摘要：

Background : Pharmacodynamic models of acetaminophen analgesia in children have not explored the efficacy of single oral doses greater than 40mg/kg. Methods : Children aged 9.0±3.0years (±SD) and weight 37.9±16.6kg undergoing outpatient tonsillectomy were randomised to receive acetaminophen elixir 40mg/kg ( n =12), high dose acetaminophen elixir 100mg/kg ( n =20) or placebo ( n =30) 0.5–1h preoperatively. No other analgesics were given. Individual acetaminophen serum concentrations and pain scores [visual analogue scale (VAS) 0–10] were measured over a 4–8h postoperative period. These data were pooled with data from a previous study investigating acetaminophen pharmacodynamics ( n =120) and analysed using a non-linear mixed effect model. Placebo effects and drug effects were modelled using effect-site concentration models. Results : A one-compartment model with first-order input, lag time and first-order elimination was used to describe the population pharmacokinetics of acetaminophen. Pharmacokinetic parameter estimates were similar to those previously described. Pharmacodynamic population parameter estimates [population variability coefficient of variation (CV)] for a maximum analgesic effect (E max ) model, in which the greatest possible pain relief (VAS 0–10) equates to an E max of 10, were E max 5.17 (64%) and 50% effective concentration 9.98mg/l (107%). The equilibration half-life (t eq ) of the analgesic effect compartment was 53min (217%). A placebo drug model for the effects of placebo response had a t eq of 1.96h (40%), an elimination half-life of 2.06h (50%) and a potency of 1.54pain relief units (24%). Conclusions : High dose acetaminophen (100mg/kg) was no more effective than 40mg/kg and was associated with increased nausea and vomiting. A target effect compartment concentration of 10mg/l is expected to produce a pain reduction of 2.6units. The placebo model accounted for a maximum pain reduction of 5.6units at 3h. The combination of placebo effect and preoperative acetaminophen 40mg/kg results in pain scores below 4units for 5h postoperatively.

展开