This application addresses the Peer Reviewed Medical Research Program Investigator-Initiated Research Award FY21 W81XWH-22-CPMRP-IIRA area of Chronic Pain Management Research Program- The investigators will utilize subjects who have sustained ankle fractures and may develop chronic pain following bone union. No attempt will be made to affect the experimental outcome in the subjects. This study will adhere to a core set of standards for rigorous study design and reporting to maximize the reproducibility and translational potential of research.

Persistent pain following bone fracture, such as neuropathic pain (NP), is a possible outcome of fracture repair following injury to the ankle and exhibits incidence rates at 1-year post-surgery of 18-42%. This pain state following bone healing (also known as bone union) will be referred to as bone fracture-associated NP (BFNP). Ankle fractures are among the most common surgically-treated fractures in adults, with the greatest incidence occurring in young males. Women are more commonly affected in other age groups. Distal radius fractures are the most common type of fracture for all age groups. Full healing from a fracture can take anywhere from several weeks to months. Pain that persists after fracture union has taken place is called chronic pain. Chronic or persistent NP is one of the worst, longest-lasting, and difficult symptom to manage after fracture repair in civilian and military populations. It is likely that some of the mechanisms leading to BFNP propagate early after injury, leading to opportunity for early interventions to prevent chronic pain.

NP associated with bone fracture originates from an injury affecting the sensory aspects of the peripheral nervous system and may be associated with abnormal sensations called dysesthesia or from normally non-painful stimuli (allodynia). The condition may have continuous and/or episodic (paroxysmal) components, with the latter resembling stabbing pain or electric shocks. The condition of NP also tends to affect defined dermatomes, and there may be limits to the area of pain. The general working principle is that the injury leading to pain must directly involve the nociceptive pathways. An additional element which can contribute to NP includes sensitization of intact, uninjured pain neurons, which innervate the region adjacent to injured nerve fibers. These changes in the uninjured neurons may induce ongoing pain and may account for certain aspects of hyperalgesia (increased sensitivity to feeling pain). Conditions associated with bone fracture-associated NP (BFNP) include traction neuropathy, nerve compression from soft tissue edema, bone fragment, implants, and/or hematoma.

In civilian adult populations, prevalence rates of NP are about 1 in every 10 adults over age 30, though the prevalence rate and people identified vary depending on the method of identification of NP. Though not distinctly defined as NP due to bone fracture, active-duty personnel and Veterans are at an increased risk of severe pain conditions compared with civilians. Given the numbers of active duty and Veterans who experience pain due to injury, the US military instituted a number of programs, guidelines and initiatives to better manage acute pain for combat-related injuries. These programs include pain control methods which can be readily administered and provide pain relief during immediate field hospital care, transport and subsequent care at military treatment facilities. Despite the instituted practices by the military, BFNP after fracture is a major problem and the literature that documents detailed outcomes of BFNP data are scarce.

Bone fracture is known to induce a complex post-fracture healing process and involves an extensive inflammatory response by immune cells. These immune cells proliferate and permeate the fracture site and secrete a range of pro-inflammatory cytokines which aid in the healing process. However, some of these same proteins are known to contribute to a variety of pain conditions/diseases including migraine, fibromyalgia, complex regional pain syndrome and neuropathic pain. To better understand the manner in which immune cell production of factors contribute to chronic pain states, the investigaotrs have embarked on a series of clinical investigations of immune cells which may contribute to chronic post-traumatic headache following mild traumatic brain injury. Like previous work by other groups, the investigators have observed a unique response by immune cell subsets that may serve to discriminate between both subacute and chronic events following traumatic injury. These attributes may prove to be diagnostic and could be regarded as a hallmark of the development of BFNP by ultimately influencing pain modulation in the clinical patient. Additional mechanisms which may contribute to BFNP include a wind-up of mechanisms in the spinal cord (central sensitization), and maladaptive neuroplasticity with changes in endogenous pain modulation. Anti-nociceptive endogenous pain modulation involves intact engagement of descending pain inhibitory pathways, which serve to protect the injured individual from transforming acute pain to a chronic pain state. However, inefficient descending pain inhibition can be a pathogenic risk factor for developing chronic pain. The degree to which an individual can be assayed for an intact endogenous pain inhibition system can be assessed using a quantitative sensory test (QST) which serves to test condition pain modulation (CPM). The provoking factor for such a generalized sensitization of the pain system could be the continuous noxious input in earlier phases of the bone fracture healing process associated with the ongoing states of inflammation.

Outcomes after trauma which contribute to chronic pain states are complex and are highlighted by a generalized failure in the clinical arena to improve patient conditions and quality of life once these conditions manifest themselves within the individual. However, recent studies have begun to yield novel insights into the injury-associated immune response which may be central to BFNP by using computational methods that account for temporal and spatial networks of mediators. Fundamental understanding of the immunologic responses associated with BFNP at distinct cross-sections in the recovery time frame and dynamically during progression of fracture healing process may yield better management and potentially mitigation of BFNP. Moreover, changing the standard of care treatment for BFNP by identifying at-risk patients early after injury could lead to decreased economic burden in treating BFNP and mitigation of the substantial decrease in quality of life these patients experience. Thus, evidenced-based and "precision" approaches to BFNP and management are greatly needed, in which mechanisms and other factors that contribute to BFNP are identified to guide treatment. The proposed project is significant because it is an essential step in understanding whether ankle fracture chronically alters biological pain risk factors. Such information is critical to 1) developing effective strategies to reduce the occurrence of BFNP, 2) providing prognostic information to individuals suffering with BFNP, and 3) designing evidenced-based and personalized treatments for BFNP.

The proposed study is innovative because it will be the first prospective human study to evaluate the impact of bone fracture on innate immune function and endogenous pain modulatory function across time. This novel information will enhance our understanding of how ankle fracture elicits pathological risk factors for BFNP. Identification of salient risk factors for the initiation and maintenance of BFNP will allow a more personalized injury prognosis to predict those at greatest risk.

Fracture Group:

Inclusion Criteria:

1. 18-85 years old
2. an isolated rotational ankle (AO/OTA 44 types A-C) fracture that is treated operatively
3. Abbreviated Injury Scale < 3 for non-extremity body systems
4. can speak, read, and understand English

Exclusion Criteria:

1. treated for a chronic pain condition prior to their qualifying injury
2. on a pain contract
3. pathologic fracture
4. Daily use of gabapentin or opiods prior to enrollment

Control Group:

Inclusion Criteria:

1. 18-85 years of age
2. can speak, read, and understand English

Exclusion Criteria:

1. Chronic pain or an ongoing acute pain condition
2. Currently or have previously sustained a bone fracture
3. Current Pain medication usage
4. Any previous orthopaedic surgical procedures
5. Must have been free of any surgeries for at least 5 years
6. Peripheral neuropathy
7. Individuals having had a major surgery or a major disease or condition, as determined by the PI, such as cardiovascular disease, metabolic disorders, renal disease, neurological disorders, or severe psychiatric conditions.

The investigators will enroll participants who have sustained rotational ankle (specifically AO/OTA 44 types AC) fractures that are treated operatively. Fracture patients will complete clinic assessment sessions at standard of care visits, including their first post-op appointment (2-3 weeks), at 6-8 weeks, at 3-4 months, and at 6-9 months post-operatively. These visits will allow assessments during the subacute and chronic stages of bone fracture associated neuropathic pain.