Clinical trial NCT02268955
Conditions: Biliary Colic
Keywords: Biliary Colic Abdominal pain Intravenous Ibuprofen
Sponsor: Valleywise Health
Start date: 2014-09-09; Completion date: 2017-06-28
Enrollment: 22 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The aim of this study is to assess the analgesic efficacy of intravenous ibuprofen given in the Emergency Department for the treatment of biliary colic. We hypothesize that intravenous ibuprofen will provide a clinically significant drop in self-reported patient pain level as measured by the visual analog scale.

Detailed description:
It is estimated over 20 million people aged 20-74 have gallbladder disease, with biliary colic being a common and painful symptom in these patients. Likely due to the relatively recent approval of intravenous ibuprofen use for fever and pain in adults, no assessment of its analgesic efficacy for biliary colic currently exists in the literature.

Utilizing a visual analog scale (VAS) for patient self-assessment of pain, this study will address this lack of evidence and identify intravenous ibuprofen's value as a novel analgesic in the treatment of biliary colic. Patients will be given a VAS at the time of study therapy administration, at 15-minute intervals during the first hour post-administration, and 30-minute intervals in the second hour. Though NSAID's have been extensively studied in the management of this phenomenon, this study aims to help optimize pain treatment of patients presenting to the Emergency Department with biliary colic, and potentially pave the way for future analgesic treatment comparison studies.

Arms: arm 1: Saline-only control group arm 2: Patients receiving intravenous ibuprofen therapy
Interventions: intervention 1: IV Ibuprofen intervention 2: Saline
Intervention descriptions: intervention 1: Intravenous ibuprofen will be administered for treatment of pain in adults presenting to the ED with biliary colic intervention 2: Saline will be administered to the placebo group

Protocol documents:
Prot_SAP_000.pdf: 
1                                                                              5/5/2014 
 
May 5, 2014 
 
PROJECT TITLE: 
Assessment of the analgesic efficacy of intravenous ibuprofen in biliary colic 
 
PRINCIPAL INVESTIGATOR: 
Dan Quan, DO 
Email: dquan@email.arizona.edu 
Phone: (602) 344 5058 
Fax:  (602) 344 1208 
 
MEDICAL STUDENT: 
Kenneth Zurcher, UA College of Medicine-Phoenix, Class of 2017 
Email: Zurcher@email.arizona.edu 
Phone: (650)703-6561 
 
PROJECT PERFORMANCE SITE: 
Maricopa Integrated Health System (MIHS) Emergency Department 
Address:  2601 E. Roosevelt St. Floor 1. Phoenix, AZ, 85008. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2                                                                              5/5/2014 
 
Table of Contents 
 
1. ABSTRACT___________________________________________________________ _________3 
2. RESEARCH QUESTION________________________________________________________ ___3 
3. INTRODUCTION AND RATIONALE__________________________________________________3 
4. METHODOLOGY________________________________________________________________5 
4.1 OBJECTIVE  
 
 
 
 
 
 
 
                          5 
4.2 STUDY DESIGN AND DURATION                                                                                                            5 
4.3 STUDY POPULATION                                                                                                                                5 
4.4 ENROLLMENT CRITERIA                                                                                                                          5 
4.5 STUDY PROCEDURES                                                                                                                               6 
4.6 RESULT INTERPRETATION AND STATISTICAL ANALYSIS                                                                    6 
4.7 POTENTIAL COMPLICATIONS AND ETHICAL CONSIDERATIONS                                                       7 
 
5. OBJECTIVE / DISCUSSION________________________________________________ __ ______7 
6. RESOURCES____________________________________________________________ _ ______7 
7. DISCONTINUATION / WITHDAWAL CRITERIA__________________________________ ______8 
8. ADVERSE EVENTS_______________________________________________________________8 
9. BUDGET / SPONSORS____________________________________________________________8 
10. CASE REPORT FORMS____________________________________________________ _______8  
11. REFERENCES___________________________________________________________________9 
                                  
 
 
 
 
 
 
 
 


3                                                                              5/5/2014 
 
1. ABSTRACT 
 
 
The aim of this study is to assess the analgesic efficacy of intravenous ibuprofen given in 
the emergency department (ED) for the treatment of biliary colic.  It is estimated over 20 million 
people aged 20-74 have gallbladder disease, with biliary colic being a common and painful 
symptom in these patients.  Likely due to the relatively recent approval of intravenous ibuprofen 
use for fever and pain in adults, no assessment of its analgesic efficacy for biliary colic currently 
exists in the literature. 
 
 
Utilizing a visual analog scale (VAS) for patient self-assessment of pain, this study will 
address this lack of evidence and identify intravenous ibuprofen’s value as a novel analgesic in 
administration, at 15-minute intervals during the first hour post-administration, and 30-minute 
intervals in the second hour.  Though NSAID’s have been extensively studied in the management 
of this phenomenon, this study aims to help optimize pain treatment of patients presenting to 
the ED with biliary colic, and potentially pave the way for future analgesic treatment comparison 
studies. 
 
2. RESEARCH QUESTION 
 
 
The aim of this study is to assess the analgesic efficacy of intravenous ibuprofen given in 
the ED for the treatment of biliary colic.  We hypothesize that intravenous ibuprofen will provide 
a clinically significant drop in self-reported patient pain levels as measured by VAS. 
 
3. INTRODUCTION AND RATIONALE 
 
Biliary colic 
 
 
It is estimated that over 20 million people aged 20-74 have gallbladder disease 
(gallstones or cholecystectomy) in the United States. 1 Biliary colic (BC) is a common symptom of 
gallstone disease, and it thought to originate from an outflow tract obstruction, resulting in 
visceral and somatic pain due to muscular spasm of the gallbladder wall.2 Constant and severe 
pain is often experienced in the right upper quadrant or epigastric regions of the abdomen and 
may last for 2-3+ hours.  In several studies BC has been shown to develop in approximately 25-
30% of cholelithiasis patients over a 10-year period.3 Often presenting to the ED, patients with 
BC frequently require rapid administration of analgesics. 
 
 
Treatment options include non-steroidal anti-inflammatory drugs (NSAIDs) or opioids, 
with NSAIDs having several potential advantages over the latter.  Opioids carry the potential for 
abuse, produce respiratory depression, sedation, and can interfere with hepatobiliary 
scintigraphy (HIDA).4 Consequently non-opioids and NSAIDs have been extensively studied in the 
treatment of biliary colic, with a number of analgesics proving effective in treating moderate to 
severe pain. 4-5 This study will continue the trend of assessing the analgesic effectiveness of 
NSAIDs by examining intravenous ibuprofen use for biliary colic in the ED. 
  
 


4                                                                              5/5/2014 
 
Intravenous ibuprofen 
 
 
In 2009, the US FDA approved intravenous ibuprofen (Caldolor®) for the management of 
mild to moderate pain, moderate to severe pain as an adjunct to opioid analgesics, and 
treatment of fever in adults.6 Intravenous ibuprofen is only the second approved intravenous 
NSAID available in the US, the other being ketorolac.  As with other NSAIDs, ibuprofen’s 
analgesic, anti-inflammatory, and antipyretic activity is thought to be achieved through direct 
binding and inhibition of cyclo-oxygenase (COX) ensymes.7 Additionally, ibuprofen is a racemic 
mixture, with the S-enantiomer being responsible for clinical activity.6 The R-enantiomer is 
thought to be a circulating reservoir for drug level maintenance, as it is proposed to be 
pharmacologically inactive and slowly and incompletely interconverts to the S-isomer. 
 
 
Several randomized, double-blind, placebo-controlled, multicenter trials have assessed 
the efficacy of 400 and 800mg doses of intravenous ibuprofen for its approved uses.  In 
Southworth et al. and Kroll et al., adult elective abdominal or orthopaedic surgery patients and 
elective abdominal hysterectomy patients, respectively were given 800 mg doses of intravenous 
ibuprofen postoperatively every 6 hours.  Results demonstrated statistically significant analgesic 
and morphine-sparing effects.8-9 In a third study assessing pain with movement following 
orthopaedic surgery, a significant reduction in pain was noted following a 30 minute infusion of 
an 800 mg does pre-operatively, and similar subsequent doses every 6 hours postoperatively.10 
Additionally, three similarly designed studies have also shown intravenous ibuprofen to resolve 
fever to a significantly greater extent than placebo.11-13 
 
 
Intravenous ibuprofen represents an exciting and largely unexplored tool in pain 
management; its analgesic effectiveness in acute or postoperative settings is currently being 
investigated in a number of ongoing clinical trials.  As a newly available intravenous NSAID, its 
application in biliary colic has likewise been unexplored.  Compared to orally administered 
ibuprofen, the expected increase in maximum plasma concentrations (Cmax) as well as faster 
time to reach these concentrations (tmax), the elimination of variability in efficacy due to variable 
absorption of oral ibuprofen by the gastrointestinal tract, and the potentially more reliable time 
of onset of analgesia, have all been noted as potential benefits of intravenous ibuprofen over 
the oral form.7 This is especially applicable to biliary colic patients presenting in the ED, where 
the reliability and speed of intravenous NSAID analgesia can present an alternative to oral or 
opioid althernatives. 
 
Rationale 
 
 
Likely due to the relatively recent approval of intravenous ibuprofen use for fever and 
pain in adults, no assessment of its analgesic efficacy for biliary colic currently exists in the 
literature.  Utilizing the VAS for pain, this study will address this lack of evidence and identify 
intravenous ibuprofen’s value as a novel analgesic in the treatment of biliary colic.  Though 
NSAID’s have been extensively studied in the management of this phenomenon, this study aims 
to help optimize pain treatment of biliary colic patients in the ED, and pave the way for future 
treatment comparison studies. 


5                                                                              5/5/2014 
 
4. METHODOLOGY 
4.1 Objective 
 
 
The aim of this study is to assess the analgesic efficacy of intravenous ibuprofen given in 
the ED for biliary colic. 
 
4.2 Study Design and Duration 
 
 
 
This is a double-blind, prospective trial of intravenous ibuprofen for treatment of pain in 
adults presenting to the ED with biliary colic.  Intravenous ibuprofen therapy will be compared to a 
saline-only control group.  Subjects will complete a self-assessment of pain using a provided VAS at 
predetermined intervals for a minimum of two hours.  A VAS will be taken every 15 minutes in the 
first hour following study therapy administration, and every 30 minutes in the second hour.  On the 
condition that the patient has not left the ED following two hours, a VAS will be taken every hour 
until discharge or transfer. 
 
4.3 Study Population 
 
 
Adults aged 18-55 presenting to the Maricopa Integrated Health System (MIHS) ED with 
right upper quadrant and epigastric abdominal pain suggestive of biliary colic will be asked to 
participate in this study.  Enrolled patients included in the study analysis group will have 
radiographic evidence or history of gallstones, with patients diagnosed with other conditions 
being excluded.   
 
4.4 Enrollment Criteria 
 
Inclusion Criteria: 
- 
Patient age 18-55 
- 
Present to ED with right upper quadrant (RUQ) abdominal pain 
- 
Suspected diagnosis of biliary colic 
- 
Negative pregnancy test for women of child-bearing potential (complete POC 
testing form) 
- 
No history of cholecystectomy 
 
         Exclusion Criteria: 
- 
Patient age <18 or >55 
- 
Incarcerated 
- 
Hemodynamic instability 
- 
Inability to reliably self-report or communicate pain intensity and pain relief 
- 
Taking warfarin 
- 
Cannot consent or are not competent to consent 
- 
Hepatic, renal, cardiac failure 
- 
NSAID or morphine allery 
- 
History of congenital bleeding diathesis or platelet dysfunction 


6                                                                              5/5/2014 
 
- 
Peptic ulcer disease 
- 
Are otherwise unsuitable for the study in the opinion of the investigator/sub-
investigators 
 
4.5 Study Procedures 
 
 
 Upon patient presentation with signs and symptoms of biliary colic, a MIHS ED nurse 
will triage with an initial VAS.  For initial temporary pain relief preceding study enrollment, 4mg 
of morphine will be administered.  Following obtaining consent to enroll in the study, a second 
VAS will be taken while the MIHS ED pharmacy randomizes study therapy-immediately 
preceding drug administration (time zero).  Patient will be randomized to a placebo group or an 
ibuprofen intravenous 800mg group.  The intravenous ibuprofen will be mixed with 250cc or 
normal saline, with an additional 250 cc saline added to the placebo group as well.   
Both groups will be infused over five minutes, and VAS scores will be taken pose therapy 
administration every 15 minutes in the first hour, and every 30 minutes in the second hour.  On 
the condition that the patient has not left the ED following 2 hours, a VAS will be taken every 
hour until discharge or transfer.  Patient may receive rescue doses of morphine at the discretion 
of the treating provider.  Patients will not be followed after discharge or transfer.  Additionally, 
the safety of a five-minute infusion of intravenous ibuprofen will be assess through any adverse 
drug events (ADEs) being noted simultaneously with every VAS administration.  ADE symptoms 
monitored will include nausea, vomiting, skin rash, headache, dizziness, hemorrhage, and 
hypotension.  Vital signs (temperature, heart rate, respirations, and blood pressure) will also be 
assessed at the time of every VAS administration. 
 
4.6 Result Interpretation and Statistical Analysis 
 
 
Analgesic efficacy will be assessed through the use of VAS scores.  A VAS score decrease 
of 33% in relation to the VAS taken at the time of therapy drug administration (time zero) will be 
considered a clinically important different in patient-perceived pain.14 
 
 
In addition to compiling summary statistics, we will use a two-way Analysis of Variance 
with post hoc two-tailed, independent-samples t-tests and pairwise t-tests (with Bonferroni 
correction) to examine the effect of intravenous ibuprofen on patients’ self-reported pain 
scores.  The between-subjects factor will be Group (control vs. treatment), and the within-
subjects factor will be Time (measured at four 15 minute intervals during the first interval and 
two half-hour intervals during the second hour). We will need a total sample size of 36 (18 in 
each group) to provide the 80% power to detect a change of at least 33% in average pain scores 
at a given time point between the groups (d=0.96) and between any two time points within each 
group (dz=0.70).  These estimates assume an alpha level of 0.05.15 All results, from both 
descriptive and inferential analysis, will be presented in table and/or graphical format. 
 
  
 
 


7                                                                              5/5/2014 
 
4.7 Potential Complications and Ethical Considerations 
 
 
Potential complications include an inability to enroll enough patients to satisfy power 
calculations and achieve statistical significance. As this is a therapy drug vs. placebo study and 
biliary colic is a common presentation in the MIHS ED, we do not foresee this as being a 
significant complication. 
 
 
All NSAIDs carry a similar side effect profile, including nausea, vomiting, skin rash, 
headache, dizziness, hemorrhage, and hypotension. Pain control and potential adverse drug 
effects will be monitored through the use of the VAS and pain assessment forms, respectively.  
Vital signs, including temperature, heart rate, respirations, and blood pressure will also be taken 
at every VAS administration.  An ethical issue taken into considerations is the pain potentially 
experienced by patients randomized to placebo.  As mentioned previously rescue opioids may 
be administered at the discretion of the treating physician if a patient’s pain in not well 
controlled. 
 
 
5. OBJECTIVE / DISCUSSION 
 
 
The aim of this study is to assess the analgesic efficacy of intravenous ibuprofen given in 
the ED for the treatment of biliary colic.  Currently no assessment of intravenous ibuprofen’s 
analgesic efficacy in patients with biliary colic exists in the literature, likely due to its recent 
approval for use in fever and pain in adults.  This study will address this lack of evidence and 
identify intravenous ibuprofen’s value as a novel analgesic in the treatment of biliary colic.  Prior 
to intravenous ibuprofen, the only other approved intravenous NSAID available in the United 
States has been intravenous ketorolac.  As such, intravenous ketorolac has been a staple of 
biliary colic treatment.  This study aims to help optimized pain treatment of biliary colic patients 
in the ED by potentially providing and alternative analgesic.  If intravenous ibuprofen is indeed 
shown to be effective this study seeks to pave the way for future treatment comparison studies.  
Additionally, intravenous analgesia provides an added benefit in patients who present with 
nausea and vomiting where oral medications may otherwise prove ineffective. 
 
6. RESOURCES 
 
 
All work for this study will be conducted at the Maricopa Integrated Health System 
(MIHS) ED under the guidance of Dr. Dan Quan.  The Maricopa Medical Center (MMC) is located 
in Maricopa County, Arizona, and features advanced medical services including adult emergency 
care.  The MMC houses a level I Trauma Center and Emergency Center, with approximately 
50,000 patients receiving urgent and emergency care each year.  The MIHS ED is actively 
involved in research as has compensated research staff and assistants available to enroll 
patients approximately 20 hours daily.  The presence of ED triage nurses will allow for efficient 
screening and enrollment of potential study participants.  Additionally we will have access to an 
MIHS biostatistician—Andrē Valdez, PhD., who will be performing statistical analyses for the 
study. 


8                                                                              5/5/2014 
 
7. DISCONTINUATION / WITHDRAWAL CRITERIA 
 
 
The principal investigator or treating physician may withdraw a subject from the study 
at any time they feel it is in the subject’s best interest, or for any other reason.  All subjects may 
voluntarily withdraw their participation in the study at any time without any change in further 
treatment. 
 
8. ADVERSE EVENTS 
 
 
All NSAIDs—including IV ibuprofen—carry a similar side effect profile, including nausea, 
vomiting, skin rash, headache, dizziness, hemorrhage, and hypotension. Pain control and 
potential adverse drug effects will be monitored through the use of the VAS and pain 
assessment forms, respectively.  Vital signs, including temperature, heart rate, respirations, and 
blood pressure will also be taken at every VAS administration.  Every patient will receive at least 
one dose of morphine, and further morphine may be administered at the discretion of the 
treating physician if a patient’s pain in not well controlled. 
 
8.1 Serious Adverse Event Reporting 
 
All serious adverse events will be reported to the IRB within 24 hours after the 
investigator or study personnel are made aware of the serious adverse event in accordance with 
the IRB adverse event reporting guidelines. 
 
 
All adverse events and serious adverse events will be followed until resolution or until 
the principal investigator deems the event to be chronic or the subject to be stable.  Adverse 
event and serious adverse event follow-up may be done by phone, unless physical follow-up is 
deemed necessary by the principal investigator. 
 
9. BUDGET / SPONSORS 
 
 
Study drug (IV ibuprofen) will be provided by Cumberland Pharmaceuticals. 
 
10. CASE REPORT FORMS 
 
 
A case report form will be completed for each subject that has signed and informed 
consent form and participated in the study.  The form will include pain assessments, ADE’s, vital 
signs, as well as diagnosis and exclusion information. 
 
 
 
 
 
 
 
 


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11. REFERENCES 
 
1. Everhart JE, Khare M, Hill M, Maurer KR.  Prevalence and ethnic differences in gallbladder 
disease in the United States.  Gastroenterology 1999; 117:632 
 
2. Newman DH, Wolfson AB.  Analgesia for the biliary colic patient.  Emergency Sedation and Pain 
Management.  Cambridge University Press; 2008. Pp. 131-4 
 
3. Colli A, Conte D, Valle SD, Sciola V, Fraquelli M. Meta-analysis: nonsteroidal anti-inflammatory 
drugs in biliary colic.  Aliment Pharmacol Ther. 2012 Jun; 35(12);1370-8 
 
4. Olson JC, McGrath NA, Schwarz DG, Cutcliffe BJ, Stern JL.  A double-blind randomized clinical 
trial evaluating the analgesic efficacy of ketorolac versus butorphanol for patients with 
suspected biliary colic in the emergency department.  Acad Emerg Med 2008;15(8):718e22. 
 
5. Henderson SO, Swadron S, Newton E. Comparison of intravenous ketorolac and meperidine in 
the treatment of biliary colic. J Emerg Med 2002;23(3):237e41. 
 
6. Caldolor (ibuprofen) injection, for intravenous use:  US prescribing information.  Nashville (TN): 
Cumberland Pharmaceuticals Inc.,2009. 
 
7. Smith HS, Voss B. Pharmacokinetics of intravenous ibuprofen:  implications of time of infusion in 
the treatment of pain and fever.  Drugs 2012; 72 (3): 327-37 
 
8. Southworth S, Peters J, Rock A, et al.  A multicenter, randomized, double-blind, placebo 
controlled trial of intravenous ibuprofen 400 and 800 mg every 6 hours in the management of 
postoperative pain.  Clin Ther 2009 Sep; 31 (9) 1922-35 
 
9. Kroll PB, Meadows L, Rock A, et al.  A multicenter, randomized, double-blind, placebo controlled 
trial of intravenous ibuprofen (i.v.-ibuprofen) in the management of postoperative pain 
following abdominal hysterectomy.  Pain Pract 2011 Jan-Feb; 11 (1): 23-32 
 
10. Singla N, Rock A, Pavliv L. A multicenter, randomized, double-blind, placebo controlled trial of 
intravenous ibuprofen (i.v.-ibuprofen) for the treatment of pain in postoperative orthopedic 
adult patients.  Pain Med 2010 Aug; 11 (8): 1284-93 
 
11. Morris PE, Pormes JT, Guntupalli KK, et al.  A multicenter, randomized, double-blind, parallel, 
placebo controlled trial to evaluate the efficacy, safety, and pharmacokinetics of intravenous 
ibuprofen for the treatment of fever in critically ill and non-critically ill adults.  Crit Care 2010; 14 
(3): R125 
 
12. Krudsood S, Tangpukdee N, Wilairatana P, et al.  Intravenous ibuprofen (IV-ibuprofen) controls 
fever effectively in adults with acute uncomplicated Plasmodium falciparum malaria but 
prolongs parasitemia.  Am J Trop Med Hyg 2010 Jul; 83 (1): 51-5 


10                                                                              5/5/2014 
 
 
13. Promes JT, Safcsak K, Pavliv L, et al. A prospective, multicenter, randomized, double-blind trial of 
IV ibuprofen for treatment of fever and pain in burn patients.  J Burn Care Res 2011 Jan-Feb; 32 
(1): 79-90 
 
14. Jenson MP, Chen C, Brugger AM.  Interpretation of visual analog scale ratings and change scores:  
a reanalysis of two clinical trials of postoperative pain.  J Pain.  2003 Sep; 4 (7): 407-14 
 
15. Erdfelder E, Faul F, Buchner A. GPOWER: a general power analysis program. Behavior Research 
Methods, Instruments, and Computers 1996; 28, 1-11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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