**Transdermal Fentanyl Uptake at Two Di**ff**erent Patch Locations in Swiss White Alpine Sheep**

**Tim Buchholz 1, Maria Hildebrand 1, Anja Heider 2, Valentina Stenger 1, Daniel Arens 1, Claudia Spadavecchia 3 and Stephan Zeiter 1,\***


Received: 20 August 2020; Accepted: 11 September 2020; Published: 17 September 2020

**Simple Summary:** Providing adequate and prolonged pain relief to sheep undergoing invasive orthopedic surgery while keeping side effects and stress for the animals at a minimum is challenging. Transdermal patches continuously releasing the synthetic opioid fentanyl through the skin, are a frequently used method in veterinary and human medicine. To refine the current analgesia protocol, we compared the uptake of fentanyl from a transdermal fentanyl patch applied at two different skin locations in sheep. The fentanyl plasma levels were measured at different time points over five days. The patch applied on the foreleg resulted in a faster fentanyl uptake with higher peaks and a longer time within or above the target fentanyl plasma concentration when compared to the one on the thorax. Additionally, it was easier to apply the patch at the foreleg than at the thorax. Our findings sugges<sup>t</sup> that the fentanyl patch should be applied to the foreleg 3–6 h before the painful insult and that its effect should last at least 48 h.

**Abstract:** When using animals in biomedical research, investigators have the responsibility to ensure adequate analgesia. Currently, transdermal fentanyl patches (TFP) are often used to provide postoperative analgesia in large laboratory animals. The aim of this study was to compare the fentanyl uptake resulting from TFP applied at two different locations, namely the foreleg and the thorax, in healthy adult sheep. Twelve sheep received a TFP with an intended dosage of 2 ug/kg/h. Blood samples were taken at different time points over a period of five days and the fentanyl plasma levels were measured. The TFP applied on the foreleg allowed a faster fentanyl uptake with higher peaks and a longer time within or above the target concentration of 0.6–1.5 ng/mL, shown to be analgesic in humans, when compared to the one on the thorax. Assuming that the effective plasma concentration described for humans is providing analgesia in sheep as well, the present findings sugges<sup>t</sup> that it should be sufficient to apply the TFP 3–6 h before the painful insult and that its effect should last at least 48 h. Furthermore, when TFP are used to provide postoperative analgesia in sheep, they should be placed on the foreleg rather than on the thorax.

**Keywords:** 3R principles; refinement; analgesia; transdermal fentanyl patch; sheep
