Non-steroidal anti-inflammatory drugs’ (NSAIDs) chronotherapy may enhance bone healing after surgery

Introduction: Effective postoperative pain control is an essential and humanitarian need for any surgical procedure , including bone fracture. Inadequate pain control may cause significant morbidity, impaired recovery and increased hospital costs. Postoperative pain is often managed with opioids ; however, with the ongoing opioid epidemic, better therapeutic strategies ar e urgently needed. Non -steroidal anti -inflammatory drugs (NSAID) could be very useful for postoperative pain management . H owever, NSAID can impair bone healing outcome by influencing key inflammatory pathways. One promising avenue for optimized pain manag ement is rooted in the body’s biological circadian rhythm. This thesis aims to contribute to gaps in the knowledge of understanding the effect of NSAIDs administration on bone healing and the effect of timing drug administration on this process. Methods: To address these objectives, I used a combination of research methodologies. First, I conducted a systematic review and meta-analysis to estimate the effect of NSAIDs administration on fractured bone healing. Second, I comprised a series of experimental trials to test the hypothesis that the timing of NSAID administration affects postoperative fracture pain behavioural indices and bone healing measurements in a murine animal model. Also, these experiments aim to identify the inflammatory cytokines and metabolic pathways affected by the timing of NSAIDs administration. Finally, I developed a randomized clinical trial protocol to test the above hypothesis in human subjects. Results: The findings from the meta -analysis of the published animal studies confirmed the negative effect of NSAIDs after bone fracture but suggested that the negative effects of NSAIDs after bone fracture is different in mice compared to another animal model, in females compared to males and in younger compared with old animals. Our results from the quality risk assessment of the included studies demonstrated poorly repo rting of randomization, blinding, allocation concealment and sample size calculation. In our experimental trials, we showed that NSAIDs’ use is most effective in managing the pain and healing of bone fracture when they are administered during the active phase of the circadian rhythm in mice after bone fracture surgery. Limiting NSAIDs treatment to the active phase of the circadian rhythm we re mediated by changes in the expression of >500 genes at the surgical site, including the clock gene Per2, and increases the serum level of anti-inflammatory cytokines interleukin-13 (IL-13), interleukin-4 (IL-4) and vascular endothelial growth factor (VEGF). Finally, we have prepared a protocol for a randomized controlled trial (RCT), which has been approved by the Ethical R eview Board at the Jordan University of Science and Technology (Irbid, Jordan). The study is currently being conducted since May 2018. Conclusion: Our systematic review and meta- analysis indicated the need to conduct more controlled and high -quality pre-clinical animal studies regarding the effect of NSAID s on bone healing. Our preclinical trials using a murine tibia fracture surgic al model demonstrated that NSAIDs are most effective in managing postoperative pain, healing and recovery when administrated during the active phase of the circadian rhythm. Our results, if confirmed in RCT in humans, may change clinical practice of all bone-related surgical interventions.