Improving Pain Management and Long Term Outcomes Following High Energy Orthopedic Trauma (Pain Study)
Condition: Orthopaedic Fractures
MeSH terms: Fractures, Bone
Study type: Interventional
Phase: Phase 3

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
    

Intervention name(s): NSAID; Gabapentinoids; placebo
Intervention type(s): Drug; Drug; Drug
Other intervention name(s): 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); 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)
Intervention MeSH terms: Ketorolac; Meloxicam; Pregabalin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Pilon fractures; Calcaneus fractures; Acute pain; Chronic pain; Isolated; unilateral; Grade I; Grade II; open; closed