Clinical trial NCT06201676: Low-Dose Short-Term Ketorolac to Reduce Chronic Opioid Use in Orthopaedic Polytrauma Patients
Official title: Low-Dose Short-Term Ketorolac to Reduce Chronic Opioid Use in Orthopaedic Polytrauma Patients
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Orthopaedic Polytrauma
Chronic Opioid Use
Keywords: orthopaedic polytrauma
chronic opioid use
NSAID
IV ketorolac
acute pain management
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
Collaborators: name: United States Department of Defense
First posted: 2024-01-11
Enrollment: 458
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Parallel, two-arm, placebo-controlled, randomized controlled trial
Primary purpose: TREATMENT

Brief 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.

Detailed 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. Once enrolled, patient randomization will be stratified by site and NISS score categorization (either 10-15 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 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.

Eligibility criteria: 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

Primary outcomes:
measure: Chronic Opioid Use
timeFrame: 6 months
Secondary outcomes:
measure: Brief Pain Inventory (BPI)
timeFrame: Enrollment, Hospital Discharge (up to 2 weeks), 2 weeks, 6 weeks, 3 months, and 6 months post-trauma
measure: Patient-Reported Outcomes Measurement Information System-Pain Interference (PROMIS-PI)
timeFrame: Hospital Discharge (up to 2 weeks), 2 weeks, 6 weeks, 3 months, and 6 months post-trauma
measure: Brief Resilience Scale (BRS)
timeFrame: Hospital Discharge (up to 2 weeks), 2 weeks, 6 weeks, 3 months, and 6 months post-trauma
measure: Visual Analogue Scale (VAS)
timeFrame: Enrollment, First Five Hospital Days, Hospital Discharge (up to 2 weeks), 2 weeks, 6 weeks, 3 months, and 6 months post-trauma
measure: Morphine Milligram Equivalents (MME)
timeFrame: Enrollment, First Five Hospital Days, Hospital Discharge (up to 2 weeks)
measure: Opioid Use
timeFrame: 2 weeks, 6 weeks, 3 months, and 6 months post-trauma
Other outcomes:
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
Study officials:
affiliation: Massachusetts General Hospital
name: Arun Aneja, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: