Low-Dose Short-Term Ketorolac to Reduce Chronic Opioid Use in Orthopaedic Polytrauma Patients

The goal of this randomized clinical trial is to learn if the use of a low-dose nonsteroidal anti-inflammatory drug (NSAID), ketorolac, reduces the rate of chronic opioid use in orthopaedic trauma patients. The main questions this study aims to answer are:

1. Are patients who are given scheduled ketorolac during the first five days of the perioperative period in combination with standard of care (SOC) multimodal analgesia (MMA) less likely to develop chronic opioid use at 6 months after injury compared to patients who SOC MMA alone?
2. Does scheduled ketorolac during the first five days of the perioperative period improve functional responses to pain at discharge, 3 months, and 6 months after injury?
3. Does early pain control provided by ketorolac decrease chronic opioid use through decreased acute pain and opioid use, improved functional responses to pain, or both?

Participants will be enrolled and randomized to either the ketorolac (treatment) group or the SOC group. Patients randomized to the ketorolac group will receive ketorolac every 6 hours for up to five days during the perioperative period; patients discharged prior to completing the five-day regimen will complete the remainder of treatment with oral ketorolac. Pain and opioid use will be measured daily during the five-day treatment period. Opioid use will be measured and functional response to pain surveys will be obtained at discharge, 2 weeks, 6 weeks, 3 months, and 6 months after injury.

Researchers will compare patients receiving ketorolac (treatment) plus SOC versus those receiving SOC alone to determine if ketorolac reduces chronic opioid use and improves the functional response to pain.

Study Overview

• Status: Recruiting
• Conditions: Chronic Opioid Use; Orthopaedic Trauma
• Intervention / Treatment: Drug: Ketorolac Injection; Other: Standard of Care (SOC) Multimodal Analgesia

Detailed Description

Background: Post-traumatic pain (PTP) can be difficult to control in orthopaedic trauma patients, particularly those with multiple injuries. Currently, opioids serve as the cornerstone for pain management despite their potential for complications including chronic use. Given this, it is not surprising that new-onset opioid abuse is a leading cause of complications following orthopaedic trauma and can be a limiting factor in delaying and/or safely resuming pre-injury responsibilities. Changes in pain management are needed to help military personnel and civilians expeditiously and safely return to their pre-injury duty. Early short-term scheduled ketorolac treatment has been shown to decrease acute pain and short and mid-term opioid use but whether this translates into decreased chronic opioid use is unknown.

Hypothesis/Objective: This study attempts to determine whether an early scheduled short-term course of ketorolac treatment has a sustained impact by decreasing chronic opioid use. The study will also investigate whether this treatment improves function and resilience as well as whether early pain control and/or the functional response to pain mediate (i.e. are responsible for / explain) the effect of the ketorolac intervention on chronic opioid use.

Specific Aims:

Aim 1: Determine whether orthopaedic trauma patients who receive a scheduled five-day course of low-dose ketorolac (15 mg IV every six hours, with transition to 10 mg orally every eight hours if discharged prior to completion of the five-day regimen) in combination with standard of care (SOC) multimodal analgesia (MMA) are less likely to develop chronic opioid use, defined as continued use at six months post-injury, compared to patients receiving SOC MMA alone.

Aim 2: Determine if patients who received a consistent five-day course of low-dose ketorolac have an improved functional response to pain measured via: 1) Brief Pain Inventory (BPI), 2) Patient-Reported Outcomes Measurement Information System - Pain Interference (PROMIS-PI), and 3) Brief Resilience Scale (BRS) scores at discharge, 3 months, and 6 months post-injury. Secondary pain outcome measures such as pain VAS and MME data will also be compared between the two groups.

Aim 3: Determine (1) the extent to which early pain control during the intervention, assessed using pain VAS and MME intake, mediates the effect of ketorolac on chronic opioid use, (2) the extent to which early pain control mediates the effect of ketorolac on the functional response to pain measures, assessed using BPI, PROMIS-PI, and BRS, and (3) the extent to which early pain control and the functional response to pain in combination or isolation mediate the effect of ketorolac on chronic opioid use.

Study Design: Adult patients (aged 18 to 70 years) with an acute orthopaedic traumatic injury undergoing operative fixation and admitted at participating Level 1 trauma centers will be enrolled. Once enrolled, patient randomization will be stratified by site and NISS score categorization (either 1-15 or greater than 15). Experienced clinical research staff will prospectively identify patients with strict adherence to all inclusion and exclusion criteria. Participants will be randomized to treatment (15 mg of ketorolac IV every 6 hours for up to 5 days in combination with SOC MMA; patients discharged prior to completing the five-day regimen will complete the remaining treatment with oral ketorolac 10 mg every 8 hours) or to SOC MMA alone. Measures of the functional response to pain including the BPI, PROMIS-PI, and BRS will be collected at hospital discharge and 3- and 6-months post-injury. Outcome measures of pain including VAS and MME will be recorded at enrollment, during the first five days of inpatient admission, at discharge, and at clinic follow-ups. The treatment and SOC groups will be compared using the intention-to-treat analyses across the primary and secondary outcomes. Mediation analyses will be used to understand how early pain control and the functional response to pain mediate the effect or lack of effect on chronic opioid use to better understand the factors that lead to this devastating complication.

• Study Type: Interventional
• Enrollment (Estimated): 458
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Arun Aneja, MD, PhD; Phone Number: 617-726-6546; Email: aaneja@mgh.harvard.edu
• Study Contact Backup: Name: Healy S. Vise, BS; Phone Number: 617-643-1232; Email: hvise@mgh.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Massachusetts General Hospital
      • Contact: Arun Aneja, MD, PhD; Email: aaneja@mgh.harvard.edu
      • Contact: Healy Vise, BS; Email: hvise@mgh.harvard.edu
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Recruiting
      • Vanderbilt University Medical Center
      • Contact: William Obremskey, MD; Email: william.obremskey@vumc.org
      • Contact: Karen M Trochez; Email: karen.m.trochez@vumc.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patient age: 18-70
• Patient or legally authorized representative (LAR) able to provide consent
• Patients with acute musculoskeletal trauma requiring surgical fixation (i.e. ORIF with plates and screws and/or intramedullary nailing)
• Anticipated hospital admission
• Patients who speak English or Spanish
• Patients who can be followed at the enrolling facility for at least 6 months

Exclusion Criteria:

• Patient age < 18 or > 70 years
• Patients with injury more than 24 hours prior to evaluation
• Patients with active hemorrhagic shock or risk of significant hemorrhage
• Patients who are pregnant or breastfeeding
• Patients with a history of active gastrointestinal bleeds or ulceration
• Patients with chronic use of steroids or immune-modulating drugs or history of organ transplantation
• Patients with preexisting chronic renal, liver, heart, or lung disease
• Patients with a creatinine ≥ 1.30 mg/dL during enrollment
• Patients with history of myocardial infarction, stroke, or bleeding disorder
• Patients with head or chest injury requiring surgical intervention
• Patients with allergy to ketorolac or hypersensitivity to aspirin
• Patients receiving chronic opioid therapy or treatment for opioid use disorder
• Patients who are current IV drug users
• Patients who require a daily NSAID or aspirin regimen, except for daily low-dose aspirin (81 mg)
• Patients with insufficient follow-up or anticipated difficulty in completing follow-up at a study site for a minimum of 6 months due to any of the follow reasons: death, no follow-up after initial discharge, severe psychiatric conditions, unstable living conditions, planned follow-up at another medical center not participating in this study, live far away from the clinic, and/or incarcerated

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Standard of Care (SOC) + Ketorolac; The treatment arm will receive a scheduled five-day course of low-dose ketorolac in addition to standard of care (SOC) multimodal analgesia according to each site's institutional protocol. Ketorolac will be administered intravenously at a dose of 15 mg every 6 hours during the perioperative period. Participants discharged prior to completing the five-day regimen will complete the remaining treatment with oral ketorolac 10 mg every 8 hours.	Drug: Ketorolac Injection; Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits analgesic activity in animal models. The mechanism of action of ketorolac, like that of other NSAIDs, is not completely understood but may be related to prostaglandin Reference ID: 3281582 3 synthetase inhibition. The biological activity of ketorolac tromethamine is associated with the S-form. Ketorolac tromethamine possesses no sedative or anxiolytic properties.; Other Names: Toradol; Other: Standard of Care (SOC) Multimodal Analgesia; Standard of care (SOC) multimodal analgesia as determined by each participating site's institutional protocol for perioperative pain management in orthopaedic trauma patients. SOC may include opioids, acetaminophen, regional anesthesia, and other non-NSAID analgesic modalities. Scheduled nonsteroidal anti-inflammatory drugs (NSAIDs), including ketorolac, are not permitted during the five-day perioperative treatment period.
Active Comparator: Standard of Care (SOC); The control arm will receive standard of care (SOC) multimodal analgesia according to each site's institutional protocol.	Other: Standard of Care (SOC) Multimodal Analgesia; Standard of care (SOC) multimodal analgesia as determined by each participating site's institutional protocol for perioperative pain management in orthopaedic trauma patients. SOC may include opioids, acetaminophen, regional anesthesia, and other non-NSAID analgesic modalities. Scheduled nonsteroidal anti-inflammatory drugs (NSAIDs), including ketorolac, are not permitted during the five-day perioperative treatment period.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Chronic Opioid Use	Defined as continued opioid use at 6 months post-trauma	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brief Pain Inventory (BPI)	Pain assessment tool that measures both the intensity of pain and interference of pain in a patient's life, including pain relief, pain quality, and patient perception of pain. Each question is scaled from 0 to 10, with a higher score meaning worse pain.	Enrollment, Hospital Discharge (up to 2 weeks), 2 weeks, 6 weeks, 3 months, and 6 months post-trauma
Patient-Reported Outcomes Measurement Information System-Pain Interference (PROMIS-PI)	NIH-validated outcome measure that assesses how pain interferes with a patient's daily activities. This is measured using a T-score metric in which 50 is the mean of a relevant reference population, and 10 is the standard deviation of the population. A higher score for this survey means a worse outcome and is representative of pain interfering more in a patient's daily activities.	Hospital Discharge (up to 2 weeks), 2 weeks, 6 weeks, 3 months, and 6 months post-trauma
Brief Resilience Scale (BRS)	Scale developed to assess a patient's ability to bounce back or recover from stress. This scale consists of 6 questions with answer choices ranging from 1-5. The total score is calculated and averaged to reflect the BRS score. BRS scores from 1.00 - 2.99 reflect low resilience, 3.00 - 4.30 reflect normal resilience, and scores from 4.31 - 5.00 reflect high resilience.	Hospital Discharge (up to 2 weeks), 2 weeks, 6 weeks, 3 months, and 6 months post-trauma
Visual Analogue Scale (VAS)	Instrument that attempts to capture a patient's perception of pain along a continuum. This will be measured on a scale of 0 - 100, with 0 being no pain, 50 being moderate pain, and 100 being the worst pain possible.	Enrollment, First Five Hospital Days, Hospital Discharge (up to 2 weeks), 2 weeks, 6 weeks, 3 months, and 6 months post-trauma
Morphine Milligram Equivalents (MME)	Calculation used to standardize opioid consumption.	Enrollment, First Five Hospital Days, Hospital Discharge (up to 2 weeks)
Opioid Use	A survey to assess if patients are using opioids in the outpatient setting	2 weeks, 6 weeks, 3 months, and 6 months post-trauma

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: United States Department of Defense
• Investigators: Principal Investigator: Arun Aneja, MD, PhD, Massachusetts General Hospital

Publications and helpful links

Helpful Links

• Pilot Study Results
• Pilot Study Results #2

Study record dates

Study Major Dates

• Study Start (Actual): February 28, 2025
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): August 31, 2027

Study Registration Dates

• First Submitted: December 16, 2023
• First Submitted That Met QC Criteria: January 10, 2024
• First Posted (Actual): January 11, 2024

Study Record Updates

• Last Update Posted (Actual): May 14, 2026
• Last Update Submitted That Met QC Criteria: May 13, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: NSAID; orthopaedic trauma; chronic opioid use; IV ketorolac; acute pain management
• Additional Relevant MeSH Terms: Wounds and Injuries; Multiple Trauma; Health Services Administration; Health Care Quality, Access, and Evaluation; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Quality of Health Care; Quality Indicators, Health Care; Indomethacin; Indoles; Ketorolac; Ketorolac Tromethamine; Standard of Care
• Other Study ID Numbers: 2023P003287; HT9425-23-1-0413 (Other Grant/Funding Number: Department of Defense PRORP)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes