Fentanyl Pharmacokinetics in Pregnant Sheep after Intravenous and Transdermal Administration to the Ewe.

Abstract

Fentanyl is used for pain treatment during pregnancy in human beings and animals. However, fentanyl pharmacokinetics during pregnancy has not been fully established. The aim of this study was to characterize fentanyl pharmacokinetics in pregnant sheep after intravenous and transdermal dosing during surgical procedure performed to ewe and foetus. Pharmacokinetic parameters reported for non-pregnant sheep and nominal transdermal dose rate were utilized for a priori calculation to achieve analgesic fentanyl concentration (0.5-2ng/ml) in maternal plasma. A total of 20 Aland landrace ewes at 118-127 gestational days were used. In the first protocol, 1week before surgery, 10 animals received 2μg/kg fentanyl intravenous bolus, and on the operation day, transdermal fentanyl patches at nominal dose rate of 2μg/kg/hr were applied to antebrachium, and ewes were then given a 2μg/kg intravenous bolus followed by an intra-operative 2.5μg/kg/hr infusion. In the second protocol, 10 animals received fentanyl only as transdermal patches on the operation day and oxycodone for rescue analgesia. The data were analysed with population pharmacokinetic modelling. Intra- and post-operative fentanyl concentrations were similar and slightly lower than the a priori predictions, and elimination and distribution clearances appeared slower during than before or after the surgery. Transdermal patches provided sustained fentanyl absorption for up to 5days, but the absorption rate was slower than the nominal dose rate and showed a high interindividual variability. Further research is warranted to evaluate the clinical relevance of the observations made in sheep.