The Prevalence of Neuropathic Pain Pathophysiology Associated With Ankle Fracture

NCT06420141 | Recruiting

• 1 other identifier: 19914
• Study Type: observational
• Target: 250
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Neuropathic Pain

Outcome Measures

Primary Outcomes (5)

• Chronic Pain Grading Scale

  Chronic Pain Grading Scale (CPGS) will be used to determine if fracture patients have pain in the chronic phase of injury (6-9 month visit). The pain intensity subscale will be used to categorize participants into those with and without chronic pain. This score is the sum of three questions (current pain, worst pain, average pain over last month), each scored on an 11-point Likert scale with responses ranging from 0-10 for a maximum of 30 points. The participant will be asked to report only on pain related to the site of fracture. Participants scoring 1-30 on the characteristic pain intensity score in the last month at the site of fracture will be classified as having chronic pain related to the fracture. Patients reporting no pain (0) at the site of fracture in the last month will be classified as having no chronic pain.

  6-9 month

• Douleur Neuropathique (Neuropathic Pain) 4

  Douleur Neuropathique (Neuropathic Pain) 4 (DN4). The DN4 is a validated and reliable screening tool for neuropathic pain consisting of 10 items. The first 7 items relate to pain quality (i.e., sensory and pain descriptors) are based on interview with the patient. The last 3 items are based on clinical examination and assess hypoesthesia to touch, and hypoesthesia to prick and brushing. The items of the DN4 are scored based on a yes (1 point)/no (0 points) answer. This leads to a score range of 0-10. The cut-off value for the classification of neuropathic pain is a total score of 4 of 10.72 The DN4 has been used to identify NP in ankle fracture patients.

  2 weeks to 1 year

• Assessment of Chronic Regional Pain Syndrome (CRPS)

  Assessment of Chronic Regional Pain Syndrome (CRPS). Presence of CRPS will be assessed in study participants beginning at the 6-8 week follow-up visit and all subsequent visits. Assessment of CRPS at earlier timepoints cannot be done rigorously as pain, motor, temperature and other changes comprising in part the CRPS diagnostic criteria can be related to the recent trauma. In addition to the QST procedures, a validated CRPS sign and symptom checklist will be administered by the study coordinator containing items in the 4 symptom and 4 sign categories needed to establish a CRPS diagnosis. For this study the investigators will employ the more rigorous CRPS Research Criteria (all symptom categories positive and 2/4 sign categories).

  2 weeks to 6-9 months

• Central Sensitization measure

  Central Sensitization measure: The most common quantitative sensory test used to measure central sensitization in human experimental studies is temporal summation of pain (TS).TS will be administered on the skin proximal to the level of injury and the contralateral uninjured side using a nylon monofilament (Touchtest Sensory Evaluator 6.65) calibrated to bend at 300g of pressure. As in previous studies, participants will rate the perceived pain intensity of a single contact of the monofilament using a 0 to 100 numeric rating scale. Then, participants will provide another pain rating following a series of 10 contacts administered at a rate of 1 contact per second, applied to the body site within an area of 1 cm2. The difference between pain ratings for the single versus multiple contacts reflects temporal summation of mechanical pain. Two trials will be administered.

  5-9 weeks to 6-9 months

• Pain Inhibitory Test

  Pain Inhibitory Test. Conditioned pain modulation (CPM) will be assessed by determining the ability of a cold pressor task to diminish pressure pain thresholds applied at a separate body site. For the conditioning stimulus, participants will immerse their non-affected hand up to the wrist in a cold water bath maintained at 10 degrees C for up to 1 minute or until they report intolerable pain.The test stimulus will be two trials of pressure pain thresholds (PPTs) administered on the left forearm. The experimenter will apply a slow constant rate of pressure and the participant will press a button when the sensation first becomes painful, at which time a device records the pressure. Three consecutive measurements with intervals of 20s will be obtained pre- and post- the conditioning stimulus.

  5-9 weeks to 6-9 months

Secondary Outcomes (2)

• Mechanical Detection Thresholds

  5-9 weeks to 6-9 months

• Pressure pain thresholds

  5-9 weeks to 6-9 months

Study Arms (2)

Fracture Group

patients with qualifying ankle fractures

Control Group

Healthy controls without an ankle fracture

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

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.

You may qualify if:

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

You may not qualify if:

• treated for a chronic pain condition prior to their qualifying injury
• on a pain contract
• pathologic fracture
• Daily use of gabapentin or opiods prior to enrollment
• Control Group:
• years of age
• can speak, read, and understand English
• Chronic pain or an ongoing acute pain condition
• Currently or have previously sustained a bone fracture
• Current Pain medication usage
• Any previous orthopaedic surgical procedures
• Must have been free of any surgeries for at least 5 years
• Peripheral neuropathy
• 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.

Sponsors & Collaborators

• Indiana University: lead

Study Sites (1)

Indiana University School of Medicine

Indianapolis, Indiana, 46202, United States

RECRUITING

Related Publications (13)

• Johansen A, Romundstad L, Nielsen CS, Schirmer H, Stubhaug A. Persistent postsurgical pain in a general population: prevalence and predictors in the Tromso study. Pain. 2012 Jul;153(7):1390-1396. doi: 10.1016/j.pain.2012.02.018. Epub 2012 Mar 24.

  PMID: 22445291 BACKGROUND

• Scheer RC, Newman JM, Zhou JJ, Oommen AJ, Naziri Q, Shah NV, Pascal SC, Penny GS, McKean JM, Tsai J, Uribe JA. Ankle Fracture Epidemiology in the United States: Patient-Related Trends and Mechanisms of Injury. J Foot Ankle Surg. 2020 May-Jun;59(3):479-483. doi: 10.1053/j.jfas.2019.09.016.

  PMID: 32354504 BACKGROUND

• Karl JW, Olson PR, Rosenwasser MP. The Epidemiology of Upper Extremity Fractures in the United States, 2009. J Orthop Trauma. 2015 Aug;29(8):e242-4. doi: 10.1097/BOT.0000000000000312.

  PMID: 25714441 BACKGROUND

• Beetar JT, Guilmette TJ, Sparadeo FR. Sleep and pain complaints in symptomatic traumatic brain injury and neurologic populations. Arch Phys Med Rehabil. 1996 Dec;77(12):1298-302. doi: 10.1016/s0003-9993(96)90196-3.

  PMID: 8976315 BACKGROUND

• Veljkovic A, Dwyer T, Lau JT, Abbas KZ, Salat P, Brull R. Neurological Complications Related to Elective Orthopedic Surgery: Part 3: Common Foot and Ankle Procedures. Reg Anesth Pain Med. 2015 Sep-Oct;40(5):455-66. doi: 10.1097/AAP.0000000000000199.

  PMID: 26192548 BACKGROUND

• Rbia N, van der Vlies CH, Cleffken BI, Selles RW, Hovius SER, Nijhuis THJ. High Prevalence of Chronic Pain With Neuropathic Characteristics After Open Reduction and Internal Fixation of Ankle Fractures. Foot Ankle Int. 2017 Sep;38(9):987-996. doi: 10.1177/1071100717712432. Epub 2017 Jul 1.

  PMID: 28670914 BACKGROUND

• Nahin RL. Severe Pain in Veterans: The Effect of Age and Sex, and Comparisons With the General Population. J Pain. 2017 Mar;18(3):247-254. doi: 10.1016/j.jpain.2016.10.021. Epub 2016 Nov 21.

  PMID: 27884688 BACKGROUND

• Vallerand AH, Cosler P, Henningfield JE, Galassini P. Pain management strategies and lessons from the military: A narrative review. Pain Res Manag. 2015 Sep-Oct;20(5):261-8. doi: 10.1155/2015/196025.

  PMID: 26448972 BACKGROUND

• Baca Q, Marti F, Poblete B, Gaudilliere B, Aghaeepour N, Angst MS. Predicting Acute Pain After Surgery: A Multivariate Analysis. Ann Surg. 2021 Feb 1;273(2):289-298. doi: 10.1097/SLA.0000000000003400.

  PMID: 31188202 BACKGROUND

• Sun S, Diggins NH, Gunderson ZJ, Fehrenbacher JC, White FA, Kacena MA. No pain, no gain? The effects of pain-promoting neuropeptides and neurotrophins on fracture healing. Bone. 2020 Feb;131:115109. doi: 10.1016/j.bone.2019.115109. Epub 2019 Nov 9.

  PMID: 31715336 BACKGROUND

• Lamparello AJ, Namas RA, Constantine G, McKinley TO, Elster E, Vodovotz Y, Billiar TR. A conceptual time window-based model for the early stratification of trauma patients. J Intern Med. 2019 Jul;286(1):2-15. doi: 10.1111/joim.12874. Epub 2019 Jan 9.

  PMID: 30623510 BACKGROUND

• McKinley TO, Gaski GE, Zamora R, Shen L, Sun Q, Namas RA, Billiar TR, Vodovotz Y. Early dynamic orchestration of immunologic mediators identifies multiply injured patients who are tolerant or sensitive to hemorrhage. J Trauma Acute Care Surg. 2021 Mar 1;90(3):441-450. doi: 10.1097/TA.0000000000002998.

  PMID: 33093290 BACKGROUND

• Almahmoud K, Abboud A, Namas RA, Zamora R, Sperry J, Peitzman AB, Truitt MS, Gaski GE, McKinley TO, Billiar TR, Vodovotz Y. Computational evidence for an early, amplified systemic inflammation program in polytrauma patients with severe extremity injuries. PLoS One. 2019 Jun 4;14(6):e0217577. doi: 10.1371/journal.pone.0217577. eCollection 2019.

  PMID: 31163056 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

blood

MeSH Terms

Conditions

Neuralgia

Condition Hierarchy (Ancestors)

Peripheral Nervous System Diseases; Neuromuscular Diseases; Nervous System Diseases; Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• Roman Natoli, MD, PhD

  Indiana University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Fletcher A White, PhD

CONTACT

317-274-5264; fawhite@iu.edu

Kelly Naugle, PhD

CONTACT

317-274-5264; kmnaugle@iu.edu

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Anesthesia

Study Record Dates

• First Submitted: March 4, 2024
• First Posted: May 17, 2024
• Study Start: January 3, 2024
• Primary Completion (Estimated): March 31, 2027
• Study Completion (Estimated): December 31, 2027
• Last Updated: June 15, 2025

Record last verified: 2025-06

Locations

US (1)