Clinical Pharmacokinetics of Methadone

Abstract

Studies with single doses of methadone have shown that the oral biological availability is 79±21%, range 41–99%. The rate of elimination is mostly due to metabolic clearance. Below a urinary pH of 6, renal clearance becomes of quantitative importance. In five subjects treated with ammonium chloride (acidic urine), the plasma half‐life of methadone was found to be 19.5±3.6 h. When treated with sodium bicarbonate the same subjects had plasma half‐lives of 42.1±8.8 h. During continuous treatment with methadone, cellular tolerance may occur and in some subjects also metabolic tolerance. In treatment of severe cancer pain such adaptive changes in methadone pharmacodynamics and pharmacokinetics are best managed by a regimen involving a fixed dose but a flexible and patient‐controlled dosage interval.

Methadone Induces the Expression of Hepatic Drug-Metabolizing Enzymes through the Activation of Pregnane X Receptor and Constitutive Androstane Receptor

“…MD is almost exclusively metabolized in the liver (Nilsson et al, 1982). The primary metabolic route involves hepatic N-demethylation and cyclization to its stable metabolite, 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine, which is pharmacologically inactive (Ferrari et al, 2004).…”

Methadone for relief of cancer pain: a review of pharmacokinetics, pharmacodynamics, drug interactions and protocols of administration

“…Methadone is both a long-and a short-acting analgesic and controls pain when it is unresponsive to other Mu agonists, such as fentanyl, hydromorphone and oxycodone [5,6,7]. Methadone, unlike morphine, lacks neuroactive metabolites, which accumulate in renal failure [3,8,9,10]. Methadone has two nonopiate analgesic receptor activities: the prevention of monoamine reuptake in the periaqueductal gray and presynaptic inhibition of N-methyl-d-asparate (NMDA) receptors [11,12,13,14].…”

Continuous epidural infusion of racemic methadone results in effective postoperative analgesia and low plasma concentrations

“…[7][8][9][10] Unlike fentanyl, however, methadone has a low plasma clearance and this property, together with its still relatively high liposolubility, can be associated with progressive increases in plasma concentrations with accumulation over the course of treatment. [10][11][12] However, little has been established firmly concerning plasma racemic methadone concentrations, although high concentration gradients resulting from intermittent boluses of methadone could, theoretically, favour intravascular absorption. Continuous epidural infusion of methadone should be effective at total doses lower than those of intermittent injections, therefore leading to lower plasma racemic methadone concentrations.…”