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Fentanyl was administered intravenously and transdermally to eight surgical patients to determine the systemic bioavailability and rate of absorption of the transdermally administered drug. Serum fentanyl concentrations reached a plateau approximately 14 h after placement of the transdermal fentanyl delivery system. This plateau was maintained until removal of the system at 24 h. The decline in serum fentanyl concentrations after removal of the transdermal system had a terminal half-life of 17.0 ± 2.3 h (mean ± SD), considerably longer than the terminal elimination half-life seen after intravenous administration of fentanyl in the same patients (6.1 ± 2.0 h). The rate of fentanyl absorption, predicted to be 100 μg/h from in vitro data, appeared to be relatively constant during a period starting 4–8 h after placement of the transdermal system until removal of the system at 24 h. The rate of absorption during this period was 91.7 ± 25.7 μg/h. After removal of the transdermal fentanyl delivery system, absorption continued at a declining rate. This indicates that the long terminal half-life of serum fentanyl concentrations after transdermal system removal is due to continued slow absorption of fentanyl, probably from a cutaneous depot of drug at the site of prior transdermal system placement. At the time of removal of the transdermal fentanyl system, 1.07 ± 0.43 mg of drug remained in this depot. Systemic fentanyl bioavailability was found to be 0.92 ± 0.33, with no evidence of significant cutaneous metabolism or degradation by the skin's bacterial flora. The transdermal administration of fentanyl produces relatively constant serum fentanyl concentrations for significant periods of time in the postsurgical patient requiring analgesic therapy.