title: Acetaminophen analgesia in children: placebo effect and pain resolution after tonsillectomy.
abstract: BACKGROUND
  Pharmacodynamic models of acetaminophen analgesia in children have 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 acetaminophen 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 [visual analogue scale (VAS) 0-10] were measured over a 4-8 h 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 (Emax) model, in which the greatest possible pain relief (VAS 0-10) equates to an Emax of 10, were Emax 5.17 (64%) and 50% effective concentration 9.98 mg/l (107%). The equilibration half-life (t(eq)) of the analgesic effect compartment was 53 min (217%). A placebo drug model for the effects of 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 effect compartment concentration of 10 mg/l is expected to produce a pain reduction of 2.6 units. The placebo model accounted for a maximum pain reduction 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 postoperatively.
authors.affiliation: Department of Anaesthesia, Auckland Children's Hospital, Zealand. bs20akiraho@hotmail.com
authors.forename: B J
authors.initials: BJ
authors.lastname: Anderson
authors.forename: G A
authors.initials: GA
authors.lastname: Woollard
authors.forename: N H
authors.initials: NH
authors.lastname: Holford
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000293:Adolescent; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008297:Male; D010149:Postoperative Pain / Q000188:drug therapy*; D015990:Placebo Effect; D011300:Preoperative Care / Q000379:methods; D014068:Tonsillectomy; D014839:Vomiting / Q000139:chemically induced
chemical_list: D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen