Perioperative pharmacodynamics of acetaminophen analgesia in children

Background: There are no adequate pharmacodynamic data relating concentrations of acetaminophen in serum to analgesia. Methods: Children undergoing outpatient tonsillectomy were administered acetaminophen either orally, 0.5-1.0 h preoperatively (n = 20), or per rectum at induction of anesthesia (n = 100). No other analgesic agents were administered. Individual concentrations of acetaminophen in serum and pain scores (0-10) measured over a 4-h postoperative period were analyzed using a nonlinear mixed-effects model (NONMEM). Results: Mean (% CV) estimates of population phanmacokinetic parameters with percent coefficient of variation, standardized to a 70-kg person, for a one-compartment model with frrst-order input, lag time, and first order-elimination were a volume of distribution of 60 (21) 1 and a clearance of 13.5 (46) 1/h. Rectally administered acetaminophen had an absorption half-life of 35 (63) min with a lag time of 40 min. The absorption half-life for the oral preparation was 4.5 (63) min without a detectable lag time. The relative bioavailability of the rectal compared with the oral formulation was 0.54, The equilibration half-time of an effect compartment was 1.6 (131) h. Pharmacodynamic population parameter estimates (percent coefficient of variation) for a fractional sigmoidal E-max model, in which the greatest possible pain relief equates to an E-max of 1, were E-max = 1, EC50 (the concentration producing 50% of E-max) = 3.4 (94) mg/l, and Hill coefficient = 0.54 (42). Conclusions: The pharmacodynamics of acetaminophen can be described using a sigmoidal E-max model with a low Hill coefficient. To achieve a mean posttonsillectomy pain score of 3.6 of 10, an effect compartment concentration of 10 mg/l is necessary.