METRC Introductions

1. Improving Pain Management and Long Term Outcomes Following High Energy Orthopaedic Trauma (PAIN Study) Pharmacist Training PIs: Renan Castillo, PhD, Johns Hopkins Srinivasa N. Raja , MD, Johns Hopkins J. Lawrence Marsh, MD, University of Iowa

2. METRC Introductions

3. Agenda • Study Introduction • Background and study rationale • Study Aims • Study Outcomes • Inclusion/Exclusion criteria • Pharmacy Procedures • Drug Receipt • Responsibilities • Study Participants • Drug Accountability • Accountability Log • Dispensing Log • Patient Ends Study • Questions to Think About • Pre-Operative Stage • Peri-Operative Stage • METRC Contact • Next Steps

4. Study Introduction

5. Background • Pain is a common consequence of orthopaedic trauma • Poor pain control predicts physical disability, delayed return to work, psychological distress, low satisfaction with healthcare, and failure to participate in physical therapy • 50% to 70% patients experience moderate/severe pain in acute care settings and report insufficient postoperative pain relief • Inadequate pain management can prolong patient recovery, increasing length of hospital stay and health-care costs • 30-50% of patients who have acute postoperative pain develop chronic pain that can have major negative effects on quality of life

6. Rationale • Preoperative and perioperative pain management has been found to substantially improve post surgical pain control in numerous settings • These techniques have not been widely used in orthopaedics due to conflicting data about increased risk of nonunion, wound closure and bleeding complications • Given the central role of pain management in the etiology of long-term disability following trauma, it is critical to definitively resolve this question in the context of a randomized clinical trial

7. Inclusion Criteria (version 9) • Patients with one of the following types of injuries: • Unilateral, Grade I &II open or closed pilon (distal tibial plafond), calcaneus, talus fractures and Lisfranc dislocations requiring operative treatment with fixation; or • Unilateral, open (type I, II, or IIIA) ankle fractures with associated dislocation on presentation (OTA 44B3 or 44C) requiring operative treatment with fixation; or • Unilateral, open or closed distal and proximal humerus (OTA 11A-C and OTA 13 A-C); or • Open femoral shaft fracture (OTA 32 A-C; Gustilo Type I-IIIC) or open or closed supracondylar femur fractures (OTA 33 A-C); or • Open or closed tibial plateau or shaft fractures (OTA 42 A-C or 43 A-C) • Any combination of the above injuries which are surgically treated as a whole. • 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. • Patients 18-80 years old inclusive • Patients who are English or Spanish competent • Treating physicians agree that none of the study drugs are indicated for standard of care treatment for this patient • Patients able to be followed at the METRC facility for at least 12 months following definitive surgical procedure

8. Exclusion Criteria • Patients unable to provide informed consent • Patients with difficult follow up • Patients with medical contraindications to using study drugs (including allergies) • Patients with other orthopedic or non-orthopedic injuries requiring operative intervention • Patients with current opioid or gabapentinoid prescription • IVDA • Transfer patients who are >48 hours post injury • Patients who are expected to have a post-surgical stay less than 24 hours. • Patients with head injuries • Patient speaks neither English nor Spanish • Patients who are pregnant or lactating at time of screening *See protocol for detailed list of exclusion criteria

9. Exclude Open Grade IIIB & C Fracture Screen High Energy Orthopedic Trauma to Ankle Figure: Medication Dosing Pre-Enrollment Closed or Open Grade I/II and selected IIIA Enroll and Randomize to Treatment Group + SOC Therapy 48 hours – definitive fixation; may include intermediate operative procedure Group A: Placebo Group B: NSAID Group C: Gabapentinoid Oral Placebo; up to 2 wks Oral NSAID (Meloxicam 7.5 mg po bid); up to 2 wks Oral Gabapentinoid (Pregabalin 75 mg po bid); up to 2 weeks If the patient experiences a surgical procedure prior to the definitive fixation (e.g. calcaneal fracture repair, or fibular and/or spanning external fixation), suspend oral therapy and initiate perioperative adjunctive analgesic therapy; otherwise PO therapy for up to 2 weeks, or through definitive fixation Oral Placebo + IV Placebo Therapy up to 1 hour prior to surgery and for 48 hours, or until resumption of oral therapy Oral Placebo + 30 mg IV ketorolac up to 1 hour prior to surgery and q6h post procedure for 48 hours or until resumption of oral therapy IV Placebo + 300 mg pregabalin po up to 1 hour prior to surgery and 75 mg po bid post procedure for 48 hours or until resumption of oral therapy Definitive Fixation Definitive fixation – up to 48 hours post op Oral Placebo + IV Placebo Therapy Oral Placebo + 30 mg IV ketorolac up to 1 hour prior to surgery and q6h for 48 hs post procedure IV Placebo + 300 mg pregabalin PO up to 1 hour prior to surgery and 75 mg PO bid post procedure for 48 hrs

10. 48 hours – definitive fixation; may include intermediate operative procedure Group A: Placebo Group B: NSAID Group C: Gabapentinoid Oral Placebo; up to 2 wks Oral NSAID (Meloxicam 7.5 mg po bid); up to 2 wks Oral Gabapentinoid (Pregabalin 75 mg po bid); up to 2 weeks Medication Source: Blister Pack

11. If the patient experiences a surgical procedure prior to the definitive fixation (e.g. calcaneal fracture repair, or fibular and/or spanning external fixation), suspend oral therapy and initiate perioperative adjunctive analgesic therapy; otherwise blister pack PO therapy for up to 2 weeks, or through definitive fixation 48 hours – definitive fixation; may include intermediate operative procedure Oral Placebo + IV Placebo Therapy up to 1 hour prior to surgery and for 48 hours, or until resumption of oral therapy Oral Placebo + 30 mg IV ketorolac up to 1 hour prior to surgery and q6h post procedure for 48 hours or until resumption of oral therapy IV Placebo + 300 mg pregabalin po up to 1 hour prior to surgery and 75 mg po bid post procedure for 48 hours or until resumption of oral therapy Intermediate Procedure Medication Source: OR Kit

12. Definitive Fixation Definitive fixation – up to 48 hours post op Oral Placebo + IV Placebo Therapy Oral Placebo + 30 mg IV ketorolac up to 1 hour prior to surgery and q6h for 48 hs post procedure IV Placebo + 300 mg pregabalin PO up to 1 hour prior to surgery and 75 mg PO bid post procedure for 48 hrs Definitive Fixation Medication Source : OR Kit

13. Pharmacy Procedures

14. Drug Receipt • All study drugs will arrive blinded from Fisher Pharmaceuticals in the following form: • Blister Pack • OR kits IV bags will be provided by the research pharmacy and billed along with other pharmacy fees

15. Blister Pack Contents 28 pillscontains either meloxicam, lyrica, or placebo

16. Operating Room Kit Contents Pre-OP Bottle: contains 2 pills either Lyrica or Placebo Post-OP Bottle: contains 4 pills either Lyrica or Placebo 9 vials: contains Ketorolac Color coded labels to place on pill bottles to indicate Pre or Post OR

17. Responsibilities • The pharmacy is responsible for drug • Receipt • Storage • Reconstitution of Ketorolac • Dispensing • Destruction • Maintenance

19. Prohibited Drugs • While on study drugs the patient are not permitted to take the following: • Ibuprofen (Advil and Motrin) • Naproxen Sodium (Aleve) • Celecoxib (Celebrex) • Aspirin • NSAIDs • Gabapenteniods

20. Study Participants • Patient will be enrolled and randomized with in 48 hours of arriving to the hospital • The Research Coordinator will get patient ID, blister pack ID and OR kit ID numbers • All ID#s plus additional pharmacy correspondence will be communicated to the pharmacy

21. Pre-Operative Stage • Once the patient is enrolled into the study they will start on pre-operative (blister pack) meds

22. Pre-Operative Stage • From the blister pack the patients will get 1 pill BID (1 pill QD for renal compromised patients or age ≥ 65 patients) for up to two weeks • If the patient goes to the OR during the time they are taking the blister pack meds, they will stop the blister pack meds and go to the peri-operative stage • When the patient is discharged they will take the blister pack home

23. Peri-Operative Stage • When the patient has an operative procedure they will receive drugs from the OR kit

24. Peri-Operative StagePre-Surgery • One hour prior to surgery the patient will get from the OR Kit: • 2 pills (1 pill for renal compromised patients or age ≥ 65 patients) • One IV bag (50 mL normal saline with or without Ketorolac) *30 mg (15 mg for renal compromised patients or age ≥ 65 patients) Ketorolac will need to be reconstituted into IV bag

25. Peri-Operative StagePost-Surgery • Up to 48 hours after surgery the patient will get: • 1 pill q12h (1 pill q24h for renal compromised patients or age ≥ 65 patients) • One IV bag q6h (50 mL normal saline with or without Ketorolac) *30 mg (15 mg for renal compromised patients or age ≥ 65 patients) Ketorolac will need to be reconstituted into IV bag

26. Drug Accountability

27. Drug Accountability Log

28. Drug Dispensing Log

29. Patient ends study

30. End of the study • The patient will bring the blister pack back with them to the pharmacy or research coordinator • The pharmacy will dispose of the pills and SAVE the blister pack card for the research coordinator • Please record pill wasting in the patient's dispensing log

31. Questions to think about

32. Pre-Operative Stage • Administration of study drugs from the blister pack while the patient is hospitalized – each site will determine if the blister pack will stay in the medication room/cart of the floor and the medication administered by the RN, or if each dose will be dispensed individually by the pharmacy. • Wasting of study drugs if the patient is receiving the peri-operative protocol – who will be responsible for ensuring this occurs? What are hospital procedures for this process? • Use of electronic medication administration records – are study drugs typically included in order sets? How will this be handled locally? • Discharging the patient with the blister pack and instructions for taking remaining medications.

33. Peri-Operative Stage • Administration of study drugs from the box of medications during this perioperative period – each site will determine if the entire box of medications will be dispensed to accompany the patient and be administered by the RN at each point a medication is due per the protocol, or if each dose will be dispensed individually by the pharmacy. • Use of electronic medication administration records – are study drugs typically included in order sets? How will this be handled locally?

34. METRC Contact

35. Study Contacts • Every site has a Pain Study Research Coordinator that will contact you • If you have questions please contact the MCC Study Manager: Tara Taylor 410-614-6081 ttaylo56@jhu.edu

36. Next Steps • If the study coordinator has not contacted you they will do so soon • Fisher will send the pharmacy the first batch of study drugs • Drugs will be shipped to address listed on DEA-223 License that was sent to Tara