Pharmacokinetics of Methadone

Abstract

Methadone is a synthetic opioid that is effective for the relief of moderate-to-severe pain and for the treatment of opioid dependence. The pharmacokinetics of methadone differ from those of morphine in that methadone has a higher bioavailability, a much longer half-life, and is hepatically metabolized by cytochrome P450 enzymes. The pharmacokinetics of methadone are variable and an understanding of the factors that impact the onset, magnitude, and duration of analgesia is required to optimize therapy. Drug interactions are common and patients receiving methadone should be monitored closely for toxicity or therapeutic failure. Special populations in whom a change from the usual dosage regimen may be necessary include pediatric patients, patients with renal failure, the elderly, and pregnant women. To achieve an optimal dosage regimen, the clinician must have an understanding of the pharmacokinetics and pharmacodynamics of methadone in addition to the relationship between these variables and their patients' demographic and pathophysiologic characteristics. AMEDLINE search was performed to identify literature published between 1966 and May 2005 relevant to the pharmacokinetics of methadone. These publications were reviewed and the literature summarized regarding unique and clinically important elements of methadone disposition including its absorption profile, distribution, and metabolism/excretion. General dosing guidelines, dosage conversions from other opioids and pharmacokinetic issues in special populations are discussed.

Pharmacotherapy of Chronic Pain

“…Methadone is also a substrate of P-glycoprotein (P-gp) [24], elux transporter, which is expressed in several eliminating tissues (intestine, liver and kidneys) [25]. Due to the induction of its own metabolism (CYP3A4 and/or P-glycoprotein induction), reported by some authors, elimination half-life is longer after the irst dose (36.7 h) [26] than during maintenance treatment [27,28].…”

The use of methadone “as needed”, is it justified?

“…The R-enantiomer(R-MET or l-isomer) has opioid activity, while the S-enantiomer (S-MET or d-isomer) has seritonergic and norepinephrine reuptake inhibition activity. 7 The R-enantiomer accounts for most of the opioid effects of methadone. Both enantiomers noncompetitively inhibit the binding of NMDA receptor ligands with a potency comparable with that of ketamine.…”

“…However, Lugo and colleagues state that "the short duration of analgesia early in therapy is often counter-intuitive to clinicians, especially in view of the very long half-life of methadone." 7 The rapid alpha elimination is largely responsible for this shortcoming, as the medication is continued and compartments equilibrate, the dosing interval may need to be changed. Therefore, what is seen clinically is a short "analgesic half life," whereas pharmacologically the metabolic half life is much longer.…”

“…Other authors have also condemned the PRN usage of methadone, stating that, "it is dangerous to prescribe additional 'as needed' doses of methadone." 7 Recommendations for the dosing of methadone have been outlined in other publications, specifically Fishman's 2002 article. 9 I would add the following:…”

“…7 It seems clear, at least to this author, that the PRN use of methadone is done based on ignorance of this medications pharmacology and complexity. The previous discussion suggests that the use of PRN methadone is not justified based on the pharmacology and pharmacokinetics.…”