Clinical trial NCT01789216: Improving Pain Management and Long Term Outcomes Following High Energy Orthopedic Trauma (Pain Study)
Official title: Improving Pain Management and Long Term Outcomes Following High Energy Orthopedic Trauma (Pain Study)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Orthopaedic Fractures
Keywords: Pilon fractures
Calcaneus fractures
Acute pain
Chronic pain
Isolated
unilateral
Grade I
Grade II
open
closed
Lead sponsor: Major Extremity Trauma Research Consortium
Sponsor class: OTHER
First posted: 2013-02-12
Enrollment: 450
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed description: 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 up to the time of definitive fixation.

Group 1: standard pain management, plus intravenous and oral placebo for up to 48 hours following definitive fixation.

Group 2: standard pain management, plus intravenous NSAIDs (ketorolac) and oral placebo for up to 48 hours following definitive fixation.

Group 3: standard pain management, plus intravenous placebo and oral pregabalin for up to 48 hours following definitive fixation.

Specific Aim 1: Evaluate the effect of standard pain management (Group 1) vs. standard pain management plus peri-operative NSAIDs (Group 2 - meloxicam + ketorolac) in the treatment of severe 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 limb fractures.

Hypothesis2a : 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 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 up to 15 months (or longer period as available) compared to baseline. The following cost-effectiveness metrics, all relative to standard of care, will be reported:

1. incremental cost per unit change in the Brief Pain Inventory
2. incremental cost per unit change in the Short Muscular Function Assessment (SFMA)
3. 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 with ankle fractures 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

Eligibility 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

Primary outcomes:
measure: Opioid Utilization
timeFrame: 1 year
measure: Persistent Pain
timeFrame: 1 year
measure: Surgery for non-union
timeFrame: 1 year
Secondary outcomes:
measure: Post Surgical Pain Intensity
timeFrame: 2 days
measure: Pre Surgical Pain Intensity
timeFrame: 2 days
measure: Length of Index Hospitalization
timeFrame: 1 year
measure: Adverse Effects and Complications
timeFrame: 2-3 weeks
measure: Functional Outcome
timeFrame: 1 year
measure: Generic Health Status
timeFrame: 1 year
measure: Depressive Symptoms
timeFrame: 1 year
measure: Post Traumatic Stress (PTSD)
timeFrame: 1 year
measure: Medical Costs
timeFrame: 1 year
measure: Fracture Severity
timeFrame: 1-2 years
measure: Fracture Classification
timeFrame: 1-2 years
Other outcomes:
measure: PTOA sub-study assessment
timeFrame: 1-2 years
Locations:
city: Miami
country: United States
facility: University of Miami Ryder Trauma Center
state: Florida
city: West Palm Beach
country: United States
facility: St. Mary's Medical Center
state: Florida
city: Indianapolis
country: United States
facility: Eskenazi Health
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Hospitals & Clinics
state: Iowa
city: Shreveport
country: United States
facility: Louisiana State University Health Sciences Center
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Baltimore
country: United States
facility: University of Maryland, R Adams Cowley Shock Trauma Center
state: Maryland
city: Boston
country: United States
facility: Boston Medical Center
state: Massachusetts
city: Minneapolis
country: United States
facility: Hennepin County Medical Center
state: Minnesota
city: Charlotte
country: United States
facility: Carolinas Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: MetroHealth Medical Center
state: Ohio
city: Hershey
country: United States
facility: Penn State University M.S. Hershey Medical Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: UT Health: The University of Texas Health Science Center at Houston Medical School
state: Texas
city: Portsmouth
country: United States
facility: Naval Medical Center Portsmouth
state: Virginia
Study officials:
affiliation: Johns Hopkins Bloomberg School of Public Health
name: Renan Castillo, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Iowa Hospitals & Clinics
name: Lawrence Marsh, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Johns Hopkins Bloomberg School of Public Health
name: Katherine Frey, RN, MPH, MS
role: STUDY_DIRECTOR
References: