ATCvet code: QN02AC90.

Methadone is structurally unrelated to other opium-derived analgesics and exists as a racemic mixture.

Each enantiomer has a separate mode of action; the d-isomer non-competitively antagonises the NMDA receptor and inhibits norepinephrine reuptake; the l-isomer is a µ-opioid receptor agonist.

There are two subtypes µ1 and µ2. The analgesic effects of methadone are believed to be mediated by both the µ1 and µ2 subtypes, whereas the µ2 subtype appears to mediate respiratory depression and inhibition of gastrointestinal motility. The µ1 subtype produces supraspinal analgesia and the µ2 receptors produce spinal analgesia.

Methadone has the ability to produce profound analgesia.

It can also be used for premedication and it can assist in the production of sedation in combination with tranquilisers or sedatives. The duration of effect may vary from 1.5-6.5 hours. Opioids produce a dose-dependent respiratory depression. Very high doses may result in convulsions.

In dogs, methadone is absorbed very rapidly (Tmax 5-15 minutes) following intramuscular injection of 0.3-0.5 mg/kg. Tmax tends to be later at the higher dose levels indicating that an increase in dose tends to prolong the absorption phase.

The rate and extent of systemic exposure of dogs to methadone appears to be characterised by dose-independent (linear) kinetics following intramuscular administration. The bioavailability is high and ranges between 65.4 and 100%, with a mean estimate of 90%. Following subcutaneous administration of 0.4 mg/kg, methadone is absorbed slower (Tmax 15-140 minutes) and bioavailability is 79 ± 22%.

In dogs, the volume of distribution at steady state (Vss) was 4.84 and 6.11 l/kg in males and females respectively. The terminal half-life is in the range 0.9-2.2 hours following intramuscular administration, and is independent of dose and sex.

The terminal half-life may be slightly longer following intravenous administration. The terminal half-life ranges from 6.4-15 hours following subcutaneous administration. Total plasma clearance (CL) of methadone following intravenous administration is high 2.92-3.56 l/h/kg or ca 70-85% of the cardiac plasma output in dogs (4.18 l/h/kg).

In cats, methadone is also rapidly absorbed following intramuscular injection (peak values occur at 20 minutes), however, when the product is administered inadvertently subcutaneously (or in another poorly vascularised area) absorption will be slower. The terminal half-life is in the range of 6-15 hours. Clearance is medium to low with a mean (sd) value of 9.06 (3.3) ml/kg/min.

Methadone is extensively protein bound (60-90%). Opioids are lipophilic and weak bases. These physiochemical properties favour intracellular accumulation. Consequently, opioids have a large volume of distribution, which greatly exceeds total body water. A small amount (3-4% in the dog) of the administered dose is excreted unchanged in the urine; the remainder is metabolised in the liver and subsequently excreted.