title: Safety studies of post-surgical buprenorphine therapy for mice.
abstract: The use of appropriate analgesia in laboratory mice may be suboptimal because of concerns about adverse events (AE). Target Animal Safety trials were conducted to determine the safety of an extended-release suspension of buprenorphine. Drug or control suspensions were injected subcutaneously in surgically-treated BALB/c mice anesthetized with ketamine-xylazine to mimic post-operative conditions in which the compound might commonly be administered. Single and repeat five-fold (5×) excesses of the 3.25 mg/kg intended dose were used to provoke potential AE. Trials included prospective measurements of weight changes, blood chemistry, hematology, and histopathology. Clinical and histopathology findings were similar in drug-treated and control mice in a four-day trial using a single 16.25 mg/kg, 5× overdose of the drug. In a 12-day trial, which used a total buprenorphine dose of 48.75 mg/kg, clinical and histopathology values were also similar in control and drug-treated female mice. In the male arm of the repeat-overdose trial, two of eight mice died on the morning of day 12, three days following the third 16.25 mg/kg overdose administration. Histopathology did not reveal a cause of death. In a 14-month trial using a single 3.25 mg/kg dose of the drug, no significant findings identified potential AE. These findings indicate a high tolerance to an extended-release buprenorphine suspension administered post-operatively in mice with appropriate husbandry.
authors.affiliation: Pharmaceutical Consulting, Lawrenceville, NJ, USA.
authors.forename: Karl A
authors.initials: KA
authors.lastname: Traul
authors.affiliation: Johns Hopkins School of Medicine, Department of Molecular and Comparative Pathobiology, Baltimore, MD, USA.
authors.forename: Jennell B
authors.initials: JB
authors.lastname: Romero
authors.affiliation: Johns Hopkins School of Medicine, Department of Molecular and Comparative Pathobiology, Baltimore, MD, USA.
authors.forename: Cory
authors.initials: C
authors.lastname: Brayton
authors.affiliation: University of Maryland, School of Medicine, Departments of Pathology, Medicine, Division of Infectious Diseases and Public Health, and the Program of Comparative Medicine, Baltimore, MD, USA.
authors.forename: Louis
authors.initials: L
authors.lastname: DeTolla
authors.affiliation: Johns Hopkins School of Medicine, Department of Molecular and Comparative Pathobiology, Baltimore, MD, USA.
authors.forename: Nadine
authors.initials: N
authors.lastname: Forbes-McBean
authors.affiliation: Virginia Commonwealth University School of Pharmacy, Department of Pharmaceutics, Richmond, VA, USA.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Halquist
authors.affiliation: Virginia Commonwealth University School of Pharmacy, Department of Pharmaceutics, Richmond, VA, USA.
authors.forename: H Thomas
authors.initials: HT
authors.lastname: Karnes
authors.affiliation: Johns Hopkins School of Medicine, Department of Neurological Surgery, Baltimore, MD, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Sarabia-Estrada
authors.affiliation: Nova Pathology, Bellingham, WA, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Tomlinson
authors.affiliation: Johns Hopkins School of Medicine, Department of Neurological Surgery, Baltimore, MD, USA.
authors.forename: Betty M
authors.initials: BM
authors.lastname: Tyler
authors.affiliation: Johns Hopkins School of Medicine, Department of Neurological Surgery, Baltimore, MD, USA.
authors.forename: Xiaobu
authors.initials: X
authors.lastname: Ye
authors.affiliation: Johns Hopkins School of Medicine, Department of Neurological Surgery, Baltimore, MD, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Zadnik
authors.affiliation: Johns Hopkins School of Medicine, Department of Neurological Surgery, Baltimore, MD, USA mguarnieri@comcast.net.
authors.forename: Michael
authors.initials: M
authors.lastname: Guarnieri
mesh_terms: D000701:Analgesics, Opioid / Q000009:adverse effects*; D000818:Animals; D001774:Blood Chemical Analysis; D002047:Buprenorphine / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006403:Hematologic Tests; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011184:Postoperative Period; D011446:Prospective Studies
chemical_list: D000701:Analgesics, Opioid; D002047:Buprenorphine
keywords: adverse events; analgesia; buprenorphine; extended-release; mice