A Pilot Study Comparing the Effectiveness of an Opioid- Sparing Analgesic Regimen and an Opioid Based Regimen on Post- Operative Pain Control in Cardiac Surgery Patients (INOVA OPIOID
Phase: PHASE2
Conditions: Pain, Postoperative
Sponsor: Inova Health Care Services

Opioid Sparing in Cardiac Surgery Pain 
 
Inova Heart and Vascular Institute 
_______________________________________________________________________________________________ 
 
______________________________________________________________________________________________ 
 
CONFIDENTIAL             Opioid Sparing Protocol                       PI: Ramesh Singh MD                             Page 1 of 13  
 
 
 
 
 
A Pilot Study Comparing the Effectiveness of an Opioid- Sparing Analgesic Regimen and an Opioid 
Based Regimen on Post- Operative Pain Control in Cardiac Surgery Patients (INOVA OPIOID) 
 
 
 
 
 
 
 
 
 
Principal Investigator: Ramesh Singh MD 
 
 
Sub-Investigator: Eric L. Sarin MD 
 
 
Site of Investigation: Inova Heart and Vascular Institute 
Falls Church, Virginia 
 
 
December 10, 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Opioid Sparing in Cardiac Surgery Pain 
 
Inova Heart and Vascular Institute 
_______________________________________________________________________________________________ 
 
______________________________________________________________________________________________ 
 
CONFIDENTIAL             Opioid Sparing Protocol                       PI: Ramesh Singh MD                             Page 2 of 13  
 
ABSTRACT 
 
  
Title:   
 
 
A Pilot Study Comparing the Effectiveness of Opioid- Sparing Analgesic Regimen and an  
 
 
 
Opioid Based Regimen on Post- Operative Pain Control in Cardiac Surgery Patients 
 
Short Title:    
 
Opioid Sparing in Post-Operative Cardiac Surgery Pain (INOVA OPIOID) 
 
Rationale:      
 
To demonstrate the effectiveness of an opioid sparing pain regimen post cardiac  
 
 
 
 
surgery to provide optimal pain relief as well as to minimize opioid related side  
 
 
 
 
effects.  
 
Objectives:     
 
We hypothesize that an opioid- sparing regimen consisting of scheduled   
 
 
 
 
acetaminophen and gabapentin for 72 hours post- operatively, will reduce  
 
 
 
 
opioid consumption, reduce opioid related side effects, and result in a decrease in   
 
 
 
overall healthcare costs.  
 
Study Type:   
 
Single center, open label, prospective, randomized clinical trial. 
 
Study Design:   
 
A total of 20 patients between the ages of 18-85 years old that have undergone  
 
 
 
 
sternotomy procedures in the context of cardiac surgery will be   
 
 
 
 
 
randomized to one of two treatment groups. 
 
Study Methodology:   
We will analyze the total opioid consumption and pain scores of sternotomy patients beginning 
 
 
 
with admission to CVICU post-surgery (day 0) through post-operative day three (day 3) in  
 
 
 
patients  receiving acetaminophen IV paired with gabapentin pro ora (PO).  
 
 
 
 
Also analyzed will be hospital length of stay, incidence of ALT/AST >3X ULN (AST >168, 
 
 
 
ALT >105), occurrence of  ileus during hospitalization, pre and post-surgical  
 
 
                     incentive spirometry tidal volume values; pre  surgery and through post- operative day three (3), 
 
 
 
number of  hours post CVICU arrival to extubation and perform cost analysis assessment of  
 
 
 
medication and hospitalization costs.  
 
Statistical Methodology:  Although underpowered for this pilot, our statistical analysis plan is designed to similarly 
assess the feasibility of the larger study to follow. Primary analyses for this pilot will be to 
determine feasibility of larger study and determine estimates of primary outcome (e.g., total 
opioid consumption, pain scores, etc.) mean and variance parameters for sample size 
calculation. Estimates for study attrition, and secondary outcomes of hospital length of stay, 
incidence of AST/ALT > 3x ULN (AST >168, ALT >105), etc. will be calculated. All 
analyses will be conducted as intent-to-treat.  
 
 
 
 
 
 
 
               
 
 
 
 
 

Opioid Sparing in Cardiac Surgery Pain 
 
Inova Heart and Vascular Institute 
_______________________________________________________________________________________________ 
 
______________________________________________________________________________________________ 
 
CONFIDENTIAL             Opioid Sparing Protocol                       PI: Ramesh Singh MD                             Page 3 of 13  
 
  
1. 
INTRODUCTION 
 
 
1.1. 
Specific Aims 
 
The management of post-operative cardiac surgery pain representative of many etiologies remains a challenge 
to clinicians. Opioid pain medications can cause or exacerbate side effects which directly contribute to 
morbidity and mortality in post- operative cardiac surgery patients, as well as cost of medication and 
hospitalization. In this study we will demonstrate that an opioid sparing, multimodal pain regimen consisting of 
intravenous acetaminophen paired with PO gabapentin will reduce opioid consumption in addition to providing 
optimal pain relief, reduce opioid related side effects, and decrease the cost of medication and hospitalization. 
Reduction in opioid consumption and pain relief will be demonstrated by decreased patient self-report of pain 
and requests for breakthrough opioid pain medication. Reduction of opioid related side effects will be 
demonstrated by lack of incidence of ileus during hospitalization, tidal volumes that return and are maintained 
at pre surgical levels through post- operative day 3, and decreased time to extubation from Cardiovascular 
Intensive Care Unit (CVICU) arrival. Increase in AST/ALT will be monitored as a safety assessment.  
Additionally, we will demonstrate a reduction in total cost of hospitalization via decreased length of stay, as 
well as decreased medication costs. 
 
1.2. 
Hypothesis  
We hypothesize that an opioid- sparing pain regimen consisting of scheduled IV acetaminophen and PO 
gabapentin for 72 hours post- operatively will reduce opioid consumption while maintaining adequate pain 
relief as evidenced by pain scores less than two (2), and minimal request for breakthrough opioid medication, 
and that reduced opioid consumption will lead to a reduction in the incidence of ileus, rapid return to pre-
surgical respiratory tidal volumes, and timely extubation, AST/ALT within normal limits, and demonstrate a 
positive effect on the cost of medication and hospitalization. 
 
1.3. 
Background and Significance  
Post-Operative Cardiac Surgery Pain 
The management of pain resultant from cardiac surgery necessitating a sternotomy is a challenging clinical 
quandary. Post cardiac surgery pain is associated with a variety of etiologies; sternotomy incision, retraction of 
the ribs and sternum with possible rib dislocation or fracture, pericardotomy, internal mammary and or 
saphenous vein harvesting, operative trauma to the parietal pleura, insertion of chest tubes, reactions to 
pacemaker wires, brachial plexus injury, insertion of mediastinal and pleural drains, and other body trauma 
occurring as a result of surgery 1, 2. Cardiac surgery patients may experience severe pain in post anesthesia 
recovery as well as upon transfer to the Cardiovascular Intensive Care Unit 3. Well controlled pain 
postoperatively is associated with positive physical and psychological outcomes. Well controlled pain 
facilitates early extubation, improves hemodynamics, improves myocardial oxygenation, improves hemostatic 
and immunologic modulation, decreases the incidence of ischemic events, maximizes chest expansion during 
respiration,  enables early ambulation 2,4,5 and is responsible for the ensuing positive clinical outcomes that are 
associated with early ambulation (eg. deep vein thrombosis prophylaxis). Optimal pain control is associated 
with lower rates of cardiovascular complications, pneumonia, and avoidance of hypercoagulability in the 
postoperative recovery period 3, 6. Equally, poorly controlled pain is responsible for elevated catecholamine 
levels which can progressively trigger myocardial ischemia, stroke, and bleeding complications 4, 25 post cardiac 
surgery. Cardiac surgery has the potential to disrupt the normal process of coagulation which could predispose 
a patient to thrombosis, this process may be attenuated by the increased physiologic benefit of adequate pain 
relief and its effect on increasing blood flow 6. 
 
The Use of Opioids for Pain Management and Their Myriad Side Effects  
Opioid analgesics have traditionally been the mainstay of treatment for postoperative cardiac surgery pain 
despite the myriad negative side effects of these medication regimens which constitute major barriers to their 
use 4, 7. These side effects are frequently dose dependent and exert a profound negative influence on patient 
recovery, early discharge, safety, and associated morbidity and mortality 1, 7. Perhaps the most significant 
effects involve the incidence of post-operative nausea and vomiting (PONV) and paralytic ileus 2, 8, 9, 10. 

Opioid Sparing in Cardiac Surgery Pain 
 
Inova Heart and Vascular Institute 
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CONFIDENTIAL             Opioid Sparing Protocol                       PI: Ramesh Singh MD                             Page 4 of 13  
 
Paralytic ileus [ileus] refers to a state of low or absent peristalsis which results in secretion accumulation in the 
gastrointestinal tract leading to symmetric abdominal distension and vomiting 11. Paralytic ileus is a significant 
contributor to mortality post cardiac surgery. Paralytic ileus etiology is multifactorial. Most commonly ileus 
results from a low gastrointestinal flow state during the perioperative period 12. Surgical stress may disrupt the 
natural arrangement of the bowel and thus impair the function of the gastrointestinal tract 10.  PONV rates post 
cardiac surgery can range from 42- 71% of cardiac surgery patient utilizing opioids for post- operative pain 9. 
PONV is associated with aspiration pneumonia, dehydration, electrolyte imbalances, which in turn may lead to 
or contribute to dysrhythmia, fluid overload, and uncontrolled pain secondary to absorption anomalies 9. PONV 
has a profound impact on a patient’s ability to participate in their recovery 1, 9  Other harmful effects of post- 
operative opioid consumption include; constipation, profound sedation, dizziness and confusion especially in 
elderly patients, suppression of gastrointestinal motility, and respiratory depression 1, 13. Also concerning is that 
severe acute pain post sternotomy is a significant predictor of chronic pain which is fraught with profound 
psychological, physical, and financial costs 3, 14, 15, including chronic incisional pain and the potential for post- 
operative opioid addiction16 which has of late reached epidemic proportions25. More than 2 million Americans 
suffer from substance abuse related to opioid consumption 25.Opioid induced hyperalgesia (OIH) is also a 
significant complication of an opioid based pain regimen. OIH is the direct sequlae of chronic opioid 
administration and results in patients developing a heightened sensitivity to pain 13.  Finally, scholarly evidence 
for the use of chronic opioids in the treatment of non-cancerous pain does not exist. In fact eminent pain 
societies recommend the use of opioid medications with “great restraint and caution” 3, 17,25. Indications for 
responsible, effective pain management favor a plan based on the individual’s unique history and condition, a 
multimodal regimen, and multidisciplinary collaboration 1, 3, 18. 
 
Multimodal Analgesia Regimens 
Multimodal pain regimens offer significantly better relief in post cardiac surgery patients 1. Selection of a 
multimodal approach for post cardiac surgery pain is advocated to reduce opioid requirements. These regimens 
should include regional anesthesia, non-narcotic medication, and additional complimentary regimens2. 
Multimodal analgesia is the mainstay of responsible comprehensive individualized pain management 13. 
Multimodal analgesia is the combination of different pharmacologic agents and routes of administration in 
order to produce analgesic effects along multiple pain pathways 13. The use of multimodal analgesia provides 
pain relief that is both potent and synergistic while minimizing possible adverse effects of the medication 13. 
Multimodal pain regimens combine agents to provide both central and peripheral analgesia 4. The use of a 
multimodal pain regimen as opposed to an opiate based regimen offers significantly better pain relief 1, 17.  
 
The Use of Gabapentin and Intravenous Acetaminophen 
Gabapentinoids are effective on centrally mediated pain pathways and thus successful in the treatment of 
neuropathic pain, they have demonstrated a reduction in acute pain and have beneficial effects on the 
development of chronic pain and pain scores post-surgery 13, 14, 19, 20, 21, 22,25. Gabapentin with its anti-
inflammatory properties offers relief superior to opiates or acetaminophen alone in cardiac surgery patients 1, 5, 
20, 21. High quality evidence confirms the effectiveness of a multimodal regimen which includes 
acetaminophen17 IV (IV APAP) is a powerful potential constituent of a multimodal pain management regimen 
post cardiac surgery. Without serious side effects and when used as recommended this medication is devoid of 
platelet, kidney, or gastrointestinal sequelae and therefore is beneficial to the cardiac surgery patient in a 
variety of ways. The intravenous route (IV APAP) ensures more efficient absorption and avoids the first- pass 
metabolism effect.  
 
Post- Operative Pain Assessment 
The Numeric Rating Scale is a one dimensional measurement of pain intensity in the adult patient. Various 
versions of this scale exist although the most commonly used version involves a 1-10 scale for scoring pain. 
Zero (0) represents no patient reported pain and 10 represents the patient reporting [the] “worst pain 
imaginable”. The scale is administered verbally and the patient translates their pain intensity to a number on the 
scale. Higher scores indicate extreme pain23, 24. 
 
 
 
Study Procedures 

Opioid Sparing in Cardiac Surgery Pain 
 
Inova Heart and Vascular Institute 
_______________________________________________________________________________________________ 
 
______________________________________________________________________________________________ 
 
CONFIDENTIAL             Opioid Sparing Protocol                       PI: Ramesh Singh MD                             Page 5 of 13  
 
 
The Cardiovascular Intensive Care Unit (CVICU) will be the setting for our clinical trial involving two groups 
of subjects and comparing the post cardiac surgery opiate based standard of care regimen in effect at the time of 
protocol development (Group 1) within the IHS/IHVI at the Inova Fairfax Medical Campus (IFMC)with a 
treatment group (Group 2). Group 2 will receive a scheduled multimodal pain regimen consisting of PO 
gabapentin paired with intravenous acetaminophen. Opiates will be available for breakthrough pain in the 
treatment group for pain scores greater than 4. The outcomes of total opioid consumption and minimum/ 
maximum pain scores will be assessed at the 24 hours, 48 hours, 72 hours, and PRN timepoints. Assessment 
will include amount of opioids consumed in both groups as well as number of requests for breakthrough pain 
medication in Group 2. 
 
The term ‘Standard of Care’ in this protocol will refer to the adapted regimen of opioid based pain relief 
prescribed at the time of protocol development at the IHS/IHVI/IFMC. 
 
Standard of Care regimens at the IHS/IFMC are revised regularly based on advances in evidence based 
practice, patient response, continuously evolving safety information, issuance of professional society practice 
guidelines, and physician recommendations.  
 
While the post cardiac surgery pain standard of care regimen currently differs from the regimen to be 
administered to the Group 1 subjects in this clinical trial there is no change to the risk benefit ratio and is 
addressed in this protocol to provide transparency of practice. Also, this study will contribute meaningful 
evidence for future modifications to the standard of care at the IHS/IHVI/IFMC. 
 
Minimum and maximum pain scores in all study groups will be assessed via Numeric Rating Scale (0-10) as 
per Inova Health System (IHS) policy; ‘Pain Management for the Adult Population’, at 24 hours, 48 hours, 72 
hours, and PRN with opioid requests in all groups and opioid administration follow up within one hour as per 
IHS inpatient medication administration policy. Follow up medication administration scores will not be 
recorded as part of study results. 
 
Secondary assessments will include the incidence of ileus both during hospitalization, increase in AST/ALT, 
post-operative tidal volumes as assessed by incentive spirometry as compared to pre- surgical values, time from 
CVICU arrival to extubation in both groups, and the effects of an opioid based regimen versus an opioid 
sparing regimen on cost of medication and hospitalization.  
 
We hypothesize that a scheduled opioid- sparing pain regimen consisting of IV APAP and PO gabapentin for 
48 hours post- operatively will reduce opioid consumption while maintaining adequate pain relief as evidenced 
by pain scores less than two (2), and a reduction in opioid consumption, and that reduced opioid consumption 
will lead to a reduction in the incidence of ileus, an opioid related side effect, no increase in AST/ALT, post-
operative tidal volumes as assessed by incentive spirometry comparable to pre- surgical values, and 
demonstrate a positive effect on the cost of medication and hospitalization. 
 
1.4 Preliminary Studies 
The objective of this pilot study is to provide evidence that multimodal pain therapy utilizing IV APAP and PO 
Gabapentin will provide more effective pain relief than standard of care opioids as evidenced by pain scores <2. 
And the reduced consumption of opioids will lead to a reduction in ileus, no increase in AST/ALT, post-operative 
tidal volumes as assessed by incentive spirometry comparable to pre- surgical values, while also showing a 
positive effect on the cost of medication and hospitalization. 
 
The Principle Investigator Ramesh Singh is a cardiothoracic surgeon at the Inova Heart and Vascular Institute 
(IHVI) with over 25 years of experience and well qualified for the design and conduct of the study. Dr. Singh has 
performed over 177 cardiothoracic surgeries at the IHVI in 2017 alone.  
  
2. STUDY DESIGN AND SUBJECT SELECTION  
 
 
2.1 Study Type 

Opioid Sparing in Cardiac Surgery Pain 
 
Inova Heart and Vascular Institute 
_______________________________________________________________________________________________ 
 
______________________________________________________________________________________________ 
 
CONFIDENTIAL             Opioid Sparing Protocol                       PI: Ramesh Singh MD                             Page 6 of 13  
 
 
 
Single center, open label, prospective, randomized clinical trial. 
 
    
2.2 Setting/Location 
 
Inova Heart and Vascular Institute (IHVI) 
 
3300 Gallows Road 
 
Falls Church, Virginia 22042 
 
 
2.3 Duration of Study 
 
Consented and randomized subjects will participate for three (3) days starting at admission to CVICU 
 
(day 0). Biological specimens will not be collected for the purposes of this study. 
 
 
 
 
2.4 Number of Subjects  
       A total of 20 patients, 10 per study arm are expected to participate in this study. 
 
 2.5 Study Population 
 2.5.1 Gender of Subjects 
 
The study population is inclusive of both genders (male and female). 
 
2.5.2 Age of Subjects 
 
Subject enrollment will be comprised of subjects 18- 85 years of age.   
 
2.5.3 Racial and Ethnic Origin  
 
The study population will be inclusive of all racial and ethnic subgroups.  
 
2.5.4 Vulnerable Populations 
 
Children, pregnant women, institutionalized persons, and persons with decisional incapacity will not be 
 
enrolled in this study. 
 
 
2.6 Recruitment  
 
Patients will be recruited upon first contact with the cardiac surgery service either while inpatient pre- 
 
surgery or outpatient at the Cardiac and Thoracic Surgery Associates office located at 2921 Telestar 
 
Court, Falls Church, Virginia during the preoperative consult/ visit. Patients will not be consented 
 
less than 24 hours before surgery to provide adequate time for participation consideration. 
 
 
2.7 Inclusion Criteria 
  1. Patient between 18 and 85 years old. 
      2. Elective or urgent surgery requiring sternotomy approach 
 3. Subject is able to read and has signed and dated the informed consent document including              
      authorization permitting release of personal health information (PHI) approved by the Inova           
      Institutional Review Board (IRB). 
 
 
2.8 Exclusion Criteria 
 
       1. Patients lacking enteral access on post-operative day 0 
 
 
2. Inability to communicate 
 
 
3. Active chronic pain with opioid therapy 
 
 
4. Active chronic use of gabapentin or pregabaldin  
 
       5. Active substance abuse 
 
 
6. Current self- report of alcoholism 
 
 
7. End stage renal disease 
 
 
8. Active renal dialysis therapy 
 
 

Opioid Sparing in Cardiac Surgery Pain 
 
Inova Heart and Vascular Institute 
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CONFIDENTIAL             Opioid Sparing Protocol                       PI: Ramesh Singh MD                             Page 7 of 13  
 
3. STUDY METHODS AND PROCEDURES 
 
 
3.1 Schedule of Assessments 
 
Schedule of Assessments 
Group 1:Standard of Care 
Group 2: Total 485 hours 
PRN opiates per patients self- report of pain. Dosing based on patient 
pain score report. 
Scheduled post-op loading dose of IV acetaminophen  1000mg X 1 dose 
AND Gabapentin 600 mg PO X 1 dose upon arrival to the Cardiovascular 
Intensive Care Unit (CVICU) 
Pain will be assessed in standard of care group every 12 hours or twice 
per day for 72 hours by study personnel. 
Pain will be assessed in standard of care group every 12 hours or twice per 
day for 72 hours by study personnel. 
Assessment of tidal volume via incentive spirometry q day by study 
personnel. 
Assessment of tidal volume via incentive spirometry q day by study 
personnel. 
1-3 (Mild pain) 
Acetaminophen 650 mg PO q4 hours (Mild pain) 
PRN 
Scheduled Acetaminophen 1000 mg IV q61,4 X 42 Hours and PO Gabapentin 
300 mg2 q8 hours X 40 Hours then discontinue2 
Then: 
Acetaminophen 1000 mg PO q6 hours PRN for pain scores 4-10 (Moderate to 
severe)4 
 
 
Patients with moderate hepatic disease and/or severe renal impairment will 
receive Acetaminophen 1000 mg PO q 12 hours X 48 hours, then q12 hours 
PRN for pain scores  1- 10 (mild to severe) 
 
Patients with Creatinine clearance <30mL/min will receive 100 mg 
Gabapentin PO q8 hours X 40 hours2 
 
First line: 
 
4-6 (Moderate pain): Tramadol 50mg PO q4 PRN 
 
Second line3: If first line is ineffective X 2 doses 
 
4-6 (Moderate pain):   Oxycodone/acetaminophen 5/325 mg PO q4 
hours  
 
     PRN  
 
 
 
7-10 (Severe pain): Hydromorphone 0.25 mg IV q3 hours PRN 
                      
 
Administered in conjunction with an opioids for moderate to severe 
breakthrough pain (Scores 4-10) 
Schedule for breakthrough pain Group 2: 
1st line: Score 4-6 Tramadol 50 mg q4 PRN 
2nd line3: Score 4-6 Oxycodone 10 mg PO q4 hours PRN 
Severe pain Score 7-10: Hydromorphone 0.25 mg IV q3 hours PRN 
1 Start 6 hours post CVICU arrival loading dose 
2 Start 8 hours post CVICU arrival loading dose 
3 If first line ineffective X 2 doses 
4 Acetaminophen administrations will not exceed 4000 mg per 24 hour period. 
5 Experimental regimen will be administered to Group 2 for 48 hours. Pain assessment will be for 72 hours beginning at time of CVICU arrival.  
 
 
3.2 Randomization  
 
Allocation of study treatment will be performed via a web-based interactive randomization system, based 
 
on a computer-generated random sequence with a random block size.  
 
 
3.3 Endpoints/Outcomes Measurements 
3.3.1 Primary Outcomes. 
 
The primary outcome will be reported as total opioid consumption in Group 2.Total opioid 
 
consumption in Group 2 will be assessed at 24 hours, 48 hours, and 72 hours from the initial dose of IV 
 
acetaminophen and PO gabapentin received upon arrival in the CVICU.  Assessment will include 
 
amount of opioids consumed as well as number of requests for breakthrough opioid pain medication in 
 
Group 2. 
 
 
 
 
Minimum and maximum pain scores in all study groups will be assessed via Numeric Rating Scale (0-10) 
 
as per Inova Health System (HIS) policy ‘Pain Management for the Adult Population’ at 24 hours, 48 
 
hour, 72 hours, and PRN with opioid request in all groups and administration follow up within one hour 
 
as per IHS inpatient medication administration policy Follow up scores will not be recorded as part of 
 
study procedure. 
 
3.3.2 Secondary Outcomes 

Opioid Sparing in Cardiac Surgery Pain 
 
Inova Heart and Vascular Institute 
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CONFIDENTIAL             Opioid Sparing Protocol                       PI: Ramesh Singh MD                             Page 8 of 13  
 
Secondary outcomes include decreased incidence of ileus, AST/ALT > 3x ULN (AST >168, ALT >105), 
post-operative tidal volumes as assessed by incentive spirometry, number of hours post CVICU arrival to 
extubation and analysis of medication and hospitalization costs. 
 
 
3.4   Consent/Assent 
 
Eligible subjects may only be included in the study after providing written (witnessed, where required by law 
 
or regulation), IRB -approved informed consent. If the subject is capable of doing so, he/she will indicate 
 
assent by personally signing and dating the written informed consent document.  Informed consent must be 
 
obtained by the Principal Investigator, Sub-Investigator, or the  Study Coordinator; individuals qualified to 
 
obtain informed consent before conducting any study-specific procedures (i.e., all of the procedures 
 
described in the protocol). The process of obtaining informed consent will be documented in the subject’s 
 
medical record as well as clinical trial source documents. 
 
 
 
 
3.4 Criteria for Withdrawal of Subjects from the Study.    
 
Subjects in the experimental groups will be withdrawn from the study if there is no enteral access beyond 
 
post- operative day 0, and for increased serum liver function values. 
 
4. STATISTICAL CONSIDERATIONS/DATA ANALYSIS 
 
 4.1 Sample Size 
Twenty subjects, 10 per arm (Group 1opiate based standard of care, and Group 2 multimodal regimen of IV 
APAP and PO gabapentin) to determine feasibility of larger study and determine estimates of primary 
outcome (i.e., total opioid consumption, pain scores, etc.) mean and variance parameters for sample size 
calculation for larger study to follow. Estimates for study attrition, and secondary outcomes of hospital length 
of stay, incidence of AST/ALT > 3x ULN, (AST >168, ALT >105) etc. will be calculated. 
 
 
4.2 Method of Data Analysis 
Although underpowered for this pilot, our statistical analysis plan is designed to similarly assess the 
feasibility of the larger study to follow. Primary analyses for this pilot will be to determine feasibility of 
larger study and determine estimates of primary outcome (e.g., total opioid consumption, pain scores, 
etc.) mean and variance parameters for sample size calculation. Estimates for study attrition, and 
secondary outcomes of hospital length of stay, incidence of AST/ALT > 3x ULN (AST >168, ALT >105) 
, etc. will be calculated. All analyses will be conducted as intent-to-treat. Data will be presented as mean 
± standard deviation or frequency and percent, where appropriate. Data will be assessed for departures 
from normality using Kolmogorov-Smirnov tests. Departures from normality will be treated using 
nonparametric tests (e.g., Wilcoxon, Kruskal-Wallis, etc.). However, given the short duration of the total 
patient enrollment and total patient time in study, we anticipate minimal missing data or patient attrition. 
Subjects with missing data ≥ 10% will be examined to determine if missing data is non-random.  
 
To test the primary hypothesis that for significant differences between groups, we will use separate GLM 
for total opioid consumption (repeated measures [3 time points], dependent variable [DV]), total number 
of breakthrough pain medication requests (DV) and medication cost (DV). Time points (n=3) to assess 
total opioid consumption and breakthrough pain medication requests will be at 24, 48 and 72 hours. 
Medication cost will be assessed once following discharge. An interaction term will be included for the 
group (n=2)* time (n=3) models (DV=total opioid consumption and breakthrough pain medication 
requests). Pain (dichotomized, pain score < 2) will be assessed using an unconditional binary logistic 
regression approach. Post-hoc testing for group comparison (Group 1 vs. Group 2) and group by time 
interaction (e.g., total opioid consumption only, etc.) will be performed using Tukey’s least significant 
difference test (LSD) for GLM models and estimation procedures (contrasts) for logistic regression 
(Group 1 vs. Group 2). To test the hypothesis that reduced opioid consumption will lead to a reduction in 
the incidence of ileus, incidence rates and 95% confidence intervals (CI) per group will be calculated and 
compared using conditional exact tests based on the binomial distribution. Secondary outcomes include 

Opioid Sparing in Cardiac Surgery Pain 
 
Inova Heart and Vascular Institute 
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CONFIDENTIAL             Opioid Sparing Protocol                       PI: Ramesh Singh MD                             Page 9 of 13  
 
hospital length of stay (LOS, days), antiemetic requirement, the incidence of AST/ALT > 3x ULN(AST 
>168, ALT >105) , the incidence of ileus during hospitalization will be calculated using either methods 
described above; GLM (LOS), unconditional logistic regression (antiemetic) or exact tests (AST/ALT, 
ileus).   
 
 
 
 
4.3 Data Storage 
 
4.3.1   Data Management 
 
Information about study subjects will be kept confidential and managed according to the 
 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). Each subject 
 
screened and enrolled will be assigned a subject identification number (SID) and a list of subjects with 
 
their corresponding SID will be maintained separately from collected data. Physical case report forms 
 
(CRF’s) will be stored at the research site in a locked office and electronic subject data will be 
 
locked in a password protected file on a secure internet server, accessed only by authorized research 
 
staff. Only members of the research team will be able to access to this data on the secure server and the 
 
file password.  
 
 
4.3.2 Records Retention 
 
The Investigator will maintain the records of drug disposition, final CRFs (CDROM copies), worksheets, 
 
source documents, and all other study-specific documentation in accordance with ICH Guidelines. 
 
Essential documents should be retained for at least three (3) years after the investigation is formally 
 
discontinued.  
 
5. HUMAN SUBJECTS PROTECTION (RISKS, BENEFITS, AND    
ALTERNATIVES) 
 
 
5.1.1 Potential Loss of Privacy 
 
Protected health information (PHI) will be collected during the study. The risk for breach of confidentiality 
 
and privacy will be minimized by shielding the subjects unlinking his or her identity from his or her personal 
 
health information. 
 
 
5.1.2 Potential Adverse Events 
 
Aside from standard of care cardiac surgery practices and procedures, no other additional treatments or 
 
procedures will be given to subjects for this trial.  
 
 
5.2 Benefits and Alternatives 
 
There are no direct benefits to the patient. Participation in the study is entirely voluntary. The alternative is 
 
not to participate in the trial. 
 
 
6. SUBJECT COMPENSATION 
    
 
 
 
 
6.1 Costs 
 
 
 There are no costs to participate in the research study. 
 
 
 
 6.2 Payment  
 
 
There will be no payment to the subject for participation in the research study. 
 
7. ADVERSE EVENT REPORTING 
   
 
 
7.1 AE Recording 
 
 
Adverse events will be collected postoperatively. For the purpose of this study, only the following  
 
 
adverse  events will be collected and reported: 

Opioid Sparing in Cardiac Surgery Pain 
 
Inova Heart and Vascular Institute 
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CONFIDENTIAL             Opioid Sparing Protocol                       PI: Ramesh Singh MD                             Page 10 of 13  
 
 
Nausea 
 
Vomiting 
 
Paralytic Ileus 
 
        
7.2 Adverse Events Treatment 
 
 
Patients will be followed for clinical outcomes. All AEs and SAEs will be collected from   
 
 
randomization through 72 hours after randomization. 
 
               
 7.3 Adverse Event Documentation   
  
 
The principal investigator has the primary responsibility for SAE identification, documentation,  
 
 
grading, and assignment of attribution to the study intervention. SAEs must be recorded in the  
 
 
AE CRF with the following information:  
 
AE term 
 
The intensity grade (CTCAE v 4.03 grading) 
 
The relationship to study procedure 
 
Attribution 
 
Duration 
 
Occurrence (known risks for study procedure-expected, unexpected) 
 
Other contributing causes 
 
Actions in response to event 
 
Outcome 
 
Criteria for SAE  
 
      
7.4 AE Grading Scale 
 
 
The descriptions and grading scales found in NCI Common Terminology Criteria for Adverse Events 
 
 
(CTCAE) version 4.03 will be used for AE reporting. Each AE term is  associated with a 5-point  
 
 
severity scale.  
 
 
8. FUNDING 
 
This is an investigator-initiated study sponsored by Inova Heart and Vascular Institute. There is no 
investigational product involved. Treatment received by the subject will be as according to main provider’s 
discretion as according to standard of care.  
 
9. CONFLICTS OF INTEREST  
 
              The investigators declare no conflicts of interest linked to this study.  
 
10.  FACILITIES AND EQUIPMENT  
                                                         
The Inova Heart and Vascular Institute (IHVI) will be the only setting for this clinical trial. IHVI equipment will 
be utilized as necessary per standard of care. 
 
11. OUTSIDE CONSULTANTS/COLLABORATORS 
  
 
There are no outside consultants/collaborators participating. 
 
12. CONTRACTURAL AGREEMENTS  
  
   

Opioid Sparing in Cardiac Surgery Pain 
 
Inova Heart and Vascular Institute 
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CONFIDENTIAL             Opioid Sparing Protocol                       PI: Ramesh Singh MD                             Page 11 of 13  
 
 
There are no contractual agreements in effect for this study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Opioid Sparing in Cardiac Surgery Pain 
 
Inova Heart and Vascular Institute 
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13. REFERENCES 
 
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Opioid Sparing in Cardiac Surgery Pain 
 
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23 
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