Retrospective investigation of an association between high-dose buprenorphine and perpetuation of post-anesthesia hyperthermia in cats following ovariohysterectomy

Buprenorphine is effective for the control of postoperative pain in cats (Steagall, Monteiro-Steagall, and Taylor 2014). Two pharmaceutical buprenorphine formulations have been approved for use in cats. The first, a low concentration buprenorphine solution (0.3 mg/ ml) was approved for use as intramuscular (IM) and intravenous (IV) injection (0.01-0.02 mg/kg) in 1995 in the United Kingdom (UK) ("Vetergesic; Ceva Animal Health 1995") and later in several other regulatory jurisdictions. It has not been approved in the United States (US) to date. In thermal threshold antinociceptive studies with the labeled dose of the low concentration buprenorphine solution, IV and IM injections to cats have a duration-of-action ranging from

“…for buprenorphine (Cannarozzo et al, 2020). The result from the present study also showed an increase in body temperature in cats administered TBS.…”

Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

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

Clark¹,

Linton²,

Freise

et al. 2022

“…Each were treated with dexamethasone and observed for the remainder of the study without further incident. As with other opioid-induced hyperthermia in cats (Cannarozzo et al, 2021;Posner et al, 2010), clinicians should be aware that TBS may cause small and transient increases in body temperature following surgery and not mistake this observation for inflammation or infection.…”

Section: Discussionmentioning

confidence: 99%

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

Clark¹,

Linton²,

Freise

et al. 2022

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.

“…Euphoria was present in at least 1 cat at all doses through 3 days post‐dosing, as was mydriasis at the 50 mg dose. The observed modest increase in body temperature is known to occur with buprenorphine in cats, though it is not generally considered to be clinically relevant (Cannarozzo et al, 2021; Posner et al, 2010; Steagall et al, 2014). The mean temperatures remained 0.6–0.9°C greater than baseline (37.4–37.8°C) through 168 h post‐dosing, but never reached ≥40.0°C in any individual cats.…”

Section: Discussionmentioning

confidence: 99%

Single‐dose pharmacokinetics and bioavailability of a novel extended duration transdermal buprenorphine solution in cats

Freise¹,

Reinemeyer

Warren

et al. 2022

A novel transdermal buprenorphine solution (TBS) was developed for evaluation in order to make available an extended duration opioid analgesic for cats. Healthy adult cats were administered a single TBS dose of 10 mg (1.57–4.35 mg/kg), 30 mg (4.72–13.0 mg/kg), or 50 mg (7.87–21.7 mg/kg) (4 cats per group) applied topically to the unclipped dorsal cervical skin and plasma buprenorphine concentrations were evaluated through 7 days. To determine the absolute bioavailability of TBS, healthy cats were administered single TBS dose of 20 mg (3.33–4.76 mg/kg) or 0.05 mg (0.008–0.011 mg/kg) IV buprenorphine (6 cats per group). The mean ± standard deviation maximum plasma buprenorphine concentrations (Cmax) were 10.5 ± 6.28, 18.6 ± 8.68, and 22.5 ± 4.47 ng/ml following 10, 30, and 50 mg doses, respectively, with the time of Cmax occurrence (tmax) typically occurring at 2–12 h post‐dosing. Mean plasma buprenorphine terminal half‐lives ranged between 78.3 and 91.2 h. Increasing the dose threefold and fivefold from the 10 mg dose increased the exposure by 2.8‐ and 3.6‐fold, respectively, indicating that plasma buprenorphine exposure increased in a less than proportional manner at doses >30 mg. Transient sedation, mydriasis, and euphoria were observed within 4 h post‐dosing. Mean rectal temperatures were increased 0.6–0.9°C greater than baseline (37.4–37.8°C) through 168 h post‐dosing. The absolute bioavailability was 16.0% (90% CI: [11.8%–21.7%]). Flip‐flop pharmacokinetics were observed with a terminal elimination half‐life of 0.82 ± 0.13 and 64.9 ± 15.0 h for IV buprenorphine and 20 mg of TBS, respectively. A single administration of TBS over a range of doses resulted in extended plasma buprenorphine concentrations and opioid physiological and behavioral effects.