Fracture Healing and Pain Tolerance in Aging Populations

Abstract

Introduction: Delayed fracture healing is associated with increased morbidity and mortality, and patients with fractures suffer from injury-associated pain as well as post- operative surgical pain. Age is associated with an increased risk of fracture and delayed/impaired fracture healing. Opioids are commonly prescribed for post-orthopedic pain mitigation. Opioids, beyond eliciting cognitive impairment, are commonly associated with tolerance and addiction. This class of drugs, including buprenorphine, may also be associated with a slower resolution of pain and functional status. Objective: Here we used a mouse femoral segmental bone defect (SBD) bone repair model to examine the impact of opioids and fracture/fracture healing on pain behaviors in old and young mice. Methods: Young (3-4-month-old) and old (22-24-month-old) C57BL/6 male mice underwent a SBD surgery (8-10 mice/group). Animals were treated with either bone morphogenetic protein 2 (BMP-2) or vehicle (saline). Bone healing was examined via longitudinal x-rays and terminal micro-computed tomography (μCT). All mice were subjected to a three-day course of buprenorphine. Stimulus dependent mechanical and thermal pain thresholds as well as stimulus independent locomotion activity and exploration behavior were determined before and after SBD surgery/opioid exposure. Addition-ally, asymmetric directed pain behaviors including flinching, licking, lifting, shaking of the ipsilateral hindlimb were assayed in both treatment groups at post-injury timepoints using 20- minute-long video sessions by blinded observers. All animal procedures were approved by the Indiana University IACUC. Results: The ability of BMP-2 to enhance SBD bone union was evident by 2 weeks post-surgery (x-ray) and the return to pre-injury levels of ambulation/locomotion activity was observed by week 4. Vehicle-treated SBD mice did not meet these milestones even at 8 weeks post-surgery. The relative change in tactile allodynia was determined between baseline and 2 weeks post-surgery for young and old mice treated with saline or BMP-2. Contrary to what would be expected, all 4 groups: old, young, healed and unhealed had a reduction of their pain threshold by ~70% at 2 weeks post-surgery (p\u3e0.05). Stimulus- independent pain behavior was also evident in both vehicle and BMP-2 treated CSD animals as defined by asymmetric directed behaviors including flinching, licking, lifting, and shaking of the ipsilateral hindlimb. Conclusion: The data indicates that post-fracture pain thresholds are similar between both healed and unhealed, young and old mice. Therefore, the effect of musculoskele-tal injury and/or buprenorphine may be responsible for the pain experienced following trauma. Distinguishing between these will be critical for further understanding how to best treat acute and chronic pain associated with musculoskeletal injury, particularly for geriatric patients