Nine-Day Target Animal Safety Study: In a 9 day safety study, 4 month old healthy cats (4/sex/group) were administered SIMBADOL subcutaneously at 0X (saline), 1X (0.24 mg/kg), 3X (0.72 mg/kg), or 5X (1.2 mg/kg) once daily. All 32 cats survived to study termination.
Buprenorphine-related clinical observations included difficulty in handling, lower incidence of urination, abnormal oral dryness, dilated pupils, and decreased pupillary light reflex. The incidence of temperatures ≥103°F was higher in the buprenorphine-treated groups compared to the control group. The highest temperature observed in the buprenorphine-treated group was 103.8°F in a 5X cat.
One 1X cat and one 3X cat experienced an episode of hyperactivity, difficulty in handling, slight disorientation, agitation, dilated pupils (which were responsive to light), and respiratory sinus arrhythmia. One 1X cat (one episode) and one 3X cat (three episodes) were reported with nystagmus. One 1X and one 3X cat were reported with decreased blink response (one episode). Three cats in the 5X group lost body weight (79 g or less) during the study which correlated with decreased food consumption. All other cats gained weight during the study.
The incidence of “moderate responses” (minor vocalization or wincing and quick resolution) and “severe responses” (tried to bite or scratch or had marked vocalization or persistent attention to the injection site) to injection was higher in the buprenorphine-treated groups compared to the control group.
Respiratory rate, heart rate, and blood pressure were similar between all groups, including the control group.
Buprenorphine-related clinical pathology findings included an increase in creatine kinase values in the 3X and 5X groups and correlated with subcutaneous inflammation at the injection sites.
Histologic lesions included minimal to moderate subacute inflammation at the injection sites, which correlated with the administration of buprenorphine compared to the control group. The incidence of inflammation was similar between buprenorphine-treated groups; however, more sites with mild and moderate inflammation were observed in the 5X group compared to the 1X and 3X groups where more sites with minimal inflammation were observed. Mineralization at an injection site was seen in one 1X and one 3X cat. Chronic inflammation in the heart (valve or myocardium) was seen in two 5X cats. Subacute liver inflammation was seen in one control cat, two 1X cats, three 3X cats, and three 5X cats. Lymphoid hyperplasia of the mediastinal lymph node was seen in one 1X cat, and acute inflammation was seen in the mediastinal lymph node of one 3X cat. Lymphoid hyperplasia of the Peyer’s Patches was seen in two 1X cats and one 5X cat. Lymphoid hyperplasia, lymphocytic infiltrate, or subacute inflammation of the stomach was seen in four 1X cats, four 3X cats, and three 5X cats. Subacute inflammation or lymphocytic infiltrate of the thyroid glands was seen in two 1X cats, one 3X cat, and four 5X cats.
Arterial Blood Pressure Study in Cats: Healthy 8.5 to 29.1 month old cats (4/sex/group) were subcutaneously administered SIMBADOL at 0.24 mg/kg (1X) or meloxicam (control), 1 hour prior to anesthetic induction for a 1 hour exploratory laparotomy. Arterial blood pressure was monitored following anesthetic induction and through laparotomy, with indirect blood pressure monitoring prior to anesthesia and for 8 hours following anesthetic recovery. All 16 animals were clinically healthy for the duration of the study. There were no differences between treatment groups in mean blood pressure during the study.
During surgery and postoperatively, heart rate was higher for the buprenorphine group. During surgery, the incidence of heart rates ≥180 beats/minute was higher in the buprenorphine-treated group compared to the control group. Post-operatively, the incidence of heart rates ≥200 beats/minute was higher in the buprenorphine-treated group compared to the control group. During surgery, respiration rate was lower for the buprenorphine group. Post-operatively, body temperature was higher for the buprenorphine group. Four cats in the buprenorphine group had temperatures ≥103°F post-operatively compared to none in the control group. The highest temperature observed in the buprenorphine group was 104.3°F. Electrocardiograms were qualitatively normal in all cats. During surgery, one cat in the buprenorphine group had hemoglobin saturation less than 90% (88% at one time point).