*2.1. Study Design*

This experimental, prospective, randomized study was approved by the Cantonal Committee for Animal Experiments of Graubünden (GR-TVB No. 35\_2018) and conducted in an AAALAC International approved facility. The sheep were randomly assigned to one of two equal groups (*n* = 6 per group) by drawing lots. An ear tag with an internal consecutive number was used as identification. In one group, the TFP (fentanyl Mepha ® Matrix patches/Mepha Pharma AG/57362) was applied to the foreleg and in the other group to the thorax (Figure 1)

**Figure 1.** Study Design Overview—The letter "F" in the first picture shows the locations of the TFP on the sheep. However, only one location was used per sheep. After application of a transdermal fentanyl patch (TFP) to one of two possible locations depending on group allocation, fentanyl plasma levels were measured at di fferent time points.

The foreleg was defined as the middle of the lateral surface starting from the elbow joint proximally and ending at carpal joint distally. The region of the thorax was defined as approx. 5 cm caudal from

the scapula, at the thorax (Figure 2). The primary outcome, the fentanyl plasma level, was measured at 12 different time points.

**Figure 2.** Transdermal fentanyl patch location—left picture: foreleg, right picture: thorax.
