Neuro-Inflammation in Extremity Trauma: Risk Verification in Elbow Trauma: The NERVE Pilot Cohort Study

Chronic pain after limb fractures remains a challenging clinical problem although scientific and technological advances have made major contributions to improve patient outcomes. Nonetheless, even with an anatomical restoration of the bone architecture, many patients still have major functional limitations and persistent pain. This results in a work productivity loss. In the United States, upper limb injuries generate the highest direct and indirect costs (740M$), followed by lower limb fractures (562M$). Although outcomes following a fracture vary significantly, a "simple" fracture occurring at any time can become a turning point in the patient's life, where they can no longer achieve their pre-fracture functional status. The Canadian Pain Task Force estimates that 8 million Canadians suffer from chronic pain, costing $40 billion annually. This includes a large and understudied group of patients with post traumatic chronic pain, which occurs in up to 50% of patients following fractures. For these patients, opioids are meant to alleviate pain, but substance use disorder is a common problem. Indeed, approximately half of all patients with fractures have significant pain leading to persistent opioid intake 3 months post injury and 40% will suffer from a neuropathic type of pain, which is poorly controlled by medications. Opioid use is also associated with an increased sensitivity to pain (hyperalgesia) and patient dissatisfaction with injury outcome. Complications from prolonged opioid use are numerous, varying from constipation to overdose death. Canada is second worldwide, behind the United States, when it comes to opioid use and mortality. The majority of opioid dependant users were first exposed to opioids through medical prescriptions. This makes it imperative to improve the understanding of pain mechanisms to find alternative treatments to opioids in the management of these injuries.

In clinical practice, it is striking to see how two patients with a similar injury can exhibit completely opposite outcomes: one who has completely healed from the injury and the other with a stiff and painful joint. The reasons for these variations are unclear. A study have shown that only 3.3% of the differences in patient pain levels could be attributed to fracture severity. Given the enormous societal burden of limb injuries it is time for research to investigate the factors that contribute to the 97% of unexplained variability related to post fracture pain. The investigator working hypothesis is that the variability in post-fracture pain is caused by differences in expression of specific proinflammatory cytokines with nociceptive effects. This would explain why most studies strictly focusing on the orthopedic component of limb injury have yielded little improvement in preventing the adverse outcomes experienced by patients, namely chronic pain and loss of function.

Basic science studies have shown that in chronic pain cases, the resolution process following initial inflammation is deficient, leading to an excessive inflammatory response spreading throughout the nervous system long after the injury. This response, globally referred to as neuroinflammation (NI), has been associated with central sensitization, central nervous system (CNS) hyperactivity, allodynia and hyperalgesia. Surprisingly, NI is hardly studied in acute fracture cases, which is shocking given that it could explain chronic pain and disability. Also, some surgical factors may increase peripheral nerve injury (PNI).

Among all upper limb fractures, elbow trauma is the injury most frequently associated with a severe impact on patient function and quality of life. One of the main causes for poor outcomes is the complexity of the elbow joint, which involves three bones and two planes of motion, essential to the position of the hand in space. The flexion extension axis is crucial for eating and hygiene, while forearm pro-supination is mandatory for most professions, from office work to manual labour. Following surgical treatment of an elbow fracture, patients often present with complications, even with adequate bone healing. Indeed, one third of patients complain of ulnar nerve symptoms after distal humerus fracture fixation, and 50% of patients treated surgically for elbow fracture-dislocations will have disabling stiffness and chronic pain. The elbow is ideal to study neuroinflammation and pain as it involves 3 major nerves close to the joint: the radial, ulnar and median nerves. Elbow injury also has a high incidence of associated mild traumatic brain injury (MTBI) and peripheral nerve injury (PNI), 20% and 15% respectively.

1.2 Neuroinflammation Neuroinflammation (NI) can take different forms: central and peripheral. Prevouis investigator's results showed that 23.5% of isolated limb injuries also exhibit a mild traumatic brain injury (mTBI). More specifically, the investigators reported that 20% of ambulatory patients with an elbow fracture have a traumatic brain injury (TBI). Previous studies done by the investigator's team showed that outcomes of patients with a TBI, even mTBI, and a fracture is much poorer, compared to a group of similar patients without TBI, causing a work cessation three time longer (averaging 299 days versus 105 days). Central NI alters acute pain and increases the risk of chronic pain following a limb injury. At the time of brain trauma, brain-resident cells, such as microglia, will produce cytokines and other inflammatory mediators that spread through the peripheral circulatory system causing hypersensitivity and peripheral pain. Damage to the blood-brain barrier (BBB) following traumatic injury, allows circulating peripheral immune cells, produced in response to the fracture and present in high numbers at the site of injury and in immune organs, and the released cytokines to reach the brain and create a hyperactive inflammatory state. Astrocytes and endothelial cells also play a key role in this phenomenon. Importantly, research on US military veterans with orthopaedic injuries has revealed that the presence of mTBI significantly increases the risk of chronic pain and NI, as measured by higher levels of TNF and IL-6. A recent article in Nature also reported that the combined impact of mTBI and fracture to the brain could be permanent, because of the brain's immune memory. Therefore, both the traumatized brain and the fractured limb will evolve more poorly than if each lesion had occurred independently.