaflets included in packs of uk methadone tablets state that the tablets are for oral use only and that use by any other route can cause serious harm. in addition to this warning, additives have now been included in the tablet formulation to make the use of them by the iv route more difficult. chemistry detection in biological fluids methadone and its major metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (eddp), are often measured in urine as part of a drug abuse testing program, in plasma or serum to confirm a diagnosis of poisoning in hospitalized victims, or in whole blood to assist in a forensic investigation of a traffic or other criminal violation or a case of sudden death. methadone usage history is considered in interpreting the results as a chronic user can develop tolerance to doses that would incapacitate an opioid-naïve individual. chronic users often have high methadone and eddp baseline values. conformation the protonated form of methadone takes on an extended conformation, while the free base is more compact. in particular, it was found that there is an interaction between the tertiary amine and the carbonyl carbon of the ketone function (r3n ••• >c=o) that limits the molecule's conformation freedom, though the distance (291 pm by x-ray) is far too long to represent a true chemical bond. 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 40 mg of methadone 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 germany's 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 (heroin), desomorphine (permonid), nicomorphine (vilan), codeine, dihydrocodeine, oxymorphone (opana), hydromorphone (dilaudid), oxycodone (oxycontin), hydrocodone (dicodid), 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. 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. the report published by the committee noted that while methadone itself was potentially addictive, it produced “considerably” less euphoria, sedation, and respiratory depression than morphine at equianalgesic doses and was thus interesting as a commercial drug. the same report also compared methadone to pethidine. german researchers reported that methadone was capable of producing strong morphine-like physical dependence, which is characterized by opioid withdrawal symptoms which are lesser in severity and intensity compared to morphine, but methadone was associated with a considerably prolonged or protracted withdrawal syndrome when compared to morphine. morphine produced higher rates of self-administration and reinforcing behaviour in both human and animal subjects when compared to both methadone and pethidine. in comparison to equianalgesic doses of pethidine (demerol), methadone was shown to produce less euphoria, but higher rates of constipation, and roughly equal levels of respiratory depression and sedation. in the early 1950s, methadone (most times the racemic hcl salts mixture) was also investigated for use as an antitussive. isomethadone, noracymethadol, laam, and normethadone were first developed in germany, united kingdom, belgium, austria, canada, and the united states in the thirty or so years after the 1937 discovery of pethidine, the first synthetic opioid used in medicine. these synthetic opioids have increased length and depth of satiating any opiate cravings and generate very strong analgesic effects due to their long metabolic half-life and strong receptor affinity at the mu-opioid receptor sites. therefore, they impart much of the satiating and anti-addictive effects of methadone by means of suppressing drug cravings. it was only in 1947 that the drug was given the generic name “methadone” by the council on pharmacy and chemistry of the american medical association. since the patent rights of the i.g. farbenkonzern and farbwerke hoechst were no longer protected, each pharmaceutical company interested in the formula could buy the rights for the commercial production of methadone for just one dollar (moll 1990). methadone was introduced into the united states in 1947 by eli lilly and company as an analgesic under the trade name dolophine. an urban myth later arose that nazi leader adolf hitler ordered the manufacture of methadone or that the brand name 'dolophine' was named after him, probably based on the similarity of “doloph” with “adolph”. (the pejorative term “adolphine” would appear in the early 1970s.) however, the name “dolophine” was a contraction of "dolo” from the latin word dolor (pain), and finis, the latin word for “end”. therefore, dolophine literally means “pain end”. methadone was studied as a treatment for opioid addiction at the addiction research center of the narcotics farm in lexington, kentucky in the 1950s, and by rockefeller university physicians robert dole and marie nyswander in the 1960s in new york city. by 1976, methadone clinics had opened in cities including chicago, new york, and new haven, with some 38,000 patients treated in new york city alone. society and culture brand names brand names include dolophine, symoron, amidone, methadose, physeptone, metadon, metadol, metadol-d, heptanon and heptadon among others. cost in the us, generic methadone tablets are inexpensive, with retail prices ranging from $0.25 to $2.50 per defined daily dose. brand-name methadone tablets may cost much more. methadone maintenance clinics in the us may be covered by private insurances, medicaid, or medicare. medicare covers methadone under the prescription drug benefit, medicare part d, when it is prescribed for pain, but not when it is used for opioid dependence treatment because it cannot be dispensed in a retail pharmacy for this purpose. in california methadone maintenance treatment is covered under the medical benefit. patients' eligibility for methadone maintenance treatment is most often contingent on them being enrolled in substance abuse counseling. people on methadone maintenance in the us either have to pay cash or if covered by insurance must complete a pre-determined number of hours per month in therapeutic groups or counseling. the united states department of veteran's affairs (va) alcohol and drug dependence rehabilitation program offers methadone services to eligible veterans enrolled in the va health care system. methadone maintenance treatment (mmt) cost analyses often compare the cost of clinic visits versus the overall societal costs of illicit opioid use. a preliminary cost analysis conducted in 2016 by the us department of defense determined that methadone treatment, which includes psychosocial