Acetaminophen analgesia in children: placebo effect and pain resolution after tonsillectomy

Background: Pharmacodynamic models of acetaminophen analgesia in children h ave not explored the efficacy of single oral doses greater than 40 mg/kg. Methods: Children aged 9.0 +/- 3.0 years (+/- SD) and weight 37.9 +/- 16.6 kg undergoing outpatient tonsillectomy were randomised to receive acetamino phen elixir 40 mg/kg (n = 12), high dose acetaminophen elixir 100 mg/kg (n = 20) or placebo (n = 30) 0.5-1 h preoperatively. No other analgesics were given. Individual acetaminophen serum concentrations and pain scores [visua l analogue scale (VAS) 0-10] were measured over a 4-8 h postoperative perio d. These data were pooled with data from a previous study investigating ace taminophen pharmacodynamics (n = 120) and analysed using a nonlinear mixed effect model. Placebo effects and drug effects were modelled using effect-s ite 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 pr eviously described. Pharmacodynamic population parameter estimates [populat ion variability coefficient of variation (CV)] for a maximum analgesic effe ct (E-max) model, in which the greatest possible pain relief (VAS 0-10) equ ates to an E-max of 10, were E-max 5.17 (64%) and 50% effective concentrati on 9.98 mg/l (107%). The equilibration half-life (t(eq)) of the analgesic e ffect compartment was 53 min (217%). A placebo drug model for the effects o f placebo response had a t(eq) of 1.96 h (40%), an elimination half-life of 2.06 h (50%) and a potency of 1.54 pain relief units (24%). Conclusions: High dose acetaminophen (100 mg/kg) was no more effective than 40 mg/kg and was associated with increased nausea and vomiting. A target e ffect compartment concentration of 10 mg/l is expected to produce a pain re duction of 2.6 units. The placebo model accounted for a maximum pain reduct ion of 5.6 units at 3 h. The combination of placebo effect and preoperative acetaminophen 40 mg/kg results in pain scores below 4 units for 5 h postop eratively.