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 molecules conformation freedom, though the distance (291 pm by X-ray) is far too long to represent a true chemical bond.
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-D-aspartate) receptor, and acts as an antagonist against glutamate. Methadone 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 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 (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. 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.