Pharmacokinetics and Efficacy of a Long-lasting, Highly Concentrated Buprenorphine Solution in Mice

Abstract

Buprenorphine is a commonly used opioid for mitigating pain in laboratory mice after surgical procedures; however, the dosing interval necessary for standard buprenorphine may require treatment every 4 to 6 h to maintain an adequate plane of analgesia. An alternative formulation that provides prolonged plasma concentration with long-lasting effects would be beneficial in achieving steady-state analgesia. We evaluated a long-lasting and highly concentrated formulation of buprenorphine(Bup-LHC) in mice. Pharmacokinetic analysis was performed to assess plasma concentrations in male C57BL/6J (B6)and female CD1 mice after subcutaneous injection of 0.9 mg/kg. The Bup-LHC formulation provided plasma drug levels that exceeded the therapeutic level for at least 12 h in male B6 mice and was below therapeutic levels by 8 h in female CD1 mice. An experimental laparotomy model was used to assess analgesic efficacy. Female CD1 mice were treated with either Bup-LHC (0.9 mg/kg) or saline at 1 h before undergoing an ovariectomy via a ventral laparotomy. At 3, 6, 12, 24, and 48 h after surgery, pain was assessed based on the following behaviors: orbital tightness, grooming, wound licking, rearing, arched posture, ataxia, piloerection, nest building, and general activity. At 3 and 6 h after surgery, Bup-LHC–treated mice had significantly less wound licking and orbital tightness and considerably higher activity levels than did saline-treated mice. At 12 h, wound licking, orbital tightness and activity in Bup-LHC–treated mice were no longer significantly different from those of saline-treated mice. The results of this study suggest that Bup-LHC at 0.9 mg/kg provides sufficient plasma concentrations for analgesia in mice for 6 to 12 h after administration, as demonstrated behaviorally for at least 6 h after surgery.

A pharmacokinetic study of extended‐release buprenorphine in cynomolgus monkeys (Macaca fasicularis)

“…Providing appropriate analgesia is seen as a moral and ethical imperative in contemporary laboratory animal medicine. Opioids are widely used in laboratory animals because of their potent analgesia, efficacy in a wide range of moderate to severe pain models, parenteral dosage form, high therapeutic index, and well defined, but minimal side effects when used appropriately, including minor effects on immune function when used appropriately 1–5 …”

“…Opioids are widely used in laboratory animals because of their potent analgesia, efficacy in a wide range of moderate to severe pain models, parenteral dosage form, high therapeutic index, and well defined, but minimal side effects when used appropriately, including minor effects on immune function when used appropriately. [1][2][3][4][5] Use of BUP is an essential part of the foundation of pain management for non-human primates. Results from an earlier pharmacokinetic (PK) study demonstrated that a single 0.2-mg/kg subcutaneous…”

Effects of Analgesics on Tumor Growth in Mouse Models of Prostate Cancer Bone Metastasis

“…Weighted κ scores measuring interrater reliability of radiographic scoring of C57BL/6 mice (0.505) indicated moderate agreement between raters. 15 Welfare indices revealed sporadic differences between groups, but no consistent effects (Figures 2 B, D, and E). Nociceptive differences (measured using Von Frey filaments) between right and left legs and locomotion (distance traveled) were not significantly different from baseline at any time point.…”

“…Weighted κ scores measuring interrater reliability of radiographic scoring of SCID mice (0.613) indicated moderate agreement between raters. 15 Welfare indices revealed sporadic differences between groups (Figures 3 B, D, and E). No significant differences in nociception were detected between any groups.…”

“…To our knowledge, no information is available on the pharmacokinetics of subcutaneous buprenorphine or carprofen until 1 or 2 h respectively after administration. 10,15 Carprofen and buprenorphine are recommended to be administered every 12 h in mice, 34 so their effects could have disappeared by the time we performed our first set of welfare tests 24 h after intratibial injection. However, administering analgesics earlier or more frequently would result in increased handling of the mice, potentially introducing a stress confounder to our experiment.…”