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

Chronic Opioid Use Clinical Trial

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06201676
• Other study ID #: 2023P003287
• Secondary ID: HT9425-23-1-0413
• Status: Not yet recruiting
• Phase: Phase 4
• Start date: July 1, 2024
• Est. completion date: August 31, 2027

Study information

• Verified date: May 2024
• Source: Massachusetts General Hospital
• Contact: Arun Aneja, MD, PhD
• Phone: 617-726-6546
• Email: aaneja[@]mgh.harvard.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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 polytrauma patients. The main questions this study aims to answer are:

1. Are patients who are given scheduled ketorolac during the first five hospital days less likely to develop chronic opioid use at 6 months after injury compared to patients who receive placebo?

2. Does scheduled ketorolac during the first five hospital days 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 placebo group to be given every 6 hours during the first five hospital days. 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 ketorolac (treatment) versus saline (placebo) to see if ketorolac reduces chronic opioid use and improves the functional response to pain.

Description:

Background: Post-traumatic pain (PTP) can be difficult to control in polytrauma patients. 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 polytrauma 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 polytrauma patients who receive IV ketorolac, 15 mg every six hours, in combination with standard of care (SOC) analgesia for the first five inpatient days are less likely to develop chronic opioid use, defined as continued use at six months post-injury, compared to patients receiving similar placebo injections in combination with SOC.

Aim 2: Determine if patients who received a consistent five-day course of low-dose ketorolac during the inpatient stay 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: Polytrauma patients aged 18 to 70 years of age with a New Injury Severity Score greater than 9, consistent with moderate injury, and anticipated admission of at least 5 days to ensure completion of the treatment will be enrolled. 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 plus SOC multimodal analgesia every 6 hours for 5 days) or control (similar volume of saline every 6 hours plus SOC multimodal analgesia for 5 days). 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 control 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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 458
• Est. completion date: August 31, 2027
• Est. primary completion date: December 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• Patient age: 18-70

• Patient or legally authorized representative (LAR) able to provide consent

• Patients with NISS > 9 at time of admission with musculoskeletal trauma requiring surgical fixation

• Anticipated admission = 5 days

• Patients who speak English or Spanish

• Patients who can be followed at our facility for at least 6 months

Exclusion Criteria:

• Patient age < 18 or > 70 years

• Patients with injury more than 24 hours prior to evaluation

• 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 infarctions, 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 with insufficient follow-up:

• Death

• No follow-up after initial discharge

• Patients who have difficulty maintaining follow-up for clinic visits, including:

• 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

• 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 hospital length of stay greater than 14 days

Related Conditions & MeSH terms

• Chronic Opioid Use
• Multiple Trauma

Intervention

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:
• Normal Saline
0.9% Sodium Chloride Injection, USP is sterile and nonpyrogenic. It is a parenteral solution containing sodium chloride in water for injection intended for intravenous administration. Each 100 mL of 0.9% Sodium Chloride Injection, USP contains 900 mg sodium chloride in water for injection. Electrolytes per 1000 mL: sodium (Na+) 154 mEq; chloride (Cl-) 154 mEq. The osmolarity is 308 mOsmol/L (calc.).

Locations

Country	Name	City	State
United States	Vanderbilt University Medical Center	Nashville	Tennessee

Sponsors (2)

Lead Sponsor	Collaborator
Massachusetts General Hospital	United States Department of Defense

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Chronic Opioid Use	Defined as continued opioid use at 6 months post-trauma	6 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Morphine Milligram Equivalents (MME)	Calculation used to standardize opioid consumption.	Enrollment, First Five Hospital Days, Hospital Discharge (up to 2 weeks)
Secondary	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

External Links

•   Pilot Study Results
•   Pilot Study Results #2