<unk>  acts by binding to the µ-opioid receptor, but also has some affinity for the NMDA receptor, an ionotropic glutamate receptor.<unk>  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<unk>  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<unk>  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<unk>  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) does not affect opioid receptors but binds to the glutamatergic NMDA (N-methyl--aspartate) receptor, and acts as an antagonist against glutamate.<unk>  has been shown to reduce neuropathic pain in rat models, primarily through NMDA receptor antagonism. Glutamate is the primary excitatory neurotransmitter in the central nervous system. NMDA receptors have a very important role in modulating long-term excitation and memory formation. NMDA antagonists such as dextromethorphan (DXM, a cough suppressant), ketamine (a dissociative anaesthetic), tiletamine (a veterinary anaesthetic) and ibogaine (from the African tree Tabernanthe iboga) 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<unk>  decreases craving for opioids and tolerance, and has been proposed as a possible mechanism for its distinguished efficacy regarding the treatment of neuropathic pain. The dextrorotary form (dextromethadone), which acts as an NMDA receptor antagonist and is devoid of opioid activity, has been shown to produce analgesia in experimental models of chronic pain.<unk>  also acted as a potent, noncompetitive α3β4 neuronal nicotinic acetylcholine receptor antagonist in rat receptors, expressed in human embryonic kidney cell lines. Metabolism<unk>  has a slow metabolism and very high fat solubility, making it longer lasting than morphine-based drugs.<unk>  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)<unk>  half-life. A longer half-life frequently allows for administration only once a day in opioid detoxification and maintenance programs. People who metabolize<unk>  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<unk> . File:Methadone.Methadone File:EDDP.EDDP File:EDMP.EDMP Route of administration The most common route of administration at a<unk>  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.<unk>  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<unk> , 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.<unk>  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<unk>  pills can cause collapsed veins, bruising, swelling, and possibly other harmful effects.<unk>  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<unk>  (flavored liquid suspension for oral dosing, commonly used for maintenance purposes) should not be injected either. Information leaflets included in packs of UK<unk>  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.
Methadone
Isomethadone
Normethadone
Levomethadone
Morphine
Buprenorphine
Codeine
Naltrexone