Evaluation of diurnal variation in fentanyl clearance

Drug disposition kinetics are commonly assumed to be time-invariant as a first approximation. In a preliminary study, 6 healthy volunteers received a constant intravenous infusion of 50 micrograms/h for 48 hours; the serum fentanyl concentration at 36 hours was lower than that at 24 hours for all 6 subjects. This suggested possible diurnal variations in fentanyl clearance. In 2 subsequent studies, with healthy volunteers receiving short infusions of fentanyl (n = 9, 150 micrograms/h for 0.33 hours every 4 hours; n = 12, 150 micrograms/h for 0.33 hours every hour, respectively), the area under the serum fentanyl concentration curve appeared to be independent of the time of infusion. Thus, there was no evidence to support a large diurnal change in fentanyl clearance. The serum fentanyl concentration-time profiles, corrected for carryover from previous doses, within each study were superimposable. This suggests that there are no diurnal changes in the distribution kinetics of fentanyl.