The pharmacokinetics of methadone in adolescents undergoing posterior spinal fusion

Abstract

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 naïve adults is 58 mcg · L(-1). Adolescents aged 12-19 years undergoing idiopathic scoliosis correction were administered 0.25 mg · kg(-1) racemic methadone IV prior to surgical incision. Arterial blood samples for methadone assay were obtained at 0 min, 5 min, 10 min, 15 min, 20 min, 40 min, 1 h, 2 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 24 h, and 48 h. Compartment analysis was undertaken using nonlinear mixed effects models. Parameter estimates were standardized to a 70-kg person using allometric models. A three-compartment linear disposition model best described observed time-concentration profiles. Population parameter estimates (between-subjects variability) were central volume (V1) 19.1 (126%) L 70 kg(-1), peripheral volumes of distribution V2 65.5 (60%) L 70 kg(-1), V3 485 (23%) L 70 kg(-1), clearance (CL) 9.3 (11%) L · h(-1) · 70 kg(-1), and inter-compartment clearances Q2 282 (95%) L · h(-1) 70 kg(-1), Q3 139 (42%) L · h(-1) 70 kg(-1). The terminal elimination half-life was 44.4 h. The mean observed methadone concentration was <58 mcg · L(-1) by the first hour after administration. 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 (0.1-0.15 mg · kg(-1) · h(-1) for 4 h) during spinal surgery to ensure adequate plasma concentrations for 24 h.