Postoperative Pain Management in Patients Undergoing Intramedullary Nail Fixation After Tibia and Femoral Fractures
Phase: PHASE4
Conditions: Femur Fracture, Tibial Fractures
Sponsor: University of Puerto Rico

 
1 
 
 
 
 
 
Title: Postoperative Pain management in Patients Undergoing IMN Fixation After Closed Tibial 
and Femoral Fractures 
NCT Number: NCT04761302 
Document Date: April 6, 2021 
 
 

Postoperative Pain Management in Patients Undergoing Intramedullary Nail (IMN) 
Fixation After Tibial and Femoral Fractures. 
PROTOCOLO: #A929O220 
2 
Investigators and Institution of Affiliation: 
Dr. Luis Lojo Sojo1- Principal Investigator 
Hans W. Hess, MD1 – Co-Principal Investigator 
Ruben Tresgallo-Pares, MD1 – Co-Principal Investigator 
Marcantonio V. Pinci, MD1 – Co-Principal Investigator 
Gerardo Olivella MD, MPH1– Study Coordinator 
Pedro J. Rullan, MD2 – Co-Principal Investigator 
Carlos Guevara Serra, BS2 – Student 
Juan Gonzalez Ramos, BS2- Student 
1. Department of Surgery-Orthopaedic Section, University of Puerto Rico Medical Sciences 
Campus, San Juan, PR 00935 
2. University of Puerto Rico Medical Sciences Campus, School of Medicine, San Juan, PR 00935 
Research Questions: 
1. Is the co-administration of intravenous ketorolac and oral acetaminophen an effective 
alternative for post-operative pain management in patients with tibial and femoral shaft 
fractures who undergo intramedullary nailing? 
Hypothesis & Scientific Aim: 
We believe that the perioperative co-administration of intravenous ketorolac and oral 
acetaminophen diminishes opioid consumption, provides adequate pain control, and has 
more tolerable side effects in patients who undergo intramedullary nailing for tibial and 
femoral shaft fractures, when compared to patients taking opioid medications for pain 
control. 
We will design an alternate pain control protocol composed of intravenous ketorolac and 
oral acetaminophen for patients who undergo intramedullary nailing for tibial and 
femoral shaft fractures to determine its efficacy when compared to pain control with 
intravenous morphine and oral oxycodone combined with acetaminophen. 
Background/Significance : 
Acute pain after a surgical procedure may occur secondary to trauma from the procedure 
itself or from procedure-related complications 1. Appropriate perioperative acute pain 
management is an important phase of patients’ recovery since the undertreatment can lead 

Postoperative Pain Management in Patients Undergoing Intramedullary Nail (IMN) 
Fixation After Tibial and Femoral Fractures. 
PROTOCOLO: #A929O220 
3 
to adverse outcomes such as: thromboembolic and pulmonary complications, additional 
time spent in an intensive care unit or hospital, hospital readmission for further pain 
management, needless suffering, impairment of health-related quality of life, and 
development of chronic pain 1. Furthermore, its overtreatment with opioid medications is 
associated with an increased risk of thromboembolic, infectious and gastrointestinal 
complications as well as increased length of hospital stay, cost of care and risk of opioid 
addiction 2. Opioid addiction has led to a nationwide public health emergency in which 
approximately 115 American patients die daily from an overdose3. 
The effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on fracture healing has 
been a controversial topic in the orthopedic scientific community for many years. These 
medications are an effective, and safe analgesic alternative drug that are commonly used 
in fracture management worldwide.11 However, many physicians in the United States 
prefer to prescribe opioids over NSAIDs in patients with long bone fractures.11 
Since orthopaedic surgeons in the United States are the third leading prescribers of opioid 
medications, it is crucial to identify other alternatives for opioid based pain management 
protocols.11 The possibility of a non-opioid pain management protocol may decrease the 
orthopaedic surgeon’s impact on the ongoing opioid epidemic. 
Perioperative administration of IV ibuprofen 800mg every 6 hours has been shown to 
effectively decrease opioid requirements and pain intensity, while demonstrating minimal 
tolerable side effects after abdominal surgery and elective orthopedic procedures 7–9. 
Gürkan et al. showed in a clinical trial that patients who received IV ibuprofen 800mg 
every 6 hours had significantly lower pain intensity measurements after total hip 
replacement. In the same way, Gupta et al., combined the same dose of ibuprofen with IV 
acetaminophen 1000mg every 6 hours, showing significant pain improvement on the 
third postoperative day of patients who underwent total hip or knee arthroplasty 6 
The authors of this study believe that the use of the pain management protocols used in 
Total Knee Arthroplasty (TKA) can be effectively used as an alternative for patients 
undergoing intramedullary nailing for femur and tibia shaft fractures. This arises from the 
idea that TKA are considered among the most painful orthopaedic procedures. Wylde et 
al. demonstrated that on postoperative day 1, 58% of TKA patients indicated to have 
moderate-severe pain, which only decreased to 43% by postoperative day 3.14 

Postoperative Pain Management in Patients Undergoing Intramedullary Nail (IMN) 
Fixation After Tibial and Femoral Fractures. 
PROTOCOLO: #A929O220 
4 
Additionally, studies have shown that patients undergoing TKA, experienced more acute 
postoperative pain than Total Hip Replacement (THR) patients.13 
Throughout this trial, we wish to determine whether oral acetaminophen and intravenous 
ketorolac are viable alternatives to opioid medication regimens for the pain management 
of Hispanic patients who undergo intramedullary nailing of tibial and femoral shaft 
fractures. 
Methodology and Study Design: 
Study Design 
A prospective, single blind, randomized control trial will be designed to evaluate 
the efficacy of NSAIDs and acetaminophen in post-operative pain control on Hispanic 
patients undergoing intramedullary nailing of tibia and femur shaft fractures at University 
District Hospital of the University of Puerto Rico at San Juan, PR. All consecutive cases 
(during a 12 month period) from the orthopedic trauma service of the University of 
Puerto Rico Orthopaedic Surgery Residency program, will be included. We will limit the 
enrollment to 150 patients. 
The study cohort will be composed of patients who underwent intramedullary 
nailing of tibial and femoral shaft fractures at our institution. The sub-groups will be 
created based on pain control protocol (opioid vs non-opioid).There will be 2 aleatory 
assigned study groups. 
Group 1 will be composed of patients receiving the following standard pain 
control protocol: ketorolac 30 mg IV every 6 hours for patients younger than 70 years vs 
ketorolac 15mg IV every 6 hours for patients older than 70 years, first dose will be 
administered 30 minutes preoperatively. An additional 1000mg of acetaminophen PO will 
be administered every 6 hours simultaneously regardless of the age group. Patients who 
determine pain to be unbearable and wish to opt out of the non-opioid group will receive 
may do so. The case will then be analyzed on an individual basis by the PI, Dr. Lojo, who 
will analyze your specific case and tailor the pain management for the individual patient. 
Group 2 will be composed of patients receiving the following pain control 
protocol: morphine 0.1 mg per kg IV every 6 hours with an additional oxycodone 
combined with acetaminophen 2 tabs PO every 6 hours. 

Postoperative Pain Management in Patients Undergoing Intramedullary Nail (IMN) 
Fixation After Tibial and Femoral Fractures. 
PROTOCOLO: #A929O220 
5 
The randomization method will be simple randomization. An unblinded research 
assistant will use an online random list generator (http://randomization.com/)12 in order to 
randomize the subjects in a 1:1 ratio to receive either an opioid or non-opioid based 
regimen. Informed written consent from all participants will be obtained. 
Inclusion Criteria: 
The target population is: female and male patients older than 18 years of age 
undergoing intramedullary nailing of tibial and femoral shaft fractures and classified as 
ASA I/ASA II as per the American Society of Anesthesiologists physical status 
classification system. 
Exclusion criteria: 
Patients with (1) a history of recent use of opioids; (2) allergy or hypersensitivity 
to NSAID; (3) impaired renal, cardiac, or hepatic function; (4) history of gastrointestinal 
bleeding; (5) history of substance abuse; (6) polytraumatized; (7) younger than 18 years 
of age; (8) unable to consent; (9) Pregnant Women; (10) Mentally Incompetent; will be 
excluded from the study. 
Variables 
Variables such as sociodemographic, past medical history, diagnosis/fracture type, 
highest educational level, allergies, history of illicit drug use, and pain intensity 
measurement using a Visual Analogue Scale for pain (VAS) score; will be obtained for all 
patients. VAS score is a previously validated questionnaire. Post-operatively the first 
questionnaire will be given 12 hour postoperatively and during subsequent twelve hours 
intervals until discharge. We will also record secondary variables such as time to GI 
motility, time to weight bearing of affected limb, resumption of ambulation, and length of 
hospital stay. Each assessment will take about 15 minutes, and the authors of this study 
estimate that the entire time per patient will be 60 minutes. The time intervals for the data 
collection chosen for this project was based on previous studies performed in our 
institution. 
Each patient will be provided with all the necessary information of the risk and 
benefits involved in this study and their intention to participate (Statement of Purpose and 
Justification). Previous authorization from the MSC - IRB office will be obtained before 
starting the research study. 

Postoperative Pain Management in Patients Undergoing Intramedullary Nail (IMN) 
Fixation After Tibial and Femoral Fractures. 
PROTOCOLO: #A929O220 
6 
Risk and Benefits: 
This study presents minimum risks for the patients. A possible risk would be a 
probable feeling of uncomfortableness due to the time it takes for the patient to complete 
the VAS instrument for pain intensity. If the pain becomes overwhelming patients may 
choose to opt out of the treatment group and have the PI (Dr. Lojo) analyze the individual 
case and tailor the pain medication to their needs. Patients will not be receiving a direct 
benefit, such as a reward, before and after the study. However, the information obtained 
during this study will help improve future doctor-patient interactions hence improving 
patient satisfaction. Risks and benefits will be explained to the patient prior to performing 
the study. 
Analytic Plan: 
Data analysis will be performed and expressed using frequency and percentages 
for categorical variables and means with standard deviation for quantitative data. In 
addition, comparisons between data will be assessed with the chi-square test and student’s 
t-test or analysis of variance (ANOVA) for categorical and quantitative variables, 
respectively. Statistical significance will be considered for p-values ≤ 0.05. 
The patients participating in the study will be assigned a sequential identification 
number (1, 2, 3, etc.) on a password protected Google Sheet (GS1), only the study’s PI, 
Dr. Lojo, and study coordinator, Dr. Olivellas will have access to this sheet. This will be 
done in order to preserve confidentiality and avoid the use of identification using the 
medical record number. Once the data is retrieved in the form of questionnaires, it will be 
recorded on a separate password protected Google Sheet (GS2) which will only have the 
sequential identification numbers (not the medical record numbers) it will be de-
identified. The master key to this code will be securely placed in a locked file in the 
research office at the Orthopedic Surgery Section office (9th floor) at the Medical 
Sciences Building. Only the PI, Co-PI, study coordinator, and medical students affiliated 
with the Orthopaedic Surgery department who have met the CITI requirements will have 
access to GS2. All statistical analyses will be performed with de-identified data. All data 
will be stored in a secured and encrypted hard disk to which outside personnel has no 
access. Once the study is completed, all electronic files will be stored for two additional 
years. Afterward, these electronic documents will be permanently deleted from all 
authorized devices by the study coordinator. 

Postoperative Pain Management in Patients Undergoing Intramedullary Nail (IMN) 
Fixation After Tibial and Femoral Fractures. 
PROTOCOLO: #A929O220 
7 
Limitations: 
Since the VAS for pain is a subjective measurement for the evaluation of pain, there is an 
inherent probability for under or over appreciation. In addition, the population selected 
may represent convenience bias due to its location on the northeast side of Puerto Rico. 
Vulnerable Populations 
Hospitalized patients, Patients age 18-20 years old, Patients older than 65 years of age. 
Consent Process: 
Upon admission to the in patient orthopaedic ward at the University District Hospital, 
patients will be approached with the opportunity to participate in the study. Patients will 
be approached by Dr. Tresgallo, Dr. Hess, Dr, Olivellas, Dr. Rullan, or Dr. Pinci, who will 
have a conversation about the risks, and benefits of the study, and its contribution to the 
medical field. Any questions that may arise will be answered at this time. Furthermore, 
the patients will be asked to explain the study in order to verify understanding. In the case 
of patients who fall within 18-20 years old, the investigators will have a conversation, 
and verify understanding from both the parents or guardians and patients. Finally, 
informed consent and assent forms will be taken and singed. Each participant, and parent 
or guardians in the case of 18-20 years of age, will be instructed on the ability to resign 
from this study at any time. 
Privacy and Confidentiality: 
References: 
1. 
American Society of Anesthesiologists. Practice Guidelines for Acute Pain 
Management in the. Anesthesiology. 2012;116(2):248-273. 
doi:10.1097/ALN.0b013e31823c1030 
2. 
Cozowicz C, Olson A, Poeran J, et al. Opioid prescription levels and postoperative 
outcomes in orthopedic surgery. Pain. 2017;158(12):2422-2430. 
doi:10.1097/j.pain.0000000000001047 
3. 
Understanding the Epidemic | Drug Overdose | CDC Injury Center. 
https://www.cdc.gov/drugoverdose/epidemic/index.html. Accessed September 30, 
2019. 

Postoperative Pain Management in Patients Undergoing Intramedullary Nail (IMN) 
Fixation After Tibial and Femoral Fractures. 
PROTOCOLO: #A929O220 
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4. 
Nadarajah V, Glazier E, Miller K, et al. Evaluation of Preoperative Pain Using 
PROMIS Pain Interference in Knee Surgery Patients. J Knee Surg. 2019;1(212). 
doi:10.1055/s-0039-1688769 
5. 
Chou R, Gordon DB, De Leon-Casasola OA, et al. Management of postoperative 
pain: A clinical practice guideline from the American pain society, the American 
society of regional anesthesia and pain medicine, and the American society of 
anesthesiologists’ committee on regional anesthesia, executive commi. J Pain. 
2016;17(2):131-157. doi:10.1016/j.jpain.2015.12.008 
6. 
Gupta A, Abubaker H, Demas E, Ahrendtsen L. A randomized trial comparing the 
safety and efficacy of intravenous ibuprofen versus ibuprofen and acetaminophen in 
knee or hip arthroplasty. Pain Physician. 2016;19(6):349-356. 
7. 
Gago Martínez A, Escontrela Rodriguez B, Planas Roca A, Martínez Ruiz A. 
Intravenous ibuprofen for treatment of post-operative pain: A multicenter, double 
blind, placebo-controlled, randomized clinical trial. PLoS One. 2016;11(5):1-16. 
doi:10.1371/journal.pone.0154004 
8. 
Singla N, Rock A, Pavliv L. Pre-Operatively_2010.Pdf. 2010:1284-1293. 
9. 
Southworth S, Peters J, Rock A, Pavliv L. 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;31(9):1922-1935. 
doi:10.1016/j.clinthera.2009.08.026 
10. 
Gürkan Y, Yörükoğlu HU, Işık E, Kuş A. The effect of ibuprofen on postoperative 
opioid consumption following total hip replacement surgery. Turkish J Anaesthesiol 
Reanim. 2019;47(1):31-34. doi:10.5152/TJAR.2018.48265 
11. 
Fader L, Whitaker J, Lopez M, et al. Tibia fractures and NSAIDs. Does it make a 
difference? A multicenter retrospective study. Injury. 2018;49(12):2290-2294. 
doi:10.1016/j.injury.2018.09.024 
12. 
Dallal G. Randomization. com. Available online at: 
http://www.randomization.com/. (2003). 
13. 
T. Thomas, C. Robinson, D. Champion, M. McKell, M. Pell. Prediction and 
assessment of the severity of postoperative pain and of satisfaction with 
management. Pain. 75 (1998), pp. 177-185 

Postoperative Pain Management in Patients Undergoing Intramedullary Nail (IMN) 
Fixation After Tibial and Femoral Fractures. 
PROTOCOLO: #A929O220 
9 
14. 
V. Wylde, J. Rooker, L. Halliday, A. Blom. Acute postoperative pain at rest after hip 
and knee arthroplasty: Severity, sensory qualities and impact on sleep. Orthopaedics 
& Traumatology: Surgery & Research. 2011;97(2):139-144.