Abstract
Adequate analgesia is essential whenever pain might occur in animal experiments. Unfortunately, the selection of suitable analgesics for mice in bone-linked models is limited. Here, we evaluated two analgesics – Tramadol [0.1 mg/ml (Tlow) vs. 1 mg/ml (Thigh)] and Buprenorphine (Bup; 0.009 mg/ml) – after a pre-surgical injection of Buprenorphine, in a mouse-osteotomy model. The aim of this study was to verify the efficacy of these opioids in alleviating pain-related behaviors, to provide evidence for adequate dosages and to examine potential side effects. High concentrations of Tramadol affected water intake, drinking frequency, food intake and body weight negatively in the first 2–3 days post-osteotomy, while home cage activity was comparable between all groups. General wellbeing parameters were strongly influenced by anesthesia and analgesics. Model-specific pain parameters did not indicate more effective pain relief at high concentrations of Tramadol. In addition, ex vivo high-resolution micro computed tomography (µCT) analysis and histology analyzing bone healing outcomes showed no differences between analgesic groups with respect to newly formed mineralized bone, cartilage and vessels. Our results show that high concentrations of Tramadol do not improve pain relief compared to low dosage Tramadol and Buprenorphine, but rather negatively affect animal wellbeing.
Highlights
Untreated or insufficiently treated pain hampers animal welfare and may have diverse and uncontrollable effects on an organism, such as impaired wound healing, blood flow disorders, or immunosuppression[1,2,3]
Video analysis for 48 h starting 9 h after osteotomy enabled the examination of the drinking frequency and the monitoring of continuous analgesia up-take (Fig. 1b,c)
This study evaluated three used analgesia protocols, Tramadol (0.1 mg/ml = Tramadol per mouse would be 0.49 mg (Tlow) vs. 1 mg/ml = Thigh) and Buprenorphine (0.009 mg/ml) administered via drinking water, in a mouse osteotomy model after a pre-operative injection of Buprenorphine
Summary
Untreated or insufficiently treated pain hampers animal welfare and may have diverse and uncontrollable effects on an organism, such as impaired wound healing, blood flow disorders, or immunosuppression[1,2,3]. The opioid Buprenorphine and the opioid analogue Tramadol are applied widely in many fields of research, empirical data on effective doses for rats and mice are rare, and dosage recommendations vary substantially in the literature. Buprenorphine is a commonly used fast acting and potent opioid that is mainly administered s.c. or i.p. in dosages of 0.05–0.75 mg/kg every 12 h recent studies indicate the short half-life and recommend the administration at every 4–6 h10. For example, is used in high dosages for bone cancer models (>50–100 mg/kg s.c.)[11], but appears effective in lower concentrations to treat acute pain[12]. To our knowledge, no evidence-based recommendations exist for the treatment of osteotomy pain with Tramadol or Buprenorphine. The need for evidence-based and empirical data on the dosage and effectiveness of analgesics in bone research is apparent and further studies must be enrolled
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