The pharmacokinetics of methadone in adolescents undergoing posterior spinal fusion

Background The optimal methadone dosing regimen for children undergoing spinal surgery is uncertain because of sparse pediatric pharmacokinetic data and a paucity of analgesic effect data. The minimum effective analgesic concentration of methadone in opioid naive adults is 58mcg center dot L-1. Methods Adolescents aged 1219years undergoing idiopathic scoliosis correction were administered 0.25mg center dot kg-1 racemic methadone IV prior to surgical incision. Arterial blood samples for methadone assay were obtained at 0min, 5min, 10min, 15min, 20min, 40min, 1h, 2h, 4h, 5h, 6h, 8h, 10h, 12h, 24h, and 48h. Compartment analysis was undertaken using nonlinear mixed effects models. Parameter estimates were standardized to a 70-kg person using allometric models. Results A three-compartment linear disposition model best described observed timeconcentration profiles. Population parameter estimates (between-subjects variability) were central volume (V1) 19.1 (126%) L 70kg-1, peripheral volumes of distribution V2 65.5 (60%) L 70kg-1, V3 485 (23%) L 70kg-1, clearance (CL) 9.3 (11%) L center dot h-1.70kg-1, and inter-compartment clearances Q2 282 (95%) L center dot h-1 70kg-1, Q3 139 (42%) L center dot h-1 70kg-1. The terminal elimination half-life was 44.4h. The mean observed methadone concentration was <58mcg center dot L-1 by the first hour after administration. Conclusions Current pharmacokinetic parameter estimates in adolescents are similar to those reported in adults. Methadone undergoes rapid redistribution after bolus administration. This may result in plasma concentrations that provide inadequate analgesia postoperatively. We would suggest following the bolus (0.25 mg.kg-1) with an infusion (0.10.15mg center dot kg-1 center dot h-1 for 4 h) during spinal surgery to ensure adequate plasma concentrations for 24h.