Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: T/A Martindale Pharma, Bampton Road, Harold Hill, Romford, RM3 8UG, United Kingdom
Pharmacotherapeutic group: Nervous system, other nervous system drugs, drugs used in addictive disorders, methadone
ATC code: N07BC02
Methadone is a strong opioid agonist with actions predominantly at the µ receptor. The analgesic activity of the race mate is almost entirely due to the 1-isomer, which is at least 10 times more potent as an analgesic than the d-isomer. The d-isomer lacks significant respiratory depressant activity but does have anti-tussive effects. Methadone also has some agonist actions at the K and δ opiate receptors. These actions result in analgesia, depression of respiration, suppression of cough, nausea and vomiting (via an effect on the chemoreceptor trigger zone) and constipation. An effect on the nucleus of the oculomotor nerve, and perhaps on opioid receptors in the pupillary muscles causes pupillary constriction. All these effects are reversible by naloxone with pA2 value similar to its antagonism of morphine. Like many basic drugs, Methadone enters mast cells and releases histamine by a non-immunological mechanism. It causes a dependence syndrome of the morphine type.
Methadone is one of the more lipid soluble opioids, and is well absorbed from the gastro-intestinal tract, but undergoes fairiy extensive first pass metabolism. It is bound to albumin and other plasma proteins and to tissue proteins (probably lipoproteins), the concentrations in lung, liver and kidneys being much higher than in blood. The phannacokinetics of Methadone are unusual, in that there is extensive binding to tissue proteins and fairiy slow transfer between some parts of this tissue reservoir and the plasma. With an intramuscular dose of 10 mg, a peak plasma concentration of 75 µg per litre is reached in one hour. With regular oral doses of 100-120 mg daily, plasma concentrations rise from trough levels of approximately 500 µg/L to a peak of about 900 µg/L in 4 hours. Marked variations in plasma levels occur in dependent persons on a stable dose of oral Methadone, without any relation to symptoms. Methadone is secreted into sweat and found in saliva and in high concentration in gastric juice. The concentration in cord blood is about half the maternal level.
The half life after a single oral dose is 12-18 (mean 15) hours, partly reflecting distribution into tissue stores, as well as metabolic and renal clearance. With regular doses, the tissue reservoir is already partly filled, and so the half life is extended to 13-47 (mean 25) hours reflecting only clearance. In the first 96 hours after administration, 15-60% can be recovered from the urine, and as the dose is increased so a higher proportion of unchanged Methadone is found there. Acidification of the urine can increase the renal clearance by a factor of at least three and thus appreciably reduce the half time of elimination.
There are no preclinical data of relevance to the prescriber, which are additional to those already included in other sections of the SmPC.
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