**3. Results**

One rabbit was excluded from the study and subsequently replaced due to CNS symptoms occurring 18 h after patch application. Necropsy revealed a thromboembolism as the most likely reason for the symptoms, caused by repeated blood withdrawal.

### *3.1. Plasma Fentanyl Concentrations*

In group 1 (outer surface of the ear; Figure 2) plasma concentrations considered to be analgesic (0.5 ng/mL) was reached in 3 out of 6 rabbits 3 h after patch application, while all the animals in this group were above threshold at 9 h. In group 3 (neck; Figure 3), 2 out of 6 animals reached threshold at 3 h, while all 6 animals at 6 h (mean plasma concentration of 1.26 ng/mL). In contrast, only 1 out of 6 rabbits in group 2 (inner surface of the ear; Figure 4) reached the threshold at 18 h, while the others stayed below the threshold for the whole duration of the study.

**Figure 2.** Fentanyl plasma concentrations group 1 (outer surface of the ear).

**Figure 3.** Fentanyl plasma concentrations group 3 (neck).

**Figure 4.** Fentanyl plasma concentrations group 2 (inner surface of the ear).

Mean steady state concentrations in group 1 and 3 were similar (2.24 and 2.23 ng/mL) but the timing was different. Group 1 reached the peak concentration at 18 h, whereas group 3 at 48 h. Every animal of group 1 reached concentrations above 0.5 ng/mL between 9 and 48 h, while animals of group 3 between 6 and 72 h after patch application (Figure 5).

**Figure 5.** Fentanyl plasma concentrations of all groups.
