Clinical trial NCT03521102
Conditions: Acute Pain
Sponsor: Montefiore Medical Center
Start date: 2018-08-20; Completion date: 2022-03-23
Enrollment: 162 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Intravenous opioids are the mainstay of acute, severe pain treatment in Emergency Departments (ED) across the country. Acetaminophen, given orally, has also been used for treatment of mild to moderate pain. The more potent intravenous (IV) form of acetaminophen has been widely used in Europe for more than 20 years as post-surgical analgesia and received full FDA approval in the USA in 2010. As part of a continuing set of studies whose goal is to optimize treatment of pain among elderly ED patients, this randomized study will compare efficacy and safety of IV acetaminophen to IV hydromorphone.

Detailed description:

Arms: arm 1: NRS pain score will be obtained at baseline, 15, 30, 45, 60, 90, 120, and 180 minutes following completion of intervention. Adverse events will be recorded every 15 minutes for the duration of the study protocol. Participants will be reassessed for the need of additional pain control at 60 minutes. arm 2: NRS pain score will be checked at 5 minutes and every 15 minutes thereafter for 120 minutes. Adverse events will be recorded every 15 minutes for the duration of the study protocol. The need for additional pain control will be assessed at 60 minutes.
Interventions: intervention 1: Acetaminophen 1000mg IV intervention 2: Hydromorphone 0.5 mg IV
Intervention descriptions: intervention 1: 1000mg of IV acetaminophen in 100ml of normal saline, administered as an intravenous drip over 10 minutes + 2ml of normal saline, administered as a slow intravenous push intervention 2: 100ml of normal saline, administered as an intravenous drip over 10 minutes, + 0.5mg of IV hydromorphone in 2ml of normal saline, administered as a slow intravenous push

Protocol documents:
Prot_SAP_001.pdf: 
An ED-based randomized trial of IV acetaminophen versus IV hydromorphone for elderly 
adults with acute severe pain. 02152018
1
Introduction 
44 million annual patient visits to US emergency departments (EDs) are caused by pain (Pletcher 
2008; Nawar 2007).  Oligoanalgesia, or the inadequate treatment of pain, has been a vexing 
problem in emergency departments (Wilson 1989, Rupp 2004, Ritsema 2007, Stalnikowicz 
2005).  Only 50% of ED patients experience at least a 2-point reduction of pain on a 0 to 10 scale 
and 75% are discharged with moderate to severe pain (Todd, 2007). Elderly patients are at even 
greater risk for undertreatment of pain. They are less likely to receive pain medication and 
experience longer delays to treatment.
Intravenous opioids are used commonly to treat acute pain in US emergency departments. These 
medications are highly efficacious and safe when used in a monitored setting such as the ED. 
Use of opioids has fallen out of favor recently because of a spike in opioid-related overdose 
deaths throughout the US. While use of opioids in the ED is unlikely to contribute to outpatient 
opioid deaths, minimizing the use of opioids in the ED will contribute to an opioid free culture, 
in which opioids are used only when absolutely necessary. Thus, highly efficacious, non-opioid 
treatments are needed.
Acetaminophen has long been a mainstay for pain treatment.  The intravenous (IV) form has 
been widely used in Europe for more than 20 years and received full FDA approval in the USA 
in 2010.  As part of a continuing set of studies whose goal is to optimize treatment of pain among 
elderly ED patients, we will conduct a randomized study in which we compare efficacy and 
safety of IV acetaminophen to IV hydromorphone.
Primary null hypothesis:  IV hydromorphone 0.5 mg IV will provide no more pain relief than 
1000 mg IV acetaminophen among elderly patients with acute severe pain as determined by 
improvement in 0-10 pain scores between baseline and 60 minutes post administration of 
investigational medication.      
IRB NUMBER: 2018-8876
IRB APPROVAL DATE: 07/17/2018


An ED-based randomized trial of IV acetaminophen versus IV hydromorphone for elderly 
adults with acute severe pain. 02152018
2
Background data.
Efficacy of IV hydromorphone in the elderly. 
In a randomized study conducted at this institution, 93 elderly ED patients (mean age 74) with 
acute pain received 0.0075mg/kg IV hydromorphone. (Chang 2009) 30 minutes after medication 
administration, 66% reported moderate to complete relief and 63% reported good to excellent 
satisfaction with the medication.
In a subsequent study, 175 elderly patients with acute severe pain were randomized to 0.5mg + 
0.5mg of IV hydromorphone (those who requested another analgesic 15 minutes after the initial 
0.5mg dose of hydromorphone were administered a second 0.5mg dose). 58% of patients 
reported adequate analgesia after the initial dose of medication.
Safety of IV hydromorphone in the elderly. In the study of 0.0075 mg/kg IV hydromorphone 
mentioned above, no patient required naloxone (to reverse the effects of hydromorphone) 
because of hemodynamic instability or respiratory compromise. Nausea and pruritis were each 
reported in <5% of the cohort. One episode of transient hypoxia was successfully treated with 
oxygen delivered by nasal cannula. Three patients developed transient systolic BP <90mmHg, 
which were successfully treated with IV saline boluses.
In the study of 0.5mg + 0.5mg IV hydromorphone, no patients required naloxone. 11% of 
patients reported nausea and 2 reported pruritis. No patient developed respiratory compromise or 
hemodynamic instability. 5% of patients experienced transient oxygen desaturations responsive 
to oxygen administration by nasal cannula. 3% of patients experienced mild hpotension 
responsive to IV saline boluses.
Efficacy of IV acetaminophen in the elderly. 107 elderly patients (mean age 73) who underwent 
major orthopedic surgery were randomized to IV acetaminophen or placebo in a series of three 
RCTs. Patients randomized to IV acetaminophen generally reported lower pain intensity and 
more satisfaction with the analgesic medication. Because of relatively small samples sizes, these 
differences did not always achieve statistical significance.  (Jahr 2012)
Safety of IV acetaminophen in the elderly. Among 107 elderly adults status post major 
orthopedic surgery who received IV acetaminophen 1000mg, adverse events did not differ from 
placebo (Jahr 2012). 
Is it unrealistic to think that acetaminophen might be as effective as hydromorphone?
In the non-elderly population, IV acetaminophen has often proven to be nearly as effective as IV 
morphine, another potent opioid (Appendix). Therefore, we believe there is equipoise in this 
study design. 
IRB NUMBER: 2018-8876
IRB APPROVAL DATE: 07/17/2018


An ED-based randomized trial of IV acetaminophen versus IV hydromorphone for elderly 
adults with acute severe pain. 02152018
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Overview. This will be a randomized, double blind, double-dummy comparative effectiveness 
study conducted in two Montefiore EDs. Ethical oversight will be provided by the Montefiore 
Medical Center IRB. This trial will be registered online at http://www.clinicaltrials.gov. 
Research setting. This study will be conducted in the Moses and Einstein EDs. Salaried, full-
time, bilingual (English and Spanish) research associates (RAs) staff the EDs 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 and have extensive experience collecting 
data for clinical trials. 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 also ask attending 
physicians if they feel a patient’s pain warrants use of parenteral opioids. The RAs will collect 
all data for the study
Population of interest:  The target population is women and men aged 65 years and older 
presenting to the emergency department with acute severe pain. We will define acute pain as 
pain that has been present for no more than seven days. We will only include patients if the ED 
attending physician believes that patient’s pain warrants IV opioids and would treat the patient 
with parenteral opioids. Patients will be excluded if they have used opioids or tramadol within 
the previous seven days, if they have had a prior adverse reaction to hydromorphone or 
acetaminophen, if they have a chronic pain syndrome, defined as use of analgesics on >10 days 
during the preceding months, if they have an oxygen saturation of <95% on room air, a 
respiratory rate < 12 breaths per minute, a systolic blood pressure < 90mmHg, or a diastolic 
blood pressure <60mmHg. Patients with cirrhosis (Childs-Pugh A or worse) will be excluded. 
Patients can only enroll once.
To participate, patients must have capacity to provide informed consent. This will be assessed in 
two ways: First, we will ask the attending physician to determine whether the patient has 
capacity to consent. Second, we will perform a rapid assessment of impaired cognition using a 
six-item screener (Appendix). (Pubmed ID 12218768)
Intervention: Patients will be randomized in a 1:1 ratio to:
Arm A: !000mg of IV acetaminophen in 100ml of normal saline, administered as an intravenous 
drip over 10 minutes, + 2ml of normal saline, administered as a slow intravenous push
Arm B: 100ml of normal saline, administered as an intravenous drip over 10 minutes, + 0.5mg of 
IV hydromorphone in 2ml of normal saline, administered as a slow intravenous push
The nurse will remove the study packet from the secured ED medication cabinet (Pyxis). The 
study packet will contain two items: a 100 ml vial containing either IV acetaminophen 1 gm (or 
100 ml normal saline placebo) and a 2 ml vial containing either hydromorphone 0.5mg (or 
normal saline placebo). IV acetaminophen and IV hydromorphone are both clear solutions that 
appear identical to normal saline.
IRB NUMBER: 2018-8876
IRB APPROVAL DATE: 07/17/2018


An ED-based randomized trial of IV acetaminophen versus IV hydromorphone for elderly 
adults with acute severe pain. 02152018
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Assignment. Will be concealed. The research pharmacist will determine assignment based on a 
random number sequence. 
Randomization. Randomization will occur in blocks of four based on a random number 
generator. 
Blinding. Research subjects, clinicians, and research personnel will be blinded. To assess the 
success of blinding, which may be threatened by the occurrence of certain medication side-
effects unique to particular arms of the trial, research subjects and research personnel will be 
asked, at the time of ED discharge, to guess which medications were administered. 
Stratification. Subjects will be stratified by study site (Moses or Einstein) 
Measures
1) Pain intensity will be measured using a verbal numerical scale of which 0 represents no pain 
and 10 represents the worst pain imaginable. This will be assessed 5, 15, 30, 45, 60, 90, 105,120, 
180, and 240 minutes after medication administration
2) Medication preference. Preference for a specific medication is a highly patient centered 
outcome, in which an individual determines for herself the benefit of a particular drug versus the 
adverse effects experienced. We will include in this study a measure that has been used in 
multiple ED-based trials—“The next time you come to the ER for treatment of abdominal pain, 
do you want to receive the same medication again?” Patients will be asked to choose among the 
following responses: “Yes,” “No,” or “Not sure”
3) Use of additional analgesic medication. The following medications will be considered 
parenteral analgesic medications: any IV or IM opioid, any IV or IM non-steroidal anti-
inflammatory drug, or IV acetaminophen if administered within 6 hours of investigational 
medication administration in the ED.
4) Use of additional medication to treat symptoms of nausea or pruritis if administered within 6 
hours of investigational medication administration in the ED.
5) ED throughput time. Time of investigational medication administration to disposition time 
(discharged from ED or decision to admit)
6) Side effects. We will use the following question: “Did you have any new symptoms that 
began only after you got the study medication?” An affirmative response will be followed by an 
open-ended question eliciting details. This will be assessed 30 and 60 minutes after medication 
administration.
7) Nausea. Patients will be asked to rate the severity of their nausea using the descriptors “none”, 
“a little” or “a lot”. This will be assessed 30 and 60 minutes after medication administration.
8) Pruritis. Patients will be asked to rate the severity of their pruritis using the descriptors 
“none”, “a little” or “a lot”. This will be assessed 30 and 60 minutes after medication 
administration.
9) Oxygen saturation. This will be measured at baseline and 5, 15, 30, 60, 90, and 120 minutes 
after medication administration.
10) Blood pressure. This will be measured at baseline and 5, 15, 30, 60, 90, and 120 minutes 
after medication administration.
Outcomes:  
Primary outcome. The primary outcome is the between group difference in change in 0-10 pain 
score between baseline and 60 minutes post administration of study medications. If required, 
patients will be eligible for rescue medication after the 60 minute assessment. 
IRB NUMBER: 2018-8876
IRB APPROVAL DATE: 07/17/2018


An ED-based randomized trial of IV acetaminophen versus IV hydromorphone for elderly 
adults with acute severe pain. 02152018
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Secondary efficacy outcomes. 
1) Zero to 10 pain scores at each of the time points described above. 
2) We will determine whether or not subjects require any additional parenteral medication for 
pain or other symptoms for four hours after medication administration
3) We will determine ED throughput time
4)  At the time of discharge from the ED, we will determine patient satisfaction with the 
medication
Safety outcomes.
1) Frequency of development of any new symptom after administration of the investigational 
medication
2) Frequency of requirement of naloxone
3) Frequency of a change in the disposition of the patient attributable to investigational 
medication
4) Rate of nausea, pruritis, oxygen desaturation and hypotension
Descriptive Variables
Background characteristics:  Age, sex, race/ethnicity, 
Cause, location of pain, and diagnosis: The location of pain will be described as: 
abdomen/pelvis, extremities, spinal (back or neck), head, chest, multiple locations, and other.  
The diagnosis will also be recorded.
Safety monitoring 
Data Safety Monitoring committee:  this committee will be headed by Dr. Polly Bijur, PhD, an 
epidemiologist, and include Dr. David Esses, MD, the director of the Moses ED.  The committee 
will meet every month with the PIs to 1) monitor adverse events and develop strategies to 
minimize these; and 2) monitor recruitment and enrollment.  
Data Management and Analysis:  
Sample size calculation:  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 wish to enroll an additional 14 subjects 
(approximately 10%) in order to account for potential protocol violations and missing data.  
Thus, our final proposed sample size is 162 subjects.  
Data Processing:  Data will be entered directly into REDCap.  
Analysis:  Descriptive data will be calculated for all variables.  The characteristics of patients in 
the two groups will be compared in order to confirm adequacy of randomization. If there is 
unequal distribution of background variables with p values of 0.15 or less, we will include them 
in a multivariable analysis of the outcomes. We will calculate the difference in NRS scores 
between baseline (time zero) and 60 minutes for the 2 groups. The difference between the two 
IRB NUMBER: 2018-8876
IRB APPROVAL DATE: 07/17/2018


An ED-based randomized trial of IV acetaminophen versus IV hydromorphone for elderly 
adults with acute severe pain. 02152018
6
groups will be reported with 95%CI. If the 95%CI of the between-group difference does not 
cross 0, the results will be considered statistically significantly different. For patients who do not 
provide a 60 minute 0-10 pain score, we will use the most proximate pain score available (we 
will use a mean score if there are two available scores equidistant from the missing 60 minute 
assessment). For patients who receive rescue analgesia prior to the 60 minute assessment, we 
will use the most recent pain score prior to rescue medication administration.
Secondary outcomes will be reported as mean or percentage with 95%CI. We will use 95% 
confidence intervals to compare means, proportions, and differences in both whenever possible.  
Multivariable analyses will use a significance criterion of p<0.05.  
Computer data security, subject confidentiality, data storage, and maintenance:  All data 
collection instruments will be secured within REDCap.  Research records will be kept under lock 
and key in the Department of Emergency. Electronic database will require a username and 
password. The PI and co-investigators will be the only ones with access to the full database 
linking study IDs to patient identifying information. The limited electronic database used for 
analysis will be in the possession of the PI and be password protected. After the data analysis has 
been completed, data will be de-identified and stored on a secure, password protected computer.
Consent. Informed consent will be obtained after the patient has been evaluated in the ED, while 
they are having acute pain. Unfortunately, there is no other feasible way to obtain consent 
because severe acute abdominal pain is not predictable. As part of this consent process, we will 
be sure that patients understand they do not have to participate in the study to obtain analgesics. 
Also, we will offer to help patients call a family member or friend to discuss the study with them 
if they wish. Finally, we will have the patient’s attending physician confirm that the patient has 
the capacity to consent to participate in the study at the time they are asked to provide consent. 
Both research associates and health care providers will participate in the consent process. Both 
will document their participation with a note in Epic and by signing the consent document.
Pyxis procedures. 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).
Description of orientation and education that providers receive about this study and about 
research procedures. This study in particular and research procedures in general are introduced 
during faculty meetings and reinforced with emails and Powerpoints. The PI then meets with 
providers in brief one-on-one sessions to describe these. Finally, the investigators and research 
associates discuss these during the in-shift briefs.
IRB NUMBER: 2018-8876
IRB APPROVAL DATE: 07/17/2018


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adults with acute severe pain. 02152018
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References
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emergency department summary.  Adv Data 2007:1-32.
Pletcher MJ, Kertesz SG, Kohn MA, et al.  Trends in opioid prescribing by race/ethnicity for 
patients seeking care in US emergency Departments.  JAMA 2008;299:70-8.
Ritsema TS, Kelen GD, Pronovost PJ, et al.  The national trend in quality of emergency 
department pain management for long bone fractures.  Acad Emerg Med 2007;14:163-9.
Rupp T, Delaney KA.  Inadequate analgesia in emergency medicine.  Ann Emerg Med 
2004;43:494-503.
Stalnikowicz R, Mahamid R, Kaspi S, et al.  Undertreatment of acute pain in the emergency 
department:  a challenge.  Int J Qual Health Care 2005;17:173-6.
Todd KH, Ducharme J, Choiniere M, et al.  Pain in the emergency department:  results of the 
pain and emergency medicine initiative (PEMI) multicenter study. J Pain 2007;8:460-6.   
Wilson JE, Pendleton JM.  Oligoanalgesia in the emergency department.  Am J Emerg Med 
1989;7:620-623.
Masoumi K, Forouzan A, Asgari Darian A et al. Comparison of clinical efficacy of intravenous 
acetaminophen with intravenous morphine in acute renal colic: a randomized, double-blind, 
controlled trial. Emerg Med Int 2014;2014:571326.
Shams Vahdati S, Morteza Baghi HR, Ghobadi J et al. Comparison of paracetamol (Apotel®) and 
morphine in reducing post pure head trauma headache. Anesth Pain Med 2014;21:e14903
Grissa MH, Claessens YE, Bouida W et al. Paracetamol vs piroxicam to relieve pain in renal 
colic. Results of a randomized controlled trial. Am J Emerg Med 2011;29:203-6.
Serinken M, Eken C, Turkcuer I et al. Intravenous paracetamol versus morphine for renal colic in 
the emergency department: a randomized double-blind controlled trial. Emerg Med J 
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Zare MA, Ghalyaie AH, Fathi M et al. Oral oxycodone plus intravenous acetaminophen versus 
intravenous morphine sulfate in acute bone fracture pain control: a double-blind placebo-
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Bektas F, Eken C, Karadeniz O et al. Intravenous paracetamol or morphine for the treatment of 
renal colic: a randomized, placebo-controlled trial. Ann Emerg Med 2009;54:568-74.
Craig M, Jeavons R, Probert J et al. Randomised comparison of intravenous paracetamol and 
intravenous morphine for acute traumatic limb pain in the emergency department. Emerg Med J 
2012;29:37-9.
Morteza-Bagi HR, Amjadi M, Mirzaii-Sousefidi R et al. The comparison of Apotel plus low dose 
morphine and full dose of morphine in pain relief in patients with acute renal colic. Addict Health 
2015;7:66-73.
Turkcuer I, Serinken M, Eken C et al. Intravenous paracetamol versus dexketoprofen in acute 
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Pickering G, Moustafa F, Macian N et al. A new transmucous-buccal formulation of 
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adults with acute severe pain. 02152018
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Azizkhani R, Pourafzali SM, Baloochestani E et al. Comparing the analgesic effect of 
intravenous acetaminophen and morphine on patients with renal colic pain referring to the 
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accuracy of acute abdominal pain with significant pain relief- a prospective, randomized, placebo 
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Appendix. Literature review
IV APAP versus IV morphine for renal colic
IV APAP versus IV morphine for other indications
Author, 
year
Indication
N
APAP
Morphine
NRS
Rescue 
meds
Craig 2011
Isolated 
limb 
trauma 
with pain 
>7/10
55
1gm 
over15 
min 
10mg
At 60 min:
APAP 
improved: 
2.4
Morphine 
improved: 
2.6 
29% in 
both 
groups
Vahdati 
2014
Post-
traumatic 
headache
60
1gm over 
10 
minutes
0.1mg/kg
At 30 min: 
APAP 
improved 5.3
Morphine 
improved4.0
Not 
reported
Ankumah 
2017
Labor
38
1gm 
2mg 
At 120 
minutes:
APAP 
APAP 53%
Morphine 
Author, 
year
N
APAP
morphine
0-10 (or 0-100) pain
scale
Rescue meds
Masoumi 
2014
110
1gm over 5-
10 min
0.1mg/kg
At 30 min:
APAP improved 4.7, 
morphine improved 2.9
morphine 55%  
APAP 31% 
Serinken 
2012
73
1gm over 2-
4 min
0.1mg/kg
At 30 min: APAP 
improved 6.4, 
morphine improved 5.7
morphine 20%  
APAP 16% 
Bektas 2009
100
1gm 
0.1mg/kg
At 30 min: APAP 
improved 43, morphine 
improved 40
APAP 46%  
morphine 49% 
Morteza-
Bagi 2015
100
1gm
5mg
At 35 min:
APAP: 1.9
Morphine: 2.0
Morphine 40%
APAP 36%
Azizkhani 
2013
124
15mg/kg 
over 15 min
0.1mg/kg
At 30 min:
APAP: 2.4
Morphine: 0.75
Not reported
Pathan 
2016
110
1gm
0.1mg/kg
At 30 min:
APAP 3.3
Morphine 3.8
APAP 20%
Morphine 23%
IRB NUMBER: 2018-8876
IRB APPROVAL DATE: 07/17/2018


An ED-based randomized trial of IV acetaminophen versus IV hydromorphone for elderly 
adults with acute severe pain. 02152018
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worsened 
1.8
Morphine 
worsened 
0.5
18%
Serinken 
2016
Sciatica
200
1gm
0.1mg/kg
At 30 
minutes:
APAP 
improved: 
2.9
Morphine 
improved 5.4
APAP 18%
Morphine 
6%
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adults with acute severe pain. 02152018
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Six-Item Screener to Identify Cognitive Impairment Among Potential Subjects for Clinical Research.
Callahan, Christopher; Unverzagt, Frederick; Hui, Siu; Perkins, Anthony; Hendrie, Hugh;  MB, ChB
Medical Care. 40(9):771-781, September 2002.
IRB NUMBER: 2018-8876
IRB APPROVAL DATE: 07/17/2018