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Improving Pain Management and Long Term Outcomes Following High Energy Orthopedic Trauma (Pain Study) (PAIN)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01789216
Recruitment Status : Completed
First Posted : February 12, 2013
Last Update Posted : March 14, 2019
Sponsor:
Information provided by (Responsible Party):
Major Extremity Trauma Research Consortium

Brief Summary:

The purpose of this study is to definitively resolve questions regarding the use of multimodal pharmacologic pain management for orthopedic trauma patients in the context of a multicenter, randomized clinical trial.

Also, as a significant proportion of this population develops chronic post traumatic osteoarthritis (PTOA), a sub-objective of this study is to examine the etiology and incidence of chronic pain and PTOA in this population.


Condition or disease Intervention/treatment Phase
Pilon Fracture Drug: NSAID Drug: Gabapentinoids Drug: placebo Phase 3

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 450 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Improving Pain Management and Long Term Outcomes Following High Energy Orthopedic Trauma (Pain Study)
Actual Study Start Date : July 2013
Actual Primary Completion Date : December 31, 2018
Actual Study Completion Date : December 31, 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Placebo Comparator: Placebo
Standard pain management + preoperative oral placebo + perioperative intravenous placebo & oral placebo. This group will serve as the control group. Patients will take an oral placebo pill twice daily for the first 14 days of the trial. A perioperative protocol will include an oral dose of placebo immediately prior to surgery and twice daily for 48 hours following any surgery, in addition to an intravenous dose of placebo immediately prior to surgery and every 6 hours for 48 hours following surgery. The oral protocol will be suspended while the patient is receiving medication from the perioperative protocol.
Drug: placebo
Active Comparator: NSAID
Standard pain management + preoperative oral meloxicam + perioperative intravenous ketorolac & oral placebo. In addition to standard of care pain management, patients randomized to the NSAID group will receive an oral 7.5 mg dose of Meloxicam twice daily, to be initiated on enrollment and continued for 14 days or through definitive fixation, whichever comes first. The proposed dosing schedule represents the maximal safe dose of an adult population. Patients will receive intravenous (IV) ketorolac dosing surrounding all operative procedures leading up to and including the definitive fixation. The oral protocol will be suspended while the patient is receiving medication from the perioperative protocol. The proposed dosing schedule of 30 mg IV every 6 hours for the first 48 hours following procedure represents the maximal generally accepted safe dose of ketorolac currently in use for orthopedic surgery.
Drug: NSAID
Other Names:
  • Meloxicam/Mobic (NDC 68382-000-01; manufacturer: Zydus; encapsulated in size AA
  • empty capsule shells, backfilled with Avicel by Fisher Clinical Services (Bristol)
  • LLC)
  • Ketorolac/Toradol (NDC 00409-3795-01; manufacturer: Hospira)

Active Comparator: Gabapentinoid
Standard pain management + preoperative pregabalin + perioperative intravenous placebo & oral pregabalin. In addition to standard of care pain management, patients randomized to the pregabalin group will receive an oral 75mg dose of pregabalin twice daily, to be initiated on enrollment and continued for 14 days or through definitive fixation, whichever comes first.
Drug: Gabapentinoids
Other Names:
  • Pregablin/Lyrica (NDC 00071-1014-68; manufacturer: Pfizer; encapsulated in size
  • AA empty capsule shells, backfilled with Avicel by Fisher Clinical Services
  • (Bristol) LLC,; Lyrica, NDC 00071-1018-68; manufacturer: Pfizer; encapsulated
  • in size AA empty capsule shells, backfilled with Avicel by Fisher Clinical
  • Services (Bristol) LLC)




Primary Outcome Measures :
  1. Opioid Utilization [ Time Frame: 1 year ]
    Morphine equivalent opioid utilization during initial hospitalization through 48 hours following definitive fixation.

  2. Persistent Pain [ Time Frame: 1 year ]
    Patient reported persistent pain states at standard of care visits 3, 6 and 12 months following hospital discharge. Measured using the Brief Pain Inventory (BPI) and an additional battery of questions to assess neuropathic pain (painDETECT).

  3. Surgery for non-union [ Time Frame: 1 year ]
    Defined as non-prophylactic surgery for nonunion performed between six months and a year following initial hospital discharge.


Secondary Outcome Measures :
  1. Post Surgical Pain Intensity [ Time Frame: 2 days ]
    Pain intensity at 12-hour intervals during the 48 hours following definitive fixation surgery. Abstracted from medical record and supplemented by participant pain logs. At least one time point will be assessed using the Multidimensional Post Surgical Pain Scale in order to study multiple pain dimensions.

  2. Pre Surgical Pain Intensity [ Time Frame: 2 days ]
    Pain intensity at 12-hour intervals between study enrollment and definitive fixation surgery. Abstracted from medical record and supplemented by participant pain logs.

  3. Length of Index Hospitalization [ Time Frame: 1 year ]
    Defined as the hospitalization during which the definitive fixation occurs. Length of stay for all other study injury related hospitalizations will also be abstracted.

  4. Adverse Effects and Complications [ Time Frame: 2-3 weeks ]
    Will include nonunion, wound closure complications, bleeding complications (particularly perioperative bleeding due to loss of platelet function and gastrointestinal bleeding), as well as pain treatment related adverse effects. These include nausea, vomiting, constipation, sedation, pruritis, respiratory depression, somnolence, dizziness, headaches, coordination problems, peripheral edema, blurred vision, gastrointestinal symptoms and irritation, renal impairment, platelet inhibition, angioedema, and post operative delirium. Adverse effects and complications will be assessed by both patient report of symptoms during the period between enrollment and 48 hours post definitive fixation, and by clinical survey of symptoms during index hospitalization and at discharge from additional surgical admissions up to definitive fixation.

  5. Functional Outcome [ Time Frame: 1 year ]
    The SMFA (Short Musculoskeletal Function Assessment) is a shorter version of the 101-item Musculoskeletal Function Assessment (MFA) questionnaire. The SMFA is a 46-item questionnaire consisting of the dysfunction index and the bother index. The dysfunction index has 34 items for assessment of patient function, while the bother index consists of 12 items designed to detect how much patients are bothered by functional items. The SMFA has been evaluated for reliability, validity and responsiveness in trauma populations. To be assessed at 6 and 12 months.

  6. Generic Health Status [ Time Frame: 1 year ]
    The generic health status will be measured by the VR-12 instrument from which a VR-6D can be computed for the purpose of a cost-utility analysis. The VR-12 is a multipurpose self-administered generic measure of health status. It was developed to measure health-related quality of life, estimate disease burden and compare disease-specific benchmarks across populations. The VR-12 items measure eight health domains: general health perceptions; physical functioning; role limitations due to physical and emotional problems; bodily pain; energy-fatigue, social functioning and mental health. The instrument produces a physical health and mental health summary measure. To be assessed at 6 and 12 months.

  7. Depressive Symptoms [ Time Frame: 1 year ]
    The presence of depressive symptoms will be measured using the nine item depression scale of the Patient Health Questionnaire (PHQ-9). The PHQ-9 is a well validated tool for assisting clinicians in diagnosing depression. There are two components of the PHQ-9: (1) assessing symptoms and functional impairment to make a tentative depression diagnosis, and (2) deriving a severity score. The PHQ-9 is based directly on the diagnostic criteria for major depressive disorder in the Diagnostic and Statistical Manual Fourth Edition (DSM-IV). To be assessed at 12 months.

  8. Post Traumatic Stress (PTSD) [ Time Frame: 1 year ]
    PTSD will be measured using the standard PTSD Checklist (PCL), a 17-item measure that elicits responses for each of the DSM-IV disorders that comprise the diagnostic criteria for PTSD (intrusive, avoidant, and arousal symptoms). The psychometric properties of the PCL have been well established and it is the most widely used measure of PTSD. Both civilian and military versions are available. The military version will be used for all those patients on active duty at the time of their injury. To be assessed at 12 months.

  9. Medical Costs [ Time Frame: 1 year ]
    Costs for the index hospitalization and subsequent hospitalizations (within one year) will be derived using hospital bills, outpatient bills and professional fees. Hospital costs will be calculated from charges at the revenue center/cost department line level using cost-to-charge ratios (CCRs) computed from the hospital-specific Medicare Cost Reports. Billing data will be supplemented or imputed by identifying medical resource utilization as documented in study case report forms, categorizing resources using standard medical billing codes, and assigning costs based on Medicare fee schedules. Of particular interest will be resource utilization and costs associated with the index hospital admission, surgical procedures for bone grafting and nonunion, subsequent admissions for complications, and post-operative follow-up care.

  10. Fracture Severity [ Time Frame: 1-2 years ]
    Fracture severity will be measured using standard of care CT scans. In severe fractures, this image will be obtained after application of a temporary joint spanning external fixator. Thus, the fracture severity analysis will be based on fractured distal tibias with limb alignment provisionally controlled. After definitive fracture reconstruction, a second CT scan will be obtained at the 3 month follow up time point, for assessment of chronic contact stress challenge. The second CT scan will be obtained for all patients for whom it is standard of care.

  11. Fracture Classification [ Time Frame: 1-2 years ]
    Fracture classification will be obtained using radiographs of the patient's injured ankle at presentation and after each surgical intervention according to standard of care practice. These radiographs will be used for clinical care, to classify the fractures, and at follow-up to assess outcome. Radiographs will be obtained at the time of initial hospital evaluation, immediately following treatment and at follow up clinic visits according to standard of care. Final clinical assessments and radiographs will be obtained as close to 12 months as routine practice allows. At practices where patients are routinely followed for more than 12 months and 24 month clinical assessments and radiographs will be conducted, at which point all study-related activities will be completed. A subset of 60 patients, identified prospectively, will provide an additional CT 3 months following definitive fixation, and will provide a final set of radiographs 24 months following definitive fixation.


Other Outcome Measures:
  1. PTOA sub-study assessment [ Time Frame: 1-2 years ]
    Among patients in the Pain study, data relevant to the development of PTOA will be collected observationally. All radiographic images, including CT scans and x-rays, taken per standard of care in the first year will be obtained. Additionally, for those patients routinely receiving follow-up beyond 12 months, weight bearing radiographs of the ankle taken at between one and two years after injury will be used to assess and characterize the development of PTOA. In the subset of 60 pilon fracture patients actively recruited into the PTOA pilot study, CT scans following definitive fixation, all radiographic images taken per standard of care, in addition to a final set of weight bearing radiographs of the ankle taken at 24 months will be used to assess and characterize the development of PTOA. The presence of PTOA will be determined using the Kellgren and Lawrence (KL) scale.



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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients with one of the following types of injuries:

    1. Unilateral, Grade I &II open or closed pilon (distal tibial plafond), calcaneus, talus fractures and Lisfranc dislocations requiring operative treatment with fixation; or
    2. Unilateral, open (type I, II, or IIIA) ankle fractures with associated dislocation on presentation (OTA 44B3 or 44C) requiring operative treatment with fixation; or
    3. Unilateral, open or closed distal and proximal humerus (OTA 11A-C and OTA 13 A-C); or
    4. Open femoral shaft fracture (OTA 32 A-C; Gustilo Type I-IIIC) or open or closed supracondylar femur fractures (OTA 33 A-C); or
    5. Open or closed tibial plateau or shaft fractures (OTA 42 A-C or 43 A-C)
    6. Any combination of the above injuries which are surgically treated as a whole
  2. Patients who present to the admitting hospital acutely or clinic following an initial assessment in the Emergency Department, for care up to 10 days following initial injury.
  3. Patients 18-80 years old inclusive.
  4. Patients who are English or Spanish competent.
  5. Treating physicians agree that none of the study drugs are indicated for standard of care treatment for this patient.
  6. Patients able to be followed at the METRC facility for at least 12 months following injury.

Exclusion Criteria:

  1. Patients unable to provide informed consent.
  2. Patients with chronic pain being presently treated with opioid or gabapentinoid prescription or any other alternative therapy.
  3. Patients who are current IVDA
  4. Patients with bilateral or ipsilateral injuries requiring surgery
  5. Patients with other orthopedic or non-orthopedic injuries requiring operative intervention
  6. Patients with severe osteopenia.
  7. Patients who are skeletally immature (defined as less than 18 years of age or no radiographic evidence of epiphyseal closure).
  8. Patients who are expected to have a post-surgical stay less than 24 hours.
  9. Patients with a history of allergy to any drugs in the study.
  10. Patients unable to swallow oral medications or without adequately functioning GI tract.
  11. Patients with a history of gastrointestinal bleeds or gastric perforation.
  12. Patients with a history of stroke or heart attack.
  13. Patients currently receiving an aspirin or NSAID regimen (exception: low dose (81 mg) aspirin. See section 6.5) Patients with any bleeding disorders.
  14. Patients with severe renal failure. Patients with moderate renal failure may participate in the study at a modified dose. See Section 9.6.
  15. Patients undergoing daily treatment with systemic glucocorticoids before surgery.
  16. Patients using angiotensin-converting enzyme (ACE) inhibitors, who may be at increased risk of developing angioedema with pregabalin.
  17. Patients likely to have severe problems maintaining follow-up, including patients diagnosed with a severe psychiatric conditions, patients who live too far outside the hospital's catchment area, patients who are incarcerated and patients who have unstable housing situations.
  18. Patients who experienced a loss of consciousness consistent with a clinical diagnosis of a closed head injury, or concern of a cerebrovascular bleed secondary to traumatic brain injury.
  19. Patients with a GCS <15
  20. Patient speaks neither English nor Spanish.
  21. Patients who are pregnant or lactating at time of screening

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01789216


Locations
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United States, Florida
University of Miami Ryder Trauma Center
Miami, Florida, United States
St. Mary's Medical Center
West Palm Beach, Florida, United States
United States, Indiana
Eskenazi Health
Indianapolis, Indiana, United States
United States, Iowa
University of Iowa Hospitals & Clinics
Iowa City, Iowa, United States
United States, Louisiana
Louisiana State University Health Sciences Center
Shreveport, Louisiana, United States
United States, Maryland
Johns Hopkins University
Baltimore, Maryland, United States
University of Maryland, R Adams Cowley Shock Trauma Center
Baltimore, Maryland, United States
United States, Massachusetts
Boston Medical Center
Boston, Massachusetts, United States
United States, Minnesota
Hennepin County Medical Center
Minneapolis, Minnesota, United States
United States, North Carolina
Carolinas Medical Center
Charlotte, North Carolina, United States
United States, Ohio
MetroHealth Medical Center
Cleveland, Ohio, United States
United States, Pennsylvania
Penn State University M.S. Hershey Medical Center
Hershey, Pennsylvania, United States
University of Pittsburgh
Pittsburgh, Pennsylvania, United States
United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States
United States, Texas
University of Texas Southwestern Medical Center
Dallas, Texas, United States
UT Health: The University of Texas Health Science Center at Houston Medical School
Houston, Texas, United States
United States, Virginia
Naval Medical Center Portsmouth
Portsmouth, Virginia, United States
Sponsors and Collaborators
Major Extremity Trauma Research Consortium
Investigators
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Principal Investigator: Renan Castillo, PhD Johns Hopkins Bloomberg School of Public Health
Principal Investigator: Lawrence Marsh, MD University of Iowa Hospitals & Clinics
Study Director: Katherine Frey, RN, MPH, MS Johns Hopkins Bloomberg School of Public Health

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Responsible Party: Major Extremity Trauma Research Consortium
ClinicalTrials.gov Identifier: NCT01789216     History of Changes
Other Study ID Numbers: W81XWH1020090
First Posted: February 12, 2013    Key Record Dates
Last Update Posted: March 14, 2019
Last Verified: March 2019
Keywords provided by Major Extremity Trauma Research Consortium:
Pilon fractures
Calcaneus fractures
Acute pain
Chronic pain
Isolated
unilateral
Grade I
Grade II
open
closed
Additional relevant MeSH terms:
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Fractures, Bone
Wounds and Injuries
Ketorolac
Ketorolac Tromethamine
Meloxicam
Pregabalin
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cyclooxygenase 2 Inhibitors
Anticonvulsants
Calcium Channel Blockers
Membrane Transport Modulators
Calcium-Regulating Hormones and Agents
Anti-Anxiety Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs