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The pharmacokinetics of fentanyl were studied in fourteen neonates undergoing major surgical procedures. Five patients were less than 1 day of age, seven ruere 1–4 days old, and two were 7–14 days old. Fentanyl was given intravenously, 10 μg/kg (n = 1), 25 μg/kg (n = 4), or 50 μg/kg (n = 9), and plasma concentrations measured at intervals of up to 18 hr. Average weight was 2.9 kg. The injection of 25 or 50 μg/kg of fentanyl over 1–3 min was hemodynamically well-tolerated by all patients. Four newborns without respiratory impairment secondary to surgery or disease needed ventilatory support for an average of 24 hr (range 11–40 hr). Plasma concentrations of fentanyl were most appropriately described by a two-compartment model. The mean ± SEM values of selected model parameters were volume of the central compartment, 1.45 ± 0.34 L/kg; volume of distribution at steady state. 5.1 ± 1 L/kg; clearance, 17.94 ± 4.38 ml·kg−1·min−1; and terminal elimination half-life (t1/2,β), 317 ± 70 min. In seven patients transient rebound in plasma fentanyl concentrations of 0.5 ng/ml or greater occurred. In three patients patients with markedly increased intraabdominal pressure, the t1/2β was 1.5–3 times the population mean. Thus fentanyl disposition in neonates is highly variable, but the t1/2β is predictably prolonged in the presence of increased abdominal pressure.