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.

Aims The aims of this study were to describe paracetamol pharmacokinetics in neonates and infants. Methods Infants in their ®rst 3 months of life (n=30) were randomised to sequentially receive one of three paracetamol formulations (dose 30±40 mg kg x1 ) over a 2 day period. The formulations were (a) elixir, (b) glycogelatin capsule suppository and (c) triglyceride base suppository. Approximately six blood samples were taken after each dose over the subsequent 10±16 h. Data were analysed using a nonlinear mixed effect model. These neonatal and infant data were then included with data from four published studies of paracetamol pharmacokinetics (n=221) and age-related pharmacokinetic changes investigated. Results Population pharmacokinetic parameter estimates and their coef®cients of variation (CV%) for a one compartment model with ®rst order input, lag time and ®rst order elimination were volume of distribution 69.9 (18%) l and clearance 13.0 (41%) l h x1 (standardized to a 70 kg person). The volume of distribution decreased exponentially with a half-life of 1.9 days from 120 l 70 kg x1 at birth to 69.9 l 70 kg x1 by 14 days. Clearance increased from birth (4.9 l h x1 70 kg x1 ) with a halflife of 3.25 months to reach 12.4 l h x1 70 kg x1 by 12 months. The absorption halflife (t abs ) for the oral preparation was 0.13 (154%) h with a lag time (t lag ) of 0.39 h (31%). Absorption parameters for the triglyceride base and capsule suppositories were t abs 1.34 (90%) h, t lag 0.14 h (31%) and t abs 0.65 (63%) h, t lag 0.54 h (31%), respectively. The t abs for elixir and capsule suppository in children under 3 months were 3.68 and 1.51 times greater than children over 3 months. The relative bioavailability of rectal formulations compared with elixir were 0.67 (30%) and 0.61 (23%) for the triglyceride base and capsule suppositories, respectively. Conclusions Total body clearance of paracetamol at birth is 62% and volume of distribution 174% that of older children. A target concentration above 10 mg l x1 in approximately 50% subjects can be achieved by a dose from 45 mg kg x1 day x1 at birth and up to 90 mg kg x1 day x1 in 5-year-old children. A reduced dose of 75 mg kg x1 day x1 in an 8-year-old child is suf®cient because clearance is a nonlinear function of weight.

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Letters Rectal and oral acetaminophenSir, Drs Hahn and colleagues measured acetaminophen serum and saliva concentrations in women after minor gynaecological surgery and reported good agreement between both methods (1). Concentrations after rectal administration of a conventional dose of acetaminophen (about 20 mg ¡ kg ª1 ) were low (8.5 mg ¡ l ª1 ), and therapeutic antipyretic concentrations (10-20 mg ¡ l ª1 ) were only achieved after repeated oral doses. Acetaminophen concentrations of 15.5 mg ¡ l ª1 were reached 6 h after the administration of an initial dose of 2000 mg rectal acetaminophen, and a repeat dose of 1000 mg oral acetaminophen 4 h later. The total dose administered (3000 mg) corresponded to approx. 43 mg ¡ kg ª1 .In a recent investigation, we observed similar acetaminophen concentrations after rectal administration to women undergoing hysterectomies (2). A single dose of 20 mg ¡ kg ª1 acetaminophen, given at induction of anaesthesia, resulted in subtherapeutic plasma levels (Ͻ10 mg ¡ l ª1 ). Twice the conventional dose (40 mg ¡ kg ª1 ) produced antipyretic plasma concentrations, but was not associated with improved postoperative analgesia or a reduction in the use of self-administered morphine at any time during the first 24 h after surgery.Effective analgesic plasma concentrations have not been defined, but are likely to be higher than those associated with antipyresis (3). We are currently investigating in a randomized, placebo-controlled study, plasma concentrations and analgesic effects after a single dose of 50 mg ¡ kg ª1 rectal acetaminophen given at induction of anaesthesia. The patient population and the study design are similar to our previous investigation. We observed maximal plasma concentrations (C max ) of 20 mg ¡ l ª1 (nΩ 11); the average time (T max ) to maximal concentration was 4 h. Six hours after drug administration, the mean acetaminophen plasma level was 16.5 mg¡l ª1 . This value is comparable to the respective concentrations reported by the authors after combined rectal and oral administration of a total dose of approx. 43 mg ¡ kg ª1 . For our patients, postoperative morphine consumption in the acetaminophen group was reduced by almost 50% (22 mg vs. 43 mg in 24 h) compared with the placebo group (nΩ12).We agree with the authors that postoperative administration of a conventional dose of rectal acetaminophen is irrational. The absorption of rectal acetaminophen is slow and maximal concentrations are reached with an average delay of 4 h. The exact dose and dosing intervals that are required to attain and sustain effective analgesic plasma concentrations have yet to be determined. Our results suggest that effective analgesic concentrations can be achieved with a single rectal dose of acetaminophen, provided the dose is large enough and given early to account for the prolonged absorption. Similiarly, with repeated dosing, acetaminophen concentrations can only be effectively sustained above the ''analgesic threshold'' if a larger dose and shorter dosing intervals than currently re...