A buprenorphine depot formulation provides effective sustained post-surgical analgesia for 72 h in mouse femoral fracture models

Abstract

Adequate pain management is essential for ethical and scientific reasons in animal experiments and should completely cover the period of expected pain without the need for frequent re-application. However, current depot formulations of Buprenorphine are only available in the USA and have limited duration of action. Recently, a new microparticulate Buprenorphine formulation (BUP-Depot) for sustained release has been developed as a potential future alternative to standard formulations available in Europe. Pharmacokinetics indicate a possible effectiveness for about 72 h. Here, we investigated whether the administration of the BUP-Depot ensures continuous and sufficient analgesia in two mouse fracture models (femoral osteotomy) and could, therefore, serve as a potent alternative to the application of Tramadol via the drinking water. Both protocols were examined for analgesic effectiveness, side effects on experimental readout, and effects on fracture healing outcomes in male and female C57BL/6N mice. The BUP-Depot provided effective analgesia for 72 h, comparable to the effectiveness of Tramadol in the drinking water. Fracture healing outcome was not different between analgesic regimes. The availability of a Buprenorphine depot formulation for rodents in Europe would be a beneficial addition for extended pain relief in mice, thereby increasing animal welfare.

Embracing ethical research: Implementing the 3R principles into fracture healing research for sustainable scientific progress

“…Besides a reliable and sufficient pain assessment and management during invasive procedures, the general enhancement of the animal's well‐being, as a positive affective state, has become more into focus to minimize potential distress, to allow for the performance of naturalistic behaviors and to avoid potential bias in behavioral assessment by using, for example, environmental enrichment and noninvasive handling tools. Several studies have shown that a stimulating living environment, including the provision of houses, tubes, swings, different nesting materials, and explorative tools, is crucial for the development of natural behavior and ensures the well‐being and health status of mice 54 . The traditional confinement and monotony in conventional husbandry can have detrimental effects on laboratory rodents including compromised mental and physical health, boredom, behavioral abnormalities/stereotypies (e.g., barbering, circling, back‐flipping, wire/food gnawing), and increased mortality 55 .…”

“…Several studies have shown that a stimulating living environment, including the provision of houses, tubes, swings, different nesting materials, and explorative tools, is crucial for the development of natural behavior and ensures the wellbeing and health status of mice. 54 The traditional confinement and laboratory rodents including compromised mental and physical health, boredom, behavioral abnormalities/stereotypies (e.g., barbering, circling, back-flipping, wire/food gnawing), and increased mortality. 55 Several resources are available as inspiration for appropriate environmental enrichment 56 (i.e., https://www.nc3rs.…”

Evaluating rearing behaviour as a model-specific pain indicator in mouse osteotomy models

“…The data in this study were collected from video material recorded during a previous study. 17 For this present study, only the subgroup of animals receiving tramadol in the drinking water for post-interventional analgesia were assessed. 17 The in vivo study was conducted according to the guidelines of the German Animal Welfare Act, National Animal Welfare Guidelines, and was approved by the local Berlin state authority (Landesamt fu¨r Gesundheit und Soziales -LAGeSo; permit number: G0044/20).…”

“…Regular health monitoring was performed according to the FELASA guidelines (sentinels were partly tested positive for Murine norovirus, Helicobacter spp., Trichomonas spp., and other flagellates). 17,25 Housing conditions included a 12/12 h light/ dark cycle (lights out from 18:00 h to 06:00 h), a room temperature of 22 AE 2 C and a humidity of 55 AE 10%. Mice had access to tap water and food (Standard mouse diet, Ssniff Spezialdi€ aten, Soest, Germany) ad libitum.…”

“…In contrast, observational scoring of the presence of limping (equivalent to lameness) might not be as precise as automatic gait analysis systems although it can be used as a basic tool to assign numerical values to walking behaviours. 11,16,17 Rearing behaviour is a natural and non-evoked behaviour displayed by many mammals, including mice and rats, and has been assessed in different contexts for over 50 years. 18 Rearing is an explorative behaviour and requires the animal to put weight on its hindlimbs to get into the upright position.…”