Multicentered masked placebo-controlled phase 2 clinical study of an extended duration transdermal buprenorphine solution for postoperative pain in cats.

A prospective, double-masked, placebo-controlled, multicentered phase 2 clinical study was conducted to select the transdermal buprenorphine solution (TBS) dosage for the control of postoperative pain in cats. One-hundred fifteen (115) cats were randomized to a single topical dose of placebo solution, low-TBS dosage (1.91-2.07 mg/kg) or high-TBS dosage (4.27-4.88 mg/kg) prior to surgical reproductive sterilization in conjunction with forelimb onychectomy. The low- and high-TBS doses were applied 2-4 and 1-2 hours prior to surgery. Interactive pain assessments and physiological variables were quantified through 96 hours post-anesthetic recovery and rescue analgesia was administered any time that analgesia was considered inadequate. Cats requiring rescue analgesia were considered treatment failures. The estimated overall treatment success rates from generalized linear mixed effects model analysis were 0.10 (95% CI: [0.02-0.36]), 0.56 (95% CI: [0.25-0.83]), 0.71 (95% CI: [0.38-0.91]) in the placebo-, low-, and high-TBS dose groups, respectively. Success rates for both TBS treatment groups were superior to placebo. Adverse events were infrequent in all treatment groups although the postoperative body temperatures over the duration of the study were on average 0.31 (95% CI: [0.08-0.55]) and 0.30 (95% CI: [0.05-0.53]) °C higher in low- and high-TBS dose cats, respectively, compared to placebo. It is concluded that both the low- and high-TBS dosages were safe and effective. The high-TBS dosage resulted in a greater proportion of treatment successes over 96 h, had a more acceptable preoperative application time of 1-2 h prior to surgery, and was therefore selected for further study.

Multicentered masked placebo-controlled phase 3 clinical study of an extended duration transdermal buprenorphine solution for post-operative pain in cats.

A prospective, double masked, placebo-controlled, multicentered phase 3 clinical study was conducted to evaluate the safety and effectiveness of transdermal buprenorphine solution (TBS) for the control of post-operative pain in cats. A total of 228 cats from 12 US investigational sites met the enrollment criteria of which 107 placebo- and 112 TBS-treated cats were included into the per protocol efficacy analysis. The dose of TBS was 8 mg (0.4 ml) to cats 1.2 to 3 kilograms and 20 mg (1 ml) to cats >3 to 7.5 kilograms applied topically to the dorsal unclipped cervical skin 1-2 h prior to the undergoing elective surgical reproductive sterilization in conjunction with forelimb onychectomy. Interactive pain assessments and physiological variables were quantified through 96 h following recovery from anesthesia, and rescue analgesia was administered any time that pain control was scored inadequate. Cats requiring rescue analgesia or experiencing an adverse event suspected to be treatment related were considered treatment failures. Sixty-five and 23 cats were considered treatment failures in the placebo and TBS groups, respectively, with most occurring on the day of surgery. The treatment success rates were 0.40 (95% confidence interval [CI]: [0.28-0.53]) and 0.81 (95% CI: [0.70-0.89]) in the placebo and TBS groups, respectively, and the difference was significant (p < .05). Adverse events occurred at a similar frequency and were not clinically meaningful in either treatment group. The post-operative body temperatures over the duration of the study were on average 0.35 (95% CI: [0.20-0.50]) °C higher than baseline in TBS-treated cats and were not clinically meaningful, an observation typical of opioids in cats. These results serve as substantial evidence that TBS is safe and effective for the control of orthopedic and soft tissue post-operative pain in cats when a single topical dose is applied 1-2 h prior to surgery.

Margin of safety of extended-duration transdermal buprenorphine solution following multiple-dose administrations to cats.

Transdermal buprenorphine solution (TBS) is approved for the control of postoperative pain in cats where a single preoperative dose provides 4 days of analgesia. It is administered as a unit dose of 8 mg to cats weighing 1.2-3 kg and 20 mg to cats weighing to >3-7.5 kg, which is equivalent to a dosage on a bodyweight basis of 2.7-6.7 mg/kg. In this safety study, the 1X dose was defined as 6.7 mg/kg. Thirty-two cats (16 males and 16 females) were randomly allocated to placebo, 1, 2, and 3X TBS administered topically to the dorsal cervical skin every 4 days for 3 doses. Clinical observations, behavioral scores, mydriasis score (yes/no), and physiological variables were assessed or measured prior to each dose administration (0 h) and at 1, 2, 4, 8, 12, 24, 36, 48, and 72 h following each treatment and prior to euthanasia on Day 12 or 13. Blood samples for clinical pathology were collected on Days - 1, 4, 8, and prior to euthanasia. There was little evidence of respiratory, cardiovascular, or gastrointestinal effects. Respiratory rates were above the reference range in all groups and lower by 10 breaths/min in the 3X group during the third dosing interval compared to placebo. There were no differences in heart rates. Constipation was transiently observed in approximately equal numbers in placebo- and TBS-treated cats. Behavioral scores showed sedation or euphoria was transient in the first dosing interval but became more prolonged with each dosing interval. Mydriasis was prolonged in the first dosing interval and diminished by the third dosing interval consistent with accommodation. Mean body temperatures in TBS-treated cats were up to 0.6°C (1.8°F) greater than placebo-treated cats. There were no clinically relevant changes to serum chemistry, hematology, or urinalysis outcomes nor gross or microscopic observations attributable to TBS. These data demonstrate that TBS is safe and well-tolerated when administered to 16-week-old cats at multiples of the approved dose and duration and supports clinical safety in the event of delayed buprenorphine metabolism, medication errors, or alterations in the dosing regimen.