<P> Methadone acts by binding to the μ - opioid receptor, but also has some affinity for the NMDA ionotropic glutamate receptor . Methadone is metabolized by CYP3A4, CYP2B6, CYP2D6 and is a substrate for the P - Glycoprotein efflux protein in the intestine and brain . The bioavailability and elimination half - life of methadone is subject to substantial inter-individual 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 . Many factors contribute to its metabolism and excretion rate including the individual's body weight, history of use / abuse, metabolic dysfunctions, renal system dysfunction, among others . </P> <P> Levomethadone (the R 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 - D - aspartate) receptor, and thus acts as a receptor antagonist against glutamate . Methadone has been shown to reduce neuropathic pain in rat models, primarily through NMDA antagonism . 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 dissociative anaesthetic, also M.O. A+ .), tiletamine (a veterinary anaesthetic) 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 . The dextrorotary form (d - methadone) acts as an NMDA antagonist and is devoid of opioid activity: it has been shown to produce analgesia in experimental models of chronic pain . Methadone also acted as a potent, noncompetitive α β neuronal nicotinic acetylcholine receptor antagonist in rat receptors, expressed in human embryonic kidney cell lines . </P> <P> 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 . </P> <P> 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 . </P>

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