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

Self Cite

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.

Section: Discussionsupporting

confidence: 88%

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

Clark¹,

Linton²,

Freise³

et al. 2022

Self Cite

“…Over the study duration, mean body temperatures were on average 0.35 (95% CI: [0.20–0.50])°C (Figure 3) higher than baseline in TBS‐treated cats. The temperature increase was similar in magnitude to that consistently observed in two laboratory studies and a clinical study of TBS in cats (Clark et al, 2022a). As before, the increased body temperature was not considered clinically meaningful.…”

Section: Discussionsupporting

confidence: 87%

“…A prior study demonstrated that following a single topical application of TBS, buprenorphine forms a depot in the skin resulting in prolonged systemic release with half‐lives of 78.3–91.2 h, typical of flip‐flop pharmacokinetics (PK) (Freise, Reinemeyer, Warren, et al, 2022) whereby the downward slope on a buprenorphine plasma concentration‐time plot is the result of drug absorption rather than drug elimination mechanisms (Toutain & Bousquet‐Melou, 2004). Two candidate doses were examined in a phase 2 clinical study (Clark et al, 2022a). In the phase 2 study, a TBS dose that was administered 1–2 h prior to surgery was differentiated from a lower TBS dose that was administered 2–4 h prior to surgery.…”

Section: Introductionmentioning

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

Self Cite

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.

“…When TBS was administered to healthy cats up to three times the labeled dose every 4 days over 12 days, respiratory rates remained above the normal range, without clinically relevant changes (Clark, Linton, Freise, Reinemeyer, et al, 2022). In laboratory and clinical studies where buprenorphine was administered with a variety of anesthetics drugs, there was a lack of respiratory depression or clinically meaningful changes in arterial or expired partial pressures of carbon dioxide (pCO 2 ; Akkerdaas et al, 2001; Bellini et al, 2017; Clark et al, 2022a, 2022b; Grint et al, 2009; Ilkiw et al, 2002; Shah et al, 2019; Warne et al, 2016).…”

Section: Pharmacology and Mechanism Of Actionmentioning

confidence: 99%

“…In a placebo‐controlled study of healthy 16‐week‐old cats, TBS was administered up to three times the labeled dose every 4 days over 12 days, and the mean body temperatures in TBS‐treated cats were up to 0.6°C higher, being transient in the first dosing interval, and not rising above normal in subsequent dosing intervals, suggestive of accommodation (Clark, Linton, Freise, Reinemeyer, et al, 2022). In two clinical studies with TBS, postoperative body temperatures were mildly increased over the study duration compared to baseline (Clark et al, 2022a, 2022b). The observed TBS‐associated modest increase in body temperature is consistent with that reported for other buprenorphine formulations used in cats and is not considered clinically relevant (Cannarozzo et al, 2020; Posner et al, 2010; Steagall et al, 2014).…”

Section: Pharmacology and Mechanism Of Actionmentioning

confidence: 99%

The history and pharmacology of buprenorphine: New advances in cats

Clark¹

2022

Self Cite

Buprenorphine was originally synthesized as an alternative opioid analgesic with antinociceptive and narcotic antagonist properties without side effects and abuse potential (Cowan et al., 1971). Designated candidate M6029 (later RC6029-M), buprenorphine was first synthesized in 1966 from thebaine, a component of opium without opiate activity (Cowan, Lewis, & Macfarlane, 1977). Buprenorphine is of the oripavine class of opioids with the chemical designation N-cyclopropylmethyl-7 a-(I-S-hydroxy, 1,2,2-trimethylpropyl)-6,