Source: Health Products Regulatory Authority (ZA) Revision Year: 2022 Publisher: Umsebe Healthcare, Unit 20, Sunclare Building, 3rd Floor, 21 Dreyer Street, Claremont, Cape Town, 7708, South Africa
Pharmacological classification: 2.9 Other analgesics
Pharmacotherapeutic group: Medicine used in opioid dependence
ATC code: N07BC02
Methadone is a narcotic analgesic that belongs to the same group as morphine. Methadone is a strong opiate/opioid agonist with actions predominantly at the ยต receptor. The analgesic activity of the racemate is almost entirely due to the l-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 ฮบ and ฮด opiate/opioid receptors.
Methadone operates in a similar way to morphine, but has a less sedative effect. The use of methadone can reduce or eliminate the effect of other opiates/opioids.
These actions result in analgesia, depression of respiration, suppression of cough, nausea and vomiting (via an effect of the chemoreceptor trigger zone) and constipation. An effect on the nucleus of the oculomotor nerve, and perhaps on opiate/opioid receptors in the pupillary muscles, causes pupillary constriction.
All these effects are reversible by naloxone with pA2 value similar to its anti-antagonism of morphine. Like many basic substances, 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 gastrointestinal tract, but undergoes fairly extensive first-pass metabolism. The bioavailability is above 80%. Steady state concentrations are reached within 5–7 days.
Methadone is bound to albumin and other plasma proteins and to tissue proteins (probably lipoproteins). The concentrations in the lung, liver and kidneys are much higher than in blood. The pharmacokinetics of methadone is unusual, in that there is extensive binding to tissue proteins and fairly slow transfer between some parts of this tissue reservoir and the plasma. Methadone is secreted in sweat and found in saliva, breast milk and in the cord blood.
Methadone is metabolised in the liver, mainly by N-demethylation and cyclisation. The metabolism of methadone is catalysed primarily by CYP3A4, but CYP2D6 and CYP2B6 are also involved, to a smaller extent. Metabolism is mainly N-demethylation, which produces the most important metabolites: 2-ethylidine, 1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenyl-1-pyrrolidine (EMDP), which are both inactive. Hydroxylation to methadol succeeded by N-demethylisation to normethadol also occurs to some extent. Other metabolic reactions also occur, and at least eight other metabolites are known.
The half-life after a single oral dose is 10–25 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 13–55 hours reflecting only clearance.
Plasma clearance is around 2 ml/min/kg. About 20 to 60% of the dose is eliminated in urine over 24 hours (about 33% in unmodified form; about 43% as EDDP and about 5–10% as EMDP).
Methadone and its metabolites are excreted to varying degree in the faeces and urine. Excretion of methadone is markedly enhanced by the acidification of the urine. About 30% of the dose is eliminated in faeces, but this percentage will normally be reduced at higher doses. About 75% of overall elimination is unconjugated.
There are no significant differences in the pharmacokinetics between men and women. The clearance of methadone is decreased only to some extent in the elderly (>65 years).
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