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

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:

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 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