Improving Pain Management and Long Term Outcomes Following High Energy Orthopedic Trauma (Pain Study) (PAIN)
|ClinicalTrials.gov Identifier: NCT01789216|
Recruitment Status : Completed
First Posted : February 12, 2013
Last Update Posted : March 14, 2019
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|
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In this study, will test whether adjunctive analgesic therapy during the pre and peri-operative period, in addition to standard of care pain management, can improve overall pain control and pain related outcomes without increasing analgesic related side effects.
Patients will be randomized into three treatment groups. The intervention will begin within 48 hours of admission and continue for no longer than two weeks or up to the time of definitive fixation.
Group 1: standard pain management, plus up to two weeks of oral placebo, plus intravenous and oral placebo for 48 hours at each surgical procedure.
Group 2: standard pain management, plus up to two weeks of oral non-steroidal anti-inflammatory drugs (NSAIDs) (meloxicam), plus intravenous NSAIDs (ketorolac) and oral placebo for 48 hours at each surgical procedure.
Group 3: standard pain management, plus up to two weeks of oral pregabalin, plus intravenous placebo and oral pregabalin for 48 hours at each surgical procedure.
Specific Aim 1: Evaluate the effect of standard pain management (Group 1) vs. standard pain management plus pre and peri-operative NSAIDs (Group 2 - meloxicam + ketorolac) in the treatment of severe lower limb fractures.
Hypothesis 1a: When compared to patients who received standard of care pain management, patients treated with NSAIDs will: (1) have reduced post operative opioid utilization; (2) report reduced levels of persistent pain; and (3) have noninferior rates of surgery for nonunion.
Hypothesis 1b: When compared to patients who received standard of care pain management, patients treated with NSAIDs will benefit from (1) improved post operative pain control; (2) improved pre operative pain control; (3) reduced lengths of stay; (4) reduced pain interference; (5) improved functional outcomes; (6) lower levels of depression and post-traumatic stress disorder (PTSD); (7) improved overall health status; and (8) have noninferior rates of analgesic treatment related side effects.
Specific Aim 2: Evaluate the effect of standard pain management (Group 1) vs. standard pain management plus pre and peri-operative pregabalin (Group 3) in the treatment of severe lower limb fractures.
Hypothesis 2a : When compared to patients who received standard of care pain management, patients treated with pregabalin will: (1) have reduced post operative opioid utilization; (2) report reduced levels of persistent pain; and (3) have noninferior rates of surgery for nonunion.
Hypothesis 2b: When compared to patients who received standard of care pain management, patients treated with pregabalin will benefit from (1) improved post operative pain control; (2) improved pre operative pain control; (3) reduced lengths of stay; (4) reduced pain interference; (5) improved functional outcomes; (6) lower levels of depression and post-traumatic stress disorder (PTSD); (7) improved overall health status; and (8) have noninferior rates of analgesic treatment related side effects.
Specific Aim 3: Estimate the incremental cost effectiveness of each adjunctive analgesic therapy relative to standard of care analgesic therapy in the treatment of severe lower limb fractures. Costs will be estimated from both the health care provider perspective and the societal perspective. The time horizon for cost-effectiveness analysis will be based on the actual period of observation . Incremental cost-effectiveness ratios will be calculated for: (a) study group 2 (NSAIDS - meloxicam + ketorolac) relative to standard of care; and (b) study group 3 (pregabalin) relative to standard of care. For purpose of cost-effectiveness analysis, the effect will be measured as unit change in specific outcome metrics at 12 months (or longer period as available) compared to baseline. The following cost-effectiveness metrics, all relative to standard of care, will be reported:
- incremental cost per unit change in the Brief Pain Inventory
- incremental cost per unit change in the Short Muscular Function Assessment (SFMA)
- incremental cost per unit change in health state preference ("utility") as derived from the VR-12
PTOA Pilot Study: Additional funding was received from NIH to conduct a pilot, observational study of post-traumatic osteoarthritis (PTOA), leveraging current resources of the Pain study. PTOA is an important outcome in the population to be enrolled in the Pain study.
The aims of the PTOA Study are to: (1) measure the incidence of PTOA and chronic pain for up to 24 months following fracture reduction surgery and (2) quantify the extent to which fracture severity and post-reduction contact stress are related to the development of PTOA. Accomplishment of these aims will require (1) for all patients in the Pain study: complete a PTOA survey at 12 months and at any subsequent visits that are conducted as part of standard of care and provide access to all standard of care imaging studies completed during the study period and (2) for a subset of 60 pilon fracture patients enrolled in the Pain study for whom post-operative CT scans are not standard of care, obtain additional consent for completion of a study-funded post-operative CT scan and 24 month radiographic study.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||450 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|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|
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.
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.
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.
- Opioid Utilization [ Time Frame: 1 year ]Morphine equivalent opioid utilization during initial hospitalization through 48 hours following definitive fixation.
- 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).
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
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
|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|
|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|
|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|