Comparative Efficacy of 4 Oral Analgesics for the Initial Management of Acute Musculoskeletal Extremity Pain
Phase: PHASE4
Conditions: Pain
Sponsor: Montefiore Medical Center

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Title:  Comparative efficacy of 4 oral analgesics for the initial management of acute musculoskeletal 
extremity pain 
 
Investigators: Andrew Chang, M.D; David Esses, M.D; E. John Gallagher, M.D. 
 
 
Objective:  To perform a randomized, double blind 4-arm clinical trial of the 
comparative efficacy of 4 oral analgesics in the initial management of acute 
musculoskeletalextremity pain presenting to the ED.   
 
Introduction 
 
According to a recent study, over 44 million emergency department (ED) visits 
per year are for a chief complaint related to pain. Approximately 29%, or 12.8 million, of 
these visits result in a prescription for an analgesic.1  Yet, there are only a handful of 
studies that compare the efficacy of acute pain management of the most commonly 
prescribed oral analgesics.2-7 
The Cochrane Collaboration has produced several reviews describing the 
effectiveness of codeine, both with and without acetaminophen, as well as a review of the 
efficacy of oxycodone alone or in combination with acetaminophen.  Indirect 
comparisons over a period of 4-6 hours demonstrated greater efficacy with oxycodone 
compared to codeine.8-10Most of the studies included in the reviews were postoperative 
dental studies utilizing extraction of the third molar as the pain model.  There are no 
Cochrane reviews that describe the efficacy of hydrocodone.   
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Two randomized controlled trials were found comparing hydrocodone and 
codeine for chronic pain.  Rodriguez et. al. found no significant difference in either 
analgesia or incidence of side effects in a study of 121 patients using 5 mg of 
hydrocodone vs. 30 mg of codeine, both in combination with 500 mg of 
acetaminophen.11Palangio et al. in a three armed study design with 469 patients, found 
greater analgesia in the 15/400 mg hydrocodone/ibuprofen group compared to the 60/600 
mg of codeine/acetaminophen.6 
We have conducted three randomized clinical trials of oral opioids for patients 
discharged from the ED following presentation for acute musculoskeletal pain.  The first 
compared hydrocodone/acetaminophen against codeine/acetaminophen and found no 
difference in change in pain intensity when patients were contacted 24-hours post-
discharge.12  The second compared oxycodone/acetaminophen against 
codeine/acetaminophen and again found no difference at 24 hours (manuscript is in 
“revise and resubmit” status).The third trial compared oxycodone/acetaminophen against 
hydrocodone/acetaminophen and also failed to show a difference in pain control at 24 
hours following ED discharge (preliminary and unpublished data).  The design of these 
studies differed from other studies of oral analgesics in that patients were called 24 hours 
after they left the ED, and they were asked to recall their pain intensity just prior to their 
most recent dose of pain medication and again 2 hours after ingestion of the study 
medications.  
An alternative to oral opioid analgesics combined with acetaminophen is the 
combination of non-steroidal antiinflammatory drugs (NSAIDS) and acetaminophen.  A 
review published in 2010 found the combination of various NSAIDS and acetaminophen 
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to be superior to acetaminophen alone in 17 of 20 studies.13The combination of ibuprofen 
and acetaminophen published since that review has been found to be more effective than 
each drug alone in 4 out of 5 trials of patients following dental surgery.14-17Only one 
small ED study that examined the effect of the 800 mg ibuprofen/1000 mg 
acetaminophen combination on musculoskeletal pain one hour after administration did 
not find it to be superior to either of the component drugs.18 
We could find only one direct comparison between an ibuprofen/acetaminophen 
combination and an oral opioid combination. Patients who received 400 mg ibuprofen/ 
1000 acetaminophen following extraction of a third molar had significantly less pain and 
greater pain relief in the 12 hour period after analgesic administration than patients who 
received 30 mg codeine/1000 mg acetaminophen.14 
For this proposed study, we wished to look at the comparative efficacy of a single 
dose of 4 oral analgesics given while the patient is still in the ED.  We believe this will 
enhance our understanding of these commonly prescribed oral analgesics by eliminating 
recall bias,which may have played a role in driving our prior findings comparing 
acetaminophen/codeine vs. hydrocodone/acetaminophen and oxycodone/acetaminophen 
toward the null of no difference among the 3 combination analgesics when assessed 24 
hours later.  
 
Methods 
 Design: 
 
This will be a randomized, double blind, comparative efficacy trial of oral 
analgesics with four single-dose treatment arms:  oxycodone 5 mg/ acetaminophen 325 
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mg, hydrocodone 5mg/acetaminophen 300mg, codeine 30 mg/acetaminophen 300mg, 
and ibuprofen 400 mg/acetaminophen1000 mg.   
 
Setting: 
The study will be performed simultaneously in 2 teaching hospitalsED’s affiliated 
with the Albert Einstein College of Medicine, both located in the Bronx, approximately 5 
miles apart, with a total of 180,000 adult visits annually.  Both EDsare staffed by trained 
bilingual (Spanish and English) salaried research associates (RAs) available 24 hours a 
day/7 days a week.  The research associates receive training in the ethical and practical 
aspects of data collection and a practicum with a senior research associate.  Some of the 
RAs have been enrolling study patients for 5-10 years.  
 
Patients: 
 
Inclusion criteria: Patients age 21 to 64 years of age; complaint of acute pain of 
less than seven days duration; location of pain in one or more extremities defined as 
distal to and including the shoulder joint in the upper extremities and distal to and 
including the hip joint in the lower extremities; radiologic evaluation is planned; and 
willingness to provide NRS pain scores after discharge from the ED.   
Exclusion criteria: Inability to reach patient on patient’s cell phone while in the 
ED; past use of methadone; chronic condition requiring frequent pain management such 
as sickle cell disease, fibromyalgia, or any neuropathy; history of an adverse reaction to 
any of the study medications; opioids taken in the past 24 hours; ibuprofen or 
acetaminophen taken in past 8 hours; pregnancy by either urine or serum HCG testing; 
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breastfeeding per patient report; history of peptic ulcer disease; report of any prior use of 
recreational narcotics; medical condition that might affect metabolism of opioid 
analgesics, acetaminophen, or ibuprofen such as hepatitis, renal insufficiency or failure, 
hypo- or hyperthyroidism, Addison’s or Cushing’s disease; taking any medicine that 
might interact with one of the study medications, such as antidepressant SSRI’s or 
Tricyclics, antipsychotics, anti-malaria medications quinidine or halofantrine, 
Amiodarone or Dronedarone, diphenhydramine, celecoxib, ranitidine, cimetidine, 
ritanovir, terbinafine, or St John’s Wort.   
 
Measures 
Pain intensity will be assessed by an 11-point numeric rating scale (NRS) where 0 
indicates no pain, 10 indicates worst possible pain.  The primary endpoint will be the 
difference between NRS pain between the time immediately prior to ingestion of the 
study medication and 2 hours later. Secondary outcomes include NRS scores at 1 
hourpain based on a 4-point Likert scale (none, mild, moderate, severe), and overall 
satisfaction with the pain medication using a 4-point Likert scale:  very satisfied, 
satisfied, unsatisfied, or very unsatisfied with the study medication.  Other outcomes 
include the incidence of side effects (nausea, vomiting, itchiness, rash,drowsiness, or 
confusion). 
Baseline information will be obtained from the patient including demographic 
characteristics and a listing of all over-the-counter, topical, and prescribed analgesics 
taken in the 24 hours prior to enrollment.  Diagnosis, rescue medication, and any other 
treatment received will be recorded, such as application of ice and splints.   
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Protocol: 
Patients will be referred to the study by the patient’s provider.  The treating 
attending will confirm that the patient has met enrollment criteria and assess whether the 
patient has capacity to provide informed consent.  RAs will describe the study in detail 
and obtain informed consent.  Following randomization all patients will have their pain 
scores assessed immediately before administration of the study drug and 1 hour later 
while in the ED.  If the patient remains in the ED, additional NRS pain scores and 
incidence of side effects will be assessed at 2 hours post-baseline.  Patients who are 
discharged prior to 2 hours will be called at the appropriate time to obtain their pain 
scores.  Since radiologic imaging is required for study entry, it is anticipated that the 
majority of patients will have most of their pain scores assessed while still in the ED.  In 
our 3 prior oral opioid studies, more than 95% of study subjects were reached by phone at 
24 hours.  Thus, we do not anticipate any difficulty in being able to contact patients up to 
2 hours after study medication is administered.   
 
An on-line random number generator (www.randomization.com) will be used to 
allocate patients in blocks of 8to one of four experimental groups: oxycodone 
5mg/acetaminophen 325mg, hydrocodone 5mg/acetaminophen 300mg, codeine 
30mg/acetaminophen 300mg, or ibuprofen 400mg/acetaminophen 1000 mg. The opioid 
and acetaminophen combinations were selected to reflect commonly used analgesics for 
musculoskeletal pain.  The choice of dose for the ibuprofen/acetaminophen combination 
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is based on a recently published study performed in the ED18and our desire to not miss an 
analgesic effect by administering a sub-therapeutic dose. 
The research pharmacist will ensure proper allocation concealment by inserting 
each study medication combination into 3 identical unmarked opaque gel capsules, filling 
any void with small quantities of lactose to equalize weight.  The capsules will be placed 
in numbered packetsby the research pharmacist working in an area distant from and 
inaccessible to ED staff.  Each packet will have a sealed opaque envelope stapled to it 
that indicates what medication it contains so that the assignment is readily available if 
this information is needed clinically due to a serious adverse reaction.   The RAs will 
retrievethe packets in sequential order and the nurse will dispense the medication to the 
patient. Patients, providers, and RAs will be blinded to study allocation.   
Patients who require rescue medications will receive oxycodone 5 mg (without 
acetaminophen).  This will be determined subjectively (i.e. if the patient requests 
additional pain medication or the treating physician decides that additional pain 
medication is needed).  Discharge medications will be administered by the treating 
physician as per his/her usual care.  
 
 
 
Data Collection and Processing 
Data will be collected on a standardized data collection instrument in REDCAP, 
an electronic data capture system. The PI will review the data collected and informed 
consent documentsweekly for accuracy and completeness.   
 
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Data analysis 
The primary data analysis will be a one-way analysis of variance testing the null 
hypothesis that there are no differences between the effect of the medications on mean 
change in pain from baseline to 2 hours post-baseline with a significance level of 0.05.  If 
there is evidence to reject the null hypothesis we will conduct the set of t-tests comparing 
all pairwise mean differences in pain. The Bonferroni method will be used to adjust the 
overall significance level of 0.05 in order to account for multiple comparisons.  The data 
will be presented as the difference between each pair of means and the set of 95% 
simultaneous Bonferroni CIs around the differences. SPSS version 22 (Chicago, IL.) will 
be used to conduct all data analyses.  Data will be stored in an identified format in the 
event that a metaanalysis of studies is performed in the future. 
 
Sample Size Calculation 
The following parameters were used to calculate the sample size:  an overall 2-
sided significance level of 0.05 (0.008 for each t-test using the Bonferroni correction), 
power of 80%, 1.3 NRS unit or greater difference in change in pain between groups 
based on a standard definition of the minimal clinically significant difference in pain, and 
a within group standard deviation of 2.6 based on estimates of variability of change in 
pain in response to oral opioid analgesics.  Using these parameters 100 patients are 
needed in each group for a total of 400 patients.   We will plan to continue to enroll 
patients until we have 400 patients with usable data (not missing primary outcome or 
other critical data points).  Based on past experience we estimate not needing more than 
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20 additional subjects to order to reach our target sample size of 400 patients.  We used 
nQuery Advisor 7.0 (Los Angeles, CA) to calculate the sample size.   
 
Data safety and monitoring 
Data monitoring committee and interim analysis.This committee will be composed of Dr. 
Polly Bijur, PhD, a statistician and epidemiologist, and Dr. Benjamin Friedman who will 
meet quarterly tomonitor adverse events, recruitment, and enrollmentAn interim analysis, 
which will be approved by the DSMC prior to randomization, will be conducted after 200 
subjects (50 in each treatment arm) with analyzable data have been enrolled. The purpose 
of the interim analysis is to identify one or more treatments that are clearly inferior or 
superior to the others. A clinically important difference in change in pain has been 
defined as 2 units or more on an NRS scale or 20 mm or more on a VAS score.  We will 
examine the point estimates of the change in pain.  If one or more arms has a mean 
decrease in pain that is at least 2 NRS units less than in other arms, that arm(s) will be 
discontinued regardless of statistical significance.   For example, if group A has mean 
pain scores that decrease from 8 NRS units to 4 NRS units over time, and group B has 
mean pain scores that decrease from 8 NRS units to 6 NRS units, we will discontinue 
treatment B.  If one group is clearly superior by this much the trial will be terminated.   
Conclusion 
 
This randomized, double-blind clinical trial is expected to further our 
understanding of the relative efficacy of 4 commonly used oral analgesics for acute 
musculoskeletal extremity pain.  In particular, we are interested in comparing the efficacy 
of high-dose ibuprofen/acetaminophen with traditional combinations of opioids and 
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acetaminophen. The results of these studies are intended to improve the emergency 
medicine physician’s ability to manage acute extremity pain in the emergency 
department. 
 
 
 
 
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