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.

Enteral administration of methadone may expedite fentanyl discontinuation and reduce the risk of withdrawal in critically ill children at high risk for opioid abstinence syndrome.

Background The lack of methadone pharmacokinetic data in children and neonates restrains dosing to achieve the target concentration in these populations. A minimum effective analgesic concentration of methadone in opioid naïve adults is 0.058 mg.L−1, while no withdrawal symptoms were observed in neonates suffering opioid withdrawal if plasma concentrations of methadone were above 0.06 mg.L−1. The racemate of methadone which is commonly used in pediatric and anaesthetic care is metabolized to EDDP (2-ethylidine-1,5-dimethyl-3,3-diphenylpyrrolidine) and EMDP (2-ethyl-5-methyl-3,3-diphenylpyrroline). Methods Data from 4 studies (age 33 weeks PMA-15 years) were pooled (n=56) for compartment analysis using nonlinear mixed effects modeling. Parameter estimates were standardized to a 70 kg person using an allometric model approach. Investigation was made of the racemate and metabolite (EDDP and EMDP) dispositions. In addition, neonatal data (n=7) allowed further study of R and S enantiomer pharmacokinetics. Results A three-compartment linear disposition model best described the observed time-concentration profiles with additional compartments for metabolites. Population parameter estimates (between subject variability) were central volume (V1) 21.5 (29%) L.70kg−1, peripheral volumes of distribution V2 75.1 (23%) L.70kg−1, V3 484 (8%) L.70kg−1, clearance (CL) 9.45 (11%) L.h−1.70kg−1 and inter-compartment clearances Q2 325 (21%) L.h−1.70kg−1, Q3 136 (14%) L.h−1.70kg−1. EDDP formation clearance was 9.1 (11%) L.h−1.70kg−1, formation clearance of EMDP from EDDP 7.4 (63%) L.h−1.70kg−1, elimination clearance of EDDP was 40.9 (26%) L.h−1.70kg−1, and the rate constant for intermediate compartments 2.17 (43%) /h. Conclusions Current pharmacokinetic parameter estimates in children and neonates are similar to those reported in adults. There was no clearance maturation with age. Neonatal enantiomer clearances were similar to those described in adults. A regimen of 0.2 mg.kg−1 per 8 h in neonates achieves a target concentration of 0.06 mg.L−1 within 36 h. Infusion, rather than intermittent dosing should be considered if this target is to be achieved in older children after cardiac surgery.

In this study, smokers deprived of nicotine required a greater amount of opiates in the first 48 hours after CABG than did nonsmokers. Healthcare providers need to be aware of the potential for increased narcotic requirements among nicotine-deprived smokers. Further study is needed to determine whether nicotine replacement lessens the requirement for postoperative analgesics in smokers.