gms | German Medical Science

Objectives: Adequate pain management is essential for ethical and scientific reasons in animal experiments. Choice of analgesics in fracture models is limited due to potential interference of anti-inflammatory drugs during the initial phase of healing. Depot formulations of Buprenorphine are only available in the US and attempts to import these to Europe have failed. Recently, development and use of a new PLGA-based microparticulate Buprenorphine formulation for sustained drug release in order to provide an alternative product in Europe was reported. Pharmacokinetic studies indicate a potential effectiveness for up to 72h. We investigated if administration of the new sustained-release buprenorphine (SR-Bup) ensures a continuous and sufficient analgesia in mouse fracture models as potent alternative to the application of tramadol via drinking water. Both pain management protocols were examined for analgesic efficacy and side effects on experimental readouts in femoral fracture models using rigid and flexible external fixators.

Methods: To include aspects such as fixation stiffness and sex, 8 groups (n=10/group) were investigated comparing post-surgical analgesia with the SR-Bup and the application of Tramadol for 1 day prior and 3 days post-surgical. Surgery was performed on 80 C57BL/6N mice (male and female) at 12 weeks age. Anesthesia was performed using isoflurane. The external fixator was fixed to the left femur, a 0.44 mm gap was created using a Gigli wire. After surgery respective mice received the SR-Bup s.c.. The other group received Tramadol via drinking water. Parameters of wellbeing and model-specific pain (gait, walking) were analyzed at different timepoints (12h - 14d post-surgery (ps)). The study was approved by the local authority (LAGeSo Berlin; No. G0044/20).

Results and conclusion: Body weight was decreased at 24h and 48h ps and reached the initial level at 72h in all groups. We observed slight differences in water uptake in the groups receiving Tramadol when compared to SR-Bup, independent of sex and fixation. A scoring system was applied to determine presence and degree of limping and dragging. Limping was partially observable in all groups for up to 72h ps with no differences between groups. Analysis of the time mice stood on the two hind legs (rear-up) during a 3 min observation time showed a decrease post surgery with no differences between treatments. Male mice showed less reduction in loading on the operated leg compared to females over 72h ps, analyzed by CatWalk. No differences were found regarding analgesia or fixation. MicroCT of the femora indicated differences between fixation methods and sexes but no obvious influence of the analgesic protocol.

Our data provide evidence that the administration of the newly developed sustained-release buprenorphine ensures a continuous and sufficient analgesia in mouse femoral fracture models without influence on the healing outcome, and therefore serves as potent alternative to the application of tramadol via drinking water.