title: Postoperative analgesia using diclofenac and acetaminophen in children.
abstract: BACKGROUND
  Diclofenac dosing in children for analgesia is currently extrapolated from adult data. Oral diclofenac 1.0 mg·kg(-1) is recommended for children aged 1-12 years. Analgesic effect from combination diclofenac/acetaminophen is unknown.
  
  
  METHODS
  Children (n = 151) undergoing tonsillectomy (c. 1995) were randomized to receive acetaminophen elixir 40 mg·kg(-1) before surgery and 20 mg·kg(-1) rectally at the end of surgery with diclofenac suspension 0.1 mg·kg(-1) , 0.5 mg·kg(-1) , or 2.0 mg·kg(-1) before surgery or placebo. A further 93 children were randomized to receive diclofenac 0.1 mg·kg(-1) , 0.5 mg·kg(-1) , or 2.0 mg·kg(-1) only. Postoperative pain was assessed (visual analogue score, VAS 0-10) at half-hourly intervals from waking until discharge. Data were pooled with those from a further 222 children and 30 adults. One-compartment models with first-order absorption and elimination described the pharmacokinetics of both medicines. Combined drug effects were described using a modified EMAX model with an interaction term. An interval-censored model described the hazard of study dropout.
  
  
  RESULTS
  Analgesia onset had an equilibration half-time of 0.496 h for acetaminophen and 0.23 h for diclofenac. The maximum effect (EMAX ) was 4.9. The concentration resulting in 50% of EMAX (C50 ) was 1.23 mg·l(-1) for diclofenac and 13.3 mg·l(-1) for acetaminophen. A peak placebo effect of 6.8 occurred at 4 h. Drug effects were additive. The hazard of dropping out was related to pain (hazard ratio of 1.35 per unit change in pain). Diclofenac 1.0 mg·kg(-1) with acetaminophen 15 mg·kg(-1) achieves equivalent analgesia to acetaminophen 30 mg·kg(-1) .
  
  
  CONCLUSIONS
  Combination therapy can be used to achieve similar analgesia with lower doses of both drugs.
authors.affiliation: Department of Anaesthesiology, University of Auckland, Auckland, New Zealand.
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Hannam
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Anderson
authors.forename: Murali
authors.initials: M
authors.lastname: Mahadevan
authors.forename: Nick H G
authors.initials: NH
authors.lastname: Holford
mesh_terms: D000082:Acetaminophen / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018712:Analgesics, Non-Narcotic / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004008:Diclofenac / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D010147:Pain Measurement / Q000706:statistics & numerical data; D010149:Postoperative Pain / Q000188:drug therapy*; D014068:Tonsillectomy; D016896:Treatment Outcome
chemical_list: D018712:Analgesics, Non-Narcotic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac; D000082:Acetaminophen
keywords: analgesia; children; dropout model; drug interactions; drugs; pharmacodynamics; pharmacokinetics