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.

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

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