Clinical trial NCT03553498
Conditions: Acute Pain
Keywords: pain opioid analgesics Emergency Department randomized controlled trial acetaminophen hydromorphone
Sponsor: Albert Einstein College of Medicine
Start date: 2018-11-27; Completion date: 2019-05-15
Enrollment: 162 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this randomized clinical trial is to compare the analgesic efficacy and side effect profile of IV acetaminophen as an analgesic adjunctive medication to IV hydromorphone for the treatment of acute pain experienced by patients in the Emergency Department (ED).

Detailed description:
Multimodal treatment of pain is a commonly used strategy to control pain by combining analgesics with different and complementary mechanisms of action. Oral acetaminophen combined with opioids is a mainstay of treatment of mild to moderate pain, while the use of IV opioids is the standard for treatment of severe pain in the Emergency Department. An IV formulation of acetaminophen is widely used in Europe and has recently been approved in the US. It has been studied for treatment of acute post-operative pain and renal colic.

This randomized trial was designed to assess the effectiveness of the combination of IV acetaminophen and IV hydromorphone as a strategy to provide more effective treatment of acute severe pain in the Emergency Department with the possibility of reducing opioid consumption. All patients received 1 mg of IV hydromorphone. They were then randomized to receive either 1 g of IV acetaminophen or 100 mL of normal saline placebo. Measures of pain, vital signs, and presence of side effects were obtained immediately before IV hydromorphone was administered. Following receipt of the acetaminophen or placebo these same variables were measured at 15 minute intervals for the next 120 minutes. Additional analgesics were administered if patients requested them. Subsequent care of the patients was at the discretion of the treating attending physician.

Arms: arm 1: 1000 mg IV acetaminophen administered over 5-10 minutes

1 mg hydromorphone administered over 5-10 minutes arm 2: 100 ml IV normal saline administered over 5-10 minutes

1 mg hydromorphone administered over 5-10 minutes
Interventions: intervention 1: IV acetaminophen intervention 2: IV placebo intervention 3: hydromorphone
Intervention descriptions: intervention 1: acetaminophen given intravenously intervention 2: given intravenously intervention 3: hydromorphone given intravenously

Protocol documents:
Prot_SAP_000.pdf: 
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CLINICAL STUDY PROTOCOL
 
Title: Randomized Clinical Trial of IV Acetaminophen as an Adjuvant Analgesic to IV 
Hydromorphone for Treatment of Acute Severe Pain in Non-Elderly Emergency Department 
Patients
 
Sponsor
Department of Emergency Medicine/Montefiore Medical Center
3411 Wayne Ave
6th Floor, 10467, Bronx, New York, United States
Protocol Version
September 5, 2018
Version 1.4
 
 
Principal InvestigatorDr. Polly Bijur
Albert Einstein College of Medicine
Bronx, NY
United States
Tel: 718-430-4217
Email: polly.bijur@einstein.yu.edu
 
Synopsis
Primary Objective
To compare the analgesic efficacy of IV acetaminophen as an analgesic adjunctive medication to IV 
hydromorphone for the treatment of acute pain in the ED.
 
Secondary Objectives (if applicable)
To compare the side effect profiles and adverse events associated with the combination of 
acetaminophen and hydromorphone vs. hydromorphone alone.
 
Primary Outcome Variables
The primary outcome is the between group difference in change in NRS pain scores from baseline 
(immediately before administration of analgesics) to 60 minutes post-baseline.
 
Secondary Outcome Variables (if applicable)
Secondary efficacy outcomes: difference in proportion of patients who choose to forego additional 
pain medication 60 minutes post-baseline when asked the question, "Do you want more pain 
medication?”; difference in proportion of patients who receive additional pain medication before 60 
minutes post-baseline ("rescue" medication) and after 60 minutes.  The incidence of adverse events 
and side effects in the two groups will be compared. 
Study Duration
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The study will continue until the enrollment target of 162 patients has been achieved.  Based upon 
prior research studies, we anticipate that it will take approximately 5 months to reach our target.
 
Study Design
This is a double-blind, parallel group, randomized controlled trial comparing the analgesic efficacy 
of the combination of 1000 mg IV acetaminophen and 1 mg IV hydromorphone versus 1 mg IV 
hydromorphone alone for the treatment of acute pain in the Emergency Department.
 
Study Population
Adult patients (21 through 64 years of age) presenting to the Emergency Department with severe 
acute pain. 
 
Number of Participants
Our target enrollment is 162 (81 in each arm).
 
Number of Study Sites
This study will be conducted in the Emergency Departments on the Moses and Einstein campuses of 
Montefiore Medical Center. 
 
Visit Schedule Table (Optional)
 
Study Flow Chart (optional)
 
1 - Introduction
1.1 Introductory Statement
An estimated 44 million visits per year to US emergency departments (EDs) are associated 
with a painful condition.(1-2) Inadequate treatment of pain, has been demonstrated in many 
emergency departments.(3-6) Despite some progress, Todd's multicenter and multi-country study 
showed that only 50% of ED patients had at least a 2-point reduction of pain on a numeric rating 
scale (NRS) and 75% were discharged with moderate to severe pain.(7)  
Intravenous acetaminophen is one drug that has been suggested to provide analgesic relief 
as good as or better than intravenous opioids in common acute painful conditions (e.g. renal colic, 
post-operative pain).(8-10)  However, studies evaluating its use have been limited by small sample 
sizes and a range of methodologic limitations.(11)  
Combination oral acetaminophen and oral opioids are commonly used in the ED.  The 
rationale for combining different classes of analgesics is that the modes of action are different and 
may be at least additive if not synergistic.  While this same rationale holds for combining 
intravenously administered acetaminophen and opioids, there have been no studies that examined 
the efficacy of this combination.  Use of combination IV analgesics may provide enhanced analgesia 
and reduce the need for additional administration of opioid analgesics. 
2 - Background
2.1 Background/prevalence of research topic
IV opioids have been the standard of care for moderate to severe pain in the ED. Recently 
non-opioid analgesics have been considered and tested for use in the ED as alternatives to IV opioid 
analgesics.  The intravenous (IV) form of acetaminophen has been widely used in Europe for more 
than 20 years. The IV form obtained full FDA approval in the USA in 2010.  A recent literature 
review revealed a total of 14 randomized controlled trials involving IV acetaminophen in the ED 
setting (11). Three of these (12-14), found a larger reduction in pain in the IV acetaminophen arm 
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than the IV opioid arm. All compared IV acetaminophen directly against another analgesic. The 
combination of acetaminophen and opioids in oral analgesics has been found repeatedly to be more 
efficacious than each alone.  We reasoned that combining IV analgesics from these two classes 
might similarly improve the efficacy of treatment.  We have not found any studies that examined IV 
acetaminophen as an adjunct to any IV opioid analgesic.
 
3 - Rationale/Significance
3.1 Problem Statement
Pain is a serious problem for many ED patients. Improving treatment is complicated by the 
increasing prevalence of opioid misuse and overdose in the outpatient setting, which has resulted 
in initiatives designed to reduce the administration and prescribing of oral opioids, and to 
substitute non-opioid medications (e.g. non-steroidal anti-inflammatories, acetaminophen) to the 
extent that such strategies are consistent with provision of satisfactory analgesia. Determining the 
optimal approach to acute pain management in the ED represents an important area of 
investigation.
 
3.2 Purpose of Study/Potential Impact
The purpose of the current study is to compare the analgesic efficacy of 1000 mg of 
acetaminophen combined with 1 mg hydromorphone to 1 mg of hydromorphone alone for the 
treatment of severe acute pain experienced by adult ED patients.  If acetaminophen proves to be an 
efficacious adjunct to hydromorphone, care of ED patients in pain may be improved. 
 
3.3 Potential Risks and Benefits
3.3.1 Potential Benefits
Determining whether IV acetaminophen is an efficacious adjunctive analgesic to IV 
hydromorphone will help the clinician choose effective therapies for the treatment of acute 
pain. Society will benefit from a greater understanding of the relative merits of opioid and non-
opioid combination analgesia.
 
3.3.2 Potential Risks
It is likely that some subjects will experience adverse medication effects.  

All opioid pain medications such as hydromorphone have side effects, which include but 
are not limited to the following:
o
Common - not serious: nausea; vomiting; itching, drowsiness; flushing, dizziness, 
feeling light headed, drowsiness, constipation
o
Uncommon - serious: low blood pressure, low heart rate, slowed breathing, and 
decreased oxygen carried by your blood. This medicine can stop your breathing 
which can be fatal if not treated promptly. 

IV acetaminophen:
o
Common side effects: nausea, vomiting and headache. 
o
Uncommon – not serious: itching, rash, constipation, stomach pain, pain at site of IV 
needle
o
Uncommon serious: none reported for short-term use
4 - Study Objectives
4.1 Hypothesis
IV hydromorphone in combination with IV acetaminophen will provide more efficacious pain relief 
compared to IV hydromorphone in combination with IV placebo (normal saline). The primary 
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outcome is the between group difference in change in NRS pain scores from baseline to 60 minutes 
post administration of study medications. 
 
4.2 Primary Objective
To compare the analgesic efficacy of adding IV acetaminophen to IV hydromorphone for the 
treatment of acute pain in non-elderly ED patients.
 
4.3 Secondary Objectives (if applicable)
To compare the side effect profiles and adverse events associated with the combination of IV 
acetaminophen and IV hydromorphone and IV hydromorphone alone.
 
5 - Study Design
5.1 General Design
This is a double-blind, parallel group, randomized controlled trial comparing the efficacy and safety 
of 1000 mg IV acetaminophen combined with 1 mg IV hydromorphone vs. 1 mg IV hydromorphone 
plus placebo for the treatment of acute severe pain (defined as < 7 days duration) in adult patients 
(age 21 through 64) presenting to the ED.
 
5.1.1 Study Duration (if applicable)
We anticipate achieving our target enrollment in approximately 5 months.
 
5.1.2 Number of Study Sites
This study will be conducted in the Emergency Departments on the Moses and Einstein campuses of 
Montefiore Medical Center. 
 
5.2 Outcome Variables
5.2.1 Primary Outcome Variables
The primary outcome is the between group difference in change in numerical rating scale (NRS) 
pain scores from baseline to 60 minutes post administration of study medications. The NRS is a 
previously validated and reproducible measure of pain intensity ranging from 0 = no pain, to 10 = 
worst possible pain. 
 
5.2.2 Secondary Outcome Variables (if applicable)
Difference in proportion of patients who choose to forego additional pain medication at 60 minutes 
post-baseline when asked the question, "Do you want more pain medication?"
Difference in proportion of patients who receive additional pain medication before 60 minutes 
post-baseline ("rescue" medication) and between 60 and 120 minutes post baseline.  Difference in 
incidence of adverse events and side effects. 
5.3 Study Population
Adult (ages 21 through 64 years of age) patients presenting to the ED with severe acute pain.
 
5.3.1 Number of Participants
148 patients are needed to detect a mean difference of 1.3 NRS units in the decrease of pain 
between the 2 treatment groups, a validated and reproducible effect size used in acute pain studies 
to indicate a minimally clinically significant difference(20-23), a within group standard deviation of 
2.8 NRS units, significance level of 0.05, and 80% power. In order to ensure enrollment of a 
minimum of 148 patients with analyzable data, an additional 14 patients (~10%) will be enrolled.  
Thus the targeted sample size is 162 patients.  
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We used nQuery Advisor version 7.0 (Los Angeles, CA) to calculate the sample size.
 
5.3.2 Eligibility Criteria 
Inclusion criteria
• Age 21 through 64 years of age:  This is a study of adult ED patients.
• Pain with onset within 7 days of the ED visit: Pain within seven days is the definition of acute pain 
that has been used in the ED literature.
• ED attending physician's judgment that the patient's pain warrants IV opioids.  
• ED attending physician's judgment that the patient has capacity to provide informed consent.
• Patients must be able to understand English or Spanish.
Exclusion criteria
• Use of opioids or tramadol within past 24 hours.
• Use of acetaminophen or non-steroidal anti-inflammatory medication within the previous 8 
hours.
• Prior adverse reaction to opioids or acetaminophen.
• Chronic pain syndrome: frequently recurrent or daily pain for at least 3 months results in 
modulation of pain perception which is thought to be due to down-regulation of pain receptors. 
Examples of chronic pain syndromes include sickle cell anemia, osteoarthritis, fibromyalgia, and 
peripheral neuropathies.
• Medical condition that might affect metabolism or opioid analgesics or acetaminophen such as 
hepatitis, renal insufficiency or failure, hypo- or hyper-thyroidism, Addison's or Cushing's 
disease
• Pregnant or breastfeeding
• Alcohol intoxication: the presence of alcohol intoxication as judged by the treating physician may 
alter pain perception.
• Suspected chronic acetaminophen or opioid use, overdose., or suicidal ideation.
• SBP <100 mmHg: Opioids can produce peripheral vasodilation that may result in orthostatic 
hypotension.
• HR < 60/min: Opioids can cause bradycardia.
• Oxygen saturation < 95% on room air: For this study, oxygen saturation must be 95% or above on 
room air in order to be enrolled.
• Use of MAO inhibitors in past 30 days: MAO inhibitors have been reported to intensify the effects 
of at least one opioid drug causing anxiety, confusion and significant respiratory depression or 
coma.
• Patients using transdermal pain patches: pain patches may influence both the amount of pain 
patients report as well as the level of relief they obtain from other treatments.
• Taking any medication that might interact with one of the study medications, such as SSRI or 
tricyclic anti-depressants, benzodiazepine, buprenorphine, antipsychotics, anti-malarial 
medications (quinidine or halofantrine), amiodarone or dronedarone, diphenhydramine, 
celecoxib, ranitidine, cimetidine, ritanovir, terbinafine or St. John's Wort.
• Patients who have been previously enrolled in this same study: Patients may only be enrolled 
once.
 
6 - Methods
6.1 Treatment - Drug
6.1.1 Identity of Investigational Product/New Drug
Both acetaminophen IV (Ofirmev) and hydromorphone IV (Dilaudid) are FDA approved for clinical 
use.
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6.1.2 Dosage, Admin, Schedule (if applicable)

All patients will receive 1 mg IV hydromorphone.

Acetaminophen + hydromorphone arm: In addition to the 1 mg IV hydromorphone patients 
will also receive 1000 mg IV acetaminophen in 100 ml normal saline over 5-10 minutes 
following randomization.

Hydromorphone arm:  In addition to the 1 mg IV hydromorphone patients will also receive  
100 ml normal saline placebo over 5-10 minutes following randomization.  
 
6.1.3 Method of Assignment/Randomization 
An on-line program (www.randomization.com) will be used by the research pharmacist to generate 
the allocation schedule.  Patients will be randomized in 27 blocks of 6.
 
6.1.4 Blinding and Procedures for Unblinding 
Research subjects, clinicians, and research personnel will be blinded.
 
6.1.5 Packaging/Labelling
The pharmacist working in an area inaccessible to ED staff will ensure blinding by creating identical 
vials containing either 1000 mg acetaminophen in 100 ml normal saline or 100 ml normal saline 
placebo and numbering them sequentially for use in this study.
 
6.1.6 Storage Conditions
Study medications will be stored in the ED PYXIS at each site.
 
6.1.7 Concomitant therapy
Administration of concomitant medications will be at the discretion of the treating clinician and 
recorded.  The administration of additional analgesics ("rescue" analgesia) will be recorded.
 
6.1.8 Restrictions
There are no relevant restrictions.
 
6.2 Assessments
6.2.1 Efficacy
Primary Outcome: 

The primary outcome is the between group difference in change in NRS pain scores from 
baseline to 60 minutes post administration of study medications.
Secondary Outcomes: 

Difference in proportion of patients who choose to forego additional pain medication at 60 
minutes post-baseline when asked the question, "Do you want more pain medication?"

Difference in proportion of patients who receive additional pain medication before 60 
minutes and between 60 and 120 minutes post-baseline ("rescue" medication).

Difference in proportion of patients who have one or more side effects in the 120 minutes..

Incidence of adverse events.
 
6.2.2 Safety
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
The Research Associate will remain at the patient's bedside for the first 5 minutes following 
the infusion of the medications.

At 5, 15, 30, 45, 60, 75, 90, 105, and 120 minutes after the end of the infusion of the study 
medication, the RA will measure vital signs (including SaO2 by pulse oximeter), and record  
adverse events if they occurred.

No further monitoring will be performed by the RA after 120 minutes.
 
6.2.2.1 Adverse Events Definition and Reporting  
The RAs will ask patients questions about side effects of the medications that include incidence of 
nausea, vomiting, and pruritis.  These are expected, usually minor adverse effects of the study 
medications.  The RAs will monitor adverse events that include alterations in vital signs: oxygen 
desaturation below 95%, hypoventilation –respiratory rate per minute below 10, hypotension – 
systolic blood pressure below 90 mmHg, and bradycardia – heart rate below 50 beats per minute. 
Thresholds for the vital signs and protocolized response to values below the thresholds are 
described below.
• Vital signs (SaO2 obtained via pulse oximetry), pulse, respiratory rate, and blood pressure) will be 
monitored at baseline, 5, 15, 30, 45, 60, 75, 90, 105, and 120 minutes post-treatment. The RAs will 
remain at the bedside during the first 5 minutes after the infusion is completed in order to monitor 
for any adverse effects such as respiratory depression (RR<10) or oxygen desaturation (<95%).
• If the SO2 drops below 95% or the RR < 10 breaths per minute, a composite set of maneuvers will be 
performed:

The pulse oximeter will be confirmed to be properly placed on the patient's finger and be 
reading the patient's pulse, as determined by an appropriate waveform on the pulse 
oximeter.

The patient, if sleeping, will be gently shaken and verbally asked to take a few deep breaths.

The head of the gurney, if in the reclined position, will be raised.
• If any patient in either arm does not achieve an oxygen saturation of 95% or above despite these 
maneuvers, or if the oxygen saturation drops below 95% a second time, the patient will be placed 
on 2 liters nasal cannula oxygen and the ED attending will be notified immediately to determine 
what additional maneuvers are needed, including consideration of administration of 0.4 mg IV 
naloxone in repeated doses as necessary.
• If the HR is below 50 beats per minute the patient will be reassessed and the ED attending will 
determine what additional maneuvers are needed, including consideration of administration of 0.4 
mg IV naloxone in repeated doses as necessary.
• If systolic BP is below 90 mmHg the patient will be reassessed, and a normal saline bolus will be 
administered if clinically indicated. The ED attending will then determine what additional 
maneuvers are needed, including consideration of administration of 0.4 mg IV naloxone in repeated 
doses as necessary.
All vital signs that fall below the thresholds described above will be reported to the Data Safety 
Monitoring (DSM) committee and included in the yearly progress report to the IRB.  The DSM 
committee will be headed by Dr. David Esses, MD, the director of the Moses ED and include Dr. 
Andrew Chang, Director of Research Albany Medical Center. The committee will meet quarterly 
with the PI to 1) monitor adverse events and develop strategies to minimize these; and 2) monitor 
recruitment and enrollment.
 
6.2.3 Pharmacokinetics (if applicable)
Acetaminophen IV
• Half-Life:  ~2.4 hours
• Onset of Action: 15 minutes (at conclusion of infusion)
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• Peak Effect: ~1 hour
• Duration: ~6 hours 
Hydromorphone IV
• Half-Life:  ~2.3 hours
• Onset of Action: 10-15 minutes
• Peak Effect: 15-30 minutes
• Duration: 2-3 hours 
 
6.2.4 Biomarkers (if applicable) - none
 
6.3 Study Procedures
• The RAs and attending physicians will identify eligible patients.  The attending physician will 
assess the patient’s capacity to consent.
• The RA and provider will describe the study to eligible patients and obtain patient consent.  Both 
will document their participation with a note in Epic and by signing the consent document. 
     This study in particular and research procedures in general are introduced during faculty 
meetings and reinforced with emails and Powerpoint presentations. The providers will be told 
that they will need to discuss the study with the patient, answer their questions, and sign 
consent document. The PI meets with providers in brief one-on-one sessions to describe the 
procedures. 
• The RA will obtain a baseline pain score and baseline vital sign information.
• The healthcare provider will place an order in Epic for the study medication. The order will 
trigger a specific pocket in Pyxis to open. The research associate and the clinical nurse will then 
complete the RA/RN checklist (Appendix) to ensure verification, retrieval and administration of 
study medications. The RA will have the nurse remove the next study packet from the PYXIS, 
which will be a 100 ml vial containing either IV acetaminophen 1000 mg or IV normal saline. The 
contents will be concealed by the research pharmacist.
• All patients will receive 1 mg IV hydromorphone.
• After receiving hydromorphone, patients will receive the blinded study medication, which will 
either be 1000 mg IV acetaminophen in 100 ml or 100 ml normal saline placebo. This will be 
administered over 5-10 minutes.
• The RA will remain at the patient's bedside for the first 5 minutes following the infusion of the 
medications.
• At 5, 15, 30, 45, 60, 75, 90, 105, and 120 minutes following the completed infusion, the RA will 
obtain an NRS pain score, vital signs (including SaO2 by pulse oximeter), and record incidence of  
side effects and adverse events.
• At 60 minutes following infusion, the RA will also ask all patients if they want additional pain 
medication. The RA will inform the treating attending physician if the patient wants additional 
analgesia. 
•  The treating physician will be notified if the patient wants more analgesics. The patient and the 
treating physician will be told that the study has finished 120 minutes after end of infusion of 
study medication. No further monitoring will be performed by the RA after 120 minutes.
• The final diagnosis will be obtained from the chart and the treating attending physician at the 
time the patient leaves the ED.
• The RA will record all medications administered in the ED and the time of their administration 
from the chart and the treating attending physician.
  
6.3.1 Study Schedule
Patients will be enrolled during a single ED visit and study participation will conclude 120 minutes 
after infusion of study medication.
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6.3.2 Informed Consent
All patients will be required to provide written informed consent prior to enrollment.
 
6.3.3 Screening
Screening, enrollment and data collection will be performed by trained, full-time, bilingual 
Research Associates (RAs) who staff the ED 24 hours per day in 8-hour shifts. All RAs have 
completed the University of Miami's Collaborative IRB Training Initiative Program for protection of 
human subjects in the social and behavioral track. We have had RAs collecting data in the 
emergency department for the past 10 years.  They are completely familiar with conducting 
research in the ED setting and understand the ethical rationale and essential nature of obtaining 
informed consent. The PI will meet several times with the RAs before the protocol is initiated to 
review the informed consent process for this study and the data collection instrument to make sure 
that the RAs understand the study and can conduct it strictly according to protocol. Their training is 
described in detail in the Appendix.
The RAs will identify patients who are potentially eligible for the study in several ways. They will 
review the presenting complaint or triage description and consider all patients with complaint or 
mention of pain as potential participants. They will ask residents, nurses, physician assistants and 
attending physicians to refer potentially eligible patients for formal assessment of eligibility. The 
attending physician will be asked if they think a patient's pain warrants use of parenteral opioids 
and if the patient has capacity to provide informed consent.
 
6.3.4 Enrollment
 
6.3.5 Study visits
Subjects will be screened, consented and enrolled during their ED visit and will complete study 
participation two hours following infusion of study medication. 
 
6.3.6 End of Study and Follow-up
Subject participation will conclude two hours after administration of study medication.  No further 
follow-up is planned.
 
6.3.7 Removal of subjects
Subjects may withdraw from study participation at any time.  Those who withdraw will receive 
"usual care" by the treating clinician.
 
6.4 Statistical Method
6.4.1 Statistical Design
The statistical design is parallel group design with patients randomly allocated to the two 
treatments. 
 
6.4.2 Sample Size Considerations  
A sample size of 148 (74 per group) was calculated based on the following parameters:  alpha = 
0.05, power = 0.8, between group delta 1.3 NRS units (commonly used in research as the minimum 
clinically significance difference or MCSD), and standard deviation of 2.8 NRS units (based on prior 
studies we have performed). We will enroll an additional 14 subjects (approximately 10%) in order 
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to account for potential protocol violations and missing data. Thus, our final sample size is 162 
subjects.
We used nQuery Advisor version 7.0 (Los Angeles, CA) to calculate the sample size.
 
6.4.3 Planned Analyses 
The planned analyses include: a comparison of the characteristics of the two treatment groups at 
baseline, the comparison of change in pain between baseline and 60 minutes post-baseline, 
comparison of proportion of patients who want additional analgesia at 60 minutes, comparison of 
the incidence of rescue medication, adverse events and side effects in the 120 minute period.
 
6.4.3.1 Primary Analyses
We will calculate the difference in NRS scores between baseline, immediately after the end of the 
infusion of the study medications (baseline) and 60 minutes for the 2 groups. An independent 
group t-test will be used to assess whether the mean change in NRS scores differ between the 
groups. If there are marked differences between the distributions of background characteristics a 
multi-variable regression will be performed to control for possible confounding. A difference of 1.3 
NRS units or greater between change in pain in the two groups will be the criterion for a minimal 
clinically significant difference. This is based on several studies that have found this difference to be 
associated with the perception of change in pain, measured by labeling this degree of change in pain 
as “a little less” or “a little more pain.” (22)
 
6.4.3.2 Secondary Objectives Analyses
We will calculate the difference in the proportion of patients in each group who choose to forego 
additional pain medication at 60 minutes post-baseline based upon a simple dichotomous yes/no 
response to the patient-centered question, "Do you want more pain medication?" A chi-square test 
will be used to compare the proportions.  We will also use chi-square tests to examine the 
proportion  of rescue medication in the two groups. If there are marked differences between the 
distribution of background characteristics a multi-variable logistic regression will be performed to 
control for possible confounding.
 
6.4.3.3 Safety
Prior experience suggests that we will have insufficient power to detect differences in the incidence 
of adverse events unless the incidence is higher and the differences between groups are much 
larger than what we have observed in the past.  Therefore we will report observed differences. Chi-
square tests to assess whether the proportion of patients with one or more side effect differs 
between treatment groups. The individual side effects will be described in tables. If there are 
marked differences between the distributions of background characteristics a multi-variable 
logistic regression will be performed to control for possible confounding.
 
6.4.3.4 Analysis of Subject Characteristics
• Background characteristics: Age, sex, race/ethnicity, initial pain intensity, nausea and vomiting 
before administration of analgesics.  Means and standard deviations, medians and interquartile 
ranges, and proportions will be used to describe the sample as appropriate.
• Cause, location of pain, and diagnosis: The etiology of pain will be described as trauma-related or 
not trauma-related. The location of pain will be described as: abdomen/pelvis, extremities, back, 
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head, chest, multiple locations, and other. The diagnosis will also be recorded.  Frequencies will 
be presented.
• Anthropometrical measures: Patients will be asked to report their height and weight.  Mean 
height and weight with standard deviations will be presented.
 
6.4.3.5 Interim Analysis (if applicable)
Dr. Andrew Chang will perform an interim analysis after half the sample is enrolled to consider 
stopping the trial if the analgesia provided by one treatment is found to be markedly superior to the 
other, or if the proportion of patients receiving rescue medication is substantially different between 
arms. We will use the Peto-Haybittle rule of requiring a p value of 0.001 or lower to indicate a 
difference between groups that would contribute to the decision to halt the trial.(24) (25)   We 
calculated the size of the effect that would lead to rejection of the null hypothesis at this level of 
significance to assess whether it was clinically reasonable. A value that is thought of as a clinically 
important difference in pain between two treatment groups is 30 mm on a 100mm VAS for pain 
(equivalent to a 3 unit decrease on an NRS).(26)  Thus, for example, a test of the difference between 
a 4.0 NRS unit decrease in pain in one group versus 1.0 NRS unit decrease in the other with a pooled 
SD of 2.8 would have a p value less than 0.001 with half the sample size. We do not plan to perform 
a test for futility. Finding that IV acetaminophen as an adjuvant medication to IV hydromorphone 
has similar efficacy as  IV hydromorphone alone is an important finding that deserves to be 
disseminated. Given well documented publication bias against negative studies it is much more 
likely that this study will be published if we continue to collect the originally planned sample size. 
One could assume that both regimens are providing adequate analgesia based on numerous studies 
of this dose of IV hydromorphone.
All adverse events will be reported promptly to the DSMB as they occur and the decision to stop the 
trial based on the incidence and severity of the adverse events will be used to determine if the trial 
should be stopped early rather than on statistical grounds.
 
6.4.3.6 Health economic evaluation
Not applicable
 
6.4.3.7 Other
 
6.4.4 Subsets and Covariates
If there are serious imbalances in background characteristics multiple regressions will be run with 
those variables as covariates for the primary outcome. No subset analyses are planned.
 
6.4.5 Handling of Missing Data 
Sensitivity analyses will be performed if there are missing primary outcome data.
 
7 - Trial Administration
7.1 Ethical Considerations
Patients will not receive any compensation for their participation in this study.  All data collected 
will be maintained within locked file cabinets or within secure databases (i.e. REDCap).
 
7.2 Institutional Review Board (IRB) Review
Institutional Review Board review and approval will be obtained. 
 
7.3 Subject Confidentiality
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All data collection instruments will be secured within REDCap. The PI and co-investigators will be 
the only ones with access to the full database linking study IDs to patient identifying information.
 
7.4 Unanticipated Problems
Unanticipated adverse events will be reported promptly to the IRB.
 
7.5 Data Quality Assurance
The REDCap data collection instrument will be designed to identify out of range or abnormal values 
(e.g. age > 64, pulse rate of 5) and data quality reports will be run weekly.  
 
7.5.1 Data Collection
All study data will be entered directly into REDCap by the Research Associates.  Signed consent 
forms will be collected and kept under lock and key in a secure location.
 
7.5.1.1 Access to Source
The PI and co-investigators will be the only ones with access to the full database linking study IDs 
to patient identifying information.
 
7.5.1.2 Data Storage/Security
All data collection instruments will be secured within REDCap and will require a username and 
password for access. Hardcopy research records (i.e. written consents) will be kept under lock and 
key in the Department of Emergency Medicine at Montefiore Medical Center's Moses Division.
 
7.6 Study Records
Study records include all paper consents, IRB associated documents (application, protocol, 
certificate of translation, etc.) and the study data stored within REDCap.
 
7.6.1 Retention of Records
After the data analysis has been completed, data will be de-identified and stored on a secure, 
password protected server. Data will be kept in case of the future need for a meta-analysis of other 
studies that our department, or other investigators, have conducted or will conduct in the future.
 
7.7 Study Monitoring
Enrollment progress will be reviewed weekly.
 
7.8 Data Monitoring Plan
Data Safety Monitoring Committee: this committee will be headed by Dr. David Esses, Director of 
the Moses Division of the Department of Emergency Medicine, and include Dr. Andrew Chang, MD, 
Vice Chair for Research, Albany Medical Center.  The committee will meet before data collection 
begins and quarterly with the PI to 1) monitor adverse events and develop strategies to minimize 
these; and 2) monitor recruitment and enrollment.  The PI will analyze the data (fully blinded) to 
provide the DSMC with information on adverse events, recruitment and enrollment.  Dr. Chang will 
conduct the interim analysis and the DSMC will review the results.   
 
7.9 Study Modification
Any study modifications will be performed in compliance with existing IRB protocols.
 
7.10 Study Discontinuation
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Study discontinuation prior to completion of target enrollment will be determined by the DSMC in 
compliance with existing IRB protocols.
 
7.11 Study Completion
Based upon prior studies, we anticipate achieving our target enrollment in approximately 5 months 
and will follow the standard IRB defined procedures for recording study milestones.
 
7.12 Funding Source
This study will be funded by the Department of Emergency Medicine
 
7.13 Publication Plan
Results of this investigation will be submitted for publication to a peer-reviewed journal in 
Emergency Medicine or Pain Management.
 
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Turkcuer I, Serinken M, Eken C, et al. Intravenous paracetamol versus dexketoprofen in acute 
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Morteza-Bagi HR, Amjadi M, Mirzaii-Sousefidi R. The Comparison of Apotel plus Low Dose of 
Morphine and Full Dose of Morphine in Pain Relief in Patients with Acute Renal Colic. Addict 
Health. 2015;7(1-2):66-73.
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Pickering G, Moustafa F, Macian N, Schmidt J, Pereira B, Dubray C. A New Transmucous-Buccal 
Formulation of Acetaminophen for Acute Traumatic Pain: A Non-inferiority, Randomized, 
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severity measured on a visual analog scale. Ann Emerg Med. 2001;38(6):633-638.
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Kendrick DB, Strout TD. The minimum clinically significant difference in patient-assigned 
numeric scores for pain. Am J Emerg Med. 2005;23(7):828-832.
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Todd KH, Funk JP. The minimum clinically important difference in physician-assigned visual 
analog pain scores. Acad Emerg Med. 1996;3(2):142-146.
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Bijur PE, Latimer CT, Gallagher EJ. Validation of a verbally administered numerical rating scale of 
acute pain for use in the emergency department. Acad Emerg Med. 2003;10(4):390-392.
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Lee JS, Hobden E, Stiell IG, Wells GA. Clinically important change in the visual analog scale after 
adequate pain control. Acad Emerg Med. 2003;10(10):1128-1130.
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APPENDIX
Research Associate Training
All data are collected by a team of research associates (RA). Research associates are required to 
have basic medical certifications, including the skills to assess vital signs and how to interact with 
people as patients. We also require them to be bilingual English and Spanish speakers because we 
believe it is essential that our research subjects represent our patient population. Prior to being 
hired, every research associate must prove their ability to speak Spanish fluently by having a 
conversation in Spanish with a departmental administrator, during which time we assess their 
ability to communicate with our patient population. After hiring, each research associate 
completes the required CITI coursework and then meets with each investigator one-on-one to 
discuss general themes of clinical research including research ethics, techniques of data collection, 
and pitfalls in data entry (incomplete data, missing data, and inaccurate data, such as race, which 
is particularly tricky in our patient population). Each new research associate then undergoes a 
two-month internship, during which time they shadow an experienced research associate, and 
learn the ins-and-outs of the job. Over these two months, the new research associate gradually 
takes on more and more responsibility under the tutelage of the seasoned research associate. At 
the end of the two-month period, each research associate has another in-person session with the 
investigators, during which time any questions are addressed.
Study specific training begins prior to IRB submission. The investigators discuss the study 
protocol and with the research associates, who are asked to provide their input. The research 
associates often comment on logistical issues of study flow. The research associates also provide 
feedback on the REDCap data collection instruments. Here too, they provide invaluable feedback 
on how to streamline these forms. Prior to initiation of the study, the investigator explains the 
study protocol and procedures to the RAs, typically using a Powerpoint presentation in groups of 
1-3 research associates. These hour-long sessions are lively and interactive. Each research 
associates then performs mock enrollments using the investigators as subjects. These sessions too 
are full of lively give and take, during which adjustments in the data collection instruments can be 
made. During study enrollment, the investigators discuss the study and any questions that arise 
with each research associate on a near daily basis. We discuss any issues that occur in procedures 
that need intervention by the investigator such as pharmacy delays, nursing unavailability, or 
questions that the ED clinicians may have brought up. The investigators provide the research 
associates with feedback on data entry—such as when free texting was used rather than 
checkboxes, or when two different symptoms were lumped into one response category. The 
investigators remain in close contact with the RA throughout enrollment—each investigator 
typically receives a half dozen calls per week when questions of eligibility arise.
The research associates are trained by the PI or the Vice Chair of Research (Dr. Ben Friedman) in any changes 
that are made in procedures.  
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Checklist for verification, retrieval and administration of study medications
Patient’s Name: 
Patient’s MRN: 
Study Protocol Name: 
________________________________________________________________________________________
Study Protocol Number: _______________________________________
Research Associate: Complete prior to drug removal
I have verified the following:
⧠   Patient meets inclusion criteria
⧠   Patient does not have any exclusions
⧠   Patient is not allergic to the drug
⧠   Consent is signed
RA Signature: 
Date___________ Time___________
Medication verification at Pyxis:  Two person (RA and Nurse) checks:
⧠  Nurse reads aloud the physician order from Epic including drug name, dose, route and 
study number while RA confirms it agrees with the consent
⧠   RA reads aloud from the consent the study drug name and study number while the 
Nurse confirms it agrees with the Pyxis screen
⧠   A patient label and the drug label from the study medication are placed on the 
medication to be administered to the patient
Verification at the Bedside: two person (RA and Nurse) checks:
⧠   Nurse and RA go to the patient and confirm the patient’s agreement to participate in the 
study     and that the consent has been signed
             ⧠      RA obtains vital signs, shares with Nurse and documents them in Red Cap
⧠   Nurse verifies the dual identifiers against the patient label to confirm that it is indeed 
the        correct patient  
 
Place patient ID label here
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Nurse signature: 
Date___________ Time 
RA signature:      ____________________________________________               
Date___________Time_________________
å
IRB NUMBER: 2018-8886
IRB APPROVAL DATE: 09/06/2018