Pharmacokinetics of methadone in children and adolescents in the perioperative period


Pharmacokinetics of methadone in children and adolescents in the perioperative period


Berde CB; Sethna NF; Holzman RS; Reidy P; Gondek EJ






Child; Analgesics; Methadone; Narcotics; adolescent; Opioid; Antitussive Agents; Biological Transport; Kinetics; Perioperative Care; Pharmacokinetics


Introduction Previous studies by Gourlay and coworkers1-3 have demonstrated that in adults undergoing surgery, methadone has slow elimination and a very long duration of effective analgesia. For children, intramuscular injections are a major source of distress in the peri-operative period. If methadone behaves in children as it does for adults, then use of methadone intravenously should provide a steady analgesic effect. For these reasons, we have undertaken studies of methadone in children and adolescents undergoing major surgery. Methods Fifteen children and adolescents, ages 1-18 years were enrolled with informed parental and patient consent according to procedures approved by the institutional Human Studies committee. Enrollment was restricted to patients requiring prolonged surgery (greater than 3 hours) and placement of arterial cannulae or multiple venous cannulae. Included in the studey were 3 one-year olds, 2 two-year olds and 2 three-year olds. Following tracheal intubation and line placement, methadone (0.2 mg/kg) was administered via rapid intravenous bolus. Heparinized plasma samples for methadone assay were obtained at approzimately 1, 2, 3, 4, 7, 10, and 30 minutes and 1, 3, 6, 12, 18, 24, 48, and 72 hours. Methadone assay (gas-liquid chromatography with mass spectrometry) yielded a lower detection limit of 5 ng/ml; for several patients the final 1-4 points fell below the detection limit and were excluded from analysis. Concentration versus time curves were fitted to a bioexponential equation using nonlinear least-squares. Results Kinetic parameters are summarized in Table 1. It is apparent that in children and adolescents ages 1 to 18 years, methadone has very prolonged elimination and a low clearance rate. For this population, regression analysis showed no dependence of half-lives or normalized volumes and clearances on patient age or weight. Areas under the concentration-versus-time curves from the equation parameters and from the trapezoid rule (model-independent) agreed to within 4%. Discussion Methadone has not been studied previously for post-operative pain in children. Observation of the patients in this study and of 16 additional children suggests that methadone provides prolonged analgesia; many children remained comfortable and required no analgesia for 12-36 hours post-operatively. Studies in progress are directed at testing these impressions via double-blinded administration and formal pain assessment scales. If these studies confirm that methadone's dynamics as well as kinetics are similar in children and adults, then peri-operative administration would be a safe, inexpensive and convenient means for providing prolonged analgesia and decreasing the use of painful intramuscular narcotic injections in children following major surgery. In adults ages 29-69 years, there was a positive correlation between age and beta half life. In the present study, we found no dependence of elimination half-life or normalized clearance on age for patients ages 1-18. The mean value for elimination half-life in the present study, 19.2 hours, is indistinguishable from that of the youngest adults in the previous study. As with adults, there is substantial variability among children in the rates and volumes of methadone distribution and elimination. It therefore seems prudent to follow an approach similar to that used in adults with titration to clinical effect. To date, at least 40 children have received methadone (via blinded or unblinded administration) in this fashion without requiring naloxone or assisted ventilation postoperatively. Further study is required before these conclusions can be extrapolated to newborns and very young infants.


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Berde CB; Sethna NF; Holzman RS; Reidy P; Gondek EJ, “Pharmacokinetics of methadone in children and adolescents in the perioperative period,” Pediatric Palliative Care Library, accessed May 24, 2024,