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.
While starting doses may be adjusted based on the amount of opioids reportedly used, most clinical guidelines suggest doses start low (e.g. at doses not exceeding 40 mg daily) and are incremented gradually. It has been found that doses of 40 mg per day were sufficient to help control the withdrawal symptoms but not enough to curb the cravings for the drug. Doses of 80 to 100 mg per day have shown higher rates of success in patients and less illicit heroin use during the maintenance therapy. However, higher doses do put a patient more at risk for overdose than a moderately low dose (e.g. 20 mg/day). Methadone maintenance has been shown to reduce the transmission of bloodborne viruses associated with opioid injection, such as hepatitis B and C, and/or HIV. The principal goals of methadone maintenance are to relieve opioid cravings, suppress the abstinence syndrome, and block the euphoric effects associated with opioids. Chronic methadone dosing will eventually lead to neuroadaptation, characterised by a syndrome of tolerance and withdrawal (dependence). However, when used correctly in treatment, maintenance therapy has been found to be medically safe, non-sedating, and can provide a slow recovery from opioid addiction. Methadone has been widely used for pregnant women addicted to opioids. Pain
Methadone is used as an analgesic in chronic pain, often in rotation with other opioids. Due to its activity at the NMDA receptor, it may be more effective against neuropathic pain; for the same reason, tolerance to the analgesic effects may be less than that of other opioids.