Pharmacokinetics and Analgesic Efficacy of a Novel Extended-Release Buprenorphine Formulation in Mice

Long-acting buprenorphine formulations present a remarkable refinement for the care and management of postoperative pain in rodents. We describe here the evaluation of a novel extended-release buprenorphine formulation (Bup ER) for use in laboratory mice. The pharmacokinetics of a single subcutaneous dose of Bup ER (5 mg/kg) were characterized in male and female CD-1 mice at 0.5, 2, 4, 8, 24, 48, 72, 96, 120, and 168 hours postinjection. Plasma buprenorphine concentrations exceeded 1 ng/mL within 0.5 hours and were maintained above this threshold for up to 120 hours postadministration. The analgesic efficacy of Bup ER was assessed using a tail flick thermal nociception assay and a plantar incisional hypersensitivity model. Mice received Bup ER (5 mg/kg SC, once) or saline (subcutaneously, once) prior to tail flick nociception testing or plantar incisional surgery with corresponding mechanical (von Frey) and thermal (Hargreaves) hypersensitivity testing. Tail flick thermal nociception testing for male and female CD-1 mice indicated significant differences in maximum possible effect between Bup ER and saline groups from 0.5 to 96 hours. Mechanical hypersensitivity was not observed in male or female Bup ER-treated groups for up to 96 hours. Although thermal hypersensitivity was observed in male and female mice that received Bup ER, mice presented significantly less thermal hypersensitivity (attenuation) compared with the saline group from 1 to 48 hours. No abnormal clinical observations were appreciated. Gross findings revealed mild erythema or alopecia at the injection site, and 3 mice developed skin ulcerations that were attributed to injection technique where use of small-gauge needles led to administration into the intradermal compared with subcutaneous space. Ulcerative lesions were not observed after procedures to confirm injection site administration were implemented. Bup ER provided effective postoperative analgesia for 48-96 hours in mice and demonstrated an extended plasma concentration profile up to 120 hours for long-acting analgesia.