A Randomized Study of Ibuprofen + Oxycodone/Acetaminophen Versus Ibuprofen + Acetaminophen for ED Patients With Insufficient Relief of Acute Musculoskeletal Pain After Treatment With Prescription Strength Ibuprofen
Phase: PHASE4
Conditions: Musculoskeletal Pain
Sponsor: Montefiore Medical Center

Acetaminophen (APAP) +/- Oxycodone
 
 
Protocol ID: 2019-10592
 
 
       NCT04122443

A randomized study of ibuprofen + oxycodone/acetaminophen versus ibuprofen 
+ acetaminophen for ED patients with insufficient relief of acute musculoskeletal 
pain after treatment with prescription strength ibuprofen. 06042019
1
Background
It is clear that many patients with acute musculoskeletal injury continue to suffer 
substantial amounts of pain despite optimal therapy with non-steroidal anti-
inflammatory drugs (NSAIDs) and even with NSAIDS combined with 
acetaminophen.(1) In head-to-head studies conducted among patients with acute 
musculoskeletal injury, oral opioids generally do not outperform NSAIDs or NSAIDs 
combined with acetaminophen.(2, 3) Similarly, studies of opioids combined with 
NSAIDs versus NSAIDs alone have not demonstrated increased efficacy of the 
combination.(4, 5) However, these results belie our clinical experience, in which 
oral opioids appear to play an important role in a select group of patients. Indeed, 
one critique of the studies mentioned above is that they generally enrolled a broad 
population of patients with acute musculoskeletal injury, rather than the population 
most likely to benefit from oral opioids: the population of patients with substantial 
persistent pain despite appropriate treatment with NSAIDs. Because of the risks 
now recognized to be associated with oral opioids, it is imperative to identify 
specific populations likely to benefit from opioids, so that risk/ benefit assessments 
among these patients can be evidence based. With this is mind, we propose a clinical 
trial in which the combination of an oral opioid with an NSAID is compared to 
NSAID therapy without an opioid among emergency department (ED) patients most 
likely to benefit from the combination: those patients who report inadequate relief 
of pain despite use of prescription-strength NSAID. We hypothesize that, among an 
enriched population of ED patients with acute musculoskeletal pain who request 
additional analgesia after treatment in the ED with an NSAID, oxycodone/ 
acetaminophen will provide superior analgesia than acetaminophen alone, as 
measured by the frequency with which patients report adequate pain control 2 
hours after medication ingestion. 
Methods
Overview. This will be a randomized, double-blind, two-stage comparative 
effectiveness study conducted in the Montefiore and Einstein EDs. In stage one, 
patients with severe acute musculoskeletal pain will be enrolled prior to treatment 
in the ED and then administered ibuprofen, an NSAID. In stage two, those who 
request additional analgesia after sufficient time has elapsed after ingestion of the 
ibuprofen will be randomized to oxycodone 10mg/ acetaminophen 650mg or 
acetaminophen 650mg alone.
IRB NUMBER: 2019-10592
IRB APPROVAL DATE: 10/17/2019
IRB NUMBER: 2019-10592
IRB APPROVAL DATE: 10/17/2019
IRB NUMBER: 2019-10592
IRB APPROVAL DATE: 10/17/2019
IRB NUMBER: 2019-10592
IRB APPROVAL DATE: 10/17/2019

A randomized study of ibuprofen + oxycodone/acetaminophen versus ibuprofen 
+ acetaminophen for ED patients with insufficient relief of acute musculoskeletal 
pain after treatment with prescription strength ibuprofen. 06042019
2
ED patient
with acute
pain. Enter
Stage 1
Stage 1
endpoint:
Sufficient relief
or insufficient
relief?
Patient’s participation
in study ends.
Discharged home on
NSAID (provider’s
choice)
Yes,
sufficient
relief
No,
insufficient
relief
Begin Stage 2.
ED patient with
insufficiently
controlled pain
Stage 2
endpoint:
Improvement in
0-10 pain scale
60-90m
2 hours
Randomized to
APAP alone or APAP
+ oxycodone
Ibuprofen 600mg PO
Figure1. Study flow diagram
Population of interest:
--Acute musculoskeletal pain: Any pain attributable to muscles, bones, joints, 
tendons, ligaments or supporting structures, as determined by the clinical team, of 
10 days duration or less. Prior to the onset of acute pain, patients cannot have 
experienced pain in the same body region during the prior six months
--Pain has to be described as moderate or severe, when the patient is asked if the 
pain is mild, moderate or severe in intensity
Exclusion criteria are as follows:
--Contraindication to NSAID
--Contraindication to acetaminophen
--Contraindication to oxycodone
--Use of an NSAID within the previous six hours
--Use of acetaminophen within the previous six hours
--Use of an opioid within the previous ten days
--Chronic pain, defined as any pain on >50% of days for at least 3 months prior to 
onset of acute pain
--Gout (a musculoskeletal pain that often requires disease-specific therapy)
IRB NUMBER: 2019-10592
IRB APPROVAL DATE: 10/17/2019
IRB NUMBER: 2019-10592
IRB APPROVAL DATE: 10/17/2019
IRB NUMBER: 2019-10592
IRB APPROVAL DATE: 10/17/2019
IRB NUMBER: 2019-10592
IRB APPROVAL DATE: 10/17/2019

A randomized study of ibuprofen + oxycodone/acetaminophen versus ibuprofen 
+ acetaminophen for ED patients with insufficient relief of acute musculoskeletal 
pain after treatment with prescription strength ibuprofen. 06042019
3
Investigational medications
In stage one, all patients will receive ibuprofen 600mg PO.
Patients eligible for stage 2 will be randomized to oxycodone 10mg/ acetaminophen 
650mg or acetaminophen 650mg alone.
The ibuprofen will not be blinded. The research pharmacist will mask the 
medication for stage 2 by placing it in unmarked capsules. Randomization will occur 
using a sequence generated at http://randomization.com. Research personnel will 
be presented with consecutive medication packets, which are to be dispensed to 
consecutive patients in sequential order.
The study will be stratified by study site.
Measures.
--Pain scales. We will use two complementary pain scales. The primary scale will be 
an 11-point numerical scale, on which patients assign their pain an integer between 
0 and 10. This scale, the numerical rating scale for pain, is commonly used in ED 
acute pain research We will also assess pain using a four-item ordinal scale, on 
which patients describe their pain using the descriptors severe, moderate, mild, or 
none. 
--Adequacy of analgesia. 
Patients will be asked the following questions: 
1) Did the medication we gave you control your pain? Answer choices: Yes (it did); 
No (It did not); and Not sure. 
2) The next time you have the same type of pain, do you want a stronger 
medication? Answer choices: Yes (I want a stronger medication); No ( I do not want 
a stronger medication); and Not sure
--Medication induced side effects. Patients will be asked if they developed any new 
symptoms they believe were caused by the investigational medications. An 
affirmative response will trigger an open-ended follow-up question eliciting details
--Satisfaction with medication. Patients will be asked if they would want to take the 
same medication during a subsequent episode of pain.
If study participants are discharged from the ED prior to completion of the study, 
they will be followed by telephone.
Outcomes.
This study will be conducted in two stages, the first stage will be non-randomized 
and open label. The second stage will be randomized and blinded. Each stage will 
have a primary outcome. Stage one will commence at the time of enrollment and 
conclude when the patient determines whether or not he or she has experienced 
sufficient analgesia. 
IRB NUMBER: 2019-10592
IRB APPROVAL DATE: 10/17/2019
IRB NUMBER: 2019-10592
IRB APPROVAL DATE: 10/17/2019
IRB NUMBER: 2019-10592
IRB APPROVAL DATE: 10/17/2019
IRB NUMBER: 2019-10592
IRB APPROVAL DATE: 10/17/2019

A randomized study of ibuprofen + oxycodone/acetaminophen versus ibuprofen 
+ acetaminophen for ED patients with insufficient relief of acute musculoskeletal 
pain after treatment with prescription strength ibuprofen. 06042019
4
The second stage will commence after the patient has determined whether or not he 
or she has experienced sufficient analgesia and conclude two hours later.
The primary outcome of the open-label stage is the patient’s determination of 
whether or not they have experienced adequate analgesia. This will be assessed 60 
minutes after receipt of the NSAID in the ED. If at this 60 minute time point the 
patient is unable to determine whether or not they have experienced adequate 
analgesia, they will be permitted to defer the decision for an additional 30 minutes.
Secondary outcomes of the open-label stage will be an assessment of medication 
induced side effects, which will be determined 60 minutes after medication 
ingestion, and at 90 and 120 minutes as well if the patient is still in the ED
The primary outcome of the blinded stage is improvement on the 0-10 pain scale 
between the time of medication ingestion and 2 hours later. Secondary outcomes 
include pain levels, adequacy of analgesia, satisfaction with the medication, and 
medication-induced side effects.
Baseline variables.
--Severity of pain, duration of pain, pain region and discharge diagnosis. 
--We will also ask the provider to predict whether or not the patient will opt for 
second stage treatment.
Analysis.
For the open-label stage, outcomes will be reported as n/N (%) with 95%CI.
Similarly for the blinded stage, outcomes will be reported as mean improvement 
between baseline and two hour with 95%CI. Between group differences will be 
reported as mean difference with 95%CI. The results will be considered statistically 
significant if the 95%CI of the between group difference does not cross 0. Missing 
primary outcome data will be managed by carrying forward pain scores closest to 
the primary outcome, which we anticipate will bias the results slightly towards the 
null hypothesis.
Sample size calculation.
We calculated a sample size of 146 (73 per group) based on the following 
parameters:  alpha = 0.05, power = 0.8, minimum clinically important difference of 
1.3 numerical rating scale (NRS) units, and standard deviation of 2.8 NRS units. We 
wish to enroll an additional 8 subjects (approximately 5%) in order to account for 
potential protocol violations and missing data. Thus, our final sample size for stage 2 is 
154 subjects.
We predict that the frequency with which patients request additional analgesia after 
completing stage 1 will be between 20 and 33%. Therefore, we may need to enroll 
770 patients in stage 1 to obtain a sufficient number of patients for stage 2, although 
IRB NUMBER: 2019-10592
IRB APPROVAL DATE: 10/17/2019
IRB NUMBER: 2019-10592
IRB APPROVAL DATE: 10/17/2019
IRB NUMBER: 2019-10592
IRB APPROVAL DATE: 10/17/2019
IRB NUMBER: 2019-10592
IRB APPROVAL DATE: 10/17/2019

A randomized study of ibuprofen + oxycodone/acetaminophen versus ibuprofen 
+ acetaminophen for ED patients with insufficient relief of acute musculoskeletal 
pain after treatment with prescription strength ibuprofen. 06042019
5
we will continue enroll patients in stage 1 only until 154 patients have been 
randomized in stage 2. 
Data Monitoring Plan.
Dr. David Esses, the director of the Moses ED and Dr. Polly Bijur, Ph.D, head of the 
Division of Research of the Department of Emergency Medicine, will meet monthly 
with the PI. This meeting will aim to 1) monitor adverse events and develop 
strategies to minimize these; and 2) monitor recruitment and enrollment.  
Data Collection.
All data will be entered directly into REDCap.
Process for enrollment and consent.
Participants will be approached for participation in the study after initial evaluation 
by the attending physician in the emergency department. The recruitment and 
consent process will be performed by the department’s research associates, with 
supervision from the study investigators. 
IRB NUMBER: 2019-10592
IRB APPROVAL DATE: 10/17/2019
IRB NUMBER: 2019-10592
IRB APPROVAL DATE: 10/17/2019
IRB NUMBER: 2019-10592
IRB APPROVAL DATE: 10/17/2019
IRB NUMBER: 2019-10592
IRB APPROVAL DATE: 10/17/2019

A randomized study of ibuprofen + oxycodone/acetaminophen versus ibuprofen 
+ acetaminophen for ED patients with insufficient relief of acute musculoskeletal 
pain after treatment with prescription strength ibuprofen. 06042019
6
References
1.
Chang AK, Bijur PE, Esses D, Barnaby DP, Baer J. Effect of a Single Dose of 
Oral Opioid and Nonopioid Analgesics on Acute Extremity Pain in the 
Emergency Department: A Randomized Clinical Trial. JAMA. 
2017;318(17):1661-7.
2.
Gong J, Colligan M, Kirkpatrick C, Jones P. Oral Paracetamol Versus 
Combination Oral Analgesics for Acute Musculoskeletal Injuries. Ann Emerg 
Med. 2019.
3.
Jones P, Dalziel SR, Lamdin R, Miles-Chan JL, Frampton C. Oral non-steroidal 
anti-inflammatory drugs versus other oral analgesic agents for acute soft 
tissue injury. Cochrane Database Syst Rev. 2015(7):CD007789.
4.
Friedman BW, Dym AA, Davitt M, Holden L, Solorzano C, Esses D, et al. 
Naproxen With Cyclobenzaprine, Oxycodone/Acetaminophen, or Placebo for 
Treating Acute Low Back Pain: A Randomized Clinical Trial. JAMA. 
2015;314(15):1572-80.
5.
Graudins A, Meek R, Parkinson J, Egerton-Warburton D, Meyer A. A 
randomised controlled trial of paracetamol and ibuprofen with or without 
codeine or oxycodone as initial analgesia for adults with moderate pain from 
limb injury. Emerg Med Australas. 2016;28(6):666-72.
IRB NUMBER: 2019-10592
IRB APPROVAL DATE: 10/17/2019
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IRB APPROVAL DATE: 10/17/2019
IRB NUMBER: 2019-10592
IRB APPROVAL DATE: 10/17/2019