Abstract:This study aimed to compare the effect of intranasal (IN) and intramuscular (IM) administration of butorphanol and zolazepam‐tiletamine (ZT) combination on intraocular pressure (IOP) and tear secretion (TS) in rabbits. Fourteen healthy male New Zealand White rabbits weighing 3.05 ± 0.72 kg, aged between 1 and 2 years old, were included in the study. Animals randomly received 0.5 mg/kg butorphanol and 15 mg/kg ZT combination either with IN or IM administration. IOP and TS were measured at baseline (T0), and followed by 5, 15, 30, 45, and 60 min after drug administration. The sedation variables, the time to onset of sedation, duration of sedation, and sedation scores were also recorded. The route of administration for the butorphanol and ZT combination had no significant effect on the mean IOP (p = .301) and TS (p = .445). Furthermore, there were no significant changes observed in the IOP (p = .472) and TS (p = .348) over time. The time to onset of sedation was earlier in the IN group (4.57 ± 0.79 min) than in the IM group (5.86 ± 0.9 min; p = .0004). The duration of sedation was significantly longer for IM (57.43 ± 3.41 min) compared with IN (45.0 ± 1.91 min; p < .0001). No significant difference in the sedation score was observed between groups at all time points. In conclusion, both IN and IM administration of the butorphanol and ZT combination in rabbits had similar effects on IOP and TS.