Assessing the Efficacy of IV Ibuprofen for Treatment of Pain in Orthopedic Trauma Patients
Phase: PHASE4
Conditions: Pain
Sponsor: Delray Medical Center

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678'<35272&2/7,7/(:  Assessing the Efficacy of IV ibuprofen for Treatment of 
Pain in Orthopedic Trauma Patients. 
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Critically ill patients may experience pain related to their underlying illness, trauma, 
disease processes, surgery or other non-surgical interventions (Tietze, 2012). The primary 
goal of analgesia is optimizing patient comfort in conjunction with balancing the negative 
physiologic responses to pain including hypermetabolism, increased oxygen 
consumption, hypercoagulability, and alterations in immune function (Tietze, 2012). 
Acute pain is defined as a, “complex, unpleasant experience with emotional and 
cognitive, as well as sensory, features that occur in response to tissue trauma” (American 
Pain Society, 2012, p. 10).
Uncontrolled or poorly managed pain leads to serious medical complications; impairs 
recovery from injury or procedures; negatively impacts quality of life; progresses to 
chronic pain, and increases morbidity, mortality and length of ICU or hospital stay 
(Malchow & Black, 2008). A number of studies indicate a high incidence of untreated 
pain in ICU settings (Malchow & Black, 2008). Payen et al. (2007) demonstrated in a 
recent study that 90% of ICU patients were treated with opioids; whereas, only 42% were 
assessed for pain. In addition, procedural analgesics and nonopioid adjuncts were only 
used approximately one third of the time. The reluctance to offer pain medication within 
the acute care setting is understandable and multifactorial.  
Evaluation and treatment of pain in trauma patients is complicated by the patient’s 
pathologic condition, the effects of medications, and the diverse interventions used in 
patient care (Freire, Afessa, Cawley, Phelps, & Bridges, 2002). Several authors suggest 
trauma complications such as hypovolemia, coagulopathies, and head and spinal cord 
injuries actually hinder administration of adequate pain control for fear that analgesics 
will cause further adverse physiological events in these patients (Lovrincevic, Kotob, & 
Santarosa, 2005; Chanques et al., 2006)  Trauma exerts pervasive effects on a multitude 
of body systems, specifically making this population more susceptible to the side effects 
of analgesics or sedative drugs (Chanques et al., 2006). Health care providers are; 
therefore, more cautious and limited in their choice of opioid medications.   
Acute pain is more difficult to manage and control if permitted to become severe; making 
prompt, preemptive, and adequate treatment imperative (APS, 2012). Acute pain is most 
often nociceptive responding to non-opioids and opioids. Pharmacological management 
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APPROVED 
 
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Jun 09, 2014
WIRB 20121749
APPROVED 
 
WIRB® 
 
 
 
 
 
Jun 09, 2014

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is the cornerstone of acute pain management with opioids being the most commonly 
prescribed class of medications and the mainstay of management in the acute care setting. 
Opioid analgesics exert their effects by binding to receptors in the central and peripheral 
nervous system and the gastrointestinal tract. The use of opioids; however, is often 
limited due to related adverse side effects including sedation, respiratory depression, 
nausea and vomiting, constipation, hallucinations, confusion, sedation, and allergic 
reactions (Bookstaver, 2010). Their use has also been linked to compromised function of 
the immune system.  
Opioids are useful in mitigating the sensation of pain but provide no benefits to the 
underlying disease process (Sinatra & Jahr, 2011). Adjunctive agents for pain including 
non-steroidal anti-inflammatory agents (NSAIDS) may be used in combination with 
opioids to mitigate the side effects of both agents by reducing the total dose required. The 
APS (2012) advocates the use of multimodal analgesia including non steroidal anti-
inflammatory agents (NSAIDS) for optimal pain control in the treatment of acute 
traumatic pain. The rationale behind multimodal therapy is to capitalize on the synergistic 
action between pharmacological agents and different techniques.
The potential side effects of opioids especially in the trauma population combined with 
recommendations for a synergistic approach to pain management suggests medications 
such as IV iIbuprofen may be beneficial in treating pain in trauma patients. Additionally, 
intravenous (IV) medications are preferred in critically ill patients because 
gastrointestinal (GI)dysfunction can lead to unpredictable absorption of medications 
given orally (Tietze, 2012). Multi-modal therapy can help avoid common complications 
of opioid-centered analgesia including physical dependence, addiction, and respiratory 
depression (Malchow & Black, 2008).
IV ibuprofen was approved for use in the United States in June of 2009 and it is indicated 
for management of mild to moderate pain, management of moderate to severe pain as an 
adjunct to opioid analgesics, and reduction of fever (Sinatra & Jahr, 2011). Similar to oral 
ibuprofen, the IV formulation can inhibit both COX-1 and COX-2. IV ibuprofen has 
more ‘balanced’ affinity for the COX isoenzymes. In key clinical trials, bleeding gastric 
and renal events were similar to placebo. This has significant implications for the clinical 
use of IV iIbuprofen. IV Caldolor is also available on the formulary of Delray Medical 
Center and has been available since late 2009.
The efficacy and safety of IVof IV ibuprofen related to pain management has mainly 
been studied with post-operative orthopedic patients. Southworth, Peters, Rock and 
Pavliv (2009) conducted a multi-center, randomized, double-blind placebo-controlled 
dose-ranging study to assess the effects of IV ibuprofen vs versus placebo in 406 patients 
undergoing orthopedic or abdominal surgery. IV ibuprofen at a dose of 800mg was 
associated with reduced morphine use during the first 24 hours (p=0.030) and significant 
reductions in pain at rest and with movement. Another study done by Kroll, Meadows, 
Rock, and Pavliv (2011) was a multi-center, randomized, double-blind, placebo-
controlled trial to evaluate the efficacy and safety of IV ibuprofen at the initiation of 
wound closure. IV iIbuprofen was continued for 8 doses and then as needed every 6 

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hours for up to 5 days following surgery. IV ibuprofen was associated with a reduction in 
morphine requirements over the first 24 hours and resulted in a significant reduction in 
pain at rest and with movement. As with the dose-ranging study there was no difference 
in treatment-emergent AE’s, including nausea and flatulence, between the study groups. 
Singla, Rock and Pavliv (2010) conducted a multi-center, randomized, double-blind 
placebo-controlled trial of IV Iibuprofen for treatment of pain in post-operative 
orthopedic adult patients. Pre and post operative administration of IV ibuprofen 
significantly reduced both pain and morphine use in orthopedic surgery patients in this 
study.
Multiple studies done with orthopedic patients have demonstrated the efficacy of using 
IV ibuprofen for treatment of acute pain leading to significant reductions in pain and 
decreased use of narcotics. Additionally, Orlando Regional Medical Center a Level I 
trauma center conducted a retrospective study of IV ibuprofen and traumatic rib fracture. 
The study demonstrated that early IV ibuprofen therapy with traumatic rib fractures 
significantly decreases narcotic requirements and resulted in clinically significant 
decreases in hospital length of stay. The authors suggest IV ibuprofen should be given 
upon admission to augment pain control and recommend a prospective study.
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1. To evaluate the effectiveness of around the clock (OTC) IV ibuprofen (8 doses) in 
decreasing pain in orthopedic trauma patients with fractures of the extremities, 
face, pelvis and/or ribs compared to patients not receiving the medication.   
2. To evaluate the effectiveness of around the clock (OTC) IV ibuprofen (8 doses) in 
decreasing the use of opioid analgesics among orthopedic trauma patients with 
fractures of the extremities, face, pelvis, and/or ribs compared to compared to 
patients not receiving the medication.   
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The goal is to enroll approximately 67 patients in each group for a total of 134 patients. 
However, the study will be reevaluated after 3 months to determine if this number needs 
to be reconsidered. 
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1. Trauma patient admitted to Trauma ICU or Trauma Step-Down Units. 
2. Fracture of ribs, face, extremities and/or pelvis 
3. Age between 18 and 75 years old 
4. Adequate IV access 
5. Able to self report and communicate pain severity 
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1. History of allergy or hypersensitivity to any component of IV iIbuprofen, aspirin 
(or aspirin related products) NSAIDs, or COX-2 inhibitors 

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2. Any intracranial or spinal cord trauma 
3. History of clinically significant bleeding disorders including ITP, DIC or platelet 
dysfunction
4. Recent history of intracranial surgery or stroke (within past 30 days) 
5. History of ulcers, gastritis or previous GI bleeding 
6. Renal Impairment (Creatinine > 3.0 mg/dL) 
7. Pregnant or breastfeeding 
8. Otherwise unsuitable in the opinion of the treating physician at time of 
randomization.  
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A good faith effort will be made to ensure that all subjects complete the study through 
day five, consistent with the provisions of informed consent and good clinical judgment 
in respect to safety. The following are potential reasons to terminate the participation of 
the subject in the study: 
• The subject’s health would be jeopardized by continued participation. 
• Withdrawal of consent: subject decides to stop participation in the study for any 
reason, or is unable to complete the study as describedǤ
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Patients who meet all the inclusion criteria and do not meet any exclusion criteria (see 
above) will be consented and randomized by the research team . team. All individuals 
who are part of the research team will work under the direct supervision of the PI, are 
responsible for completing NIH or other demonstration of completion of a course in 
Good Clinical Practice training in addition to Delray Medical Center’s (DMC) specific 
research training including confidentiality and compliance requirements.  
Once the patient has been identified as an eligible candidate for the study based on the 
inclusion/exclusion criteria the research team will confirm with the treating physician that 
there are no other factors preventing the patient from being enrolled in the study. The 
inclusion/exclusion (I/E) sheet is completed and initialed by the treating physician and 
by the member of the research team. The patient is then approached for informed consent. 
Once the patient has signed the informed consent, a copy is will be provided to the 
patient and , one is will be placed in the chart (per hospital protocol). The signed I/E 
sheet is placed in a designated IV iIbuprofen binder within each unit.  
Once the patient has signed the informed consent and the I/E sheet has been completed,
the research team member will place the order set (already created and made available to 
the research team) in the computer under Dr. Weisz (PI) as protocol orders. The orders 
will include a pharmacy consult and will , bbe flagged as a study protocol. Study
ProtocolT and the research team member will also be responsible for notifying pharmacy 
that there is a newly consented research patient. The pharmacy has a pre-generated 
numbers list used to randomize patients. The numbers are listed on the spreadsheet in 

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athe random order and patients are assigned a number as they are enrolled in the study. 
Everyone besides theWith the exception of the research staff including pharmacy, the PI,
study coordinator, trauma nurses and the nurse researcher working with patients, all 
others will be blinded as to who receives IV Iibuprofen. The study can be unblinded at 
any time during the study in the event of patient complications or other extenuating 
circumstances. IV bags will be labeled as IV iIbuprofen when they are sent to the trauma 
units making the placebo and medication bags appear the same..
The Trauma Research Nursetrauma nurse(s)  iswill be responsible for retrieving the
collected information from the binder and keeping track of research patients and
collectingstudy data through day five. The patient once enrolled in the study will have 
pain measured using either a Visual Analog Scale (VAS)/FACES or a Numerical Rating 
Scale (NRS). The FACES Sscale verbal assessment ranges from 0 (no hurtpain) to 10 
(worste pain imaginablepossible pain) and the NRS ranges from 0 (nNo pain) to 10 
(wWorst pPossible pPain). A baseline pain score will be obtained prior to administering 
either the placebo or the IV iIbuprofen. Additional pain medication will be provided as 
per Standardized IV iIbuprofen Order Set. The patient will then have pain assessed as per 
hospital specific protocol within the trauma units. Additionally pain should be assessed 
prior to and following administration of any pain medication. For the purposes of the 
study, pain assessments will be obtained for both groups from nurse charting at hHours 4, 
8, 12, 16, 20, 24, 28, 32, 36, 40, 44, & 48 and then twice daily for a total of five days. A 
pain score may be obtained from the nursing documentation if it has been done within + 
or – two hours of the times stated above.
Sixty-seven patients will receive the placebo and 67 patients will receive the IV 
iIbuprofen based on a random numbering system per pharmacy. There is just one order 
set entered into the computer at this time; patients will receive the same prn pain 
medications and IV Pepcid dosage regardless of whether they are in the placebo or the IV 
iIbuprofen group. All patients will receive a total of 8 doses of the medication or the 
placebo (800mg IV iIbuprofen/placebo over 30 minutes) along with 20 mg IV/po Pepcid 
for 48 hours.
IV Ibuprofen Order Set
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a. IV iIbuprofen 800mg IV Q6 hours (x 8 doses) 
b. Pepcid 20mg po or IV BID 
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Administration of pain medications are based on the patient’s self assessment 
of pain using a Visual Analog Scale (VAS)/FACES (0-10) or Numerical 
Rating Scale (NRS) (0-10). Patient must be able to self report pain.
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• Tylenol 650mg po/pr prn Q4h

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• Oxycodone 5mg 1 tab po q 4Q4h
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• Oxycodone 10mg po q4Q4h
• Morphine 1mg IV Q4h 
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• Morphine Sulfate 2mg IV Q3h 
• Dilaudid 1mg IV Q4h 
• May give 1 tab of Oxycodone 5mg po Q4h for breakthrough pain
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• Morphine Sulfate 4mg IV Q3 
• Dilaudid 2mg IV Q3 
• May give 1 tab of Oxycodone 5mg po Q4h for breakthrough pain 
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• Decrease in reported pain using the FACES or Numerical Rating Scale NRS) 
during the initial 48 hour time period 
• Decrease in the use of opioid medications during the initial 48 hour period. 
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• Decrease in reported pain using the FACES or Numerical Rating Scale (NRS)
over a five day time period 
• Decrease in the use of opioid medications over a five day time period. 
• Decrease in hospital and ICU length of stay 
• Rate of treatment failure (defined as the requirement of additional pain 
medications within the 48 hour window). 
Information that may be gathered about the patient include age, race, type of injuries, co-
morbidities, medical history, self-reported pain levels, lab values, vital signs, type and 
amount of narcotic pain medications, length of hospital stay, patient outcomes, continued 
use of IV ibuprofen and other factors which in the opinion of the investigator may be 
significant to the study. 
Charts will be flagged should a patient need to go to surgery or the operating room (OR); 
indicating the patient is on the IV iIbuprofen Study. An attempt will be made to maintain 

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a standardized OR sedation medication regimen for these patients and to resume the 
standardized prn pain medication order set per protocol upon return to the trauma units. 
The study drug IV ibuprofen has been approved by the FDA in the United States since 
June of 2009 and is indicated for management of mild to moderate pain, management of 
moderate to severe pain as an adjunct to opioid analgesics, and reduction of fever (Sinatra 
& Jahr, 2011). It has been used and approved for use in trauma and acute care patients 
and is on the formulary at our facility since late 2009. The administration of Pepcid to all 
trauma patients is a standard prophylaxis for prevention of GI complications given within 
our trauma unit.  
The goal of this study is not to assess the pharmacokinetics of IV ibuprofen as a drug 
which has been determined by the FDA, but to determine its efficacy in managing pain in 
a particular subset of patients; i.e. that of trauma patients with fractures of the extremities, 
pelvis and/or ribs. The patients are assessed by the trauma surgeons during daily rounds 
and notified of the medications the patient is currently taking. Should there be any 
changes in lab values, patient status or condition the trauma surgeons will assess the 
patient as they would any other patient who had been given this medication for treatment 
of pain or medical condition and make appropriate clinical decisions. The trauma 
surgeons are made aware that the patient is in the study via rounds and through the 
computerized charting system.  
To supplement safety for research patients, the PI and Research Coordinator will monitor 
daily vital signs, intake and output and lab work upon admission, Day 1, Day 2 and Day 5 
with special attention paid to consistent elevated blood pressure, elevated creatinine 
clearance (>3,0 mg/dL), anemia (decreased Hgb, Hct, RBC), fluid retention, edema, 
increased bleeding times (PT, PTT & INR), significantly elevated liver enzymes (ALT, 
AST) and signs and symptoms of GI bleeding (abdominal pain or cramping, blood 
streaked stools, constipation, melena or coffee ground emesis). It should be noted that 
most adverse events associated with IV Ibuprofen are related to extended or long term 
use; whereas, this protocol involves only 8 doses of the medication. The information 
collected and monitored by the research team will include those tests done as standard of 
care procedures and not for the specific purposes of the research; therefore some results 
may not be obtained but data will be included if it is within + or – 3 days after completion 
of the study (Day 5) .
Unexpected Problems (AE’s and SAE’s)Adverse Events (AE’s) or Serious Adverse 
Events (SAE’s)
The risks associated with taking this medication are clearly outlined in the informed 
consent. Serious risks include cardiovascular thrombotic events; heart attacks; strokes and 
GI bleeding, ulceration or perforation of the stomach or intestines. Other common risks 
may include allergic reaction, edema; hypertension; exfoliative dermatitis, fluid retention, 
anemia, increased bleeding time, other GI side effects like nausea/vomiting, diarrhea or 

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abdominal pain; and elevated liver enzymes. All these symptoms have been identified by 
the FDA as risks. 
Unexpected problems that are adverse events (AE’s) or serious adverse events (SAE’s)
will be reported through 3 days post infusion (Days 1-5) and in accordance with hospital 
policy and WIRB reporting requirements for unanticipated or unexpected problems upon 
review by the Principal Investigator within 10 working days of the time the investigator 
becomes aware of them.  
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Data will be entered into an Excel spreadsheet. Data will be kept confidential at all times. 
Safeguards to ensure confidentiality will include National Institutes of Health (NIH) or 
Collaborative Institutional Training Initiative (CITI) Good Clinical Practice (GCP)
training by study personnel, maintaining the data in a password protected site, and 
securing all hardware that would contain any files with PHI.  All findings and reported 
data will be de-identified.
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Good Clinical Practice (GCP) is the international ethical and scientific quality standard 
for designing, conducting, recording and reporting studies that involve the participation 
of human subjects. This study will be conducted in compliance with GCP and the 
applicable national regulations so as to assure that the rights, safety, and well being of the 
participating study subjects are protected and consistent with the ethical principles that 
have their origin in the Declaration of Helsinki. 
The Investigator (according to national provisions) is responsible for following the 
regional law where the study is to be conducted to obtain written approval for the clinical 
study protocol (including all substantial protocol amendments), the subjects informed 
consent (including written assent, when applicable), informed consent updates, subject 
recruitment procedures (e.g., advertisements) and any other information to be provided to 
subjects from an Institutional Ethics Committee (IEC)/Institutional Review Board (IRB)
that complies with the local regulatory requirements.  
Written approval of the study must be obtained from the IRB prior to the study being 
implemented. Copies of approval documentation will be maintained by both the 
Investigator and authorized representative in the designated study documentation files.
As patients in this study may not be able to provide informed consent at baseline due to 
clinical status, informed consent will be obtained following the regional law where the 
study is being conducted, under the guidance of the IRB while remaining fully compliant 
with International Conference on Harmonisation (ICH) guidelines.
The investigator is responsible for assuring the appropriate content of the informed 
consent form (ICF) and that informed consent is obtained from each subject in 

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accordance with the applicable local regulations and guidelines. The original singed
signed informed consent is to be retained in the study documentation files. The subject’s 
medical records should also document that the informed consent form was signed and 
dated and that the appropriate local legal requirements regarding informed consent were 
followed.
The Investigator or designated person(s) will give the subject information about the study 
in a form that the subject can read and understand. If the subject is unable to read, oral 
information on the study will need to be provided to the subject in the presence of a 
witness, if applicable, according to regional law. The subject will be informed that he/she 
could may withdraw form from the trial at any time, for any reason, without risk to their 
treatment plan or medical care.
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Statistical analysis will be done primarily using IBM SPSS Statistical Software; 
occasionally other software may be used.  
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American Pain Society. (2010, January). 2SWLPL]LQJWKHWUHDWPHQWRISDLQLQSDWLHQWVZLWK
DFXWHSUHVHQWDWLRQV (Position Statement). Retrieved from American Pain Society: 
www.ampainsoc.org
Bayouth, L., Safcsak, K., Cheatham, M. L., Smith, C. P., Bierrer, K. L., & Promes, J. T. 
Early intravenous ibuprofen decreases narcotic requirement and length of stay 
following traumatic rib fracture. Orlando Regional Medical Center & University 
of Central Florida School of Medicine. Retrieved from 
www.surgicalcriticalcare.net (713).
Bookstaver, P. B., Miller, A. D., Rudsill, C. N., & Norris, L. B. (2010). Intravenous 
ibuprofen:  the first injectable product for the treatment of pain and fever. -RXUQDO
RI3DLQ5HVHDUFK, 67-79. Retrieved from 
www.ncbi.nlm.nih.gov/pmc/articles/PMC3004645 
Chanques, G., Jaber, S., Barbotte, E., Violet, S., Sebbane, M., Perrigault, P., Mann, C., 
Lefrant, J., & Eledjam, J. (2006). Impact of systematic evaluation of pain and 
agitation in an intensive care unit. &ULWLFDO&DUH0HGLFLQH, (6), 1691-1699. doi: 
10.1097/01.ccm.0000218416.62457.56 
Freire, A., Afessa, B., Cawley, P., Phelps, S., & Bridges, L. (2002). Characteristics 
associated with analgesia ordering in the intensive care unit and relationships with 
outcome. &ULWLFDO&DUH0HGLFLQH, (11), 2468-2472. doi: 
10.1097/01.ccm.0000034695.18650.2a 
Kroll, P. B., Meadows, L., Rock, A., & Pavliv, L. (2011). A multicenter, randomized, 
double-blind, placebo-controlled trial of intravenous ibuprofen (iv-ibuprofen) in 
the management of postoperative pain following abdominal hysterectomy.3DLQ
3UDFWLFH(1), 23-32. doi:10.1111/j.1533-2500.2010.00402.x

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Lovrincevic, M., Kotob, F., & Santarosa, J. (2005). Pain management in the trauma 
setting. 6HPLQDUVLQ$QHVWKHVLD3HULRSHUDWLYH0HGLFLQHDQG3DLQ, , 34-40. doi: 
10.1053/j.sane.2004.11.002
Malchow, R. J. & Black, I. H. (2008). The evolution of pain management in the critically 
ill trauma patient:  Emerging concepts from the global war on terrorism. &ULWLFDO
&DUH0HGLFLQH(7), S346-S357. 
Payen J. F., Chanques, G., Mantz, J. et al. (2007). Current practices in sedation and 
analgesia for mechanically ventilated critically ill patients: A prospective 
multicenter patient-based study. $QHVWKHVLRORJ\, 687-695. 
Promes, J. T., Safcsak, K., Pavliv, L. R. P., Voss, B., & Rock, A. (2011). A prospective, 
multicenter, randomized, double-blind trial of IV ibuprofen for treatment of fever 
and pain in burn patients.-RXUQDORI%XUQ&DUH	5HVHDUFK(1), 79-90.
Sinatra, R. S. & Jahr, J. S. (2011, June). Special Report:  Multimodal management of 
acute pain:  The role of IV NSAIDS. 3KDUPDF\3UDFWLFH1HZV Retrieved from 
http://www.pharmacypracticenews.com/download/SR1124_WM.pdf 
Singla, N., Rock, A., & Pavliv, L. (2010). A multi-center, randomized, double-blind 
placebo-controlled trial of intravenous-ibuprofen (IV-ibuprofen) for treatment of 
pain in post-operative orthopedic adult patients.3DLQ0HGLFLQH(8), 1284-1293. 
doi:10.1111/j.1526-4637.2010.00896.x
Southworth, S., Peters, J., Rock, A., & Pavliv, L. (2009). A multicenter, randomized, 
double-blind, placebo- controlled trial of intravenous ibuprofen 400 and 800 mg 
every 6 hours in the management of postoperative pain.&OLQLFDO7KHUDSHXWLFV
(9), 1922-1935. doi:10.1016/j.clin 
Tietze, K. J. (2012, August 27). Pain control in the critically ill adult patient. 8S7R'DWH
Retrieved from http://www.uptodate.com