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Reduction of pain and improved muscle biology with the administration of losartan and delayed exercise in a murine trauma model

Life-altering orthopaedic trauma contributes largely towards morbidity, mortality and healthcare costs in many communities. Arising from causes such as falls and motor vehicle collisions, these complex, multisystem injuries can have an enormous impact on the affected patient’s quality of life. During the healing process, it is well known that early mobilization and exercise are beneficial with respect to functional status, pain control and overall long-term outcomes. However, inappropriate timing of exercise can cause greater harm and increased pain. Thus, there is uncertainty about when to begin exercise after orthopaedic trauma. Also, patients who are immobilized or have various co-morbidities are unable to exercise post-injury. For these patients, innovations in pharmaceutical methods that can recapitulate the positive effects of mobilization and exercise are required. Additionally, acute and chronic pain is a significant issue in orthopaedic trauma. Often, this pain is treated with opioids, which are very effective analgesics but come with the great burden of addiction. This has partly contributed to the ongoing opioid crisis that has ensnared communities across North America. Finding an alternative to opioids for effective pain control would potentially diminish this public health problem. In a recent article published in The Journal of Physiology, Tawfik et al. (2020) have addressed all of the factors outlined above, providing a step toward achieving the desired improvements in the treatment of orthopaedic injuries. Tawfik et al. (2020) used a modified approach to previously described mouse models of orthopaedic trauma aiming to better simulate the complexities of human injury. They used poly-trauma to induce the major manifestations of orthopaedic injury, including nociceptive sensitization, bone fracture and muscle fibrosis. It was confirmed that exercise enhances recovery after injury and they further investigated how the timing of exercise plays a role on bone callus formation, muscle regeneration and pain thresholds. They compared mice that were exposed to early exercise (beginning immediately after injury) and late exercise (beginning 1 week after injury) and were able to demonstrate that the timeframe of exercise is relevant. The results indicate that the late exercise group ran more, had reduced bone callus sizes at 2 and 4 weeks, showed reduced muscle fibrosis, and had an earlier greater muscle cross-sectional area (CSA) indicating greater muscle regeneration. Interestingly, the early exercise group displayed increased muscle fibrosis compared to the control (no exercise) group and no significant increase in mean CSA. Tawfik et al. (2020) then went on to investigate whether the effects of exercise can be mimicked by an angiotensin II receptor blocker (ARB), losartan, which had previously shown to cause an increase in the number of regenerating fibres and a decrease in muscle fibrosis in a model of direct gastrocnemius injury. In their present study, losartan resulted in an almost complete prevention of allodynia, decreased muscle fibrosis and a right shift in fibre size suggesting improved muscle fibre regeneration, although there was no difference in mean muscle CSA or bone callus volumes. The results of the study by Tawfik et al. (2020) are of great value to the scientific community and future patients. Below, we describe the impact of this research, as well as potential improvements and future directions to the experiments. Tawfik et al. (2020) have contributed greatly to the scientific and medical communities, providing strong evidence that can enhance future studies and treatments for orthopaedic trauma. To begin, the study has provided details and began the validation of a new murine orthopaedic trauma model that is more representative of complex, multisystem human orthopaedic trauma. In particular, this model creates significant muscle damage, which is essential given that bone injury rarely happens in isolation to other systems. Moreover, the findings obtained can influence physician advice pertaining to the timing of exercise following trauma. Currently, recommending the timing of exercise following injury is considered on a patient-by-patient basis and has minimal scientific evidence. The present study has provided some preliminary evidence to suggest that delayed exercise can be beneficial as investigated via robust behavioural, biochemical and histological methods. Furthermore, the study has provided some clarity regarding the use of losartan and the mechanism behind the effects of the drug on allodynia. Because losartan is a well-tolerated, well-known, affordable and non-addictive pharmacological agent, it is a great candidate for treatment. Indeed, losartan is on the World Health Organization’s list of essential medications. Moreover, falls in the geriatric population are a major cause of orthopaedic trauma. Losartan can be used to control hypertension and cardiac hypertrophy and, thus, it is an appropriate choice because these co-morbidities are very common in the older population. As mentioned above, the use of losartan can reduce the need of opioids for pain relief, which is beneficial not only for dampening the current opioid crisis, but also because opioids can cause drowsiness and unsteadiness increasing the risk of additional falls and subsequent trauma. Finally, insights into the effects of losartan on pain control can potentially applied to other pain disorders, such as fibromyalgia or polymyalgia rheumatica. Given the useful insights of the study by Tawfik et al. (2020), there are a number of additional experiments and studies to advance this research that are worth mentioning. To begin, given that increased age is a risk factor for falls and thus orthopaedic trauma, it is worth conducting experiments with older mice to for increased relevance in the human