Clinical trial NCT02926573
Conditions: Head and Neck Cancer Acute Pain Postoperative Pain
Keywords: oral cavity oropharynx hypopharynx and larynx
Sponsor: Washington University School of Medicine
Start date: 2016-06-24; Completion date: 2017-06-21
Enrollment: 123 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Patient satisfaction with healthcare is increasingly being utilized as a metric to reflect provider and hospital quality of care. Furthermore, at the core of a healthcare team and healthcare system is the desire to provide patients with the best possible care in order to achieve the best possible outcomes. Providers have the duty to identify areas of needed improvement within the domains of treatment. An area of need that is ubiquitous within medicine is pain control; in this case acute postoperative pain control is the targeted condition. Studies have already shown that better control of acute postoperative pain leads to shortened hospital stays, reduced hospital costs and patient morbidity, improved patient satisfaction and a reduced likelihood of developing chronic pain. Research within the field of pain management has definitively revealed that a combination of different medication regimens can control acute postoperative pain better than narcotics alone. In particular, the medication gabapentin has been shown to improve acute postop pain in many kinds of surgical settings, and it is a safe medication with arguably fewer side effects than narcotics. The investigators know that certain groups of post surgical otolaryngology patients can be at risk for high levels of postoperative pain. Given all of this information, physicians have a responsibility to utilize medications such as gabapentin to do a better job of controlling patient's pain. This investigation is a quality improvement project designed to elucidate the benefits of gabapentin in pain management in patients undergoing surgery of the head and neck mucosal surfaces. It will provide much needed data in an understudied population and ultimately will improve the practice of pain management, patient satisfaction and quality of care delivered in the Barnes otolaryngology department.

Detailed description:

Arms: arm 1: Gabapentin liquid by mouth or Per Tube 300mg twice a day arm 2: Placebo liquid by mouth or Per Tube twice a day
Interventions: intervention 1: Gabapentin intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
The effect of gabapentin on perioperative pain control among head and 
neck surgery patients 
 
NCT# NCT02926573 
 
 
Document Version Date:  04/11/2017 
 
IRB Approval Date:  04/25/2017 


 
CONFIDENTIAL 
 
CLINICAL RESEARCH PROTOCOL 
 
 
 
 
 
 
 
 
THE EFFECT OF GABAPENTIN ON PERIOPERATIVE PAIN 
CONTROL AMONG HEAD AND NECK SURGERY PATIENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Initial version: 3/31/2016 
Amended: 
7/31/2016 
Amended: 
12/1/2016 
Amended:  
1/20/2017 
Amended:           2/10/2017 
Amended:            2/20/2017 
Amended:            3/18/2017 
Amended: 
4/11/2017 


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Table of Contents 
 
STUDY SUMMARY ...................................................................................................................................... 1 
1 
INTRODUCTION .................................................................................................................................. 2 
1.1 
BACKGROUND ................................................................................................................................ 2 
1.2 
INVESTIGATIONAL AGENT ................................................................................................................ 2 
1.3 
CLINICAL DATA .............................................................................................................................. 2 
1.4 
DOSE RATIONALE AND RISK/BENEFITS ............................................................................................ 3 
2 
STUDY OBJECTIVES ......................................................................................................................... 3 
3 
STUDY DESIGN ................................................................................................................................... 3 
3.1 
GENERAL DESIGN .......................................................................................................................... 3 
3.2 
PRIMARY STUDY ENDPOINTS .......................................................................................................... 6 
3.3 
SECONDARY STUDY ENDPOINTS ..................................................................................................... 6 
3.4 
PRIMARY SAFETY ENDPOINTS ......................................................................................................... 8 
4 
SUBJECT SELECTION AND WITHDRAWAL .................................................................................... 8 
4.1 
INCLUSION CRITERIA ...................................................................................................................... 8 
4.2 
EXCLUSION CRITERIA ..................................................................................................................... 8 
4.3 
SUBJECT RECRUITMENT AND SCREENING ....................................................................................... 8 
4.4 
EARLY WITHDRAWAL OF SUBJECTS................................................................................................. 9 
4.4.1 
When and How to Withdraw Subjects ..................................................................................... 9 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects .......................................................... 9 
5 
STUDY DRUG ...................................................................................................................................... 9 
5.1 
DESCRIPTION ................................................................................................................................. 9 
5.2 
TREATMENT REGIMEN .................................................................................................................... 9 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ....................................................... 10 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ................................................................... 10 
5.5 
SUBJECT COMPLIANCE MONITORING ............................................................................................. 10 
5.6 
PRIOR AND CONCOMITANT THERAPY ............................................................................................. 10 
5.7 
PACKAGING ................................................................................................................................. 10 
5.8 
BLINDING OF STUDY DRUG ........................................................................................................... 11 
5.9 
RECEIVING, STORAGE, DISPENSING AND RETURN .......................................................................... 11 
5.9.1 
Receipt of Drug Supplies ....................................................................................................... 11 
5.9.2 
Storage .................................................................................................................................. 11 
5.9.3 
Dispensing of Study Drug ...................................................................................................... 11 
5.9.4 
Return or Destruction of Study Drug ..................................................................................... 11 
6 
STUDY PROCEDURES ..................................................................................................................... 11 
7 
STATISTICAL PLAN ......................................................................................................................... 12 
7.1 
SAMPLE SIZE DETERMINATION ...................................................................................................... 12 
7.2 
STATISTICAL METHODS ................................................................................................................ 12 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ....................................................................................... 12 
8 
SAFETY AND ADVERSE EVENTS ................................................................................................... 13 
8.1 
DEFINITIONS ................................................................................................................................ 13 
8.2 
RECORDING OF ADVERSE EVENTS ................................................................................................ 14 
8.3 
UNBLINDING PROCEDURES ........................................................................................................... 14 
8.4 
MEDICAL MONITORING ................................................................................................................. 15 
9 
DATA HANDLING AND RECORD KEEPING ................................................................................... 15 
 


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10 
STUDY MONITORING ....................................................................................................................... 15 
10.1 
STUDY MONITORING PLAN ............................................................................................................ 15 
11. MEDICATION PROCESSING .................................................................................................... 15 
13 
REFERENCES ................................................................................................................................... 16 
 
 


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List of Abbreviations 
 
 
HCAHPS- Hospital Consumer Assessment of Healthcare Providers and Systems 
 
PRC-Professional Research Consultants  
 
FDA – Food and Drug Administration 
 
VAS – Visual Analog Scale 
 
POD – post-operative day 
 
 
 
 
 
 
 
 


[Insert short name of protocol here] 
 
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Study Summary 
Title 
The effect of gabapentin on perioperative pain control among head and neck 
surgery patients 
Short Title 
Gaba RCT 
Protocol Number 
1.6 (sixth amended version) 
Phase 
Phase 4 
Methodology 
Prospective randomized double-blind controlled trial  
Study Duration 
2 years 
Study Center(s) 
Barnes Jewish Hospital 
Objectives 
Determine the effectiveness of gabapentin for reducing narcotic requirements 
and subjective pain scores in postoperative head and neck mucosal cancer 
patients.  Determine the ability of gabapentin to improve patient satisfaction 
with pain management. Track inpatient length of stay.  
Number of Subjects 
120 
Diagnosis and Main 
Inclusion Criteria 
Adult head and neck patients undergoing oral cavity, oropharynx, larynx and 
hypopharynx resection (mucosal head and neck surgeries) 
Study Product, Dose, 
Route, Regimen 
Gabapentin liquid by mouth or Per Tube 300mg BID vs placebo 
Duration 
of 
administration 
Day of surgery and up to three days post operatively depending on the hospital 
stay.   
Reference therapy 
Placebo 
Statistical 
Methodology 
Bivariate analysis using independent samples t-test for continuous variables 
and chi square test for categorical variables will be used to compare between 
treatment groups 
 


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1 Introduction 
This document is a protocol for a human research study to be conducted according to US and 
international standards of Good Clinical Practice compliant to all associated Federal and applicable local 
and University research requirements, approved by the Institutional Review Board.  
1.1 Background 
High-quality healthcare is accessible, safe, efficient, patient-centered and imperative for good treatment 
outcomes.  In this era of healthcare reform, patient satisfaction has increasingly become an important 
metric of hospital performance.  The Medicare Hospital Value Based Purchasing Program utilizes patient 
reported satisfaction scores as a reflection of the quality of care delivered by hospital systems and 
clinician teams.  The scores resulting from these reports are integrated into the formula with which 
hospitals are reimbursed for Medicare patients. 
 
An important patient-physician interface in quality healthcare is the treatment of pain, and the treatment of 
acute postoperative pain is particularly relevant for surgical specialties.  Effective management of 
postoperative pain increases patient satisfaction, reduces hospital costs, reduces postoperative morbidity 
and shortens hospitalizations8.  HCAHP and PRC data from the Barnes Jewish Hospital otolaryngology 
inpatient unit reveals that postoperative otolaryngology patient satisfaction with pain control is routinely 
lower than the 75th percentile of all hospitals nationally surveyed.  Traditionally, pain regimens rely heavily 
on the use of narcotics, which are associated with nausea, vomiting, delirium, and decreased bowel 
motility.  These side effects have the potential to increase length of hospitalization and decrease patient 
satisfaction.  Moreover, otolaryngology patients often undergo very painful and functionally debilitating 
surgeries of the head and neck and are at increased risk for postoperative pain due to both the 
neuroanatomy of this region and the need to swallow postoperatively8.   Postoperative pain control in this 
population is critical for patient satisfaction and an expedited return to a functional swallowing status. 
 
Within the field of pain management is the practice of multimodal pain therapy.  This strategy employs 
non-narcotic medications working synergistically to improve pain control, decreasing narcotic medication 
requirements and narcotic-associated side effects8.  Studies utilizing multimodal pain regimens 
demonstrate such benefits in acute postoperative pain management2-5.  Gabapentin is a non-narcotic 
pain medication often used in multimodal pain regimens that has been shown to reduce acute 
postoperative pain.  
1.2 Investigational Agent 
Gabapentin is a non-narcotic medication developed to target neuropathic pain1.  It is an amino acid 1-
(aminomethyl)cyclohexaneacetic acid that is structurally related to the inhibitory neurotransmitter GABA 
(gamma-aminobutyric acid), without modifying the binding, metabolism, or elimination of GABA.  In vitro 
studies have demonstrated gabapentin binding sites in the rat brain, but the functional implication and the 
mechanism of its analgesic and anticonvulsant activity remains unknown in humans.  The oral 
bioavailability of gabapentin decreases as dose increases.  Its half-life is 5-7 hours, and it is eliminated by 
renal excretion without chemical alteration.  Dose adjustments are recommended for creatinine clearance 
less than 30 mL/min.  It is FDA approved since 1993 for post-herpetic neuralgia and epilepsy, and has 
been widely applied in neuropathic pain management.  It is also frequently used for acute postoperative 
pain, and meta-analysis of randomized controlled trials shows it to be an effective pain management 
strategy in postoperative patients.  The major adverse reactions reported were, in descending frequency, 
dizziness, sedation, asthenia, diarrhea, dry mouth, constipation, nausea, and vomiting 23. 
1.3 Clinical Data to Date 
Numerous randomized controlled trials demonstrated that gabapentin effectively reduced narcotic use 
and improved subjective pain in various surgical populations, such as gynecology-oncology and 
orthopedic surgery9-15.  Meta-analyses of these pooled trials reported an overall trend toward improved 
pain control and decreased postoperative narcotic use with gabapentin, despite the heterogeneity of the 
included studies6,16-19.  A small number of studies have examined the use of gabapentin in postoperative 


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otolaryngology patients and suggest a potential benefit in improving postoperative pain control after 
thyroidectomy, endoscopic sinus surgery, oral cavity resection with reconstruction, and tonsillectomy9-15. 
Most of the studies demonstrated an improvement with only one preoperative dose.  To date, no 
randomized control trials have been conducted with gabapentin use in adult otolaryngology patients 
undergoing all types of head and neck mucosal surgeries, which is an at-risk population for high levels of 
postsurgical pain. 
1.4 Dose Rationale and Risk/Benefits 
Dosing regimen of gabapentin will be 300 mg PO preoperatively, followed by 300 mg BID until POD 2 or 
the day of discharge, whichever comes first. Note that on the morning of POD3 at 7am, a VAS will be 
obtained to reflect the POD 2 7pm dose.  The liquid formulation will be used postoperatively given the 
possibility of dysphagia or postoperative NPO status potentially requiring a feeding tube.  The optimal 
dosage for gabapentin in acute postoperative pain is unknown.  Recommended gabapentin regimen for 
treatment of post-herpetic neuralgia is a 300 mg/day on day 1, 300 mg BID on day 2, 300 mg TID on day 
3, and subsequently up-titrated as needed to 600 mg TID23.  Prior studies using gabapentin for 
postoperative pain control in otolaryngology patients have primarily administered a single preoperative 
dose ranging from 100 mg to 1200 mg9-15. Data was inconsistent as some studies showed efficacy at low 
dosages and some showed no difference at high dosages, and an optimal dose regimen remains to be 
determined.  For this study a relatively low dosage was chosen to minimize sedation side effects, as 
included participants are likely to be gabapentin-naïve.  The perioperative BID dosing period was chosen 
to better elucidate the effects of gabapentin in the acute, postoperative period, as many head and neck 
mucosal resections cause significant pain for several days after the procedure.  The majority of head and 
neck inpatient stays are between 2-3 days, with some staying as short as 1 day and some as long as a 
few weeks.  At this dose and schedule, gabapentin side effects are minimized so that subject risk is also 
minimized without compromising medication analgesic abilities.  Collaboration with the inpatient pain 
management team also supports the expectation that this dose and time regimen will be effective and will 
minimize side effects.  
 
Post-operative swallow results will be collected from the medical record on those patients receiving post 
op swallow therapy per routine care.  The post-operative swallow evaluation will be observational, based 
solely on the discretion of the surgeon and is not required per the research protocol.  
2 Study Objectives 
This investigation is a quality improvement initiative designed to elucidate the benefit of gabapentin in 
pain management in subjects undergoing surgical resection of head and neck mucosal surfaces. 
 
Primary Objective 
To assess the efficacy of gabapentin on decreasing narcotic requirements for treatment of acute 
postoperative pain in head and neck patients undergoing surgical resection of mucosal surfaces. 
 
Secondary Objectives 
To assess subjective pain scores and participant satisfaction with pain control.  
 
3 Study Design 
3.1 General Design 
This is a prospective, randomized, double-blind, placebo-controlled study with the intent of providing high 
quality and reproducible data.  The study subjects include adult otolaryngology patients over the age of 
18 years undergoing open or endoscopic/robotic resection involving the mucosal surfaces of the oral 
cavity, oropharynx, hypopharynx and larynx in a single tertiary academic center.  Participants are 
recruited from the otolaryngology head and neck cancer clinic during their preoperative visits.  The 
duration of subject participation includes the subsequent inpatient hospitalization following definitive 


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cancer resection up to two days after surgery.   Subjects will be given the placebo or gabapentin for up to 
two days post op or until discharge, whichever comes first.   
 
Potential subjects will be recruited from the patient population in the head and neck surgery clinic, 11th 
floor CAM, the center for outpatient health or at other outpatient or inpatient sites related to their pre-
surgical planning visits.  Eligible patients will be identified before their scheduled appointments via review 
of medical records in Allscripts by a study team member and approached either in the exam room during 
their scheduled appointment with the head and neck surgeons or afterwards via telephone call.  The 
study will be explained to them and a copy of the consent form will be provided after it has been signed.  
Patients will be reminded that participation is voluntary and will in no way affect their current or future care 
related to their head and neck health needs. Patients will be given time to ask questions and will have the 
option to consider participation and enroll at a subsequent appointment before their planned procedure. 
The consent process will take place in a private room.  Steps to avoid coercion include proper training in 
informed consent, private discussion rooms in which the surgeon is not present, and patients will be 
reassured that their care from their head and neck surgeon will not be affected by their decision to 
participate or to not participate.  Patients will be made aware that their postoperative care will not be 
limited by participation in this study, meaning that they will not be denied needed and appropriate narcotic 
pain medications simply because they are enrolled.  Written informed consent will be obtained prior to the 
start of research related procedures. 
 
 
 


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**Note that IV and PO or per tube morphine will be used in amounts equivalent to the dilaudid and oxycodone medications 
above if an allergy or intolerance to dilaudid or oxycodone exist. 
 
Subjects will present for their planned procedures to the pre-op surgery office and will be taken to the pre-
op holding area as per usual hospital procedure.  A study team member will meet the subject in the pre-
op holding area and will administer the pre-op medication approximately 1 hour prior to surgery start time. 
Patients will not be excluded if surgery start time is delayed past 1 hour.  An investigational pharmacist 
will deliver the medication appropriately labeled with patient name and study number to the pre-op 
holding area.  This oral administration is safe per consultation with the anesthesia faculty member of this 
project.  Additionally, on the day of surgery a study member will place pain medication orders in compass 
on hold for post op care.  These orders will be 1000mg of Tylenol PO or per tube Q6 hours (or Q12 hours 
if the patient has hepatic insufficiency), oxycodone 5-10mg Q4 hours PRN pain (5mg if pain less than or 
equal to 5/10, 10mg if greater than 5/10), and dilaudid 0.25-0.5mg Q2 hours PRN breakthrough pain 
(0.25mg if pain less than or equal to 5/10, 0.5mg if greater than 5/10).  Alternatives to these medications 
in case of allergy or intolerance is 1-2mg IV morphine Q2 hours PRN pain (1mg if pain less than or equal 
to 5/10, 2mg if greater than 5/10) and 7.5-15mg PO/PT liquid IR morphine Q4 hours PRN pain (7.5mg if 
pain less than or equal to 5/10, 15mg if greater than 5/10).  Additionally, the study team member will 
place the appropriate investigational drug order in compass.  The subject will be able to receive increases 
in pain medications as deemed appropriate by the inpatient treating physicians.  They will not have any 
limitations set on pain medications simply because they are involved in the study.  The subject will then 
proceed with surgery as planned. No alterations to intraoperative medications or anesthetic agents will be 
made based on study participation. 
 
The subject will return to the PACU after extubation.  If the subject had to remain intubated, he or she will 
be withdrawn from the study as he or she cannot complete pain scores while sedated. Additionally, if the 
subject is at any point during the study placed on alcohol withdrawal medication protocols, he or she will 
be withdrawn from the study.  The study team member administering the preoperative dose will remind 
anesthesia to use the same post-operative initial pain management options in the PACU at least initially, 
again with no restrictions on dose escalations that are needed.  The PACU can increase the dose of 
postoperative pain medications based on patient need and MD approval as per the usual PACU protocol 
without restriction based on a subject’s study participation.  Subjects will remain in the PACU per the 
usual protocol until the required level of alertness and clinical stability are reached for transfer, and their 
PACU medication sheet will be copied and added to their hard copy file for use later during 


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tabulation/data anaylsis of the pain meds they required The VAS score obtained after surgery will be 
completed 45 minutes to 1 hour after extubation in the PACU.  
 
Note that subjects must have completed surgery (extubated) by 5PM in order to receive the 7PM dose 
after their surgery.  Otherwise, this dose is to be skipped and the next dose administered will be at 7AM 
the next day.  VAS scores can still be obtained at 45 minutes to 1 hour postoperatively, however, even if 
the case finishes later than 5pm. On POD 1-2, subjects will be given BID medications at 7am and 7pm 
per the study protocol and VAS scores will be obtained prior to medication administration   A separate 
VAS will be obtained at 10am on POD1 and POD 2.  ON POD 3 a 7am VAS will be obtained but no study 
medication given. This last VAS concludes participation in the study.  Discharge surveys will be 
administered at this point if they have not been already (ie if the patient remained an inpatient for longer 
than 2 days postop).   
The investigational pharmacist will have delivered the medication dose in a properly labeled container to 
the 6200 inpatient floor prior to scheduled doses, and the medications will be stored in patient labeled 
bins in the locked medication refrigerator.  All VAS scores will be obtained with subject privacy optimized, 
including drawing the curtain in subject room to separate the sides of the room from any potential 
roommate.  Also, the research team member will not vocalize a subject’s status as a study patient.  VAS 
scores will be obtained at rest, with cough and following a swallowing gesture.  Scores are captured by 
providing the subject with a pen and asking the subject to mark the location of their pain on a line 
measuring 10cm during each phase of the VAS.   The scale is a validated tool that measures 10cm in 
size and is marked “no pain” on the far left and “worst pain” on the far right.  The subject marks their pain 
level on the scale and the study team member will measure with a ruler and record the resulting number 
in the study database.    
Subjects will fill out a discharge survey before they are discharged or at the completion of their 
participation to rate their satisfaction with their inpatient pain control.  This survey will be a hard copy 
labeled with study ID and the data will be entered into the study database.  All hard copy data will be 
stored in a locked cabinet accessible only to the study team.  At the end of the study, all hard copy data 
will be properly destroyed.   
 
Subjects will have 24/7 access to members of the study team should questions or concerns arise while 
they are actively participating in the study as well as up to 30 days after completion of the study.   
 
Note that study medication wrappers have patient names on them as a safety mechanism to make sure 
medications are given to the proper patient.  These wrappers and labels will be saved in the patient 
folders which are secured in a locked cabinet where only study team members have access.  Empty and 
unlabeled medication syringes will be discarded in the red biohazard bins inside patient rooms.  
3.2 Primary Study Endpoints 
The primary study endpoint is postoperative narcotic consumption.  Average daily narcotic use from 
postoperative admission to the last dose of pain medication on POD 2, or the day of discharge, whichever 
comes sooner, will be calculated. Total amount of narcotic use in morphine equivalents will be divided by 
the total hours of inpatient hospitalization, multiplied by 24 hours, to obtain the average daily narcotic 
consumption. 
3.3 Secondary Study Endpoints 
The secondary endpoints include (a) subject satisfaction with pain control, (b) VAS pain scores, (c) 
patient baseline pain perceptions (d) hospital length of stay, and (e) potential side effects of the 
medication.  
 
(a) Subject satisfaction with pain control will be captured in a survey administered at POD 2 after the 
AM dose administration, or after the AM dose administration on the day of discharge, whichever 
comes sooner.  Two of the survey questions will mirror those on the HCAPHS surveys, listed as 
followed (see attached “post-treatment questionnaire”): 
 
1. How often was your pain well controlled? 


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0) Never 
1) Sometimes 
2) Usually 
3) Always 
 
2. How often did the hospital staff do everything they could to help you with your pain? 
0) Never 
1) Sometimes 
2) Usually 
3) Always 
 
3. How satisfied are you with your overall pain control? 
0) Very dissatisfied 
1) Somewhat dissatisfied 
2) Neutral 
3) Somewhat satisfied 
4) Very satisfied 
 
4. Was there anything else that we could have done to make your pain control better during your 
inpatient stay? 
A point system is created with the sum of the numeric values assigned to questions 1-3 on a scale of 
0 to 10, with a score of 0-3 indicates overall dissatisfaction, 4 indicates neutrality, and 5-10 suggests 
overall satisfaction.  This will be analyzed as an ordinal variable. 
 
(b) VAS pain scores will be assessed 45min to 1 hour after surgery and then three times a day on 
POD 1-2 and once on POD 3, or until day of discharge, whichever comes sooner. A standardized 
VAS form will be given to subjects with verbal instruction to first “mark on the line the point that 
you feel represents your current pain level when you’re resting.”  This is followed by asking the 
subject to gesture swallowing and “mark another point on the line that represents your pain level 
when you swallow.”  Lastly, the subject will be asked to cough and to “mark the final point on the 
line that represents your pain when you cough.”  The study team member administering the test 
will annotate what each mark represents (rest, swallow, and cough).  The scale contains a 10-cm 
line from “no pain” on the left to “extreme pain” on the right (see “VAS form”).  The distance in 
centimeters from the left of the line to the center of the patient’s three marks will be recorded.  
The results from all available VAS scores for each subject will be averaged and included in the 
final analysis.  
 
(c) The subject’s belief in pain medication efficacy and pain tolerance will be assessed from a short 
survey obtained preoperatively during the office visit (see “pre-treatment questionnaire”). This 
includes the following questions: 
 
1. In the past, how effective are narcotic pain medications (such as morphine, Vicodin, Norco, 
Percocet, oxycodone, Dilaudid) at controlling your pain? 
0) Very ineffective 
1) Somewhat ineffective 
2) Somewhat effective 
3) Very effective 
 
2. In the past, how has your pain tolerance been? 
0) Very poor 
1) Somewhat poor 
2) Somewhat tolerant 
3) Very tolerant 


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3. Do you experience a significant amount of pain on a daily basis aside from the pain due to 
your current head and neck condition? 
1) Yes I do 
2) No I do not 
The results of these questions will be reported separately in the final analyses. 
 
(d) Hospital length of stay will be calculated for each subject. 
 
(e) During the VAS scores, study team members will also collect information about potential 
medication side effects, including those that are commonly associated with gabapentin or with 
narcotic medications.  
3.4 Primary Safety Endpoints 
The primary safety endpoints are the rate and severity of drug-related adverse events.  Adverse events 
will be monitored and recorded by study team members during subject inpatient stay.  These events will 
be reviewed by the principal investigator and categorized into “drug-related”, “likely drug-related”, and 
“unlikely drug-related.”  Any significant adverse events determined to be likely drug related will be 
reported to the OHRP within a 24 hour time period and stopping the study for the subject will be 
discussed.  A safety meeting will be held half way through the study with the PI and all involved faculty 
mentors to determine if an interim analysis is necessary, This analysis would be considered necessary if 
a significant number of adverse events likely related to the study medication were occurring, and an 
analysis to make sure the study was not causing harm to the treatment group was needed. 
4 Subject Selection and Withdrawal 
4.1 Inclusion Criteria 
 
Subjects undergoing definitive mucosal head and neck resection including oral cavity, 
oropharynx, larynx, and hypopharynx 
 
At least 1 night of planned inpatient stay 
4.2 Exclusion Criteria 
 
Incapable of giving informed consent 
 
Age < 18 
 
GFR < 30 
 
Allergy to gabapentin  
 
Baseline gabapentin or lyrica use 
 
Chronic opioid use for over 6 months 
4.3 Subject Recruitment and Screening 
Subjects will be recruited either in the outpatient head and neck clinic prior to their planned surgeries or 
over the phone after this clinic appointment by designated study team members.  Potentially eligible 
patients will be identified by study team members prior to their scheduled appointments via the outpatient 
medical records system.  Patient recruited by phone will be able to sign the informed consent prior to 
surgery either at a subsequent surgical planning visit or in the pre-op holding are on the day of surgery.  
Eligible subjects will be consented in a private setting and the study outline explained to the patient. 
Written informed consent will be obtained from those patients who wish to participate.  Patients may 
choose to think about study participation but will need to decide and provide written consent prior to the 
day of surgery, either at their subsequent preoperative anesthesia clinic appointment or medical 
oncology/radiation oncology appointments.  Study team members will be properly trained in the informed 
consent process.  


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4.4 Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
Subjects may be withdrawn from the study prior to the expected completion if they develop 
hypersensitivity reactions to the study drug, are unable to swallow all study drugs in the study period, or 
choose to withdrawal for other reasons.  They will also be withdrawn if they remain sedated or intubated 
after the surgery or are placed on alcohol withdrawal medication protocols, which also cause significant 
sedation.  Subjects without a feeding tube who are unable, or unwilling, to swallow medications after 
surgery will not be given a feeding tube to remain in the study.  A 20% dropout rate was anticipated and 
accounted for in the sample size calculation.  Subjects will be able to withdraw on a continual basis 
throughout their participation.  Withdraw can be requested either by the subject or by any team member if 
medical significant adverse reactions are observed.  All withdraws will be reviewed by the principle 
investigator.  No subject will be denied the ability to withdraw. The withdraw process will begin 
immediately when deemed necessary or when desired by the subject, and documentation of the reason 
and time of withdraw will be performed.   
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
Withdrawn subjects will be excluded in the final data analysis. The reasons for withdrawal will be 
recorded and reported separately in the study data outcomes. 
 
4.4.3 Definitions 
Subject withdraw: Withdraw is defined as a subject who signed the informed consent document and for 
whatever reason dropped out of the study before completion, whether by choice or by exclusion criteria 
(ie- staying intubated the night after surgery). 
 
Subject screen fail: A screen fail is defined as a subject who has been recruited to participate and 
approached but does not meet all inclusion criteria.  
 
5 Study Drug  
5.1 Description 
300mg of liquid gabapentin or an equal volume of placebo will be pre-packaged by the investigational 
pharmacist in a labeled medication syringe or in a marked bag with a capsule.  An unblinded study team 
member in charge of the randomization process will indicate to the pharmacy which subjects are to 
receive what medication.  The blinded study team members will not know which medication contains 
placebo or gabapentin.  
5.2 Treatment Regimen 
Subjects will receive either placebo or gabapentin 300 mg PO the preoperative holding area 
approximately 1 hour before their procedure is scheduled to begin.  This first dose will designate the day 
of their procedure as POD 0.  If the procedure ends late in the evening (ie not extubated before 5pm), and 
the subject is not able to receive the second POD 0 dose by 7 PM, then this second POD 0 dose will be 
skipped.   Participants will then receive either placebo or 300 mg of gabapentin BID POD 1- POD 2.  
Dosing will end either on POD 2 after the PM dose or on day of discharge after the AM dose, whichever 
comes first.  VAS scores will be collected 45 minutes- 1 hour post extubation on POD as well as TID on 
POD 1-2 and one time at 7am on POD 3 (see above protocol flowsheet).  


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5.3 Method for Assigning Subjects to Treatment Groups 
After a subject consents to study, the unblinded data manager will randomize the subject into active or 
placebo group and assigned an enrollment ID.  The enrollment ID is given to any subject who signs 
consent. If the subject then proceeds to start the study and receive a medication dose, they will also be 
given a subject ID which reflects their randomization group.  The study ID reflects randomization while the 
enrollment ID is used to enter them into OnCore and track their consent.  
5.4 Preparation and Administration of Study Drug 
The Investigational Pharmacist will mix and prepare the study medications necessary for each subject.  A 
pharmacist will deliver the medication to the preop holding unit or the floor and a designated study team 
member will administer it.  Please see section 5.7 below for mixing and packaging details. Contact 
information for the pharmacy for this project is pharmacist Kathryn Vehe at 314-795-7286. 
 
Inpatient pharmacists will be responsible for delivering the medication to the floor prior to the AM dose 
and to the PM dose, as well as will deliver the medication to the pre-op holding area prior to a subject’s 
procedure. Formal training for all study team members who will be administering the study drug or 
obtaining the VAS pain scores is required prior to subject interaction. 
5.5 Subject Compliance Monitoring 
The study team members will directly administer each study medication dosage during the study period 
and record adherence to study protocol.  If a dose is missed during this period, the subject will remain in 
the study through the completion of the protocol.  The decision to include data from subjects with missed 
doses will be made at the discretion of the principle investigator and statistician at the conclusion of the 
study.   Data integrity will be maintained such that subjects who are excluded for missed doses will be 
consistent among cases.  
5.6 Prior and Concomitant Therapy 
Every subject will have standard postoperative narcotic medications made available: 
 IV Dilaudid 0.25-0.5mg q2h PRN breakthrough pain (pain equal to or less than 5/10 will get 
0.25mg and pain >5/10 will get 0.5mg).  
 PO/PT oxycodone 5-10mg q4h PRN pain (pain equal to or less than 5/10 will get 5mg, and pain 
greater than 5/10 will get 10mg).  
 PO/PT acetaminophen 1000mg q6h for pain in non-cirrhotic patients, and 1000mg q12h in 
cirrhotic patients 
 Morphine IV and PO liquid equivalents will be substituted in cases of oxycode or dilaudid 
allergies. 1-2mg IV morphine Q2 hours PRN will be substituted for 0.25-0.5mg dilaudid for 
breakthrough pain (pain equal to or less than 5/10 will get 1mg and pain >5/10 will get 2mg).   
PRN liquid IR morphine 7.5-15mg will be substituted Q4 hours for oxycodone PRN for pain (pain 
equal to or less than 5/10 will get 7.5mg, and pain greater than 5/10 will get 15mg) 
 Study team members will place an order in compass for study investigation drug administration 
as per BJC protocol for investigational drug use.   
 
These medications can be up-titrated as needed at the discretion of the physicians managing the 
patient’s care as part of the routine postoperative management. 
5.7 Packaging 
 Study medications will be in liquid or capsule form.  Gabapentin comes as a standard liquid form 
of 250mg/5ml. Capsules will be used for the pre-operative dose, and will come as single capsules 
in bags labeled with study ID and name.  For post-operative doses, 6ml of either gabapentin or 
placebo will be packaged into a brown 20ml plastic syringe.  Each syringe will have the subject 
name and study ID on it.  The pharmacy will be made aware of all upcoming study subjects and 
will prepare the medications approximately 24 hours prior to administration, and will store these at 


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4 degrees Celsius.  The medications will be stored prior to dosing on the floor in a locked fridge in 
patient specific compartments, as per the floor medication protocol.  
5.8 Blinding of Study Drug 
The study team members administering the medications will be blinded towards whether a subject 
receives the study drug or the placebo.  The data manager who does not participate in data collection or 
have direct subject interaction, as well as the pharmacist preparing the medications, will be unblinded. 
5.9 Receiving, Storage, Dispensing and Return 
5.9.1 Receipt of Drug Supplies 
Investigational pharmacists will be responsible for medication delivery prior to planned doses.  They will 
be alerted to upcoming procedures that involve study subjects.  They will be responsible for delivering the 
medication to the inpatient floor and in the preoperative holding area.  Any damaged or unusable study 
drug in a given shipment will be documented in the study files and discarded. 
5.9.2 Storage 
Medications will be stored by the investigational pharmacy in a designated, locked area at 4 degrees 
Celsius. They will be stored on the inpatient floor in a locked, 4 degree fridge in patient specific 
compartments per the floor medication storage protocols.  
5.9.3 Dispensing of Study Drug 
The study team members administering the medications will receive the medication from the 
investigational pharmacist.  They will then administer the medication and record the time of administration 
and the subject identification number in the subject’s study flow sheet (“Gaba project subject study flow 
chart” attached). 
5.9.4 Return or Destruction of Study Drug 
At the completion of the study, there will be a final reconciliation of medications consumed.  This 
reconciliation will be logged on the drug reconciliation form, signed and dated.  Any discrepancies noted 
will be investigated, resolved, and documented.  Medication syringes will be discarded in the red 
biohazard containers in accordance with hospital policy and documented in the study files. Any labels or 
bags with patient names will be discarded in the shred bins on the 6200 floor or in the preop holding unit.  
 
6 Study Procedures 
The study procedures are outlined below and represented in the attached “Gaba project subject study 
flow chart”.  
 
Clinic Visit 
 
Consent. 
 
Pre-treatment questionnaire. 
 
Randomization group will be assigned by the study data manager after she is notified of subject 
agreement to participate. 
Day of Surgery 
 
One dose of study drug will be administered preoperatively according to subject’s randomization 
group approximately 1 hour prior to procedure start time.  The coordinator administering the 
medication will tape a study reminder sheet for anesthesia to the chart and will place an order in 
the chart that allows the participant to take the preop medication dose, and the RN to chart this 
dose as a study medication.  


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 
Standard pain medications orders will be provided. Morphine will be used as a substitute for 
dilaudid or oxycodone allergies or intolerances. These will be up-titrated as needed per discretion 
of service residents and attending physicians. 
 
One VAS score will be obtained 45 minutes to 1 hour postoperatively regardless of extubation 
time. 
 
One postoperative dose of study drug and VAS will be administered at 7pm if subjects are 
extubated by 5PM 
Post-Operative Day (POD) 1-2 
 
TID VAS scores will be obtained, two of which will be prior to drug administrations. 
 
BID study drug administration will be conducted according to subject’s randomization groups. 
POD 3  
 
POD 3 VAS at 7am will be obtained.  
POD 3 or Day of Discharge 
 
Post-treatment pain satisfaction questionnaire will be conducted either after the AM dose on POD 
3 or on date of discharge, whichever comes sooner. 
7 Statistical Plan 
7.1 Sample Size Determination 
Sample size calculations were performed based on prior studies with gabapentin use in otolaryngology 
patients undergoing thyroidectomy21.  A study by Al-Mujadid et al in a population of patients undergoing 
elective thyroidectomy reported that total morphine consumption in the placebo group in the first 24 hours 
post surgery required a mean of 29.5mg of morphine with a standard deviation of 9.9mg.  Assuming that 
this magnitude of effect variability will hold true in this project population, it is estimated that 46 subjects 
per group (total n=92) will be needed to detect with an 80% power at the 2-sided alpha level of 0.05 a 
difference of 20% or greater in average morphine dose (effect size d=0.6) between the placebo and 
gabapentin groups.  Assuming a 20% drop out rate, 116 subjects will be enrolled in this study.  The 
volume of eligible subjects for this study is predicted to meet the calculated sample size within two years 
of study start time. A review of surgical procedures meeting inclusion criteria performed over a sample 
three month time frame ranged from 12 to 17 procedures a month.  
Note that IV morphine equivalents will be used rather than PO.  
7.2 Statistical Methods 
Descriptive statistics will be used to describe distribution of demographics. Bivariate analysis using 
independent samples t-test for continuous variables and chi square test for categorical variables will be 
used to compare distribution of characteristics between treatment groups to ensure successful 
randomization. 
Note that in discrepancies of data between reports, such as pack years smoked by a patient, an average 
of the reported amounts will be used to ensure consistency between data reporting fluctuations.  
 
The primary and secondary outcome measures will be compared between the two treatment groups via 
bivariate analyses.  In addition, a General Linear Model (GLM) approach will be used to explore the 
impact of gabapentin as compared to placebo on each of the outcomes of interest after controlling for 
potential cofounders that were unevenly distributed between the two groups.  The estimated mean 
difference and 95% confidence interval will be reported. 


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7.3 Subject Population(s) for Analysis 
Protocol-compliant subjects who received all study drugs up to the conduction of post-treatment 
questionnaire will be included for analysis.  Subjects with missed medication doses will go on to complete 
the protocol, and per the discretion of the principle investigator and statistician may or may not be 
included in the data analysis.  Data integrity will be maintained such that subjects who are excluded for 
missed doses will be consistent among cases. 
 
8 Safety and Adverse Events 
8.1 Definitions 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
 Unexpected in nature, severity, or frequency  (i.e. not described in study-related documents such 
as the IRB-approved protocol or consent form, the investigators brochure, etc) 
 Related or possibly related to participation in the research (i.e. possibly related means there is a 
reasonable possibility that the incident experience, or outcome may have been caused by the 
procedures involved in the research) 
 Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm). 
 
 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study.  Intercurrent illnesses or injuries that occur during the study period will be 
regarded as adverse events (meaning that the event does not necessarily have to be likely related to the 
study drug to be considered an adverse event).  However, not all adverse events will meet criteria for 
reporting.  Abnormal results of diagnostic procedures will be reported as adverse events if the 
abnormality: 
 results in study withdrawal 
 is associated with a serious adverse event (see definition below) 
 is associated with clinical signs or symptoms that are considered significant and likely related to 
study participation  
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 
 
Serious Adverse Event 
Adverse events are classified as serious, moderate or mild.  .  A serious adverse event is any AE that is:  
 fatal 
 life-threatening 
 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event 
 
Mild and Moderate adverse events: 
A moderate adverse event is one that requires a medical intervention such as medication for nausea, but 
that does not cause permanent clinical harm and that does resolve in a reasonable amount of time. 
 
A mild adverse event is one that causes mild clinical effect and may or may not require medical 
intervention. It is expected to resolve completely with observation or medical treatment.  
 
 
Adverse Event Reporting  


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The study period during which adverse events that are deemed reportable will be the period from the day 
of surgery to the end of the study, which is POD 3 or sooner if discharge is sooner than POD 3. Ideally, 
these events will be reported to the PI within 24 hours of their occurrence.  Serious AE must be reported 
within 24 hours, however. Additionally, subjects will be provided with contact information for the study 
member that is in charge of adverse event follow up (Melanie Townsend, PI).  They will be instructed to 
contact this person with questions related to the study, adverse events or side effects experienced after 
discharge so that the study members can be alerted to any events that may be related to the medication. 
Any severe adverse events or moderate events thought likely to be related to the study medication that 
are reported to the PI during this 30 day window will be recorded.    Adverse events that occur during the 
inpatient study period and are significant/severe as defined above or that are unusual will be required to 
be reported in the adverse events log. The PI will be made aware of all of these events immediately after 
they occur.    All adverse events regardless of grade and attribution will be collected.  The PI will sign off 
on all adverse events that are recorded in the adverse event log.  
 
For all severe AEs or AEs that are unexpected and thought likely related to the study medication, an IRB 
reportable event form will be submitted. All adverse events, whether mild, moderate or severe, will be 
reviewed at the safety meeting by all team members and faculty advisors to ensure that proper reporting 
has occurred.   
 
 
Post-study Adverse Event 
All unresolved adverse events will be followed by the investigator until the events are resolved, the 
subject is lost to follow-up, or the adverse event is otherwise explained.  At the last scheduled visit, the 
investigator will instruct each subject to report any subsequent event(s) that the subject, or the subject’s 
personal physician, believes might reasonably be related to participation in this study in the 30 days 
window follow discharge.   
8.2 Eliciting Adverse Events from Subjects  
At each interaction with the subject, the investigator will seek information on adverse events by specific 
questioning and, as appropriate, by examination.  Information on all adverse events will be recorded 
immediately in the data recording form that is used to record subject data at each interaction.  Reporting 
of these events is as outlined above.  Specific side effects that will be elicited at each interaction include 
nausea, vomiting, dizziness and sedation.   
 
8.3 Unblinding Procedures 
For this study only the data manager and pharmacy will be unblinded to the study drug and placebo 
assignments.  Unblinding of the rest of the study investigators will occur after assurance that data 
collection has completed.  If any subject data is intentionally or unintentionally unblinded, the event will be 
documented in detail in the study documents within 48 hours.  Any unblinding that occurs during the study 
period for an individual participant will result in exclusion of that participant’s data from final analysis.  
Study investigators must report unblinding to the PI within a 24 hour time period and must document the 
event.  Subjects will immediately be made aware of the unblinding and will be withdrawn from completing 
the protocol.  
Stopping Rules  
The study will be terminated prematurely if 50% or more of the subjects receiving study drug (gabapentin 
or placebo) experience significant adverse events as defined above in section 8.1.  The study will not be 
prematurely stopped if subjects experience less significant medication side effects, specifically nausea, 
vomiting, dizziness and sedation.  A review of adverse events will be conducted at 25% by the PI and at 
50% enrollment by the entire team to ensure that they are properly tracked.  


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8.4 Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study.  This safety 
monitoring will include careful assessment and appropriate reporting of adverse events as noted above, 
as well as the construction and implementation of a site data and safety-monitoring plan (see section 10 
Monitoring).  Medical monitoring will include a regular assessment of the number and type of serious 
adverse events.   A safety meeting will be held half way through enrollment as described above, 
9 Data Handling and Record Keeping 
9.1 Confidentiality 
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).   
Source data will be kept primarily in the electronic forms using REDCap for data collection.  Paper forms 
including the original consents, questionnaires, VAS pain score sheets, adverse event reporting forms 
etc. will be kept in a locked cabinet that only study team members have access to.  At the conclusion of 
the study, after data has been entered into a password protected spread sheet, these records will be 
destroyed in the proper manner in shred it bins where patient information is normally placed.  The official 
source document and case report form for this study will be the REDCap database. 
 
 
All research records will be maintained in the Outcomes Office, 8th floor McMillan for 7 years after study 
completion per WU record retention policy.  
 
10 Study Monitoring 
10.1 Study Monitoring Plan 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, an 
independent Data and Safety Monitoring Committee (DSMC) will be specifically convened for this trial to 
review toxicity data at least every 6 months.  A DSMC will consist of no fewer than 3 members including 2 
clinical investigators and a biostatistician.  Like investigators, DSMC members are subject to the 
Washington University School of Medicine policies regarding standards of conduct. Individuals invited to 
serve on the DSMC will disclose any potential conflicts of interest to the trial principal investigator and/or 
appropriate university officials, in accordance with institution policies. Potential conflicts that develop 
during a trial or a member’s tenure on a DSMC must also be disclosed.  
 
The DSM report will be prepared by the study statistician with assistance from the study team, will be 
reviewed by the DSMC, and will be submitted to the Quality Assurance and Safety Monitoring Committee 
(QASMC).  This report will include: 
 
 
HRPO protocol number, protocol title, Principal Investigator name, data coordinator name, 
regulatory coordinator name, and statistician 
 
Date of initial HRPO approval, date of most recent consent HRPO approval/revision, date of 
HRPO expiration, date of most recent QA audit, study status, and phase of study 
 
History of study including summary of substantive amendments; summary of accrual suspensions 
including start/stop dates and reason; and summary of protocol exceptions, error, or breach of 
confidentiality including start/stop dates and reason 
 
Study-wide target accrual and study-wide actual accrual  
 
Protocol activation date  
 
Average rate of accrual observed in year 1, year 2, and subsequent years  
 
Expected accrual end date and accrual by cohort 


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 
Objectives of protocol with supporting data and list the number of participants who have met each 
objective 
 
Measures of efficacy 
 
Early stopping rules with supporting data and list the number of participants who have met the 
early stopping rules 
 
Summary of toxicities separated by cohorts with the number of dose-limiting toxicities indicated 
 
Abstract submissions/publications 
 
Summary of any recent literature that may affect the safety or ethics of the study 
 
Further DSMC responsibilities are described in the DSMC charter. 
 
The study principal investigator and coordinator will monitor for serious toxicities on an ongoing basis. 
Once the principal investigator or coordinator becomes aware of an adverse event, the AE will be 
reported to the HRPO and QASMC according to institutional guidelines (please refer to Section 7.0). 
 
Refer to the Washington University Quality Assurance and Data Safety Monitoring Committee Policies 
and Procedures for full details on the responsibilities of the DSMC at https://siteman.wustl.edu/wp-
content/uploads/2015/10/QASMC-Policies-and-Procedures-03.31.2015.pdf 
11 Medication processing  
 
11.1 Medication Processing 
All unused medications will be picked up from the pharmacy within 12 hours of the time they are 
determined to be not needed or not used.  The pharmacy will be alerted in real time that the medication 
was not needed so that they can expect to pick it up.  A confirmation communication will be sent to the 
study team once the medication is retrieved to ensure that it is properly picked up. 
12 References 
1. Chang C.Y., Challa C.K., Shah J., Eloy J.D. Gabapentin in acute postoperative pain management.  
BioMed Research International Vol. 2014.  2014.  
2. Rafiq, Sulman, et al. "Multimodal analgesia versus traditional opiate based analgesia after cardiac 
surgery, a randomized controlled trial." J. Cardiothorac. Surg 10 (2014): 1749-8090. 
3. Kehlet H, Jensen TS, Woolf CJ: Persistent postsurgical pain: risk factors and prevention.  Lancet 
2006 May 13, 367(9522):1618-1625.  
4. Kehlet H: Multimodal approach to postoperative recovery. Curr Opin Crit Care 2009 Aug, 15(4):355-
358.  
5. Kong VK, Irwin MG: Gabapentin: a multimodal perioperative drug? Br J Anaesth 2007 Dec, 
99(6):775-786.  
6. Tiippana EM, Hamunen K, Vesa KK, Kalso E. Do surgical patients benefit from perioperative 
gabapentin/pregabalin? A systematic review of ef fi cacy and safety. Anesth Analg. 2007;104(6): 
1545–56. 
7. Clarke H, Bonin RP, Orser BA, Englesakis M, Wijeysundera DN, Katz J. The prevention of chronic 
postsurgical pain using gabapentin and pregabalin: A combined systematic review and meta-analysis. 
Anesth Analg. 2012;115:428–42 
8. Levine, Adam I., Satish Govindaraj, and Samuel DeMaria, eds. Anesthesiology and Otolaryngology. 
Springer, 2013. 
9. Lee J.H., Lee H.K., Chun N.H., So Y., Lim C.Y.  The prophylactic effects of gabapentin on 
postoperative sore throat after thyroid surgery.   Korean Journal of Anesthesiology 2013 64:2 (138-
142). 
10. Mohammed M.H., Fahmy A.M., Hakim K.Y.K. Preoperative gabapentin augments intraoperative 
hypotension and reduces postoperative opioid requirements with functional endoscopic sinus surgery. 
Egyptian Journal of Anaesthesia 2012 28:3 (189-192). 


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11. Ahn S.H., Lee J.H., Min K.T. The prophylactic effects of gabapentin on postoperative sore throat after 
thyroid surgery.  European Journal of Anaesthesiology 2012 29 SUPPL. 50 (202). 
12. Chiu T.W., Leung C.C.H., Lau E.Y.K., Burd A. Analgesic effects of preoperative gabapentin after 
tongue reconstruction with the anterolateral thigh flap. Hong Kong Medical Journal 2012 18:1 (30-34)  
13. Kazak Z., Mortimer N., Mekerci S. Single dose of preoperative analgesia with gabapentin (600 mg) is 
safe and effective in monitored anesthesia care for nasal surgery. European Archives of Oto-Rhino-
Laryngology 2010 267:5 (731-736).  
14. Jeon E.-J., Park Y.-S., Park S.S., Lee S.-K., Kim D.-H. The effectiveness of gabapentin on post-
tonsillectomy pain control. European Archives of Oto-Rhino-Laryngology 2009 266:10 (1605-1609). 
15. Turan A., Memi; D., Karamanlio;lu B., Yaiz R., Pamuk; Z., Yavuz E. The analgesic effects of 
gabapentin in monitored anesthesia care for ear-nose-throat surgery.  Anesthesia and Analgesia 
2004 99:2 (375-378). 
16. Hurley RW, Cohen SP, Williams KA, Rowlingson AJ, Wu CL. The analgesic effects of perioperative 
gabapentin on postoperative pain: A meta-analysis. Reg Anesth Pain Med. 2006;31:237–47. 
17. Peng PW, Wijeysundera DN, Li CC. Use of gabapentin for perioperative pain control—A meta-
analysis. Pain Res Manag. 2007;12:85–92. 
18. Seib RK, Paul JE. Preoperative gabapentin for postoperative analgesia: A meta-analysis. Can J 
Anaesth. 2006;53:461–9. 
19. Clivatti J., Sakata R.K., Issy A.M. Review of the use of gabapentin in the control of postoperative 
pain.  Revista Brasileira de Anestesiologia 2009 59:1 (87-98). 
20. Schmidt, Peter C., et al. "Perioperative Gabapentinoids: Choice of Agent, Dose, Timing, and Effects 
on Chronic Postsurgical Pain." Survey of Anesthesiology 58.2 (2014): 96-97. 
21. Al-Mujadid, Hussain, et al. Preemptive gabapentin reduces postoperative pain and opioid demand 
following thyroid surgery. Canadian Journal of Anesthesia. March 2006, Volume 53, Issue 3, pp 268-
273. 
22. Sally L. Collins, R. Andrew Moore, Henry J. McQuay.  The Visual Analogue Scale: what is moderate 
pain in millimeters? Pain (Impact Factor: 5.21). 09/1997; 72(1-2):95-7. 
23. Accessfda.gov. Keyword “gabapentin”. PDF title: Neurontin. Parke-Davis Division of Pfizer Inc, NY, 
NY 10017.  April 2009.   
  


The effect of gabapentin on perioperative pain control among head and 
neck surgery patients 
 
NCT# NCT02926573 
 
 
Document Version Date:  03/18/2017 
 
IRB Approval Date:  03/20/2017 


 
CONFIDENTIAL 
 
CLINICAL RESEARCH PROTOCOL 
 
 
 
 
 
 
 
 
THE EFFECT OF GABAPENTIN ON PERIOPERATIVE PAIN 
CONTROL AMONG HEAD AND NECK SURGERY PATIENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Initial version: 3/31/2016 
Amended: 
[7/31/2016] 
Amended: 
[12/1/2016] 
Amended:  
[1/20/17] 
Amended:           [2/10/17] 
Amended            [2/20/17] 
Amended            [3/18/17] 


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Table of Contents 
 
STUDY SUMMARY ...................................................................................................................................... 1 
1 
INTRODUCTION .................................................................................................................................. 2 
1.1 
BACKGROUND ................................................................................................................................ 2 
1.2 
INVESTIGATIONAL AGENT ................................................................................................................ 2 
1.3 
CLINICAL DATA .............................................................................................................................. 2 
1.4 
DOSE RATIONALE AND RISK/BENEFITS ............................................................................................ 3 
2 
STUDY OBJECTIVES ......................................................................................................................... 3 
3 
STUDY DESIGN ................................................................................................................................... 3 
3.1 
GENERAL DESIGN .......................................................................................................................... 3 
3.2 
PRIMARY STUDY ENDPOINTS .......................................................................................................... 6 
3.3 
SECONDARY STUDY ENDPOINTS ..................................................................................................... 6 
3.4 
PRIMARY SAFETY ENDPOINTS ......................................................................................................... 8 
4 
SUBJECT SELECTION AND WITHDRAWAL .................................................................................... 8 
4.1 
INCLUSION CRITERIA ...................................................................................................................... 8 
4.2 
EXCLUSION CRITERIA ..................................................................................................................... 8 
4.3 
SUBJECT RECRUITMENT AND SCREENING ....................................................................................... 8 
4.4 
EARLY WITHDRAWAL OF SUBJECTS................................................................................................. 9 
4.4.1 
When and How to Withdraw Subjects ..................................................................................... 9 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects .......................................................... 9 
5 
STUDY DRUG ...................................................................................................................................... 9 
5.1 
DESCRIPTION ................................................................................................................................. 9 
5.2 
TREATMENT REGIMEN .................................................................................................................... 9 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ....................................................... 10 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ................................................................... 10 
5.5 
SUBJECT COMPLIANCE MONITORING ............................................................................................. 10 
5.6 
PRIOR AND CONCOMITANT THERAPY ............................................................................................. 10 
5.7 
PACKAGING ................................................................................................................................. 10 
5.8 
BLINDING OF STUDY DRUG ........................................................................................................... 11 
5.9 
RECEIVING, STORAGE, DISPENSING AND RETURN .......................................................................... 11 
5.9.1 
Receipt of Drug Supplies ....................................................................................................... 11 
5.9.2 
Storage .................................................................................................................................. 11 
5.9.3 
Dispensing of Study Drug ...................................................................................................... 11 
5.9.4 
Return or Destruction of Study Drug ..................................................................................... 11 
6 
STUDY PROCEDURES ..................................................................................................................... 11 
7 
STATISTICAL PLAN ......................................................................................................................... 12 
7.1 
SAMPLE SIZE DETERMINATION ...................................................................................................... 12 
7.2 
STATISTICAL METHODS ................................................................................................................ 12 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ....................................................................................... 12 
8 
SAFETY AND ADVERSE EVENTS ................................................................................................... 13 
8.1 
DEFINITIONS ................................................................................................................................ 13 
8.2 
RECORDING OF ADVERSE EVENTS ................................................................................................ 14 
8.3 
UNBLINDING PROCEDURES ........................................................................................................... 14 
8.4 
MEDICAL MONITORING ................................................................................................................. 15 
9 
DATA HANDLING AND RECORD KEEPING ................................................................................... 15 
 


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10 
STUDY MONITORING ....................................................................................................................... 15 
10.1 
STUDY MONITORING PLAN ............................................................................................................ 15 
11. Medicaiton processing ............................................................................................................ 15 
13 
REFERENCES ................................................................................................................................... 16 
 
 


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List of Abbreviations 
 
 
HCAHPS- Hospital Consumer Assessment of Healthcare Providers and Systems 
 
PRC-Professional Research Consultants  
 
FDA – Food and Drug Administration 
 
VAS – Visual Analog Scale 
 
POD – post-operative day 
 
 
 
 
 
 
 
 


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Study Summary 
Title 
The effect of gabapentin on perioperative pain control among head and neck 
surgery patients 
Short Title 
Gaba RCT 
Protocol Number 
1.5 (fifth amended version) 
Phase 
Phase 4 
Methodology 
Prospective randomized double-blind controlled trial  
Study Duration 
2 years 
Study Center(s) 
Barnes Jewish Hospital 
Objectives 
Determine the effectiveness of gabapentin for reducing narcotic requirements 
and subjective pain scores in postoperative head and neck mucosal cancer 
patients.  Determine the ability of gabapentin to improve patient satisfaction 
with pain management. Track inpatient length of stay.  
Number of Subjects 
120 
Diagnosis and Main 
Inclusion Criteria 
Adult head and neck patients undergoing oral cavity, oropharynx, larynx and 
hypopharynx resection (mucosal head and neck surgeries) 
Study Product, Dose, 
Route, Regimen 
Gabapentin liquid by mouth or Per Tube 300mg BID vs placebo 
Duration 
of 
administration 
Day of surgery and up to three days post operatively depending on the hospital 
stay.   
Reference therapy 
Placebo 
Statistical 
Methodology 
Bivariate analysis using independent samples t-test for continuous variables 
and chi square test for categorical variables will be used to compare between 
treatment groups 
 


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1 Introduction 
This document is a protocol for a human research study to be conducted according to US and 
international standards of Good Clinical Practice compliant to all associated Federal and applicable local 
and University research requirements, approved by the Institutional Review Board.  
1.1 Background 
High-quality healthcare is accessible, safe, efficient, patient-centered and imperative for good treatment 
outcomes.  In this era of healthcare reform, patient satisfaction has increasingly become an important 
metric of hospital performance.  The Medicare Hospital Value Based Purchasing Program utilizes patient 
reported satisfaction scores as a reflection of the quality of care delivered by hospital systems and 
clinician teams.  The scores resulting from these reports are integrated into the formula with which 
hospitals are reimbursed for Medicare patients. 
 
An important patient-physician interface in quality healthcare is the treatment of pain, and the treatment of 
acute postoperative pain is particularly relevant for surgical specialties.  Effective management of 
postoperative pain increases patient satisfaction, reduces hospital costs, reduces postoperative morbidity 
and shortens hospitalizations8.  HCAHP and PRC data from the Barnes Jewish Hospital otolaryngology 
inpatient unit reveals that postoperative otolaryngology patient satisfaction with pain control is routinely 
lower than the 75th percentile of all hospitals nationally surveyed.  Traditionally, pain regimens rely heavily 
on the use of narcotics, which are associated with nausea, vomiting, delirium, and decreased bowel 
motility.  These side effects have the potential to increase length of hospitalization and decrease patient 
satisfaction.  Moreover, otolaryngology patients often undergo very painful and functionally debilitating 
surgeries of the head and neck and are at increased risk for postoperative pain due to both the 
neuroanatomy of this region and the need to swallow postoperatively8.   Postoperative pain control in this 
population is critical for patient satisfaction and an expedited return to a functional swallowing status. 
 
Within the field of pain management is the practice of multimodal pain therapy.  This strategy employs 
non-narcotic medications working synergistically to improve pain control, decreasing narcotic medication 
requirements and narcotic-associated side effects8.  Studies utilizing multimodal pain regimens 
demonstrate such benefits in acute postoperative pain management2-5.  Gabapentin is a non-narcotic 
pain medication often used in multimodal pain regimens that has been shown to reduce acute 
postoperative pain.  
1.2 Investigational Agent 
Gabapentin is a non-narcotic medication developed to target neuropathic pain1.  It is an amino acid 1-
(aminomethyl)cyclohexaneacetic acid that is structurally related to the inhibitory neurotransmitter GABA 
(gamma-aminobutyric acid), without modifying the binding, metabolism, or elimination of GABA.  In vitro 
studies have demonstrated gabapentin binding sites in the rat brain, but the functional implication and the 
mechanism of its analgesic and anticonvulsant activity remains unknown in humans.  The oral 
bioavailability of gabapentin decreases as dose increases.  Its half-life is 5-7 hours, and it is eliminated by 
renal excretion without chemical alteration.  Dose adjustments are recommended for creatinine clearance 
less than 30 mL/min.  It is FDA approved since 1993 for post-herpetic neuralgia and epilepsy, and has 
been widely applied in neuropathic pain management.  It is also frequently used for acute postoperative 
pain, and meta-analysis of randomized controlled trials shows it to be an effective pain management 
strategy in postoperative patients.  The major adverse reactions reported were, in descending frequency, 
dizziness, sedation, asthenia, diarrhea, dry mouth, constipation, nausea, and vomiting 23. 
1.3 Clinical Data to Date 
Numerous randomized controlled trials demonstrated that gabapentin effectively reduced narcotic use 
and improved subjective pain in various surgical populations, such as gynecology-oncology and 
orthopedic surgery9-15.  Meta-analyses of these pooled trials reported an overall trend toward improved 
pain control and decreased postoperative narcotic use with gabapentin, despite the heterogeneity of the 
included studies6,16-19.  A small number of studies have examined the use of gabapentin in postoperative 


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otolaryngology patients and suggest a potential benefit in improving postoperative pain control after 
thyroidectomy, endoscopic sinus surgery, oral cavity resection with reconstruction, and tonsillectomy9-15. 
Most of the studies demonstrated an improvement with only one preoperative dose.  To date, no 
randomized control trials have been conducted with gabapentin use in adult otolaryngology patients 
undergoing all types of head and neck mucosal surgeries, which is an at-risk population for high levels of 
postsurgical pain. 
1.4 Dose Rationale and Risk/Benefits 
Dosing regimen of gabapentin will be 300 mg PO preoperatively, followed by 300 mg BID until POD 2 or 
the day of discharge, whichever comes first. Note that on the morning of POD3 at 7am, a VAS will be 
obtained to reflect the POD 2 7pm dose.  The liquid formulation will be used postoperatively given the 
possibility of dysphagia or postoperative NPO status potentially requiring a feeding tube.  The optimal 
dosage for gabapentin in acute postoperative pain is unknown.  Recommended gabapentin regimen for 
treatment of post-herpetic neuralgia is a 300 mg/day on day 1, 300 mg BID on day 2, 300 mg TID on day 
3, and subsequently up-titrated as needed to 600 mg TID23.  Prior studies using gabapentin for 
postoperative pain control in otolaryngology patients have primarily administered a single preoperative 
dose ranging from 100 mg to 1200 mg9-15. Data was inconsistent as some studies showed efficacy at low 
dosages and some showed no difference at high dosages, and an optimal dose regimen remains to be 
determined.  For this study a relatively low dosage was chosen to minimize sedation side effects, as 
included participants are likely to be gabapentin-naïve.  The perioperative BID dosing period was chosen 
to better elucidate the effects of gabapentin in the acute, postoperative period, as many head and neck 
mucosal resections cause significant pain for several days after the procedure.  The majority of head and 
neck inpatient stays are between 2-3 days, with some staying as short as 1 day and some as long as a 
few weeks.  At this dose and schedule, gabapentin side effects are minimized so that subject risk is also 
minimized without compromising medication analgesic abilities.  Collaboration with the inpatient pain 
management team also supports the expectation that this dose and time regimen will be effective and will 
minimize side effects.  
 
Post-operative swallow results will be collected from the medical record on those patients receiving post 
op swallow therapy per routine care.  The post-operative swallow evaluation will be observational, based 
solely on the discretion of the surgeon and is not required per the research protocol.  
2 Study Objectives 
This investigation is a quality improvement initiative designed to elucidate the benefit of gabapentin in 
pain management in subjects undergoing surgical resection of head and neck mucosal surfaces. 
 
Primary Objective 
To assess the efficacy of gabapentin on decreasing narcotic requirements for treatment of acute 
postoperative pain in head and neck patients undergoing surgical resection of mucosal surfaces. 
 
Secondary Objectives 
To assess subjective pain scores and participant satisfaction with pain control.  
 
  
3 Study Design 
3.1 General Design 
This is a prospective, randomized, double-blind, placebo-controlled study with the intent of providing high 
quality and reproducible data.  The study subjects include adult otolaryngology patients over the age of 
18 years undergoing open or endoscopic/robotic resection involving the mucosal surfaces of the oral 
cavity, oropharynx, hypopharynx and larynx in a single tertiary academic center.  Participants are 
recruited from the otolaryngology head and neck cancer clinic during their preoperative visits.  The 
duration of subject participation includes the subsequent inpatient hospitalization following definitive 


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cancer resection up to two days after surgery.   Subjects will be given the placebo or gabapentin for up to 
two days post op or until discharge, whichever comes first.   
 
Potential subjects will be recruited from the patient population in the head and neck surgery clinic, 11th 
floor CAM, the center for outpatient health or at other outpatient or inpatient sites related to their pre-
surgical planning visits.  Eligible patients will be identified before their scheduled appointments via review 
of medical records in Allscripts by a study team member and approached either in the exam room during 
their scheduled appointment with the head and neck surgeons or afterwards via telephone call.  The 
study will be explained to them and a copy of the consent form will be provided after it has been signed.  
Patients will be reminded that participation is voluntary and will in no way affect their current or future care 
related to their head and neck health needs. Patients will be given time to ask questions and will have the 
option to consider participation and enroll at a subsequent appointment before their planned procedure. 
The consent process will take place in a private room.  Steps to avoid coercion include proper training in 
informed consent, private discussion rooms in which the surgeon is not present, and patients will be 
reassured that their care from their head and neck surgeon will not be affected by their decision to 
participate or to not participate.  Patients will be made aware that their postoperative care will not be 
limited by participation in this study, meaning that they will not be denied needed and appropriate narcotic 
pain medications simply because they are enrolled.  Written informed consent will be obtained prior to the 
start of research related procedures. 
 
 
 


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**Note that IV and PO or per tube morphine will be used in amounts equivalent to the dilaudid and oxycodone medications 
above if an allergy or intolerance to dilaudid or oxycodone exist. 
 
Subjects will present for their planned procedures to the pre-op surgery office and will be taken to the pre-
op holding area as per usual hospital procedure.  A study team member will meet the subject in the pre-
op holding area and will administer the pre-op medication approximately 1 hour prior to surgery start time. 
Patients will not be excluded if surgery start time is delayed past 1 hour.  An investigational pharmacist 
will deliver the medication appropriately labeled with patient name and study number to the pre-op 
holding area.  This oral administration is safe per consultation with the anesthesia faculty member of this 
project.  Additionally, on the day of surgery a study member will place pain medication orders in compass 
on hold for post op care.  These orders will be 1000mg of Tylenol PO or per tube Q6 hours (or Q12 hours 
if the patient has hepatic insufficiency), oxycodone 5-10mg Q4 hours PRN pain (5mg if pain less than or 
equal to 5/10, 10mg if greater than 5/10), and dilaudid 0.25-0.5mg Q2 hours PRN breakthrough pain 
(0.25mg if pain less than or equal to 5/10, 0.5mg if greater than 5/10).  Alternatives to these medications 
in case of allergy or intolerance is 1-2mg IV morphine Q2 hours PRN pain (1mg if pain less than or equal 
to 5/10, 2mg if greater than 5/10) and 7.5-15mg PO/PT liquid IR morphine Q4 hours PRN pain (7.5mg if 
pain less than or equal to 5/10, 15mg if greater than 5/10).  Additionally, the study team member will 
place the appropriate investigational drug order in compass.  The subject will be able to receive increases 
in pain medications as deemed appropriate by the inpatient treating physicians.  They will not have any 
limitations set on pain medications simply because they are involved in the study.  The subject will then 
proceed with surgery as planned. No alterations to intraoperative medications or anesthetic agents will be 
made based on study participation. 
 
The subject will return to the PACU after extubation.  If the subject had to remain intubated, he or she will 
be withdrawn from the study as he or she cannot complete pain scores while sedated. Additionally, if the 
subject is at any point during the study placed on alcohol withdrawal medication protocols, he or she will 
be withdrawn from the study.  The study team member administering the preoperative dose will remind 
anesthesia to use the same post-operative initial pain management options in the PACU at least initially, 
again with no restrictions on dose escalations that are needed.  The PACU can increase the dose of 
postoperative pain medications based on patient need and MD approval as per the usual PACU protocol 
without restriction based on a subject’s study participation.  Subjects will remain in the PACU per the 
usual protocol until the required level of alertness and clinical stability are reached for transfer, and their 
PACU medication sheet will be copied and added to their hard copy file for use later during 


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tabulation/data anaylsis of the pain meds they required The VAS score obtained after surgery will be 
completed 45 minutes to 1 hour after extubation in the PACU.  
 
Note that subjects must have completed surgery (extubated) by 5PM in order to receive the 7PM dose 
after their surgery.  Otherwise, this dose is to be skipped and the next dose administered will be at 7AM 
the next day.  VAS scores can still be obtained at 45 minutes to 1 hour postoperatively, however, even if 
the case finishes later than 5pm. On POD 1-2, subjects will be given BID medications at 7am and 7pm 
per the study protocol and VAS scores will be obtained prior to medication administration   A separate 
VAS will be obtained at 10am on POD1 and POD 2.  ON POD 3 a 7am VAS will be obtained but no study 
medication given. This last VAS concludes participation in the study.  Discharge surveys will be 
administered at this point if they have not been already (ie if the patient remained an inpatient for longer 
than 2 days postop).   
The investigational pharmacist will have delivered the medication dose in a properly labeled container to 
the 6200 inpatient floor prior to scheduled doses, and the medications will be stored in patient labeled 
bins in the locked medication refrigerator.  All VAS scores will be obtained with subject privacy optimized, 
including drawing the curtain in subject room to separate the sides of the room from any potential 
roommate.  Also, the research team member will not vocalize a subject’s status as a study patient.  VAS 
scores will be obtained at rest, with cough and following a swallowing gesture.  Scores are captured by 
providing the subject with a pen and asking the subject to mark the location of their pain on a line 
measuring 10cm during each phase of the VAS.   The scale is a validated tool that measures 10cm in 
size and is marked “no pain” on the far left and “worst pain” on the far right.  The subject marks their pain 
level on the scale and the study team member will measure with a ruler and record the resulting number 
in the study database.    
Subjects will fill out a discharge survey before they are discharged or at the completion of their 
participation to rate their satisfaction with their inpatient pain control.  This survey will be a hard copy 
labeled with study ID and the data will be entered into the study database.  All hard copy data will be 
stored in a locked cabinet accessible only to the study team.  At the end of the study, all hard copy data 
will be properly destroyed.   
 
Subjects will have 24/7 access to members of the study team should questions or concerns arise while 
they are actively participating in the study as well as up to 30 days after completion of the study.   
 
Note that study medication wrappers have patient names on them as a safety mechanism to make sure 
medications are given to the proper patient.  These wrappers and labels will be saved in the patient 
folders which are secured in a locked cabinet where only study team members have access.  Empty and 
unlabeled medication syringes will be discarded in the red biohazard bins inside patient rooms.  
3.2 Primary Study Endpoints 
The primary study endpoint is postoperative narcotic consumption.  Average daily narcotic use from 
postoperative admission to the last dose of pain medication on POD 2, or the day of discharge, whichever 
comes sooner, will be calculated. Total amount of narcotic use in morphine equivalents will be divided by 
the total hours of inpatient hospitalization, multiplied by 24 hours, to obtain the average daily narcotic 
consumption. 
3.3 Secondary Study Endpoints 
The secondary endpoints include (a) subject satisfaction with pain control, (b) VAS pain scores, (c) 
patient baseline pain perceptions (d) hospital length of stay, and (e) potential side effects of the 
medication.  
 
(a) Subject satisfaction with pain control will be captured in a survey administered at POD 2 after the 
AM dose administration, or after the AM dose administration on the day of discharge, whichever 
comes sooner.  Two of the survey questions will mirror those on the HCAPHS surveys, listed as 
followed (see attached “post-treatment questionnaire”): 
 
1. How often was your pain well controlled? 


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0) Never 
1) Sometimes 
2) Usually 
3) Always 
 
2. How often did the hospital staff do everything they could to help you with your pain? 
0) Never 
1) Sometimes 
2) Usually 
3) Always 
 
3. How satisfied are you with your overall pain control? 
0) Very dissatisfied 
1) Somewhat dissatisfied 
2) Neutral 
3) Somewhat satisfied 
4) Very satisfied 
 
4. Was there anything else that we could have done to make your pain control better during your 
inpatient stay? 
A point system is created with the sum of the numeric values assigned to questions 1-3 on a scale of 
0 to 10, with a score of 0-3 indicates overall dissatisfaction, 4 indicates neutrality, and 5-10 suggests 
overall satisfaction.  This will be analyzed as an ordinal variable. 
 
(b) VAS pain scores will be assessed 45min to 1 hour after surgery and then three times a day on 
POD 1-2 and once on POD 3, or until day of discharge, whichever comes sooner. A standardized 
VAS form will be given to subjects with verbal instruction to first “mark on the line the point that 
you feel represents your current pain level when you’re resting.”  This is followed by asking the 
subject to gesture swallowing and “mark another point on the line that represents your pain level 
when you swallow.”  Lastly, the subject will be asked to cough and to “mark the final point on the 
line that represents your pain when you cough.”  The study team member administering the test 
will annotate what each mark represents (rest, swallow, and cough).  The scale contains a 10-cm 
line from “no pain” on the left to “extreme pain” on the right (see “VAS form”).  The distance in 
centimeters from the left of the line to the center of the patient’s three marks will be recorded.  
The results from all available VAS scores for each subject will be averaged and included in the 
final analysis.  
 
(c) The subject’s belief in pain medication efficacy and pain tolerance will be assessed from a short 
survey obtained preoperatively during the office visit (see “pre-treatment questionnaire”). This 
includes the following questions: 
 
1. In the past, how effective are narcotic pain medications (such as morphine, Vicodin, Norco, 
Percocet, oxycodone, Dilaudid) at controlling your pain? 
0) Very ineffective 
1) Somewhat ineffective 
2) Somewhat effective 
3) Very effective 
 
2. In the past, how has your pain tolerance been? 
0) Very poor 
1) Somewhat poor 
2) Somewhat tolerant 
3) Very tolerant 


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3. Do you experience a significant amount of pain on a daily basis aside from the pain due to 
your current head and neck condition? 
1) Yes I do 
2) No I do not 
The results of these questions will be reported separately in the final analyses. 
 
(d) Hospital length of stay will be calculated for each subject. 
 
(e) During the VAS scores, study team members will also collect information about potential 
medication side effects, including those that are commonly associated with gabapentin or with 
narcotic medications.  
3.4 Primary Safety Endpoints 
The primary safety endpoints are the rate and severity of drug-related adverse events.  Adverse events 
will be monitored and recorded by study team members during subject inpatient stay.  These events will 
be reviewed by the principal investigator and categorized into “drug-related”, “likely drug-related”, and 
“unlikely drug-related.”  Any significant adverse events determined to be likely drug related will be 
reported to the OHRP within a 24 hour time period and stopping the study for the subject will be 
discussed.  A safety meeting will be heald half way through the study with the PI and all involved faculty 
mentors to determine if an interim analysis is necessary, This analysis would be considered necessary if 
a significant number of adverse events likely related to the study medication were occurring, and an 
analysis to make sure the study was not causing harm to the treatment group was needed. 
4 Subject Selection and Withdrawal 
4.1 Inclusion Criteria 
 
Subjects undergoing definitive mucosal head and neck resection including oral cavity, 
oropharynx, larynx, and hypopharynx 
 
At least 1 night of planned inpatient stay 
4.2 Exclusion Criteria 
 
Incapable of giving informed consent 
 
Age < 18 
 
GFR < 30 
 
Allergy to gabapentin  
 
Baseline gabapentin or lyrica use 
 
Chronic opioid use for over 6 months 
4.3 Subject Recruitment and Screening 
Subjects will be recruited either in the outpatient head and neck clinic prior to their planned surgeries or 
over the phone after this clinic appointment by designated study team members.  Potentially eligible 
patients will be identified by study team members prior to their scheduled appointments via the outpatient 
medical records system.  Patient recruited by phone will be able to sign the informed consent prior to 
surgery either at a subsequent surgical planning visit or in the pre-op holding are on the day of surgery.  
Eligible subjects will be consented in a private setting and the study outline explained to the patient. 
Written informed consent will be obtained from those patients who wish to participate.  Patients may 
choose to think about study participation but will need to decide and provide written consent prior to the 
day of surgery, either at their subsequent preoperative anesthesia clinic appointment or medical 
oncology/radiation oncology appointments.  Study team members will be properly trained in the informed 
consent process.  


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4.4 Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
Subjects may be withdrawn from the study prior to the expected completion if they develop 
hypersensitivity reactions to the study drug, are unable to swallow all study drugs in the study period, or 
choose to withdrawal for other reasons.  They will also be withdrawn if they remain sedated or intubated 
after the surgery or are placed on alcohol withdrawal medication protocols, which also cause significant 
sedation.  Subjects without a feeding tube who are unable, or unwilling, to swallow medications after 
surgery will not be given a feeding tube to remain in the study.  A 20% dropout rate was anticipated and 
accounted for in the sample size calculation.  Subjects will be able to withdraw on a continual basis 
throughout their participation.  Withdraw can be requested either by the subject or by any team member if 
medical significant adverse reactions are observed.  All withdraws will be reviewed by the principle 
investigator.  No subject will be denied the ability to withdraw. The withdraw process will begin 
immediately when deemed necessary or when desired by the subject, and documentation of the reason 
and time of withdraw will be performed.   
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
Withdrawn subjects will be excluded in the final data analysis. The reasons for withdrawal will be 
recorded and reported separately in the study data outcomes. 
 
4.4.3 Definitions 
Subject withdraw: Withdraw is defined as a subject who signed the informed consent document and for 
whatever reason dropped out of the study before completion, whether by choice or by exclusion criteria 
(ie- staying intubated the night after surgery). 
 
Subject screen fail: A screen fail is defined as a subject who has been recruited to participate and 
approached but does not meet all inclusion criteria.  
 
5 Study Drug  
5.1 Description 
300mg of liquid gabapentin or an equal volume of placebo will be pre-packaged by the investigational 
pharmacist in a labeled medication syringe or in a marked bag with a capsule.  An unblinded study team 
member in charge of the randomization process will indicate to the pharmacy which subjects are to 
receive what medication.  The blinded study team members will not know which medication contains 
placebo or gabapentin.  
5.2 Treatment Regimen 
Subjects will receive either placebo or gabapentin 300 mg PO the preoperative holding area 
approximately 1 hour before their procedure is scheduled to begin.  This first dose will designate the day 
of their procedure as POD 0.  If the procedure ends late in the evening (ie not extubated before 5pm), and 
the subject is not able to receive the second POD 0 dose by 7 PM, then this second POD 0 dose will be 
skipped.   Participants will then receive either placebo or 300 mg of gabapentin BID POD 1- POD 2.  
Dosing will end either on POD 2 after the PM dose or on day of discharge after the AM dose, whichever 
comes first.  VAS scores will be collected 45 minutes- 1 hour post extubation on POD as well as TID on 
POD 1-2 and one time at 7am on POD 3 (see above protocol flowsheet).  


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5.3 Method for Assigning Subjects to Treatment Groups 
After a subject consents to study, the unblinded data manager will randomize the subject into active or 
placebo group and assigned an enrollment ID.  The enrollment ID is given to any subject who signs 
consent. If the subject then proceeds to start the study and receive a medication dose, they will also be 
given a subject ID which reflects their randomization group.  The study ID reflects randomization while the 
enrollment ID is used to enter them into OnCore and track their consent.  
5.4 Preparation and Administration of Study Drug 
The Investigational Pharmacist will mix and prepare the study medications necessary for each subject.  A 
pharmacist will deliver the medication to the preop holding unit or the floor and a designated study team 
member will administer it.  Please see section 5.7 below for mixing and packaging details. Contact 
information for the pharmacy for this project is pharmacist Kathryn Vehe at 314-795-7286. 
 
Inpatient pharmacists will be responsible for delivering the medication to the floor prior to the AM dose 
and to the PM dose, as well as will deliver the medication to the pre-op holding area prior to a subject’s 
procedure. Formal training for all study team members who will be administering the study drug or 
obtaining the VAS pain scores is required prior to subject interaction. 
5.5 Subject Compliance Monitoring 
The study team members will directly administer each study medication dosage during the study period 
and record adherence to study protocol.  If a dose is missed during this period, the subject will remain in 
the study through the completion of the protocol.  The decision to include data from subjects with missed 
doses will be made at the discretion of the principle investigator and statistician at the conclusion of the 
study.   Data integrity will be maintained such that subjects who are excluded for missed doses will be 
consistent among cases.  
5.6 Prior and Concomitant Therapy 
Every subject will have standard postoperative narcotic medications made available: 
 IV Dilaudid 0.25-0.5mg q2h PRN breakthrough pain (pain equal to or less than 5/10 will get 
0.25mg and pain >5/10 will get 0.5mg).  
 PO/PT oxycodone 5-10mg q4h PRN pain (pain equal to or less than 5/10 will get 5mg, and pain 
greater than 5/10 will get 10mg).  
 PO/PT acetaminophen 1000mg q6h for pain in non-cirrhotic patients, and 1000mg q12h in 
cirrhotic patients 
 Morphine IV and PO liquid equivalents will be substituted in cases of oxycode or dilaudid 
allergies. 1-2mg IV morphine Q2 hours PRN will be substituted for 0.25-0.5mg dilaudid for 
breakthrough pain (pain equal to or less than 5/10 will get 1mg and pain >5/10 will get 2mg).   
PRN liquid IR morphine 7.5-15mg will be substituted Q4 hours for oxycodone PRN for pain (pain 
equal to or less than 5/10 will get 7.5mg, and pain greater than 5/10 will get 15mg) 
 Study team members will place an order in compass for study investigation drug administration 
as per BJC protocol for investigational drug use.   
 
These medications can be up-titrated as needed at the discretion of the physicians managing the 
patient’s care as part of the routine postoperative management. 
5.7 Packaging 
 Study medications will be in liquid or capsule form.  Gabapentin comes as a standard liquid form 
of 250mg/5ml. Capsules will be used for the pre-operative dose, and will come as single capsules 
in bags labeled with study ID and name.  For post-operative doses, 6ml of either gabapentin or 
placebo will be packaged into a brown 20ml plastic syringe.  Each syringe will have the subject 
name and study ID on it.  The pharmacy will be made aware of all upcoming study subjects and 
will prepare the medications approximately 24 hours prior to administration, and will store these at 


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4 degrees Celsius.  The medications will be stored prior to dosing on the floor in a locked fridge in 
patient specific compartments, as per the floor medication protocol.  
5.8 Blinding of Study Drug 
The study team members administering the medications will be blinded towards whether a subject 
receives the study drug or the placebo.  The data manager who does not participate in data collection or 
have direct subject interaction, as well as the pharmacist preparing the medications, will be unblinded. 
5.9 Receiving, Storage, Dispensing and Return 
5.9.1 Receipt of Drug Supplies 
Investigational pharmacists will be responsible for medication delivery prior to planned doses.  They will 
be alerted to upcoming procedures that involve study subjects.  They will be responsible for delivering the 
medication to the inpatient floor and in the preoperative holding area.  Any damaged or unusable study 
drug in a given shipment will be documented in the study files and discarded. 
5.9.2 Storage 
Medications will be stored by the investigational pharmacy in a designated, locked area at 4 degrees 
Celsius. They will be stored on the inpatient floor in a locked, 4 degree fridge in patient specific 
compartments per the floor medication storage protocols.  
5.9.3 Dispensing of Study Drug 
The study team members administering the medications will receive the medication from the 
investigational pharmacist.  They will then administer the medication and record the time of administration 
and the subject identification number in the subject’s study flow sheet (“Gaba project subject study flow 
chart” attached). 
5.9.4 Return or Destruction of Study Drug 
At the completion of the study, there will be a final reconciliation of medications consumed.  This 
reconciliation will be logged on the drug reconciliation form, signed and dated.  Any discrepancies noted 
will be investigated, resolved, and documented.  Medication syringes will be discarded in the red 
biohazard containers in accordance with hospital policy and documented in the study files. Any labels or 
bags with patient names will be discarded in the shred bins on the 6200 floor or in the preop holding unit.  
 
6 Study Procedures 
The study procedures are outlined below and represented in the attached “Gaba project subject study 
flow chart”.  
 
Clinic Visit 
 
Consent. 
 
Pre-treatment questionnaire. 
 
Randomization group will be assigned by the study data manager after she is notified of subject 
agreement to participate. 
Day of Surgery 
 
One dose of study drug will be administered preoperatively according to subject’s randomization 
group approximately 1 hour prior to procedure start time.  The coordinator administering the 
medication will tape a study reminder sheet for anesthesia to the chart and will place an order in 
the chart that allows the participant to take the preop medication dose, and the RN to chart this 
dose as a study medication.  


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 
Standard pain medications orders will be provided. Morphine will be used as a substitute for 
dilaudid or oxycodone allergies or intolerances. These will be up-titrated as needed per discretion 
of service residents and attending physicians. 
 
One VAS score will be obtained 45 minutes to 1 hour postoperatively regardless of extubation 
time. 
 
One postoperative dose of study drug and VAS will be administered at 7pm if subjects are 
extubated by 5PM 
Post-Operative Day (POD) 1-2 
 
TID VAS scores will be obtained, two of which will be prior to drug administrations. 
 
BID study drug administration will be conducted according to subject’s randomization groups. 
POD 3  
 
POD 3 VAS at 7am will be obtained.  
POD 3 or Day of Discharge 
 
Post-treatment pain satisfaction questionnaire will be conducted either after the AM dose on POD 
3 or on date of discharge, whichever comes sooner. 
7 Statistical Plan 
7.1 Sample Size Determination 
Sample size calculations were performed based on prior studies with gabapentin use in otolaryngology 
patients undergoing thyroidectomy21.  A study by Al-Mujadid et al in a population of patients undergoing 
elective thyroidectomy reported that total morphine consumption in the placebo group in the first 24 hours 
post surgery required a mean of 29.5mg of morphine with a standard deviation of 9.9mg.  Assuming that 
this magnitude of effect variability will hold true in this project population, it is estimated that 46 subjects 
per group (total n=92) will be needed to detect with an 80% power at the 2-sided alpha level of 0.05 a 
difference of 20% or greater in average morphine dose (effect size d=0.6) between the placebo and 
gabapentin groups.  Assuming a 20% drop out rate, 116 subjects will be enrolled in this study.  The 
volume of eligible subjects for this study is predicted to meet the calculated sample size within two years 
of study start time. A review of surgical procedures meeting inclusion criteria performed over a sample 
three month time frame ranged from 12 to 17 procedures a month.  
Note that IV morphine equivalents will be used rather than PO.  
7.2 Statistical Methods 
Descriptive statistics will be used to describe distribution of demographics. Bivariate analysis using 
independent samples t-test for continuous variables and chi square test for categorical variables will be 
used to compare distribution of characteristics between treatment groups to ensure successful 
randomization. 
Note that in discrepancies of data between reports, such as pack years smoked by a patient, an average 
of the reported amounts will be used to ensure consistency between data reporting fluctuations.  
 
The primary and secondary outcome measures will be compared between the two treatment groups via 
bivariate analyses.  In addition, a General Linear Model (GLM) approach will be used to explore the 
impact of gabapentin as compared to placebo on each of the outcomes of interest after controlling for 
potential cofounders that were unevenly distributed between the two groups.  The estimated mean 
difference and 95% confidence interval will be reported. 


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7.3 Subject Population(s) for Analysis 
Protocol-compliant subjects who received all study drugs up to the conduction of post-treatment 
questionnaire will be included for analysis.  Subjects with missed medication doses will go on to complete 
the protocol, and per the discretion of the principle investigator and statistician may or may not be 
included in the data analysis.  Data integrity will be maintained such that subjects who are excluded for 
missed doses will be consistent among cases. 
 
8 Safety and Adverse Events 
8.1 Definitions 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
 Unexpected in nature, severity, or frequency  (i.e. not described in study-related documents such 
as the IRB-approved protocol or consent form, the investigators brochure, etc) 
 Related or possibly related to participation in the research (i.e. possibly related means there is a 
reasonable possibility that the incident experience, or outcome may have been caused by the 
procedures involved in the research) 
 Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm). 
 
 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study.  Intercurrent illnesses or injuries that occur during the study period will be 
regarded as adverse events (meaning that the event does not necessary have to be likely related to the 
study drug to be considered an adverse event).  However, not all adverse events will meet criteria for 
reporting.  Abnormal results of diagnostic procedures will be reported as adverse events if the 
abnormality: 
 results in study withdrawal 
 is associated with a serious adverse event (see definition below) 
 is associated with clinical signs or symptoms that are considered significant and likely related to 
study participation  
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 
 
Serious Adverse Event 
Adverse events are classified as serious, moderate or mild.  .  A serious adverse event is any AE that is:  
 fatal 
 life-threatening 
 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 a new congenital anomaly or birth defect 
 an important medical event 
 
Mild and Moderate adverse events: 
A moderate adverse event is one that requires a medical intervention such as medication for nausea, but 
that does not cause permanent clinical harm and that does resolve in a reasonable amount of time. 
 
A mild adverse event is one that causes mild clinical effect and may or may not require medical 
intervention. It is expected to resolve completely with observation or medical treatment.  
 
 
Adverse Event Reporting  


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The study period during which adverse events that are deemed reportable  must be reported will be the 
period from the day of surgery to the end of the study, which is POD 3 or sooner if discharge is sooner 
than POD 3. Ideally, these events will be reported to the PI within 24 hours of their occurrence.  Serious 
AE must be reported within 24 hours, however. Additionally, subjects will be provided with contact 
information for the study member that is in charge of adverse event follow up (Melanie Townsend, PI).  
They will be instructed to contact this person with questions related to the study, adverse events or side 
effects experienced after discharge so that the study members can be alerted to any events that may be 
related to the medication. Any severe adverse events or moderate events thought likely to be related to 
the study medication that are reported to the PI during this 30 day window will be recorded.    Adverse 
events that occur during the inpatient study period and are significant/severe as defined above or that are 
unusual will be required to be reported in the adverse events log. The PI will be made aware of all of 
these events immediately after they occur.  Events that are mild will not be required to be recorded in the 
adverse events log.  Events that are moderate and thought likely related to the study medication will be 
reported.  Events that are moderate but deemed unlikely to be due to the study medication will not be 
required to be reported in the adverse events log.  However, these events may still be recorded in the 
adverse events log at the discretion of the PI.  The PI will sign off on all adverse events that are recorded 
in the adverse event log.  
 
For all severe AE or AE that are unexpected and thought likely related to the study medication, an IRB 
event form will be submitted. For moderate events thought likely to be due to the medication or 
unexpected, an event form will be submitted at at the discretion of the PI. This design is intended to make 
sure that if subjects seem to be having symptoms that aren’t expected to be caused by study participation 
but are noted in multiple subjects, then this gets reported.  However, those side effects that are common 
after surgery (such as sedation or nausea) that could also be related to study medications are noted in 
the AE log when appropriate but not generating multiple IRB reportable event forms.  The goal is to 
ensure subject safety and also only report appropriate events to the IRB.  All adverse events, whether 
mild, moderate or severe, will be reviewed at the safety meeting by all team members and faculty 
advisors to ensure that proper reporting has occurred.   
 
 
Post-study Adverse Event 
All unresolved adverse events will be followed by the investigator until the events are resolved, the 
subject is lost to follow-up, or the adverse event is otherwise explained.  At the last scheduled visit, the 
investigator will instruct each subject to report any subsequent event(s) that the subject, or the subject’s 
personal physician, believes might reasonably be related to participation in this study in the 30 days 
window follow discharge.   
8.2 Elliciting Adverse Events from Subjects  
At each interaction with the subject, the investigator will seek information on adverse events by specific 
questioning and, as appropriate, by examination.  Information on all adverse events will be recorded 
immediately in the data recording form that is used to record subject data at each interaction.  Reporting 
of these events is as outlined above.  Specific side effects that will be elicited at each interaction include 
nausea, vomiting, dizziness and sedation.   
 
8.3 Unblinding Procedures 
For this study only the data manager and pharmacy will be unblinded to the study drug and placebo 
assignments.  Unblinding of the rest of the study investigators will occur after assurance that data 
collection has completed.  If any subject data is intentionally or unintentionally unblinded, the event will be 
documented in detail in the study documents within 48 hours.  Any unblinding that occurs during the study 
period for an individual participant will result in exclusion of that participant’s data from final analysis.  
Study investigators must report unblinding to the PI within a 24 hour time period and must document the 
event.  Subjects will immediately be made aware of the unblinding and will be withdrawn from completing 
the protocol.  


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Stopping Rules  
The study will be terminated prematurely if 50% or more of the subjects receiving study drug (gabapentin 
or placebo) experience significant adverse events as defined above in section 8.1.  The study will not be 
prematurely stopped if subjects experience less significant medication side effects, specifically nausea, 
vomiting, dizziness and sedation.  A review of adverse events will be conducted at 25% by the PI and at 
50% enrollment by the entire team to ensure that they are properly tracked.  
8.4 Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study.  This safety 
monitoring will include careful assessment and appropriate reporting of adverse events as noted above, 
as well as the construction and implementation of a site data and safety-monitoring plan (see section 10 
Monitoring).  Medical monitoring will include a regular assessment of the number and type of serious 
adverse events.   A safety meeting will be held half way through enrollment as described above, 
9 Data Handling and Record Keeping 
9.1 Confidentiality 
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).   
Source data will be kept primarily in the electronic forms using REDCap for data collection.  Paper forms 
including the original consents, questionnaires, VAS pain score sheets, adverse event reporting forms 
etc. will be kept in a locked cabinet that only study team members have access to.  At the conclusion of 
the study, after data has been entered into a password protected spread sheet, these records will be 
destroyed in the proper manner in shred it bins where patient information is normally placed.  The official 
source document and case report form for this study will be the REDCap database. 
 
 
All research records will be maintained in the Outcomes Office, 8th floor McMillan for 7 years after study 
completion per WU record retention policy.  
 
10 Study Monitoring 
10.1 Study Monitoring Plan 
This study will be monitored in real time for each subject by the PI and study team.  At minimum, with 
25% accrual goal all adverse events and data collection forms will be reviewed by the PI and discussed 
among the study team.  At our interim safety meeting, we determined by our AE log that significant 
adverse events were not occurring to study patients and events that were moderate and likely related to 
the medication also were extremely infrequent. We determined at that time that a third party officer review 
was unnecessary, especially in light of the fact that we were aware at that point that an audit would occur.  
We will proceed to study completion without this third party review.  We also will be reporting our study 
events and AE events in a DSM log to the Siteman monitoring committee, which will also serve as a third 
party review.  
 
11 Medication processing  
 


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11.1 Medicaiton Processing 
All unused medications will be picked up from the pharmacy within 12 hours of the time they are 
determined to be not needed or not used.  The pharmacy will be alerted in real time that the medication 
was not needed so that they can expect to pick it up.  A confirmation communication will be sent to the 
study team once the medication is retrieved to ensure that it is properly picked up. 
12 References 
1. Chang C.Y., Challa C.K., Shah J., Eloy J.D. Gabapentin in acute postoperative pain management.  
BioMed Research International Vol. 2014.  2014.  
2. Rafiq, Sulman, et al. "Multimodal analgesia versus traditional opiate based analgesia after cardiac 
surgery, a randomized controlled trial." J. Cardiothorac. Surg 10 (2014): 1749-8090. 
3. Kehlet H, Jensen TS, Woolf CJ: Persistent postsurgical pain: risk factors and prevention.  Lancet 
2006 May 13, 367(9522):1618-1625.  
4. Kehlet H: Multimodal approach to postoperative recovery. Curr Opin Crit Care 2009 Aug, 15(4):355-
358.  
5. Kong VK, Irwin MG: Gabapentin: a multimodal perioperative drug? Br J Anaesth 2007 Dec, 
99(6):775-786.  
6. Tiippana EM, Hamunen K, Vesa KK, Kalso E. Do surgical patients benefit from perioperative 
gabapentin/pregabalin? A systematic review of ef fi cacy and safety. Anesth Analg. 2007;104(6): 
1545–56. 
7. Clarke H, Bonin RP, Orser BA, Englesakis M, Wijeysundera DN, Katz J. The prevention of chronic 
postsurgical pain using gabapentin and pregabalin: A combined systematic review and meta-analysis. 
Anesth Analg. 2012;115:428–42 
8. Levine, Adam I., Satish Govindaraj, and Samuel DeMaria, eds. Anesthesiology and Otolaryngology. 
Springer, 2013. 
9. Lee J.H., Lee H.K., Chun N.H., So Y., Lim C.Y.  The prophylactic effects of gabapentin on 
postoperative sore throat after thyroid surgery.   Korean Journal of Anesthesiology 2013 64:2 (138-
142). 
10. Mohammed M.H., Fahmy A.M., Hakim K.Y.K. Preoperative gabapentin augments intraoperative 
hypotension and reduces postoperative opioid requirements with functional endoscopic sinus surgery. 
Egyptian Journal of Anaesthesia 2012 28:3 (189-192). 
11. Ahn S.H., Lee J.H., Min K.T. The prophylactic effects of gabapentin on postoperative sore throat after 
thyroid surgery.  European Journal of Anaesthesiology 2012 29 SUPPL. 50 (202). 
12. Chiu T.W., Leung C.C.H., Lau E.Y.K., Burd A. Analgesic effects of preoperative gabapentin after 
tongue reconstruction with the anterolateral thigh flap. Hong Kong Medical Journal 2012 18:1 (30-34)  
13. Kazak Z., Mortimer N., Mekerci S. Single dose of preoperative analgesia with gabapentin (600 mg) is 
safe and effective in monitored anesthesia care for nasal surgery. European Archives of Oto-Rhino-
Laryngology 2010 267:5 (731-736).  
14. Jeon E.-J., Park Y.-S., Park S.S., Lee S.-K., Kim D.-H. The effectiveness of gabapentin on post-
tonsillectomy pain control. European Archives of Oto-Rhino-Laryngology 2009 266:10 (1605-1609). 
15. Turan A., Memi; D., Karamanlio;lu B., Yaiz R., Pamuk; Z., Yavuz E. The analgesic effects of 
gabapentin in monitored anesthesia care for ear-nose-throat surgery.  Anesthesia and Analgesia 
2004 99:2 (375-378). 
16. Hurley RW, Cohen SP, Williams KA, Rowlingson AJ, Wu CL. The analgesic effects of perioperative 
gabapentin on postoperative pain: A meta-analysis. Reg Anesth Pain Med. 2006;31:237–47. 
17. Peng PW, Wijeysundera DN, Li CC. Use of gabapentin for perioperative pain control—A meta-
analysis. Pain Res Manag. 2007;12:85–92. 
18. Seib RK, Paul JE. Preoperative gabapentin for postoperative analgesia: A meta-analysis. Can J 
Anaesth. 2006;53:461–9. 
19. Clivatti J., Sakata R.K., Issy A.M. Review of the use of gabapentin in the control of postoperative 
pain.  Revista Brasileira de Anestesiologia 2009 59:1 (87-98). 
20. Schmidt, Peter C., et al. "Perioperative Gabapentinoids: Choice of Agent, Dose, Timing, and Effects 
on Chronic Postsurgical Pain." Survey of Anesthesiology 58.2 (2014): 96-97. 


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21. Al-Mujadid, Hussain, et al. Preemptive gabapentin reduces postoperative pain and opioid demand 
following thyroid surgery. Canadian Journal of Anesthesia. March 2006, Volume 53, Issue 3, pp 268-
273. 
22. Sally L. Collins, R. Andrew Moore, Henry J. McQuay.  The Visual Analogue Scale: what is moderate 
pain in millimeters? Pain (Impact Factor: 5.21). 09/1997; 72(1-2):95-7. 
23. Accessfda.gov. Keyword “gabapentin”. PDF title: Neurontin. Parke-Davis Division of Pfizer Inc, NY, 
NY 10017.  April 2009.   
  


The effect of gabapentin on perioperative pain control among head and 
neck surgery patients 
 
NCT# NCT02926573 
 
 
Document Version Date:  02/20/2017 
 
IRB Approval Date:  03/13/2017 


 
CONFIDENTIAL 
 
CLINICAL RESEARCH PROTOCOL 
 
 
 
 
 
 
 
 
THE EFFECT OF GABAPENTIN ON PERIOPERATIVE PAIN 
CONTROL AMONG HEAD AND NECK SURGERY PATIENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Initial version: 3/31/2016 
Amended: 
[7/31/2016] 
Amended: 
[12/1/2016] 
Amended:  
[1/20/17] 
Amended:           [2/10/17] 
Amended            [2/20/17] 


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Table of Contents 
 
STUDY SUMMARY ...................................................................................................................................... 1 
1 
INTRODUCTION .................................................................................................................................. 2 
1.1 
BACKGROUND ................................................................................................................................ 2 
1.2 
INVESTIGATIONAL AGENT ................................................................................................................ 2 
1.3 
CLINICAL DATA .............................................................................................................................. 2 
1.4 
DOSE RATIONALE AND RISK/BENEFITS ............................................................................................ 3 
2 
STUDY OBJECTIVES ......................................................................................................................... 3 
3 
STUDY DESIGN ................................................................................................................................... 3 
3.1 
GENERAL DESIGN .......................................................................................................................... 3 
3.2 
PRIMARY STUDY ENDPOINTS .......................................................................................................... 6 
3.3 
SECONDARY STUDY ENDPOINTS ..................................................................................................... 6 
3.4 
PRIMARY SAFETY ENDPOINTS ......................................................................................................... 8 
4 
SUBJECT SELECTION AND WITHDRAWAL .................................................................................... 8 
4.1 
INCLUSION CRITERIA ...................................................................................................................... 8 
4.2 
EXCLUSION CRITERIA ..................................................................................................................... 8 
4.3 
SUBJECT RECRUITMENT AND SCREENING ....................................................................................... 8 
4.4 
EARLY WITHDRAWAL OF SUBJECTS............................................................................................... 98 
4.4.1 
When and How to Withdraw Subjects ................................................................................... 98 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects .......................................................... 9 
5 
STUDY DRUG ...................................................................................................................................... 9 
5.1 
DESCRIPTION ................................................................................................................................. 9 
5.2 
TREATMENT REGIMEN .................................................................................................................... 9 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ..................................................... 109 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ................................................................. 109 
5.5 
SUBJECT COMPLIANCE MONITORING ........................................................................................... 109 
5.6 
PRIOR AND CONCOMITANT THERAPY ........................................................................................... 109 
5.7 
PACKAGING ................................................................................................................................. 10 
5.8 
BLINDING OF STUDY DRUG ....................................................................................................... 1110 
5.9 
RECEIVING, STORAGE, DISPENSING AND RETURN ...................................................................... 1110 
5.9.1 
Receipt of Drug Supplies ................................................................................................... 1110 
5.9.2 
Storage .............................................................................................................................. 1110 
5.9.3 
Dispensing of Study Drug .................................................................................................. 1110 
5.9.4 
Return or Destruction of Study Drug ................................................................................. 1110 
6 
STUDY PROCEDURES ................................................................................................................. 1110 
7 
STATISTICAL PLAN ..................................................................................................................... 1211 
7.1 
SAMPLE SIZE DETERMINATION .................................................................................................. 1211 
7.2 
STATISTICAL METHODS ............................................................................................................ 1211 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ................................................................................... 1211 
8 
SAFETY AND ADVERSE EVENTS ............................................................................................... 1312 
8.1 
DEFINITIONS ............................................................................................................................ 1312 
8.2 
RECORDING OF ADVERSE EVENTS ............................................................................................ 1413 
8.3 
UNBLINDING PROCEDURES ....................................................................................................... 1413 
8.4 
MEDICAL MONITORING ............................................................................................................. 1513 
9 
DATA HANDLING AND RECORD KEEPING ............................................................................... 1514 
 


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10 
STUDY MONITORING ................................................................................................................... 1514 
10.1 
STUDY MONITORING PLAN ........................................................................................................ 1514 
11. Medicaiton processing ............................................................................................................ 15 
13 
REFERENCES ................................................................................................................................... 16 
 
 


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List of Abbreviations 
 
 
HCAHPS- Hospital Consumer Assessment of Healthcare Providers and Systems 
 
PRC-Professional Research Consultants  
 
FDA – Food and Drug Administration 
 
VAS – Visual Analog Scale 
 
POD – post-operative day 
 
 
 
 
 
 
 
 


[Insert short name of protocol here] 
 
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Study Summary 
Title 
The effect of gabapentin on perioperative pain control among head and neck 
surgery patients 
Short Title 
Gaba RCT 
Protocol Number 
1.4 (fourth amended version) 
Phase 
Phase 4 
Methodology 
Prospective randomized double-blind controlled trial  
Study Duration 
2 years 
Study Center(s) 
Barnes Jewish Hospital 
Objectives 
Determine the effectiveness of gabapentin for reducing narcotic requirements 
and subjective pain scores in postoperative head and neck mucosal cancer 
patients.  Determine the ability of gabapentin to improve patient satisfaction 
with pain management. Track inpatient length of stay.  
Number of Subjects 
120 
Diagnosis and Main 
Inclusion Criteria 
Adult head and neck patients undergoing oral cavity, oropharynx, larynx and 
hypopharynx resection (mucosal head and neck surgeries) 
Study Product, Dose, 
Route, Regimen 
Gabapentin liquid by mouth or Per Tube 300mg BID vs placebo 
Duration 
of 
administration 
Day of surgery and up to three days post operatively depending on the hospital 
stay.   
Reference therapy 
Placebo 
Statistical 
Methodology 
Bivariate analysis using independent samples t-test for continuous variables 
and chi square test for categorical variables will be used to compare between 
treatment groups 
 


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1 Introduction 
This document is a protocol for a human research study to be conducted according to US and 
international standards of Good Clinical Practice compliant to all associated Federal and applicable local 
and University research requirements, approved by the Institutional Review Board.  
1.1 Background 
High-quality healthcare is accessible, safe, efficient, patient-centered and imperative for good treatment 
outcomes.  In this era of healthcare reform, patient satisfaction has increasingly become an important 
metric of hospital performance.  The Medicare Hospital Value Based Purchasing Program utilizes patient 
reported satisfaction scores as a reflection of the quality of care delivered by hospital systems and 
clinician teams.  The scores resulting from these reports are integrated into the formula with which 
hospitals are reimbursed for Medicare patients. 
 
An important patient-physician interface in quality healthcare is the treatment of pain, and the treatment of 
acute postoperative pain is particularly relevant for surgical specialties.  Effective management of 
postoperative pain increases patient satisfaction, reduces hospital costs, reduces postoperative morbidity 
and shortens hospitalizations8.  HCAHP and PRC data from the Barnes Jewish Hospital otolaryngology 
inpatient unit reveals that postoperative otolaryngology patient satisfaction with pain control is routinely 
lower than the 75th percentile of all hospitals nationally surveyed.  Traditionally, pain regimens rely heavily 
on the use of narcotics, which are associated with nausea, vomiting, delirium, and decreased bowel 
motility.  These side effects have the potential to increase length of hospitalization and decrease patient 
satisfaction.  Moreover, otolaryngology patients often undergo very painful and functionally debilitating 
surgeries of the head and neck and are at increased risk for postoperative pain due to both the 
neuroanatomy of this region and the need to swallow postoperatively8.   Postoperative pain control in this 
population is critical for patient satisfaction and an expedited return to a functional swallowing status. 
 
Within the field of pain management is the practice of multimodal pain therapy.  This strategy employs 
non-narcotic medications working synergistically to improve pain control, decreasing narcotic medication 
requirements and narcotic-associated side effects8.  Studies utilizing multimodal pain regimens 
demonstrate such benefits in acute postoperative pain management2-5.  Gabapentin is a non-narcotic 
pain medication often used in multimodal pain regimens that has been shown to reduce acute 
postoperative pain.  
1.2 Investigational Agent 
Gabapentin is a non-narcotic medication developed to target neuropathic pain1.  It is an amino acid 1-
(aminomethyl)cyclohexaneacetic acid that is structurally related to the inhibitory neurotransmitter GABA 
(gamma-aminobutyric acid), without modifying the binding, metabolism, or elimination of GABA.  In vitro 
studies have demonstrated gabapentin binding sites in the rat brain, but the functional implication and the 
mechanism of its analgesic and anticonvulsant activity remains unknown in humans.  The oral 
bioavailability of gabapentin decreases as dose increases.  Its half-life is 5-7 hours, and it is eliminated by 
renal excretion without chemical alteration.  Dose adjustments are recommended for creatinine clearance 
less than 30 mL/min.  It is FDA approved since 1993 for post-herpetic neuralgia and epilepsy, and has 
been widely applied in neuropathic pain management.  It is also frequently used for acute postoperative 
pain, and meta-analysis of randomized controlled trials shows it to be an effective pain management 
strategy in postoperative patients.  The major adverse reactions reported were, in descending frequency, 
dizziness, sedation, asthenia, diarrhea, dry mouth, constipation, nausea, and vomiting 23. 
1.3 Clinical Data to Date 
Numerous randomized controlled trials demonstrated that gabapentin effectively reduced narcotic use 
and improved subjective pain in various surgical populations, such as gynecology-oncology and 
orthopedic surgery9-15.  Meta-analyses of these pooled trials reported an overall trend toward improved 
pain control and decreased postoperative narcotic use with gabapentin, despite the heterogeneity of the 
included studies6,16-19.  A small number of studies have examined the use of gabapentin in postoperative 


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otolaryngology patients and suggest a potential benefit in improving postoperative pain control after 
thyroidectomy, endoscopic sinus surgery, oral cavity resection with reconstruction, and tonsillectomy9-15. 
Most of the studies demonstrated an improvement with only one preoperative dose.  To date, no 
randomized control trials have been conducted with gabapentin use in adult otolaryngology patients 
undergoing all types of head and neck mucosal surgeries, which is an at-risk population for high levels of 
postsurgical pain. 
1.4 Dose Rationale and Risk/Benefits 
Dosing regimen of gabapentin will be 300 mg PO preoperatively, followed by 300 mg BID until POD 2 or 
the day of discharge, whichever comes first. Note that on the morning of POD3 at 7am, a VAS will be 
obtained to reflect the POD 2 7pm dose.  The liquid formulation will be used postoperatively given the 
possibility of dysphagia or postoperative NPO status potentially requiring a feeding tube.  The optimal 
dosage for gabapentin in acute postoperative pain is unknown.  Recommended gabapentin regimen for 
treatment of post-herpetic neuralgia is a 300 mg/day on day 1, 300 mg BID on day 2, 300 mg TID on day 
3, and subsequently up-titrated as needed to 600 mg TID23.  Prior studies using gabapentin for 
postoperative pain control in otolaryngology patients have primarily administered a single preoperative 
dose ranging from 100 mg to 1200 mg9-15. Data was inconsistent as some studies showed efficacy at low 
dosages and some showed no difference at high dosages, and an optimal dose regimen remains to be 
determined.  For this study a relatively low dosage was chosen to minimize sedation side effects, as 
included participants are likely to be gabapentin-naïve.  The perioperative BID dosing period was chosen 
to better elucidate the effects of gabapentin in the acute, postoperative period, as many head and neck 
mucosal resections cause significant pain for several days after the procedure.  The majority of head and 
neck inpatient stays are between 2-3 days, with some staying as short as 1 day and some as long as a 
few weeks.  At this dose and schedule, gabapentin side effects are minimized so that subject risk is also 
minimized without compromising medication analgesic abilities.  Collaboration with the inpatient pain 
management team also supports the expectation that this dose and time regimen will be effective and will 
minimize side effects.  
 
Post-operative swallow results will be collected from the medical record on those patients receiving post 
op swallow therapy per routine care.  The post-operative swallow evaluation will be observational, based 
solely on the discretion of the surgeon and is not required per the research protocol.  
2 Study Objectives 
This investigation is a quality improvement initiative designed to elucidate the benefit of gabapentin in 
pain management in subjects undergoing surgical resection of head and neck mucosal surfaces. 
 
Primary Objective 
To assess the efficacy of gabapentin on decreasing narcotic requirements for treatment of acute 
postoperative pain in head and neck patients undergoing surgical resection of mucosal surfaces. 
 
Secondary Objectives 
To assess subjective pain scores and participant satisfaction with pain control.  
 
  
3 Study Design 
3.1 General Design 
This is a prospective, randomized, double-blind, placebo-controlled study with the intent of providing high 
quality and reproducible data.  The study subjects include adult otolaryngology patients over the age of 
18 years undergoing open or endoscopic/robotic resection involving the mucosal surfaces of the oral 
cavity, oropharynx, hypopharynx and larynx in a single tertiary academic center.  Participants are 
recruited from the otolaryngology head and neck cancer clinic during their preoperative visits.  The 
duration of subject participation includes the subsequent inpatient hospitalization following definitive 


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cancer resection up to two days after surgery.   Subjects will be given the placebo or gabapentin for up to 
two days post op or until discharge, whichever comes first.   
 
Potential subjects will be recruited from the patient population in the head and neck surgery clinic, 11th 
floor CAM, the center for outpatient health or at other outpatient or inpatient sites related to their pre-
surgical planning visits.  Eligible patients will be identified before their scheduled appointments via review 
of medical records in Allscripts by a study team member and approached either in the exam room during 
their scheduled appointment with the head and neck surgeons or afterwards via telephone call.  The 
study will be explained to them and a copy of the consent form will be provided after it has been signed.  
Patients will be reminded that participation is voluntary and will in no way affect their current or future care 
related to their head and neck health needs. Patients will be given time to ask questions and will have the 
option to consider participation and enroll at a subsequent appointment before their planned procedure. 
The consent process will take place in a private room.  Steps to avoid coercion include proper training in 
informed consent, private discussion rooms in which the surgeon is not present, and patients will be 
reassured that their care from their head and neck surgeon will not be affected by their decision to 
participate or to not participate.  Patients will be made aware that their postoperative care will not be 
limited by participation in this study, meaning that they will not be denied needed and appropriate narcotic 
pain medications simply because they are enrolled.  Written informed consent will be obtained prior to the 
start of research related procedures. 
 
 
 


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**Note that IV and PO or per tube morphine will be used in amounts equivalent to the dilaudid and oxycodone medications 
above if an allergy or intolerance to dilaudid or oxycodone exist. 
 
Subjects will present for their planned procedures to the pre-op surgery office and will be taken to the pre-
op holding area as per usual hospital procedure.  A study team member will meet the subject in the pre-
op holding area and will administer the pre-op medication approximately 1 hour prior to surgery start time. 
Patients will not be excluded if surgery start time is delayed past 1 hour.  An investigational pharmacist 
will deliver the medication appropriately labeled with patient name and study number to the pre-op 
holding area.  This oral administration is safe per consultation with the anesthesia faculty member of this 
project.  Additionally, on the day of surgery a study member will place pain medication orders in compass 
on hold for post op care.  These orders will be 1000mg of Tylenol PO or per tube Q6 hours (or Q12 hours 
if the patient has hepatic insufficiency), oxycodone 5-10mg Q4 hours PRN pain (5mg if pain less than or 
equal to 5/10, 10mg if greater than 5/10), and dilaudid 0.25-0.5mg Q2 hours PRN breakthrough pain 
(0.25mg if pain less than or equal to 5/10, 0.5mg if greater than 5/10).  Alternatives to these medications 
in case of allergy or intolerance is 1-2mg IV morphine Q2 hours PRN pain (1mg if pain less than or equal 
to 5/10, 2mg if greater than 5/10) and 7.5-15mg PO/PT liquid IR morphine Q4 hours PRN pain (7.5mg if 
pain less than or equal to 5/10, 15mg if greater than 5/10).  Additionally, the study team member will 
place the appropriate investigational drug order in compass.  The subject will be able to receive increases 
in pain medications as deemed appropriate by the inpatient treating physicians.  They will not have any 
limitations set on pain medications simply because they are involved in the study.  The subject will then 
proceed with surgery as planned. No alterations to intraoperative medications or anesthetic agents will be 
made based on study participation. 
 
The subject will return to the PACU after extubation.  If the subject had to remain intubated, he or she will 
be withdrawn from the study as he or she cannot complete pain scores while sedated. Additionally, if the 
subject is at any point during the study placed on alcohol withdrawal medication protocols, he or she will 
be withdrawn from the study.  The study team member administering the preoperative dose will remind 
anesthesia to use the same post-operative initial pain management options in the PACU at least initially, 
again with no restrictions on dose escalations that are needed.  The PACU can increase the dose of 
postoperative pain medications based on patient need and MD approval as per the usual PACU protocol 
without restriction based on a subject’s study participation.  Subjects will remain in the PACU per the 
usual protocol until the required level of alertness and clinical stability are reached for transfer, and their 
PACU medication sheet will be copied and added to their hard copy file for use later during 


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tabulation/data anaylsis of the pain meds they required The VAS score obtained after surgery will be 
completed 45 minutes to 1 hour after extubation in the PACU.  
 
Note that subjects must have completed surgery (extubated) by 5PM in order to receive the 7PM dose 
after their surgery.  Otherwise, this dose is to be skipped and the next dose administered will be at 7AM 
the next day.  VAS scores can still be obtained at 45 minutes to 1 hour postoperatively, however, even if 
the case finishes later than 5pm. On POD 1-2, subjects will be given BID medications at 7am and 7pm 
per the study protocol and VAS scores will be obtained prior to medication administration   A separate 
VAS will be obtained at 10am on POD1 and POD 2.  ON POD 3 a 7am VAS will be obtained but no study 
medication given. This last VAS concludes participation in the study.  Discharge surveys will be 
administered at this point if they have not been already (ie if the patient remained an inpatient for longer 
than 2 days postop).   
The investigational pharmacist will have delivered the medication dose in a properly labeled container to 
the 6200 inpatient floor prior to scheduled doses, and the medications will be stored in patient labeled 
bins in the locked medication refrigerator.  All VAS scores will be obtained with subject privacy optimized, 
including drawing the curtain in subject room to separate the sides of the room from any potential 
roommate.  Also, the research team member will not vocalize a subject’s status as a study patient.  VAS 
scores will be obtained at rest, with cough and following a swallowing gesture.  Scores are captured by 
providing the subject with a pen and asking the subject to mark the location of their pain on a line 
measuring 10cm during each phase of the VAS.   The scale is a validated tool that measures 10cm in 
size and is marked “no pain” on the far left and “worst pain” on the far right.  The subject marks their pain 
level on the scale and the study team member will measure with a ruler and record the resulting number 
in the study database.    
Subjects will fill out a discharge survey before they are discharged or at the completion of their 
participation to rate their satisfaction with their inpatient pain control.  This survey will be a hard copy 
labeled with study ID and the data will be entered into the study database.  All hard copy data will be 
stored in a locked cabinet accessible only to the study team.  At the end of the study, all hard copy data 
will be properly destroyed.   
 
Subjects will have 24/7 access to members of the study team should questions or concerns arise while 
they are actively participating in the study as well as up to 30 days after completion of the study.   
 
Note that study medication wrappers have patient names on them as a safety mechanism to make sure 
medications are given to the proper patient.  These wrappers and labels will be saved in the patient 
folders which are secured in a locked cabinet where only study team members have access.  Empty and 
unlabeled medication syringes will be discarded in the red biohazard bins inside patient rooms.  
3.2 Primary Study Endpoints 
The primary study endpoint is postoperative narcotic consumption.  Average daily narcotic use from 
postoperative admission to the last dose of pain medication on POD 2, or the day of discharge, whichever 
comes sooner, will be calculated. Total amount of narcotic use in morphine equivalents will be divided by 
the total hours of inpatient hospitalization, multiplied by 24 hours, to obtain the average daily narcotic 
consumption. 
3.3 Secondary Study Endpoints 
The secondary endpoints include (a) subject satisfaction with pain control, (b) VAS pain scores, (c) 
patient baseline pain perceptions (d) hospital length of stay, and (e) potential side effects of the 
medication.  
 
(a) Subject satisfaction with pain control will be captured in a survey administered at POD 2 after the 
AM dose administration, or after the AM dose administration on the day of discharge, whichever 
comes sooner.  Two of the survey questions will mirror those on the HCAPHS surveys, listed as 
followed (see attached “post-treatment questionnaire”): 
 
1. How often was your pain well controlled? 


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0) Never 
1) Sometimes 
2) Usually 
3) Always 
 
2. How often did the hospital staff do everything they could to help you with your pain? 
0) Never 
1) Sometimes 
2) Usually 
3) Always 
 
3. How satisfied are you with your overall pain control? 
0) Very dissatisfied 
1) Somewhat dissatisfied 
2) Neutral 
3) Somewhat satisfied 
4) Very satisfied 
 
4. Was there anything else that we could have done to make your pain control better during your 
inpatient stay? 
A point system is created with the sum of the numeric values assigned to questions 1-3 on a scale of 
0 to 10, with a score of 0-3 indicates overall dissatisfaction, 4 indicates neutrality, and 5-10 suggests 
overall satisfaction.  This will be analyzed as an ordinal variable. 
 
(b) VAS pain scores will be assessed 45min to 1 hour after surgery and then three times a day on 
POD 1-2 and once on POD 3, or until day of discharge, whichever comes sooner. A standardized 
VAS form will be given to subjects with verbal instruction to first “mark on the line the point that 
you feel represents your current pain level when you’re resting.”  This is followed by asking the 
subject to gesture swallowing and “mark another point on the line that represents your pain level 
when you swallow.”  Lastly, the subject will be asked to cough and to “mark the final point on the 
line that represents your pain when you cough.”  The study team member administering the test 
will annotate what each mark represents (rest, swallow, and cough).  The scale contains a 10-cm 
line from “no pain” on the left to “extreme pain” on the right (see “VAS form”).  The distance in 
centimeters from the left of the line to the center of the patient’s three marks will be recorded.  
The results from all available VAS scores for each subject will be averaged and included in the 
final analysis.  
 
(c) The subject’s belief in pain medication efficacy and pain tolerance will be assessed from a short 
survey obtained preoperatively during the office visit (see “pre-treatment questionnaire”). This 
includes the following questions: 
 
1. In the past, how effective are narcotic pain medications (such as morphine, Vicodin, Norco, 
Percocet, oxycodone, Dilaudid) at controlling your pain? 
0) Very ineffective 
1) Somewhat ineffective 
2) Somewhat effective 
3) Very effective 
 
2. In the past, how has your pain tolerance been? 
0) Very poor 
1) Somewhat poor 
2) Somewhat tolerant 
3) Very tolerant 


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3. Do you experience a significant amount of pain on a daily basis aside from the pain due to 
your current head and neck condition? 
1) Yes I do 
2) No I do not 
The results of these questions will be reported separately in the final analyses. 
 
(d) Hospital length of stay will be calculated for each subject. 
 
(e) During the VAS scores, study team members will also collect information about potential 
medication side effects, including those that are commonly associated with gabapentin or with 
narcotic medications.  
3.4 Primary Safety Endpoints 
The primary safety endpoints are the rate and severity of drug-related adverse events.  Adverse events 
will be monitored and recorded by study team members during subject inpatient stay.  These events will 
be reviewed by the principal investigator and categorized into “drug-related”, “likely drug-related”, and 
“unlikely drug-related.”  Any significant adverse events determined to be likely drug related will be 
reported to the OHRP within a 24 hour time period and stopping the study for the subject will be 
discussed.  A safety meeting will be heald half way through the study with the PI and all involved faculty 
mentors to determine if an interim analysis is necessary, This analysis would be considered necessary if 
a significant number of adverse events likely related to the study medication were occurring, and an 
analysis to make sure the study was not causing harm to the treatment group was needed. 
4 Subject Selection and Withdrawal 
4.1 Inclusion Criteria 
 
Subjects undergoing definitive mucosal head and neck resection including oral cavity, 
oropharynx, larynx, and hypopharynx 
 
At least 1 night of planned inpatient stay 
4.2 Exclusion Criteria 
 
Incapable of giving informed consent 
 
Age < 18 
 
GFR < 30 
 
Allergy to gabapentin  
 
Baseline gabapentin or lyrica use 
 
Chronic opioid use for over 6 months 
4.3 Subject Recruitment and Screening 
Subjects will be recruited either in the outpatient head and neck clinic prior to their planned surgeries or 
over the phone after this clinic appointment by designated study team members.  Potentially eligible 
patients will be identified by study team members prior to their scheduled appointments via the outpatient 
medical records system.  Patient recruited by phone will be able to sign the informed consent prior to 
surgery either at a subsequent surgical planning visit or in the pre-op holding are on the day of surgery.  
Eligible subjects will be consented in a private setting and the study outline explained to the patient. 
Written informed consent will be obtained from those patients who wish to participate.  Patients may 
choose to think about study participation but will need to decide and provide written consent prior to the 
day of surgery, either at their subsequent preoperative anesthesia clinic appointment or medical 
oncology/radiation oncology appointments.  Study team members will be properly trained in the informed 
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4.4 Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
Subjects may be withdrawn from the study prior to the expected completion if they develop 
hypersensitivity reactions to the study drug, are unable to swallow all study drugs in the study period, or 
choose to withdrawal for other reasons.  They will also be withdrawn if they remain sedated or intubated 
after the surgery or are placed on alcohol withdrawal medication protocols, which also cause significant 
sedation.  Subjects without a feeding tube who are unable, or unwilling, to swallow medications after 
surgery will not be given a feeding tube to remain in the study.  A 20% dropout rate was anticipated and 
accounted for in the sample size calculation.  Subjects will be able to withdraw on a continual basis 
throughout their participation.  Withdraw can be requested either by the subject or by any team member if 
medical significant adverse reactions are observed.  All withdraws will be reviewed by the principle 
investigator.  No subject will be denied the ability to withdraw. The withdraw process will begin 
immediately when deemed necessary or when desired by the subject, and documentation of the reason 
and time of withdraw will be performed.   
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
Withdrawn subjects will be excluded in the final data analysis. The reasons for withdrawal will be 
recorded and reported separately in the study data outcomes. 
 
4.4.3 Definitions 
Subject withdraw: Withdraw is defined as a subject who signed the informed consent document and for 
whatever reason dropped out of the study before completion, whether by choice or by exclusion criteria 
(ie- staying intubated the night after surgery). 
 
Subject screen fail: A screen fail is defined as a subject who has been recruited to participate and 
approached but does not meet all inclusion criteria.  
 
5 Study Drug  
5.1 Description 
300mg of liquid gabapentin or an equal volume of placebo will be pre-packaged by the investigational 
pharmacist in a labeled medication syringe or in a marked bag with a capsule.  An unblinded study team 
member in charge of the randomization process will indicate to the pharmacy which subjects are to 
receive what medication.  The blinded study team members will not know which medication contains 
placebo or gabapentin.  
5.2 Treatment Regimen 
Subjects will receive either placebo or gabapentin 300 mg PO the preoperative holding area 
approximately 1 hour before their procedure is scheduled to begin.  This first dose will designate the day 
of their procedure as POD 0.  If the procedure ends late in the evening (ie not extubated before 5pm), and 
the subject is not able to receive the second POD 0 dose by 7 PM, then this second POD 0 dose will be 
skipped.   Participants will then receive either placebo or 300 mg of gabapentin BID POD 1- POD 2.  
Dosing will end either on POD 2 after the PM dose or on day of discharge after the AM dose, whichever 
comes first.  VAS scores will be collected 45 minutes- 1 hour post extubation on POD as well as TID on 
POD 1-2 and one time at 7am on POD 3 (see above protocol flowsheet).  


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5.3 Method for Assigning Subjects to Treatment Groups 
After a subject consents to study, the unblinded data manager will randomize the subject into active or 
placebo group and assigned an enrollment ID.  The enrollment ID is given to any subject who signs 
consent. If the subject then proceeds to start the study and receive a medication dose, they will also be 
given a subject ID which reflects their randomization group.  The study ID reflects randomization while the 
enrollment ID is used to enter them into OnCore and track their consent.  
5.4 Preparation and Administration of Study Drug 
The Investigational Pharmacist will mix and prepare the study medications necessary for each subject.  A 
pharmacist will deliver the medication to the preop holding unit or the floor and a designated study team 
member will administer it.  Please see section 5.7 below for mixing and packaging details. Contact 
information for the pharmacy for this project is pharmacist Kathryn Vehe at 314-795-7286. 
 
Inpatient pharmacists will be responsible for delivering the medication to the floor prior to the AM dose 
and to the PM dose, as well as will deliver the medication to the pre-op holding area prior to a subject’s 
procedure. Formal training for all study team members who will be administering the study drug or 
obtaining the VAS pain scores is required prior to subject interaction. 
5.5 Subject Compliance Monitoring 
The study team members will directly administer each study medication dosage during the study period 
and record adherence to study protocol.  If a dose is missed during this period, the subject will remain in 
the study through the completion of the protocol.  The decision to include data from subjects with missed 
doses will be made at the discretion of the principle investigator and statistician at the conclusion of the 
study.   Data integrity will be maintained such that subjects who are excluded for missed doses will be 
consistent among cases.  
5.6 Prior and Concomitant Therapy 
Every subject will have standard postoperative narcotic medications made available: 
 IV Dilaudid 0.25-0.5mg q2h PRN breakthrough pain (pain equal to or less than 5/10 will get 
0.25mg and pain >5/10 will get 0.5mg).  
 PO/PT oxycodone 5-10mg q4h PRN pain (pain equal to or less than 5/10 will get 5mg, and pain 
greater than 5/10 will get 10mg).  
 PO/PT acetaminophen 1000mg q6h for pain in non-cirrhotic patients, and 1000mg q12h in 
cirrhotic patients 
 Morphine IV and PO liquid equivalents will be substituted in cases of oxycode or dilaudid 
allergies. 1-2mg IV morphine Q2 hours PRN will be substituted for 0.25-0.5mg dilaudid for 
breakthrough pain (pain equal to or less than 5/10 will get 1mg and pain >5/10 will get 2mg).   
PRN liquid IR morphine 7.5-15mg will be substituted Q4 hours for oxycodone PRN for pain (pain 
equal to or less than 5/10 will get 7.5mg, and pain greater than 5/10 will get 15mg) 
 Study team members will place an order in compass for study investigation drug administration 
as per BJC protocol for investigational drug use.   
 
These medications can be up-titrated as needed at the discretion of the physicians managing the 
patient’s care as part of the routine postoperative management. 
5.7 Packaging 
 Study medications will be in liquid or capsule form.  Gabapentin comes as a standard liquid form 
of 250mg/5ml. Capsules will be used for the pre-operative dose, and will come as single capsules 
in bags labeled with study ID and name.  For post-operative doses, 6ml of either gabapentin or 
placebo will be packaged into a brown 20ml plastic syringe.  Each syringe will have the subject 
name and study ID on it.  The pharmacy will be made aware of all upcoming study subjects and 
will prepare the medications approximately 24 hours prior to administration, and will store these at 


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4 degrees Celsius.  The medications will be stored prior to dosing on the floor in a locked fridge in 
patient specific compartments, as per the floor medication protocol.  
5.8 Blinding of Study Drug 
The study team members administering the medications will be blinded towards whether a subject 
receives the study drug or the placebo.  The data manager who does not participate in data collection or 
have direct subject interaction, as well as the pharmacist preparing the medications, will be unblinded. 
5.9 Receiving, Storage, Dispensing and Return 
5.9.1 Receipt of Drug Supplies 
Investigational pharmacists will be responsible for medication delivery prior to planned doses.  They will 
be alerted to upcoming procedures that involve study subjects.  They will be responsible for delivering the 
medication to the inpatient floor and in the preoperative holding area.  Any damaged or unusable study 
drug in a given shipment will be documented in the study files and discarded. 
5.9.2 Storage 
Medications will be stored by the investigational pharmacy in a designated, locked area at 4 degrees 
Celsius. They will be stored on the inpatient floor in a locked, 4 degree fridge in patient specific 
compartments per the floor medication storage protocols.  
5.9.3 Dispensing of Study Drug 
The study team members administering the medications will receive the medication from the 
investigational pharmacist.  They will then administer the medication and record the time of administration 
and the subject identification number in the subject’s study flow sheet (“Gaba project subject study flow 
chart” attached). 
5.9.4 Return or Destruction of Study Drug 
At the completion of the study, there will be a final reconciliation of medications consumed.  This 
reconciliation will be logged on the drug reconciliation form, signed and dated.  Any discrepancies noted 
will be investigated, resolved, and documented.  Medication syringes will be discarded in the red 
biohazard containers in accordance with hospital policy and documented in the study files. Any labels or 
bags with patient names will be discarded in the shred bins on the 6200 floor or in the preop holding unit.  
 
6 Study Procedures 
The study procedures are outlined below and represented in the attached “Gaba project subject study 
flow chart”.  
 
Clinic Visit 
 
Consent. 
 
Pre-treatment questionnaire. 
 
Randomization group will be assigned by the study data manager after she is notified of subject 
agreement to participate. 
Day of Surgery 
 
One dose of study drug will be administered preoperatively according to subject’s randomization 
group approximately 1 hour prior to procedure start time.  The coordinator administering the 
medication will tape a study reminder sheet for anesthesia to the chart and will place an order in 
the chart that allows the participant to take the preop medication dose, and the RN to chart this 
dose as a study medication.  


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 
Standard pain medications orders will be provided. Morphine will be used as a substitute for 
dilaudid or oxycodone allergies or intolerances. These will be up-titrated as needed per discretion 
of service residents and attending physicians. 
 
One VAS score will be obtained 45 minutes to 1 hour postoperatively regardless of extubation 
time. 
 
One postoperative dose of study drug and VAS will be administered at 7pm if subjects are 
extubated by 5PM 
Post-Operative Day (POD) 1-2 
 
TID VAS scores will be obtained, two of which will be prior to drug administrations. 
 
BID study drug administration will be conducted according to subject’s randomization groups. 
POD 3  
 
POD 3 VAS at 7am will be obtained.  
POD 3 or Day of Discharge 
 
Post-treatment pain satisfaction questionnaire will be conducted either after the AM dose on POD 
3 or on date of discharge, whichever comes sooner. 
7 Statistical Plan 
7.1 Sample Size Determination 
Sample size calculations were performed based on prior studies with gabapentin use in otolaryngology 
patients undergoing thyroidectomy21.  A study by Al-Mujadid et al in a population of patients undergoing 
elective thyroidectomy reported that total morphine consumption in the placebo group in the first 24 hours 
post surgery required a mean of 29.5mg of morphine with a standard deviation of 9.9mg.  Assuming that 
this magnitude of effect variability will hold true in this project population, it is estimated that 46 subjects 
per group (total n=92) will be needed to detect with an 80% power at the 2-sided alpha level of 0.05 a 
difference of 20% or greater in average morphine dose (effect size d=0.6) between the placebo and 
gabapentin groups.  Assuming a 20% drop out rate, 116 subjects will be enrolled in this study.  The 
volume of eligible subjects for this study is predicted to meet the calculated sample size within two years 
of study start time. A review of surgical procedures meeting inclusion criteria performed over a sample 
three month time frame ranged from 12 to 17 procedures a month.  
Note that IV morphine equivalents will be used rather than PO.  
7.2 Statistical Methods 
Descriptive statistics will be used to describe distribution of demographics. Bivariate analysis using 
independent samples t-test for continuous variables and chi square test for categorical variables will be 
used to compare distribution of characteristics between treatment groups to ensure successful 
randomization. 
Note that in discrepancies of data between reports, such as pack years smoked by a patient, an average 
of the reported amounts will be used to ensure consistency between data reporting fluctuations.  
 
The primary and secondary outcome measures will be compared between the two treatment groups via 
bivariate analyses.  In addition, a General Linear Model (GLM) approach will be used to explore the 
impact of gabapentin as compared to placebo on each of the outcomes of interest after controlling for 
potential cofounders that were unevenly distributed between the two groups.  The estimated mean 
difference and 95% confidence interval will be reported. 


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7.3 Subject Population(s) for Analysis 
Protocol-compliant subjects who received all study drugs up to the conduction of post-treatment 
questionnaire will be included for analysis.  Subjects with missed medication doses will go on to complete 
the protocol, and per the discretion of the principle investigator and statistician may or may not be 
included in the data analysis.  Data integrity will be maintained such that subjects who are excluded for 
missed doses will be consistent among cases. 
 
8 Safety and Adverse Events 
8.1 Definitions 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
 Unexpected in nature, severity, or frequency  (i.e. not described in study-related documents such 
as the IRB-approved protocol or consent form, the investigators brochure, etc) 
 Related or possibly related to participation in the research (i.e. possibly related means there is a 
reasonable possibility that the incident experience, or outcome may have been caused by the 
procedures involved in the research) 
 Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm). 
 
 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study.  Intercurrent illnesses or injuries that occur during the study period will be 
regarded as adverse events (meaning that the event does not necessary have to be likely related to the 
study drug to be considered an adverse event).  However, not all adverse events will meet criteria for 
reporting.  Abnormal results of diagnostic procedures will be reported as adverse events if the 
abnormality: 
 results in study withdrawal 
 is associated with a serious adverse event (see definition below) 
 is associated with clinical signs or symptoms that are considered significant and likely related to 
study participation  
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 
 
Serious Adverse Event 
Adverse events are classified as serious, moderate or mild.  .  A serious adverse event is any AE that is:  
 fatal 
 life-threatening 
 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event 
 
Mild and Moderate adverse events: 
A moderate adverse event is one that requires a medical intervention such as medication for nausea, but 
that does not cause permanent clinical harm and that does resolve in a reasonable amount of time. 
 
A mild adverse event is one that causes mild clinical effect and may or may not require medical 
intervention. It is expected to resolve completely with observation or medical treatment.  
 
 
Adverse Event Reporting  


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The study period during which adverse events that are deemed reportable  must be reported will be the 
period from the day of surgery to the end of the study, which is POD 3 or sooner if discharge is sooner 
than POD 3. Ideally, these events will be reported to the PI within 24 hours of their occurrence.  Serious 
AE must be reported within 24 hours, however. Additionally, subjects will be provided with contact 
information for the study member that is in charge of adverse event follow up (Melanie Townsend, PI).  
They will be instructed to contact this person with questions related to the study, adverse events or side 
effects experienced after discharge so that the study members can be alerted to any events that may be 
related to the medication. Any severe adverse events or moderate events thought likely to be related to 
the study medication that are reported to the PI during this 30 day window will be recorded.    Adverse 
events that occur during the inpatient study period and are significant/severe as defined above or that are 
unusual will be required to be reported in the adverse events log. The PI will be made aware of all of 
these events immediately after they occur.  Events that are mild will not be required to be recorded in the 
adverse events log.  Events that are moderate and thought likely related to the study medication will be 
reported.  Events that are moderate but deemed unlikely to be due to the study medication will not be 
required to be reported in the adverse events log.  However, these events may still be recorded in the 
adverse events log at the discretion of the PI.  The PI will sign off on all adverse events that are recorded 
in the adverse event log.  
 
For all severe AE or AE that are unexpected and thought likely related to the study medicaiton, an IRB 
event form will be submitted. For  moderate events thought likely to be due to the medication or 
unexpected, an event form will be submitted at at the discretion of the PI. This design is intended to make 
sure that if subjects seem to be having symptoms that aren’t expected to be caused by study participation 
but are noted in multiple subjects, then this gets reported.  However, those side effects that are common 
after surgery (such as sedation or nausea) that could also be related to study medications are noted in 
the AE log when appropriate but not generating multiple IRB reportable event forms.  The goal is to 
ensure subject safety and also only report appropriate events to the IRB.  All adverse events, whether 
mild, moderate or severe, will be reviewed at the safety meeting by all team members and faculty 
advisors to ensure that proper reporting has occurred.   
 
 
Post-study Adverse Event 
All unresolved adverse events will be followed by the investigator until the events are resolved, the 
subject is lost to follow-up, or the adverse event is otherwise explained.  At the last scheduled visit, the 
investigator will instruct each subject to report any subsequent event(s) that the subject, or the subject’s 
personal physician, believes might reasonably be related to participation in this study in the 30 days 
window follow discharge.   
8.2 Elliciting Adverse Events from Subjects  
At each interaction with the subject, the investigator will seek information on adverse events by specific 
questioning and, as appropriate, by examination.  Information on all adverse events will be recorded 
immediately in the data recording form that is used to record subject data at each interaction.  Reporting 
of these events is as outlined above.  Specific side effects that will be elicited at each interaction include 
nausea, vomiting, dizziness and sedation.   
 
8.3 Unblinding Procedures 
For this study only the data manager and pharmacy will be unblinded to the study drug and placebo 
assignments.  Unblinding of the rest of the study investigators will occur after assurance that data 
collection has completed.  If any subject data is intentionally or unintentionally unblinded, the event will be 
documented in detail in the study documents within 48 hours.  Any unblinding that occurs during the study 
period for an individual participant will result in exclusion of that participant’s data from final analysis.  
Study investigators must report unblinding to the PI within a 24 hour time period and must document the 
event.  Subjects will immediately be made aware of the unblinding and will be withdrawn from completing 
the protocol.  


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Stopping Rules  
The study will be terminated prematurely if 50% or more of the subjects receiving study drug (gabapentin 
or placebo) experience significant adverse events as defined above in section 8.1.  The study will not be 
prematurely stopped if subjects experience less significant medication side effects, specifically nausea, 
vomiting, dizziness and sedation.  A review of adverse events will be conducted at 25% by the PI and at 
50% enrollment by the entire team to ensure that they are properly tracked.  
8.4 Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study.  This safety 
monitoring will include careful assessment and appropriate reporting of adverse events as noted above, 
as well as the construction and implementation of a site data and safety-monitoring plan (see section 10 
Monitoring).  Medical monitoring will include a regular assessment of the number and type of serious 
adverse events.   A safety meeting will be held half way through enrollment as described above, 
9 Data Handling and Record Keeping 
9.1 Confidentiality 
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).   
Source data will be kept primarily in the electronic forms using REDCap for data collection.  Paper forms 
including the original consents, questionnaires, VAS pain score sheets, adverse event reporting forms 
etc. will be kept in a locked cabinet that only study team members have access to.  At the conclusion of 
the study, after data has been entered into a password protected spread sheet, these records will be 
destroyed in the proper manner in shred it bins where patient information is normally placed.  The official 
source document and case report form for this study will be the REDCap database. 
 
 
All research records will be maintained in the Outcomes Office, 8th floor McMillan for 7 years after study 
completion per WU record retention policy.  
 
10 Study Monitoring 
10.1 Study Monitoring Plan 
This study will be monitored in real time for each subject by the PI and study team.  At minimum, with 
25% accrual goal all adverse events and data collection forms will be reviewed by the PI and discussed 
among the study team. A designated, third party safety officer will review the study approximately half 
way through to ensure that subjects are not being harmed by this study.  At our interim safety meeting, 
we determined by our AE log that significant adverse events were not occurring to study patients and 
events that were moderate and likely related to the medication also were extremely infrequent. We 
determined at that time that a third party officer review was unnecessary, especially in light of the fact that 
we were aware at that point that an audit would occur.  We will proceed to study completion without this 
third party review.  We also will be reporting our study events and AE events in a DSM log to the Siteman 
monitoring committee, which will also serve as a third party review.  
 
11 Medication processing  
 


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11.1 Medicaiton Processing 
All unused medications will be picked up from the pharmacy within 12 hours of the time they are 
determined to be not needed or not used.  The pharmacy will be alerted in real time that the medication 
was not needed so that they can expect to pick it up.  A confirmation communication will be sent to the 
study team once the medication is retrieved to ensure that it is properly picked up. 
12 References 
1. Chang C.Y., Challa C.K., Shah J., Eloy J.D. Gabapentin in acute postoperative pain management.  
BioMed Research International Vol. 2014.  2014.  
2. Rafiq, Sulman, et al. "Multimodal analgesia versus traditional opiate based analgesia after cardiac 
surgery, a randomized controlled trial." J. Cardiothorac. Surg 10 (2014): 1749-8090. 
3. Kehlet H, Jensen TS, Woolf CJ: Persistent postsurgical pain: risk factors and prevention.  Lancet 
2006 May 13, 367(9522):1618-1625.  
4. Kehlet H: Multimodal approach to postoperative recovery. Curr Opin Crit Care 2009 Aug, 15(4):355-
358.  
5. Kong VK, Irwin MG: Gabapentin: a multimodal perioperative drug? Br J Anaesth 2007 Dec, 
99(6):775-786.  
6. Tiippana EM, Hamunen K, Vesa KK, Kalso E. Do surgical patients benefit from perioperative 
gabapentin/pregabalin? A systematic review of ef fi cacy and safety. Anesth Analg. 2007;104(6): 
1545–56. 
7. Clarke H, Bonin RP, Orser BA, Englesakis M, Wijeysundera DN, Katz J. The prevention of chronic 
postsurgical pain using gabapentin and pregabalin: A combined systematic review and meta-analysis. 
Anesth Analg. 2012;115:428–42 
8. Levine, Adam I., Satish Govindaraj, and Samuel DeMaria, eds. Anesthesiology and Otolaryngology. 
Springer, 2013. 
9. Lee J.H., Lee H.K., Chun N.H., So Y., Lim C.Y.  The prophylactic effects of gabapentin on 
postoperative sore throat after thyroid surgery.   Korean Journal of Anesthesiology 2013 64:2 (138-
142). 
10. Mohammed M.H., Fahmy A.M., Hakim K.Y.K. Preoperative gabapentin augments intraoperative 
hypotension and reduces postoperative opioid requirements with functional endoscopic sinus surgery. 
Egyptian Journal of Anaesthesia 2012 28:3 (189-192). 
11. Ahn S.H., Lee J.H., Min K.T. The prophylactic effects of gabapentin on postoperative sore throat after 
thyroid surgery.  European Journal of Anaesthesiology 2012 29 SUPPL. 50 (202). 
12. Chiu T.W., Leung C.C.H., Lau E.Y.K., Burd A. Analgesic effects of preoperative gabapentin after 
tongue reconstruction with the anterolateral thigh flap. Hong Kong Medical Journal 2012 18:1 (30-34)  
13. Kazak Z., Mortimer N., Mekerci S. Single dose of preoperative analgesia with gabapentin (600 mg) is 
safe and effective in monitored anesthesia care for nasal surgery. European Archives of Oto-Rhino-
Laryngology 2010 267:5 (731-736).  
14. Jeon E.-J., Park Y.-S., Park S.S., Lee S.-K., Kim D.-H. The effectiveness of gabapentin on post-
tonsillectomy pain control. European Archives of Oto-Rhino-Laryngology 2009 266:10 (1605-1609). 
15. Turan A., Memi; D., Karamanlio;lu B., Yaiz R., Pamuk; Z., Yavuz E. The analgesic effects of 
gabapentin in monitored anesthesia care for ear-nose-throat surgery.  Anesthesia and Analgesia 
2004 99:2 (375-378). 
16. Hurley RW, Cohen SP, Williams KA, Rowlingson AJ, Wu CL. The analgesic effects of perioperative 
gabapentin on postoperative pain: A meta-analysis. Reg Anesth Pain Med. 2006;31:237–47. 
17. Peng PW, Wijeysundera DN, Li CC. Use of gabapentin for perioperative pain control—A meta-
analysis. Pain Res Manag. 2007;12:85–92. 
18. Seib RK, Paul JE. Preoperative gabapentin for postoperative analgesia: A meta-analysis. Can J 
Anaesth. 2006;53:461–9. 
19. Clivatti J., Sakata R.K., Issy A.M. Review of the use of gabapentin in the control of postoperative 
pain.  Revista Brasileira de Anestesiologia 2009 59:1 (87-98). 
20. Schmidt, Peter C., et al. "Perioperative Gabapentinoids: Choice of Agent, Dose, Timing, and Effects 
on Chronic Postsurgical Pain." Survey of Anesthesiology 58.2 (2014): 96-97. 


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21. Al-Mujadid, Hussain, et al. Preemptive gabapentin reduces postoperative pain and opioid demand 
following thyroid surgery. Canadian Journal of Anesthesia. March 2006, Volume 53, Issue 3, pp 268-
273. 
22. Sally L. Collins, R. Andrew Moore, Henry J. McQuay.  The Visual Analogue Scale: what is moderate 
pain in millimeters? Pain (Impact Factor: 5.21). 09/1997; 72(1-2):95-7. 
23. Accessfda.gov. Keyword “gabapentin”. PDF title: Neurontin. Parke-Davis Division of Pfizer Inc, NY, 
NY 10017.  April 2009.   
  


The effect of gabapentin on perioperative pain control among head and 
neck surgery patients 
 
NCT# NCT02926573 
 
 
Document Version Date:  02/10/2017 
 
IRB Approval Date:  02/17/2017 


 
CONFIDENTIAL 
 
CLINICAL RESEARCH PROTOCOL 
 
 
 
 
 
 
 
 
THE EFFECT OF GABAPENTIN ON PERIOPERATIVE PAIN 
CONTROL AMONG HEAD AND NECK SURGERY PATIENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Initial version: 3/31/2016 
Amended: 
[7/31/2016] 
Amended: 
[12/1/2016] 
Amended:  
[1/20/17] 


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Table of Contents 
 
STUDY SUMMARY ...................................................................................................................................... 1 
1 
INTRODUCTION .................................................................................................................................. 2 
1.1 
BACKGROUND ................................................................................................................................ 2 
1.2 
INVESTIGATIONAL AGENT ................................................................................................................ 2 
1.3 
CLINICAL DATA .............................................................................................................................. 2 
1.4 
DOSE RATIONALE AND RISK/BENEFITS ............................................................................................ 3 
2 
STUDY OBJECTIVES ......................................................................................................................... 3 
3 
STUDY DESIGN ................................................................................................................................... 3 
3.1 
GENERAL DESIGN .......................................................................................................................... 3 
3.2 
PRIMARY STUDY ENDPOINTS .......................................................................................................... 6 
3.3 
SECONDARY STUDY ENDPOINTS ..................................................................................................... 6 
3.4 
PRIMARY SAFETY ENDPOINTS ......................................................................................................... 8 
4 
SUBJECT SELECTION AND WITHDRAWAL .................................................................................... 8 
4.1 
INCLUSION CRITERIA ...................................................................................................................... 8 
4.2 
EXCLUSION CRITERIA ..................................................................................................................... 8 
4.3 
SUBJECT RECRUITMENT AND SCREENING ....................................................................................... 8 
4.4 
EARLY WITHDRAWAL OF SUBJECTS................................................................................................. 9 
4.4.1 
When and How to Withdraw Subjects ..................................................................................... 9 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects .......................................................... 9 
5 
STUDY DRUG ...................................................................................................................................... 9 
5.1 
DESCRIPTION ................................................................................................................................. 9 
5.2 
TREATMENT REGIMEN .................................................................................................................... 9 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ....................................................... 10 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ................................................................... 10 
5.5 
SUBJECT COMPLIANCE MONITORING ............................................................................................. 10 
5.6 
PRIOR AND CONCOMITANT THERAPY ............................................................................................. 10 
5.7 
PACKAGING ................................................................................................................................. 10 
5.8 
BLINDING OF STUDY DRUG ........................................................................................................... 11 
5.9 
RECEIVING, STORAGE, DISPENSING AND RETURN .......................................................................... 11 
5.9.1 
Receipt of Drug Supplies ....................................................................................................... 11 
5.9.2 
Storage .................................................................................................................................. 11 
5.9.3 
Dispensing of Study Drug ...................................................................................................... 11 
5.9.4 
Return or Destruction of Study Drug ..................................................................................... 11 
6 
STUDY PROCEDURES ..................................................................................................................... 11 
7 
STATISTICAL PLAN ......................................................................................................................... 12 
7.1 
SAMPLE SIZE DETERMINATION ...................................................................................................... 12 
7.2 
STATISTICAL METHODS ................................................................................................................ 12 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ....................................................................................... 12 
8 
SAFETY AND ADVERSE EVENTS ................................................................................................... 13 
8.1 
DEFINITIONS ................................................................................................................................ 13 
8.2 
RECORDING OF ADVERSE EVENTS ................................................................................................ 14 
8.3 
UNBLINDING PROCEDURES ........................................................................................................... 14 
8.4 
MEDICAL MONITORING ................................................................................................................. 14 
9 
DATA HANDLING AND RECORD KEEPING ................................................................................... 15 
 


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10 
STUDY MONITORING ....................................................................................................................... 15 
10.1 
STUDY MONITORING PLAN ............................................................................................................ 15 
 
13 
REFERENCES ................................................................................................................................... 15 
 
 


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List of Abbreviations 
 
 
HCAHPS- Hospital Consumer Assessment of Healthcare Providers and Systems 
 
PRC-Professional Research Consultants  
 
FDA – Food and Drug Administration 
 
VAS – Visual Analog Scale 
 
POD – post-operative day 
 
 
 
 
 
 
 
 


[Insert short name of protocol here] 
 
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Study Summary 
Title 
The effect of gabapentin on perioperative pain control among head and neck 
surgery patients 
Short Title 
Gaba RCT 
Protocol Number 
1.3 (third amended version) 
Phase 
Phase 4 
Methodology 
Prospective randomized double-blind controlled trial  
Study Duration 
2 years 
Study Center(s) 
Barnes Jewish Hospital 
Objectives 
Determine the effectiveness of gabapentin for reducing narcotic requirements 
and subjective pain scores in postoperative head and neck mucosal cancer 
patients.  Determine the ability of gabapentin to improve patient satisfaction 
with pain management. Track inpatient length of stay.  
Number of Subjects 
120 
Diagnosis and Main 
Inclusion Criteria 
Adult head and neck patients undergoing oral cavity, oropharynx, larynx and 
hypopharynx resection (mucosal head and neck surgeries) 
Study Product, Dose, 
Route, Regimen 
Gabapentin liquid by mouth or Per Tube 300mg BID vs placebo 
Duration 
of 
administration 
Day of surgery and up to three days post operatively depending on the hospital 
stay.   
Reference therapy 
Placebo 
Statistical 
Methodology 
Bivariate analysis using independent samples t-test for continuous variables 
and chi square test for categorical variables will be used to compare between 
treatment groups 
 


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1 Introduction 
This document is a protocol for a human research study to be conducted according to US and 
international standards of Good Clinical Practice compliant to all associated Federal and applicable local 
and University research requirements, approved by the Institutional Review Board.  
1.1 Background 
High-quality healthcare is accessible, safe, efficient, patient-centered and imperative for good treatment 
outcomes.  In this era of healthcare reform, patient satisfaction has increasingly become an important 
metric of hospital performance.  The Medicare Hospital Value Based Purchasing Program utilizes patient 
reported satisfaction scores as a reflection of the quality of care delivered by hospital systems and 
clinician teams.  The scores resulting from these reports are integrated into the formula with which 
hospitals are reimbursed for Medicare patients. 
 
An important patient-physician interface in quality healthcare is the treatment of pain, and the treatment of 
acute postoperative pain is particularly relevant for surgical specialties.  Effective management of 
postoperative pain increases patient satisfaction, reduces hospital costs, reduces postoperative morbidity 
and shortens hospitalizations8.  HCAHP and PRC data from the Barnes Jewish Hospital otolaryngology 
inpatient unit reveals that postoperative otolaryngology patient satisfaction with pain control is routinely 
lower than the 75th percentile of all hospitals nationally surveyed.  Traditionally, pain regimens rely heavily 
on the use of narcotics, which are associated with nausea, vomiting, delirium, and decreased bowel 
motility.  These side effects have the potential to increase length of hospitalization and decrease patient 
satisfaction.  Moreover, otolaryngology patients often undergo very painful and functionally debilitating 
surgeries of the head and neck and are at increased risk for postoperative pain due to both the 
neuroanatomy of this region and the need to swallow postoperatively8.   Postoperative pain control in this 
population is critical for patient satisfaction and an expedited return to a functional swallowing status. 
 
Within the field of pain management is the practice of multimodal pain therapy.  This strategy employs 
non-narcotic medications working synergistically to improve pain control, decreasing narcotic medication 
requirements and narcotic-associated side effects8.  Studies utilizing multimodal pain regimens 
demonstrate such benefits in acute postoperative pain management2-5.  Gabapentin is a non-narcotic 
pain medication often used in multimodal pain regimens that has been shown to reduce acute 
postoperative pain.  
1.2 Investigational Agent 
Gabapentin is a non-narcotic medication developed to target neuropathic pain1.  It is an amino acid 1-
(aminomethyl)cyclohexaneacetic acid that is structurally related to the inhibitory neurotransmitter GABA 
(gamma-aminobutyric acid), without modifying the binding, metabolism, or elimination of GABA.  In vitro 
studies have demonstrated gabapentin binding sites in the rat brain, but the functional implication and the 
mechanism of its analgesic and anticonvulsant activity remains unknown in humans.  The oral 
bioavailability of gabapentin decreases as dose increases.  Its half-life is 5-7 hours, and it is eliminated by 
renal excretion without chemical alteration.  Dose adjustments are recommended for creatinine clearance 
less than 30 mL/min.  It is FDA approved since 1993 for post-herpetic neuralgia and epilepsy, and has 
been widely applied in neuropathic pain management.  It is also frequently used for acute postoperative 
pain, and meta-analysis of randomized controlled trials shows it to be an effective pain management 
strategy in postoperative patients.  The major adverse reactions reported were, in descending frequency, 
dizziness, sedation, asthenia, diarrhea, dry mouth, constipation, nausea, and vomiting 23. 
1.3 Clinical Data to Date 
Numerous randomized controlled trials demonstrated that gabapentin effectively reduced narcotic use 
and improved subjective pain in various surgical populations, such as gynecology-oncology and 
orthopedic surgery9-15.  Meta-analyses of these pooled trials reported an overall trend toward improved 
pain control and decreased postoperative narcotic use with gabapentin, despite the heterogeneity of the 
included studies6,16-19.  A small number of studies have examined the use of gabapentin in postoperative 


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otolaryngology patients and suggest a potential benefit in improving postoperative pain control after 
thyroidectomy, endoscopic sinus surgery, oral cavity resection with reconstruction, and tonsillectomy9-15. 
Most of the studies demonstrated an improvement with only one preoperative dose.  To date, no 
randomized control trials have been conducted with gabapentin use in adult otolaryngology patients 
undergoing all types of head and neck mucosal surgeries, which is an at-risk population for high levels of 
postsurgical pain. 
1.4 Dose Rationale and Risk/Benefits 
Dosing regimen of gabapentin will be 300 mg PO preoperatively, followed by 300 mg BID until POD 2 or 
the day of discharge, whichever comes first. Note that on the morning of POD3 at 7am, a VAS will be 
obtained to reflect the POD 2 7pm dose.  The liquid formulation will be used postoperatively given the 
possibility of dysphagia or postoperative NPO status potentially requiring a feeding tube.  The optimal 
dosage for gabapentin in acute postoperative pain is unknown.  Recommended gabapentin regimen for 
treatment of post-herpetic neuralgia is a 300 mg/day on day 1, 300 mg BID on day 2, 300 mg TID on day 
3, and subsequently up-titrated as needed to 600 mg TID23.  Prior studies using gabapentin for 
postoperative pain control in otolaryngology patients have primarily administered a single preoperative 
dose ranging from 100 mg to 1200 mg9-15. Data was inconsistent as some studies showed efficacy at low 
dosages and some showed no difference at high dosages, and an optimal dose regimen remains to be 
determined.  For this study a relatively low dosage was chosen to minimize sedation side effects, as 
included participants are likely to be gabapentin-naïve.  The perioperative BID dosing period was chosen 
to better elucidate the effects of gabapentin in the acute, postoperative period, as many head and neck 
mucosal resections cause significant pain for several days after the procedure.  The majority of head and 
neck inpatient stays are between 2-3 days, with some staying as short as 1 day and some as long as a 
few weeks.  At this dose and schedule, gabapentin side effects are minimized so that subject risk is also 
minimized without compromising medication analgesic abilities.  Collaboration with the inpatient pain 
management team also supports the expectation that this dose and time regimen will be effective and will 
minimize side effects.  
 
Post-operative swallow results will be collected from the medical record on those patients receiving post 
op swallow therapy per routine care.  The post-operative swallow evaluation will be observational, based 
solely on the discretion of the surgeon and is not required per the research protocol.  
2 Study Objectives 
This investigation is a quality improvement initiative designed to elucidate the benefit of gabapentin in 
pain management in subjects undergoing surgical resection of head and neck mucosal surfaces. 
 
Primary Objective 
To assess the efficacy of gabapentin on decreasing narcotic requirements for treatment of acute 
postoperative pain in head and neck patients undergoing surgical resection of mucosal surfaces. 
 
Secondary Objectives 
To assess subjective pain scores and participant satisfaction with pain control.  
 
  
3 Study Design 
3.1 General Design 
This is a prospective, randomized, double-blind, placebo-controlled study with the intent of providing high 
quality and reproducible data.  The study subjects include adult otolaryngology patients over the age of 
18 years undergoing open or endoscopic/robotic resection involving the mucosal surfaces of the oral 
cavity, oropharynx, hypopharynx and larynx in a single tertiary academic center.  Participants are 
recruited from the otolaryngology head and neck cancer clinic during their preoperative visits.  The 
duration of subject participation includes the subsequent inpatient hospitalization following definitive 


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cancer resection up to two days after surgery.   Subjects will be given the placebo or gabapentin for up to 
two days post op or until discharge, whichever comes first.   
 
Potential subjects will be recruited from the patient population in the head and neck surgery clinic, 11th 
floor CAM, the center for outpatient health or at other outpatient or inpatient sites related to their pre-
surgical planning visits.  Eligible patients will be identified before their scheduled appointments via review 
of medical records in Allscripts by a study team member and approached either in the exam room during 
their scheduled appointment with the head and neck surgeons or afterwards via telephone call.  The 
study will be explained to them and a copy of the consent form will be provided after it has been signed.  
Patients will be reminded that participation is voluntary and will in no way affect their current or future care 
related to their head and neck health needs. Patients will be given time to ask questions and will have the 
option to consider participation and enroll at a subsequent appointment before their planned procedure. 
The consent process will take place in a private room.  Steps to avoid coercion include proper training in 
informed consent, private discussion rooms in which the surgeon is not present, and patients will be 
reassured that their care from their head and neck surgeon will not be affected by their decision to 
participate or to not participate.  Patients will be made aware that their postoperative care will not be 
limited by participation in this study, meaning that they will not be denied needed and appropriate narcotic 
pain medications simply because they are enrolled.  Written informed consent will be obtained prior to the 
start of research related procedures. 
 
 
 


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**Note that IV and PO or per tube morphine will be used in amounts equivalent to the dilaudid and oxycodone medications 
above if an allergy or intolerance to dilaudid or oxycodone exist. 
 
Subjects will present for their planned procedures to the pre-op surgery office and will be taken to the pre-
op holding area as per usual hospital procedure.  A study team member will meet the subject in the pre-
op holding area and will administer the pre-op medication approximately 1 hour prior to surgery start time. 
Patients will not be excluded if surgery start time is delayed past 1 hour.  An investigational pharmacist 
will deliver the medication appropriately labeled with patient name and study number to the pre-op 
holding area.  This oral administration is safe per consultation with the anesthesia faculty member of this 
project.  Additionally, on the day of surgery a study member will place pain medication orders in compass 
on hold for post op care.  These orders will be 1000mg of Tylenol PO or per tube Q6 hours (or Q12 hours 
if the patient has hepatic insufficiency), oxycodone 5-10mg Q4 hours PRN pain (5mg if pain less than or 
equal to 5/10, 10mg if greater than 5/10), and dilaudid 0.25-0.5mg Q2 hours PRN breakthrough pain 
(0.25mg if pain less than or equal to 5/10, 0.5mg if greater than 5/10).  Alternatives to these medications 
in case of allergy or intolerance is 1-2mg IV morphine Q2 hours PRN pain (1mg if pain less than or equal 
to 5/10, 2mg if greater than 5/10) and 7.5-15mg PO/PT liquid IR morphine Q4 hours PRN pain (7.5mg if 
pain less than or equal to 5/10, 15mg if greater than 5/10).  Additionally, the study team member will 
place the appropriate investigational drug order in compass.  The subject will be able to receive increases 
in pain medications as deemed appropriate by the inpatient treating physicians.  They will not have any 
limitations set on pain medications simply because they are involved in the study.  The subject will then 
proceed with surgery as planned. No alterations to intraoperative medications or anesthetic agents will be 
made based on study participation. 
 
The subject will return to the PACU after extubation.  If the subject had to remain intubated, he or she will 
be withdrawn from the study as he or she cannot complete pain scores while sedated. Additionally, if the 
subject is at any point during the study placed on alcohol withdrawal medication protocols, he or she will 
be withdrawn from the study.  The study team member administering the preoperative dose will remind 
anesthesia to use the same post-operative initial pain management options in the PACU at least initially, 
again with no restrictions on dose escalations that are needed.  The PACU can increase the dose of 
postoperative pain medications based on patient need and MD approval as per the usual PACU protocol 
without restriction based on a subject’s study participation.  Subjects will remain in the PACU per the 
usual protocol until the required level of alertness and clinical stability are reached for transfer, and their 
PACU medication sheet will be copied and added to their hard copy file for use later during 


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tabulation/data anaylsis of the pain meds they required The VAS score obtained after surgery will be 
completed 45 minutes to 1 hour after extubation in the PACU.  
 
Note that subjects must have completed surgery (extubated) by 5PM in order to receive the 7PM dose 
after their surgery.  Otherwise, this dose is to be skipped and the next dose administered will be at 7AM 
the next day.  VAS scores can still be obtained at 45 minutes to 1 hour postoperatively, however, even if 
the case finishes later than 5pm. On POD 1-2, subjects will be given BID medications at 7am and 7pm 
per the study protocol and VAS scores will be obtained prior to medication administration   A separate 
VAS will be obtained at 10am on POD1 and POD 2.  ON POD 3 a 7am VAS will be obtained but no study 
medication given. This last VAS concludes participation in the study.  Discharge surveys will be 
administered at this point if they have not been already (ie if the patient remained an inpatient for longer 
than 2 days postop).   
The investigational pharmacist will have delivered the medication dose in a properly labeled container to 
the 6200 inpatient floor prior to scheduled doses, and the medications will be stored in patient labeled 
bins in the locked medication refrigerator.  All VAS scores will be obtained with subject privacy optimized, 
including drawing the curtain in subject room to separate the sides of the room from any potential 
roommate.  Also, the research team member will not vocalize a subject’s status as a study patient.  VAS 
scores will be obtained at rest, with cough and following a swallowing gesture.  Scores are captured by 
providing the subject with a pen and asking the subject to mark the location of their pain on a line 
measuring 10cm during each phase of the VAS.   The scale is a validated tool that measures 10cm in 
size and is marked “no pain” on the far left and “worst pain” on the far right.  The subject marks their pain 
level on the scale and the study team member will measure with a ruler and record the resulting number 
in the study database.    
Subjects will fill out a discharge survey before they are discharged or at the completion of their 
participation to rate their satisfaction with their inpatient pain control.  This survey will be a hard copy 
labeled with study ID and the data will be entered into the study database.  All hard copy data will be 
stored in a locked cabinet accessible only to the study team.  At the end of the study, all hard copy data 
will be properly destroyed.   
 
Subjects will have 24/7 access to members of the study team should questions or concerns arise while 
they are actively participating in the study as well as up to 30 days after completion of the study.   
 
Note that study medication wrappers have patient names on them as a safety mechanism to make sure 
medications are given to the proper patient.  These wrappers and labels will be saved in the patient 
folders which are secured in a locked cabinet where only study team members have access.  Empty and 
unlabeled medication syringes will be discarded in the red biohazard bins inside patient rooms.  
3.2 Primary Study Endpoints 
The primary study endpoint is postoperative narcotic consumption.  Average daily narcotic use from 
postoperative admission to the last dose of pain medication on POD 2, or the day of discharge, whichever 
comes sooner, will be calculated. Total amount of narcotic use in morphine equivalents will be divided by 
the total hours of inpatient hospitalization, multiplied by 24 hours, to obtain the average daily narcotic 
consumption. 
3.3 Secondary Study Endpoints 
The secondary endpoints include (a) subject satisfaction with pain control, (b) VAS pain scores, (c) 
patient baseline pain perceptions (d) hospital length of stay, and (e) potential side effects of the 
medication.  
 
(a) Subject satisfaction with pain control will be captured in a survey administered at POD 2 after the 
AM dose administration, or after the AM dose administration on the day of discharge, whichever 
comes sooner.  Two of the survey questions will mirror those on the HCAPHS surveys, listed as 
followed (see attached “post-treatment questionnaire”): 
 
1. How often was your pain well controlled? 


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0) Never 
1) Sometimes 
2) Usually 
3) Always 
 
2. How often did the hospital staff do everything they could to help you with your pain? 
0) Never 
1) Sometimes 
2) Usually 
3) Always 
 
3. How satisfied are you with your overall pain control? 
0) Very dissatisfied 
1) Somewhat dissatisfied 
2) Neutral 
3) Somewhat satisfied 
4) Very satisfied 
 
4. Was there anything else that we could have done to make your pain control better during your 
inpatient stay? 
A point system is created with the sum of the numeric values assigned to questions 1-3 on a scale of 
0 to 10, with a score of 0-3 indicates overall dissatisfaction, 4 indicates neutrality, and 5-10 suggests 
overall satisfaction.  This will be analyzed as an ordinal variable. 
 
(b) VAS pain scores will be assessed 45min to 1 hour after surgery and then three times a day on 
POD 1-2 and once on POD 3, or until day of discharge, whichever comes sooner. A standardized 
VAS form will be given to subjects with verbal instruction to first “mark on the line the point that 
you feel represents your current pain level when you’re resting.”  This is followed by asking the 
subject to gesture swallowing and “mark another point on the line that represents your pain level 
when you swallow.”  Lastly, the subject will be asked to cough and to “mark the final point on the 
line that represents your pain when you cough.”  The study team member administering the test 
will annotate what each mark represents (rest, swallow, and cough).  The scale contains a 10-cm 
line from “no pain” on the left to “extreme pain” on the right (see “VAS form”).  The distance in 
centimeters from the left of the line to the center of the patient’s three marks will be recorded.  
The results from all available VAS scores for each subject will be averaged and included in the 
final analysis.  
 
(c) The subject’s belief in pain medication efficacy and pain tolerance will be assessed from a short 
survey obtained preoperatively during the office visit (see “pre-treatment questionnaire”). This 
includes the following questions: 
 
1. In the past, how effective are narcotic pain medications (such as morphine, Vicodin, Norco, 
Percocet, oxycodone, Dilaudid) at controlling your pain? 
0) Very ineffective 
1) Somewhat ineffective 
2) Somewhat effective 
3) Very effective 
 
2. In the past, how has your pain tolerance been? 
0) Very poor 
1) Somewhat poor 
2) Somewhat tolerant 
3) Very tolerant 


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3. Do you experience a significant amount of pain on a daily basis aside from the pain due to 
your current head and neck condition? 
1) Yes I do 
2) No I do not 
The results of these questions will be reported separately in the final analyses. 
 
(d) Hospital length of stay will be calculated for each subject. 
 
(e) During the VAS scores, study team members will also collect information about potential 
medication side effects, including those that are commonly associated with gabapentin or with 
narcotic medications.  
3.4 Primary Safety Endpoints 
The primary safety endpoints are the rate and severity of drug-related adverse events.  Adverse events 
will be monitored and recorded by study team members during subject inpatient stay.  These events will 
be reviewed by the principal investigator and categorized into “drug-related”, “likely drug-related”, and 
“unlikely drug-related.”  Any significant adverse events determined to be likely drug related will be 
reported to the OHRP within a 24 hour time period and stopping the study for the subject will be 
discussed.  A safety meeting will be heald half way through the study with the PI and all involved faculty 
mentors to determine if an interim analysis is necessary, This analysis would be considered necessary if 
a significant number of adverse events likely related to the study medication were occurring, and an 
analysis to make sure the study was not causing harm to the treatment group was needed. 
4 Subject Selection and Withdrawal 
4.1 Inclusion Criteria 
 
Subjects undergoing definitive mucosal head and neck resection including oral cavity, 
oropharynx, larynx, and hypopharynx 
 
At least 1 night of planned inpatient stay 
4.2 Exclusion Criteria 
 
Incapable of giving informed consent 
 
Age < 18 
 
GFR < 30 
 
Allergy to gabapentin  
 
Baseline gabapentin or lyrica use 
 
Chronic opioid use for over 6 months 
4.3 Subject Recruitment and Screening 
Subjects will be recruited either in the outpatient head and neck clinic prior to their planned surgeries or 
over the phone after this clinic appointment by designated study team members.  Potentially eligible 
patients will be identified by study team members prior to their scheduled appointments via the outpatient 
medical records system.  Patient recruited by phone will be able to sign the informed consent prior to 
surgery either at a subsequent surgical planning visit or in the pre-op holding are on the day of surgery.  
Eligible subjects will be consented in a private setting and the study outline explained to the patient. 
Written informed consent will be obtained from those patients who wish to participate.  Patients may 
choose to think about study participation but will need to decide and provide written consent prior to the 
day of surgery, either at their subsequent preoperative anesthesia clinic appointment or medical 
oncology/radiation oncology appointments.  Study team members will be properly trained in the informed 
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4.4 Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
Subjects may be withdrawn from the study prior to the expected completion if they develop 
hypersensitivity reactions to the study drug, are unable to swallow all study drugs in the study period, or 
choose to withdrawal for other reasons.  They will also be withdrawn if they remain sedated or intubated 
after the surgery or are placed on alcohol withdrawal medication protocols, which also cause significant 
sedation.  Subjects without a feeding tube who are unable, or unwilling, to swallow medications after 
surgery will not be given a feeding tube to remain in the study.  A 20% dropout rate was anticipated and 
accounted for in the sample size calculation.  Subjects will be able to withdraw on a continual basis 
throughout their participation.  Withdraw can be requested either by the subject or by any team member if 
medical significant adverse reactions are observed.  All withdraws will be reviewed by the principle 
investigator.  No subject will be denied the ability to withdraw. The withdraw process will begin 
immediately when deemed necessary or when desired by the subject, and documentation of the reason 
and time of withdraw will be performed.   
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
Withdrawn subjects will be excluded in the final data analysis. The reasons for withdrawal will be 
recorded and reported separately in the study data outcomes. 
 
4.4.3 Definitions 
Subject withdraw: Withdraw is defined as a subject who signed the informed consent document and for 
whatever reason dropped out of the study before completion, whether by choice or by exclusion criteria 
(ie- staying intubated the night after surgery). 
 
Subject screen fail: A screen fail is defined as a subject who has been recruited to participate and 
approached but does not meet all inclusion criteria.  
 
5 Study Drug  
5.1 Description 
300mg of liquid gabapentin or an equal volume of placebo will be pre-packaged by the investigational 
pharmacist in a labeled medication syringe or in a marked bag with a capsule.  An unblinded study team 
member in charge of the randomization process will indicate to the pharmacy which subjects are to 
receive what medication.  The blinded study team members will not know which medication contains 
placebo or gabapentin.  
5.2 Treatment Regimen 
Subjects will receive either placebo or gabapentin 300 mg PO the preoperative holding area 
approximately 1 hour before their procedure is scheduled to begin.  This first dose will designate the day 
of their procedure as POD 0.  If the procedure ends late in the evening (ie not extubated before 5pm), and 
the subject is not able to receive the second POD 0 dose by 7 PM, then this second POD 0 dose will be 
skipped.   Participants will then receive either placebo or 300 mg of gabapentin BID POD 1- POD 2.  
Dosing will end either on POD 2 after the PM dose or on day of discharge after the AM dose, whichever 
comes first.  VAS scores will be collected 45 minutes- 1 hour post extubation on POD as well as TID on 
POD 1-2 and one time at 7am on POD 3 (see above protocol flowsheet).  


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5.3 Method for Assigning Subjects to Treatment Groups 
After a subject consents to study, the unblinded data manager will randomize the subject into active or 
placebo group and assigned an enrollment ID.  The enrollment ID is given to any subject who signs 
consent. If the subject then proceeds to start the study and receive a medication dose, they will also be 
given a subject ID which reflects their randomization group.  The study ID reflects randomization while the 
enrollment ID is used to enter them into OnCore and track their consent.  
5.4 Preparation and Administration of Study Drug 
The Investigational Pharmacist will mix and prepare the study medications necessary for each subject.  A 
pharmacist will deliver the medication to the preop holding unit or the floor and a designated study team 
member will administer it.  Please see section 5.7 below for mixing and packaging details. Contact 
information for the pharmacy for this project is pharmacist Kathryn Vehe at 314-795-7286. 
 
Inpatient pharmacists will be responsible for delivering the medication to the floor prior to the AM dose 
and to the PM dose, as well as will deliver the medication to the pre-op holding area prior to a subject’s 
procedure. Formal training for all study team members who will be administering the study drug or 
obtaining the VAS pain scores is required prior to subject interaction. 
5.5 Subject Compliance Monitoring 
The study team members will directly administer each study medication dosage during the study period 
and record adherence to study protocol.  If a dose is missed during this period, the subject will remain in 
the study through the completion of the protocol.  The decision to include data from subjects with missed 
doses will be made at the discretion of the principle investigator and statistician at the conclusion of the 
study.   Data integrity will be maintained such that subjects who are excluded for missed doses will be 
consistent among cases.  
5.6 Prior and Concomitant Therapy 
Every subject will have standard postoperative narcotic medications made available: 
 IV Dilaudid 0.25-0.5mg q2h PRN breakthrough pain (pain equal to or less than 5/10 will get 
0.25mg and pain >5/10 will get 0.5mg).  
 PO/PT oxycodone 5-10mg q4h PRN pain (pain equal to or less than 5/10 will get 5mg, and pain 
greater than 5/10 will get 10mg).  
 PO/PT acetaminophen 1000mg q6h for pain in non-cirrhotic patients, and 1000mg q12h in 
cirrhotic patients 
 Morphine IV and PO liquid equivalents will be substituted in cases of oxycode or dilaudid 
allergies. 1-2mg IV morphine Q2 hours PRN will be substituted for 0.25-0.5mg dilaudid for 
breakthrough pain (pain equal to or less than 5/10 will get 1mg and pain >5/10 will get 2mg).   
PRN liquid IR morphine 7.5-15mg will be substituted Q4 hours for oxycodone PRN for pain (pain 
equal to or less than 5/10 will get 7.5mg, and pain greater than 5/10 will get 15mg) 
 Study team members will place an order in compass for study investigation drug administration 
as per BJC protocol for investigational drug use.   
 
These medications can be up-titrated as needed at the discretion of the physicians managing the 
patient’s care as part of the routine postoperative management. 
5.7 Packaging 
 Study medications will be in liquid or capsule form.  Gabapentin comes as a standard liquid form 
of 250mg/5ml. Capsules will be used for the pre-operative dose, and will come as single capsules 
in bags labeled with study ID and name.  For post-operative doses, 6ml of either gabapentin or 
placebo will be packaged into a brown 20ml plastic syringe.  Each syringe will have the subject 
name and study ID on it.  The pharmacy will be made aware of all upcoming study subjects and 
will prepare the medications approximately 24 hours prior to administration, and will store these at 


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4 degrees Celsius.  The medications will be stored prior to dosing on the floor in a locked fridge in 
patient specific compartments, as per the floor medication protocol.  
5.8 Blinding of Study Drug 
The study team members administering the medications will be blinded towards whether a subject 
receives the study drug or the placebo.  The data manager who does not participate in data collection or 
have direct subject interaction, as well as the pharmacist preparing the medications, will be unblinded. 
5.9 Receiving, Storage, Dispensing and Return 
5.9.1 Receipt of Drug Supplies 
Investigational pharmacists will be responsible for medication delivery prior to planned doses.  They will 
be alerted to upcoming procedures that involve study subjects.  They will be responsible for delivering the 
medication to the inpatient floor and in the preoperative holding area.  Any damaged or unusable study 
drug in a given shipment will be documented in the study files and discarded. 
5.9.2 Storage 
Medications will be stored by the investigational pharmacy in a designated, locked area at 4 degrees 
Celsius. They will be stored on the inpatient floor in a locked, 4 degree fridge in patient specific 
compartments per the floor medication storage protocols.  
5.9.3 Dispensing of Study Drug 
The study team members administering the medications will receive the medication from the 
investigational pharmacist.  They will then administer the medication and record the time of administration 
and the subject identification number in the subject’s study flow sheet (“Gaba project subject study flow 
chart” attached). 
5.9.4 Return or Destruction of Study Drug 
At the completion of the study, there will be a final reconciliation of medications consumed.  This 
reconciliation will be logged on the drug reconciliation form, signed and dated.  Any discrepancies noted 
will be investigated, resolved, and documented.  Medication syringes will be discarded in the red 
biohazard containers in accordance with hospital policy and documented in the study files. Any labels or 
bags with patient names will be discarded in the shred bins on the 6200 floor or in the preop holding unit.  
 
6 Study Procedures 
The study procedures are outlined below and represented in the attached “Gaba project subject study 
flow chart”.  
 
Clinic Visit 
 
Consent. 
 
Pre-treatment questionnaire. 
 
Randomization group will be assigned by the study data manager after she is notified of subject 
agreement to participate. 
Day of Surgery 
 
One dose of study drug will be administered preoperatively according to subject’s randomization 
group approximately 1 hour prior to procedure start time.  The coordinator administering the 
medication will tape a study reminder sheet for anesthesia to the chart and will place an order in 
the chart that allows the participant to take the preop medication dose, and the RN to chart this 
dose as a study medication.  


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 
Standard pain medications orders will be provided. Morphine will be used as a substitute for 
dilaudid or oxycodone allergies or intolerances. These will be up-titrated as needed per discretion 
of service residents and attending physicians. 
 
One VAS score will be obtained 45 minutes to 1 hour postoperatively regardless of extubation 
time. 
 
One postoperative dose of study drug and VAS will be administered at 7pm if subjects are 
extubated by 5PM 
Post-Operative Day (POD) 1-2 
 
TID VAS scores will be obtained, two of which will be prior to drug administrations. 
 
BID study drug administration will be conducted according to subject’s randomization groups. 
POD 3  
 
POD 3 VAS at 7am will be obtained.  
POD 3 or Day of Discharge 
 
Post-treatment pain satisfaction questionnaire will be conducted either after the AM dose on POD 
3 or on date of discharge, whichever comes sooner. 
7 Statistical Plan 
7.1 Sample Size Determination 
Sample size calculations were performed based on prior studies with gabapentin use in otolaryngology 
patients undergoing thyroidectomy21.  A study by Al-Mujadid et al in a population of patients undergoing 
elective thyroidectomy reported that total morphine consumption in the placebo group in the first 24 hours 
post surgery required a mean of 29.5mg of morphine with a standard deviation of 9.9mg.  Assuming that 
this magnitude of effect variability will hold true in this project population, it is estimated that 46 subjects 
per group (total n=92) will be needed to detect with an 80% power at the 2-sided alpha level of 0.05 a 
difference of 20% or greater in average morphine dose (effect size d=0.6) between the placebo and 
gabapentin groups.  Assuming a 20% drop out rate, 116 subjects will be enrolled in this study.  The 
volume of eligible subjects for this study is predicted to meet the calculated sample size within two years 
of study start time. A review of surgical procedures meeting inclusion criteria performed over a sample 
three month time frame ranged from 12 to 17 procedures a month.  
7.2 Statistical Methods 
Descriptive statistics will be used to describe distribution of demographics. Bivariate analysis using 
independent samples t-test for continuous variables and chi square test for categorical variables will be 
used to compare distribution of characteristics between treatment groups to ensure successful 
randomization. 
 
The primary and secondary outcome measures will be compared between the two treatment groups via 
bivariate analyses.  In addition, a General Linear Model (GLM) approach will be used to explore the 
impact of gabapentin as compared to placebo on each of the outcomes of interest after controlling for 
potential cofounders that were unevenly distributed between the two groups.  The estimated mean 
difference and 95% confidence interval will be reported. 
7.3 Subject Population(s) for Analysis 
Protocol-compliant subjects who received all study drugs up to the conduction of post-treatment 
questionnaire will be included for analysis.  Subjects with missed medication doses will go on to complete 
the protocol, and per the discretion of the principle investigator and statistician may or may not be 


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included in the data analysis.  Data integrity will be maintained such that subjects who are excluded for 
missed doses will be consistent among cases. 
 
8 Safety and Adverse Events 
8.1 Definitions 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
 Unexpected in nature, severity, or frequency  (i.e. not described in study-related documents such 
as the IRB-approved protocol or consent form, the investigators brochure, etc) 
 Related or possibly related to participation in the research (i.e. possibly related means there is a 
reasonable possibility that the incident experience, or outcome may have been caused by the 
procedures involved in the research) 
 Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm). 
 
 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study.  Intercurrent illnesses or injuries will be regarded as adverse events.  
Abnormal results of diagnostic procedures are considered to be adverse events if the abnormality: 
 results in study withdrawal 
 is associated with a serious adverse event 
 is associated with clinical signs or symptoms 
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
 fatal 
 life-threatening 
 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event 
 
Mild and Moderate adverse events: 
A moderate adverse event is one that requires a medical intervention such as medication for nausea, but 
that does not cause permanent clinical harm and that does resolve in a reasonable amount of time. 
 
A mild adverse event is one that causes mild clinical effect and may or may not require medical 
intervention. It is expected to resolve completely with observation or medical treatment.  
 
Adverse Event Reporting Period 
The study period during which adverse events that are deemed likely related to the study medication and 
unexpected or significant must be reported will be the period from the day of surgery to the end of the 
study, which is POD 3 or sooner if discharge is sooner than POD 3.  Additionally, subjects will be 
provided with contact information for the study member that is in charge of adverse event follow up 
(Melanie Townsend, PI).  They will be instructed to contact this person with questions related to the study, 
adverse events or side effects experienced after discharge so that the study members can be alerted to 
any events that may be related to the medication.  Reporting of these events via an adverse event report 
will be up to the discretion of the PI.  Subjects will be advised that the medication does not remain in the 


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body several days after discontinuation, but they will be able to report events at any point after study 
participation.  
 
For all severe or unexpected adverse events, an IRB event form will be submitted. For mild or moderate 
events, and event form will be submitted if the event is one that is likely related to the medication and is 
an event that is not considered an expected side effect of gabapentin. Mild or moderate events that do 
not resolve within an appropriate time frame will also be reported to the IRB.  Mild and moderate events 
will be reviewed by the PI and deemed appropriate for reporting. All adverse events, whether mild, 
moderate or severe, will be reviewed at the safety meeting by all team members and faculty advisors to 
ensure that proper reporting has occurred.   
 
 
Post-study Adverse Event 
All unresolved adverse events will be followed by the investigator until the events are resolved, the 
subject is lost to follow-up, or the adverse event is otherwise explained.  At the last scheduled visit, the 
investigator will instruct each subject to report any subsequent event(s) that the subject, or the subject’s 
personal physician, believes might reasonably be related to participation in this study.   
8.2 Recording of Adverse Events 
At each interaction with the subject, the investigator will seek information on adverse events by specific 
questioning and, as appropriate, by examination.  Information on all adverse events will be recorded 
immediately in the source document located on the secure wustl box for this study.  All clearly related 
signs, symptoms, and abnormal diagnostic procedures results will be recorded in the source document. 
Specific side effects that will be elicited at each interaction include nausea, vomiting, dizziness and 
sedation.   
 
The clinical course of any adverse event will be followed until resolution, stabilization, or until it has been 
determined that the study treatment or participation is not the cause.  Serious adverse events that are still 
ongoing at the end of the study period will be followed up to determine the final outcome.  Any serious 
adverse event that occurs after the study period and is considered to be possibly related to the study drug 
or study participation will be recorded and reported immediately to the IRB. 
 
8.3 Unblinding Procedures 
For this study only the data manager and pharmacy will be unblinded to the study drug and placebo 
assignments.  Unblinding of the rest of the study investigators will occur after assurance that data 
collection has completed.  If any subject data is intentionally or unintentionally unblinded, the event will be 
documented in detail in the study documents within 48 hours.  Any unblinding that occurs during the study 
period for an individual participant will result in exclusion of that participant’s data from final analysis.  
Study investigators must report unblinding to the PI within a 24 hour time period and must document the 
event.  Subjects will immediately be made aware of the unblinding and will be withdrawn from completing 
the protocol.  
Stopping Rules  
The study will be terminated prematurely if 50% or more of the subjects receiving study drug (gabapentin 
or placebo) experience significant adverse events as defined above in section 8.1.  The study will not be 
prematurely stopped if subjects experience less significant medication side effects, specifically nausea, 
vomiting, dizziness and sedation.  A review of adverse events will be conducted at 25% by the PI and at 
50% enrollment by the entire team to ensure that they are properly tracked.  
8.4 Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study.  This safety 
monitoring will include careful assessment and appropriate reporting of adverse events as noted above, 
as well as the construction and implementation of a site data and safety-monitoring plan (see section 10 


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Monitoring).  Medical monitoring will include a regular assessment of the number and type of serious 
adverse events.   A safety meeting will be held half way through enrollment as described above, 
9 Data Handling and Record Keeping 
9.1 Confidentiality 
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).   
Source data will be kept primarily in the electronic forms using REDCap for data collection.  Paper forms 
including the original consents, questionnaires, VAS pain score sheets, adverse event reporting forms 
etc. will be kept in a locked cabinet that only study team members have access to.  At the conclusion of 
the study, after data has been entered into a password protected spread sheet, these records will be 
destroyed in the proper manner in shred it bins where patient information is normally placed.  The official 
source document and case report form for this study will be the REDCap database. 
 
 
All research records will be maintained in the Outcomes Office, 8th floor McMillan for 7 years after study 
completion per WU record retention policy.  
 
10 Study Monitoring 
10.1 Study Monitoring Plan 
This study will be monitored in real time for each subject by the PI and study team.  At minimum, with 
25% accrual goal all adverse events and data collection forms will be reviewed by the PI and discussed 
among the study team. A designated, third party safety officer will review the study approximately half 
way through to ensure that subjects are not being harmed by this study.  
 
 
11 References 
1. Chang C.Y., Challa C.K., Shah J., Eloy J.D. Gabapentin in acute postoperative pain management.  
BioMed Research International Vol. 2014.  2014.  
2. Rafiq, Sulman, et al. "Multimodal analgesia versus traditional opiate based analgesia after cardiac 
surgery, a randomized controlled trial." J. Cardiothorac. Surg 10 (2014): 1749-8090. 
3. Kehlet H, Jensen TS, Woolf CJ: Persistent postsurgical pain: risk factors and prevention.  Lancet 
2006 May 13, 367(9522):1618-1625.  
4. Kehlet H: Multimodal approach to postoperative recovery. Curr Opin Crit Care 2009 Aug, 15(4):355-
358.  
5. Kong VK, Irwin MG: Gabapentin: a multimodal perioperative drug? Br J Anaesth 2007 Dec, 
99(6):775-786.  
6. Tiippana EM, Hamunen K, Vesa KK, Kalso E. Do surgical patients benefit from perioperative 
gabapentin/pregabalin? A systematic review of ef fi cacy and safety. Anesth Analg. 2007;104(6): 
1545–56. 
7. Clarke H, Bonin RP, Orser BA, Englesakis M, Wijeysundera DN, Katz J. The prevention of chronic 
postsurgical pain using gabapentin and pregabalin: A combined systematic review and meta-analysis. 
Anesth Analg. 2012;115:428–42 
8. Levine, Adam I., Satish Govindaraj, and Samuel DeMaria, eds. Anesthesiology and Otolaryngology. 
Springer, 2013. 
9. Lee J.H., Lee H.K., Chun N.H., So Y., Lim C.Y.  The prophylactic effects of gabapentin on 
postoperative sore throat after thyroid surgery.   Korean Journal of Anesthesiology 2013 64:2 (138-
142). 


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10. Mohammed M.H., Fahmy A.M., Hakim K.Y.K. Preoperative gabapentin augments intraoperative 
hypotension and reduces postoperative opioid requirements with functional endoscopic sinus surgery. 
Egyptian Journal of Anaesthesia 2012 28:3 (189-192). 
11. Ahn S.H., Lee J.H., Min K.T. The prophylactic effects of gabapentin on postoperative sore throat after 
thyroid surgery.  European Journal of Anaesthesiology 2012 29 SUPPL. 50 (202). 
12. Chiu T.W., Leung C.C.H., Lau E.Y.K., Burd A. Analgesic effects of preoperative gabapentin after 
tongue reconstruction with the anterolateral thigh flap. Hong Kong Medical Journal 2012 18:1 (30-34)  
13. Kazak Z., Mortimer N., Mekerci S. Single dose of preoperative analgesia with gabapentin (600 mg) is 
safe and effective in monitored anesthesia care for nasal surgery. European Archives of Oto-Rhino-
Laryngology 2010 267:5 (731-736).  
14. Jeon E.-J., Park Y.-S., Park S.S., Lee S.-K., Kim D.-H. The effectiveness of gabapentin on post-
tonsillectomy pain control. European Archives of Oto-Rhino-Laryngology 2009 266:10 (1605-1609). 
15. Turan A., Memi; D., Karamanlio;lu B., Yaiz R., Pamuk; Z., Yavuz E. The analgesic effects of 
gabapentin in monitored anesthesia care for ear-nose-throat surgery.  Anesthesia and Analgesia 
2004 99:2 (375-378). 
16. Hurley RW, Cohen SP, Williams KA, Rowlingson AJ, Wu CL. The analgesic effects of perioperative 
gabapentin on postoperative pain: A meta-analysis. Reg Anesth Pain Med. 2006;31:237–47. 
17. Peng PW, Wijeysundera DN, Li CC. Use of gabapentin for perioperative pain control—A meta-
analysis. Pain Res Manag. 2007;12:85–92. 
18. Seib RK, Paul JE. Preoperative gabapentin for postoperative analgesia: A meta-analysis. Can J 
Anaesth. 2006;53:461–9. 
19. Clivatti J., Sakata R.K., Issy A.M. Review of the use of gabapentin in the control of postoperative 
pain.  Revista Brasileira de Anestesiologia 2009 59:1 (87-98). 
20. Schmidt, Peter C., et al. "Perioperative Gabapentinoids: Choice of Agent, Dose, Timing, and Effects 
on Chronic Postsurgical Pain." Survey of Anesthesiology 58.2 (2014): 96-97. 
21. Al-Mujadid, Hussain, et al. Preemptive gabapentin reduces postoperative pain and opioid demand 
following thyroid surgery. Canadian Journal of Anesthesia. March 2006, Volume 53, Issue 3, pp 268-
273. 
22. Sally L. Collins, R. Andrew Moore, Henry J. McQuay.  The Visual Analogue Scale: what is moderate 
pain in millimeters? Pain (Impact Factor: 5.21). 09/1997; 72(1-2):95-7. 
23. Accessfda.gov. Keyword “gabapentin”. PDF title: Neurontin. Parke-Davis Division of Pfizer Inc, NY, 
NY 10017.  April 2009.   
  


The effect of gabapentin on perioperative pain control among head and 
neck surgery patients 
 
NCT# NCT02926573 
 
 
Document Version Date:  12/01/2016 
 
IRB Approval Date:  12/27/2016 


 
CONFIDENTIAL 
 
CLINICAL RESEARCH PROTOCOL 
 
 
 
 
 
 
 
 
THE EFFECT OF GABAPENTIN ON PERIOPERATIVE PAIN 
CONTROL AMONG HEAD AND NECK SURGERY PATIENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Initial version: 3/31/2016 
Amended: 
[7/31/2016] 
Amended: 
[12/1/2016] 


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Table of Contents 
 
STUDY SUMMARY ...................................................................................................................................... 1 
1 
INTRODUCTION .................................................................................................................................. 2 
1.1 
BACKGROUND ................................................................................................................................ 2 
1.2 
INVESTIGATIONAL AGENT ................................................................................................................ 2 
1.3 
CLINICAL DATA .............................................................................................................................. 2 
1.4 
DOSE RATIONALE AND RISK/BENEFITS ............................................................................................ 3 
2 
STUDY OBJECTIVES ......................................................................................................................... 3 
3 
STUDY DESIGN ................................................................................................................................... 3 
3.1 
GENERAL DESIGN .......................................................................................................................... 3 
3.2 
PRIMARY STUDY ENDPOINTS .......................................................................................................... 6 
3.3 
SECONDARY STUDY ENDPOINTS ..................................................................................................... 6 
3.4 
PRIMARY SAFETY ENDPOINTS ......................................................................................................... 8 
4 
SUBJECT SELECTION AND WITHDRAWAL .................................................................................... 8 
4.1 
INCLUSION CRITERIA ...................................................................................................................... 8 
4.2 
EXCLUSION CRITERIA ..................................................................................................................... 8 
4.3 
SUBJECT RECRUITMENT AND SCREENING ....................................................................................... 8 
4.4 
EARLY WITHDRAWAL OF SUBJECTS................................................................................................. 9 
4.4.1 
When and How to Withdraw Subjects ..................................................................................... 9 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects .......................................................... 9 
5 
STUDY DRUG ...................................................................................................................................... 9 
5.1 
DESCRIPTION ................................................................................................................................. 9 
5.2 
TREATMENT REGIMEN .................................................................................................................... 9 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ....................................................... 10 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ................................................................... 10 
5.5 
SUBJECT COMPLIANCE MONITORING ............................................................................................. 10 
5.6 
PRIOR AND CONCOMITANT THERAPY ............................................................................................. 10 
5.7 
PACKAGING ................................................................................................................................. 10 
5.8 
BLINDING OF STUDY DRUG ........................................................................................................... 11 
5.9 
RECEIVING, STORAGE, DISPENSING AND RETURN .......................................................................... 11 
5.9.1 
Receipt of Drug Supplies ....................................................................................................... 11 
5.9.2 
Storage .................................................................................................................................. 11 
5.9.3 
Dispensing of Study Drug ...................................................................................................... 11 
5.9.4 
Return or Destruction of Study Drug ..................................................................................... 11 
6 
STUDY PROCEDURES ..................................................................................................................... 11 
7 
STATISTICAL PLAN ......................................................................................................................... 12 
7.1 
SAMPLE SIZE DETERMINATION ...................................................................................................... 12 
7.2 
STATISTICAL METHODS ................................................................................................................ 12 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ....................................................................................... 12 
8 
SAFETY AND ADVERSE EVENTS ................................................................................................... 13 
8.1 
DEFINITIONS ................................................................................................................................ 13 
8.2 
RECORDING OF ADVERSE EVENTS ................................................................................................ 14 
8.3 
UNBLINDING PROCEDURES ........................................................................................................... 14 
8.4 
MEDICAL MONITORING ................................................................................................................. 14 
9 
DATA HANDLING AND RECORD KEEPING ................................................................................... 15 
 


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10 
STUDY MONITORING ....................................................................................................................... 15 
10.1 
STUDY MONITORING PLAN ............................................................................................................ 15 
 
13 
REFERENCES ................................................................................................................................... 15 
 
 


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List of Abbreviations 
 
 
HCAHPS- Hospital Consumer Assessment of Healthcare Providers and Systems 
 
PRC-Professional Research Consultants  
 
FDA – Food and Drug Administration 
 
VAS – Visual Analog Scale 
 
POD – post-operative day 
 
 
 
 
 
 
 
 


[Insert short name of protocol here] 
 
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Study Summary 
Title 
The effect of gabapentin on perioperative pain control among head and neck 
surgery patients 
Short Title 
Gaba RCT 
Protocol Number 
1.2 (first amended version) 
Phase 
Phase 4 
Methodology 
Prospective randomized double-blind controlled trial followed by observational 
follow up study 
Study Duration 
2 years 
Study Center(s) 
Barnes Jewish Hospital 
Objectives 
Determine the effectiveness of gabapentin for reducing narcotic requirements 
and subjective pain scores in postoperative head and neck mucosal cancer 
patients.  Determine the ability of gabapentin to improve patient satisfaction 
with pain management. Track inpatient length of stay. Observation of post op 
swallow function.  
Number of Subjects 
120 
Diagnosis and Main 
Inclusion Criteria 
Adult head and neck patients undergoing oral cavity, oropharynx, larynx and 
hypopharynx resection (mucosal head and neck surgeries) 
Study Product, Dose, 
Route, Regimen 
Gabapentin liquid by mouth or Per Tube 300mg BID vs placebo 
Duration 
of 
administration 
Day of surgery and up to three days post operatively depending on the hospital 
stay.   
Reference therapy 
Placebo 
Statistical 
Methodology 
Bivariate analysis using independent samples t-test for continuous variables 
and chi square test for categorical variables will be used to compare between 
treatment groups 
 


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1 Introduction 
This document is a protocol for a human research study to be conducted according to US and 
international standards of Good Clinical Practice compliant to all associated Federal and applicable local 
and University research requirements, approved by the Institutional Review Board.  
1.1 Background 
High-quality healthcare is accessible, safe, efficient, patient-centered and imperative for good treatment 
outcomes.  In this era of healthcare reform, patient satisfaction has increasingly become an important 
metric of hospital performance.  The Medicare Hospital Value Based Purchasing Program utilizes patient 
reported satisfaction scores as a reflection of the quality of care delivered by hospital systems and 
clinician teams.  The scores resulting from these reports are integrated into the formula with which 
hospitals are reimbursed for Medicare patients. 
 
An important patient-physician interface in quality healthcare is the treatment of pain, and the treatment of 
acute postoperative pain is particularly relevant for surgical specialties.  Effective management of 
postoperative pain increases patient satisfaction, reduces hospital costs, reduces postoperative morbidity 
and shortens hospitalizations8.  HCAHP and PRC data from the Barnes Jewish Hospital otolaryngology 
inpatient unit reveals that postoperative otolaryngology patient satisfaction with pain control is routinely 
lower than the 75th percentile of all hospitals nationally surveyed.  Traditionally, pain regimens rely heavily 
on the use of narcotics, which are associated with nausea, vomiting, delirium, and decreased bowel 
motility.  These side effects have the potential to increase length of hospitalization and decrease patient 
satisfaction.  Moreover, otolaryngology patients often undergo very painful and functionally debilitating 
surgeries of the head and neck and are at increased risk for postoperative pain due to both the 
neuroanatomy of this region and the need to swallow postoperatively8.   Postoperative pain control in this 
population is critical for patient satisfaction and an expedited return to a functional swallowing status. 
 
Within the field of pain management is the practice of multimodal pain therapy.  This strategy employs 
non-narcotic medications working synergistically to improve pain control, decreasing narcotic medication 
requirements and narcotic-associated side effects8.  Studies utilizing multimodal pain regimens 
demonstrate such benefits in acute postoperative pain management2-5.  Gabapentin is a non-narcotic 
pain medication often used in multimodal pain regimens that has been shown to reduce acute 
postoperative pain.  
1.2 Investigational Agent 
Gabapentin is a non-narcotic medication developed to target neuropathic pain1.  It is an amino acid 1-
(aminomethyl)cyclohexaneacetic acid that is structurally related to the inhibitory neurotransmitter GABA 
(gamma-aminobutyric acid), without modifying the binding, metabolism, or elimination of GABA.  In vitro 
studies have demonstrated gabapentin binding sites in the rat brain, but the functional implication and the 
mechanism of its analgesic and anticonvulsant activity remains unknown in humans.  The oral 
bioavailability of gabapentin decreases as dose increases.  Its half-life is 5-7 hours, and it is eliminated by 
renal excretion without chemical alteration.  Dose adjustments are recommended for creatinine clearance 
less than 30 mL/min.  It is FDA approved since 1993 for post-herpetic neuralgia and epilepsy, and has 
been widely applied in neuropathic pain management.  It is also frequently used for acute postoperative 
pain, and meta-analysis of randomized controlled trials shows it to be an effective pain management 
strategy in postoperative patients.  The major adverse reactions reported were, in descending frequency, 
dizziness, sedation, asthenia, diarrhea, dry mouth, constipation, nausea, and vomiting 23. 
1.3 Clinical Data to Date 
Numerous randomized controlled trials demonstrated that gabapentin effectively reduced narcotic use 
and improved subjective pain in various surgical populations, such as gynecology-oncology and 
orthopedic surgery9-15.  Meta-analyses of these pooled trials reported an overall trend toward improved 
pain control and decreased postoperative narcotic use with gabapentin, despite the heterogeneity of the 
included studies6,16-19.  A small number of studies have examined the use of gabapentin in postoperative 


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otolaryngology patients and suggest a potential benefit in improving postoperative pain control after 
thyroidectomy, endoscopic sinus surgery, oral cavity resection with reconstruction, and tonsillectomy9-15. 
Most of the studies demonstrated an improvement with only one preoperative dose.  To date, no 
randomized control trials have been conducted with gabapentin use in adult otolaryngology patients 
undergoing all types of head and neck mucosal surgeries, which is an at-risk population for high levels of 
postsurgical pain. 
1.4 Dose Rationale and Risk/Benefits 
Dosing regimen of gabapentin will be 300 mg PO preoperatively, followed by 300 mg BID until POD 2 or 
the day of discharge, whichever comes first. Note that on the morning of POD3 at 7am, a VAS will be 
obtained to reflect the POD 2 7pm dose.  The liquid formulation will be used postoperatively given the 
possibility of dysphagia or postoperative NPO status potentially requiring a feeding tube.  The optimal 
dosage for gabapentin in acute postoperative pain is unknown.  Recommended gabapentin regimen for 
treatment of post-herpetic neuralgia is a 300 mg/day on day 1, 300 mg BID on day 2, 300 mg TID on day 
3, and subsequently up-titrated as needed to 600 mg TID23.  Prior studies using gabapentin for 
postoperative pain control in otolaryngology patients have primarily administered a single preoperative 
dose ranging from 100 mg to 1200 mg9-15. Data was inconsistent as some studies showed efficacy at low 
dosages and some showed no difference at high dosages, and an optimal dose regimen remains to be 
determined.  For this study a relatively low dosage was chosen to minimize sedation side effects, as 
included participants are likely to be gabapentin-naïve.  The perioperative BID dosing period was chosen 
to better elucidate the effects of gabapentin in the acute, postoperative period, as many head and neck 
mucosal resections cause significant pain for several days after the procedure.  The majority of head and 
neck inpatient stays are between 2-3 days, with some staying as short as 1 day and some as long as a 
few weeks.  At this dose and schedule, gabapentin side effects are minimized so that subject risk is also 
minimized without compromising medication analgesic abilities.  Collaboration with the inpatient pain 
management team also supports the expectation that this dose and time regimen will be effective and will 
minimize side effects.  
 
Post-operative swallow results will be collected from the medical record on those patients receiving post 
op swallow therapy per routine care.  The post-operative swallow evaluation will be observational, based 
solely on the discretion of the surgeon and is not required per the research protocol.  
2 Study Objectives 
This investigation is a quality improvement initiative designed to elucidate the benefit of gabapentin in 
pain management in subjects undergoing surgical resection of head and neck mucosal surfaces. 
 
Primary Objective 
To assess the efficacy of gabapentin on decreasing narcotic requirements for treatment of acute 
postoperative pain in head and neck patients undergoing surgical resection of mucosal surfaces. 
 
Secondary Objectives 
To assess subjective pain scores and participant satisfaction with pain control.  
 
Observational outcomes 
Hospital length of stay and post-operative swallow function if assessed.  
3 Study Design 
3.1 General Design 
This is a prospective, randomized, double-blind, placebo-controlled study with the intent of providing high 
quality and reproducible data.  The study subjects include adult otolaryngology patients over the age of 
18 years undergoing open or endoscopic/robotic resection involving the mucosal surfaces of the oral 
cavity, oropharynx, hypopharynx and larynx in a single tertiary academic center.  Participants are 
recruited from the otolaryngology head and neck cancer clinic during their preoperative visits.  The 


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duration of subject participation includes the subsequent inpatient hospitalization following definitive 
cancer resection up to two days after surgery.   Subjects will be given the placebo or gabapentin for up to 
two days post op or until discharge, whichever comes first.   
 
Potential subjects will be recruited from the patient population in the head and neck surgery clinic, 11th 
floor CAM, the center for outpatient health or at other outpatient or inpatient sites related to their pre-
surgical planning visits.  Eligible patients will be identified before their scheduled appointments via review 
of medical records in Allscripts by a study team member and approached either in the exam room during 
their scheduled appointment with the head and neck surgeons or afterwards via telephone call.  The 
study will be explained to them and a copy of the consent form will be provided after it has been signed.  
Patients will be reminded that participation is voluntary and will in no way affect their current or future care 
related to their head and neck health needs. Patients will be given time to ask questions and will have the 
option to consider participation and enroll at a subsequent appointment before their planned procedure. 
The consent process will take place in a private room.  Steps to avoid coercion include proper training in 
informed consent, private discussion rooms in which the surgeon is not present, and patients will be 
reassured that their care from their head and neck surgeon will not be affected by their decision to 
participate or to not participate.  Patients will be made aware that their postoperative care will not be 
limited by participation in this study, meaning that they will not be denied needed and appropriate narcotic 
pain medications simply because they are enrolled.  Written informed consent will be obtained prior to the 
start of research related procedures. 
 
 
 


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**Note that IV and PO or per tube morphine will be used in amounts equivalent to the dilaudid and oxycodone medications 
above if an allergy or intolerance to dilaudid or oxycodone exist. 
 
Subjects will present for their planned procedures to the pre-op surgery office and will be taken to the pre-
op holding area as per usual hospital procedure.  A study team member will meet the subject in the pre-
op holding area and will administer the pre-op medication approximately 1 hour prior to surgery start time. 
Patients will not be excluded if surgery start time is delayed past 1 hour.  An investigational pharmacist 
will deliver the medication appropriately labeled with patient name and study number to the pre-op 
holding area.  This oral administration is safe per consultation with the anesthesia faculty member of this 
project.  Additionally, on the day of surgery a study member will place pain medication orders in compass 
on hold for post op care.  These orders will be 1000mg of Tylenol PO or per tube Q6 hours (or Q12 hours 
if the patient has hepatic insufficiency), oxycodone 5-10mg Q4 hours PRN pain (5mg if pain less than or 
equal to 5/10, 10mg if greater than 5/10), and dilaudid 0.25-0.5mg Q2 hours PRN breakthrough pain 
(0.25mg if pain less than or equal to 5/10, 0.5mg if greater than 5/10).  Alternatives to these medications 
in case of allergy or intolerance is 1-2mg IV morphine Q2 hours PRN pain (1mg if pain less than or equal 
to 5/10, 2mg if greater than 5/10) and 7.5-15mg PO/PT liquid IR morphine Q4 hours PRN pain (7.5mg if 
pain less than or equal to 5/10, 15mg if greater than 5/10).  Additionally, the study team member will 
place the appropriate investigational drug order in compass.  The subject will be able to receive increases 
in pain medications as deemed appropriate by the inpatient treating physicians.  They will not have any 
limitations set on pain medications simply because they are involved in the study.  The subject will then 
proceed with surgery as planned. No alterations to intraoperative medications or anesthetic agents will be 
made based on study participation. 
 
The subject will return to the PACU after extubation.  If the subject had to remain intubated, he or she will 
be withdrawn from the study as he or she cannot complete pain scores while sedated. Additionally, if the 
subject is at any point during the study placed on alcohol withdrawal medication protocols, he or she will 
be withdrawn from the study.  The study team member administering the preoperative dose will remind 
anesthesia to use the same post-operative initial pain management options in the PACU at least initially, 
again with no restrictions on dose escalations that are needed.  The PACU can increase the dose of 
postoperative pain medications based on patient need and MD approval as per the usual PACU protocol 
without restriction based on a subject’s study participation.  Subjects will remain in the PACU per the 
usual protocol until the required level of alertness and clinical stability are reached for transfer, and their 
PACU medication sheet will be copied and added to their hard copy file for use later during 


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tabulation/data anaylsis of the pain meds they required The VAS score obtained after surgery will be 
completed 45 minutes to 1 hour after extubation in the PACU.  
 
Note that subjects must have completed surgery (extubated) by 5PM in order to receive the 7PM dose 
after their surgery.  Otherwise, this dose is to be skipped and the next dose administered will be at 7AM 
the next day.  VAS scores can still be obtained at 45 minutes to 1 hour postoperatively, however, even if 
the case finishes later than 5pm. On POD 1-2, subjects will be given BID medications at 7am and 7pm 
per the study protocol and VAS scores will be obtained prior to medication administration   A separate 
VAS will be obtained at 10am on POD1 and POD 2.  ON POD 3 a 7am VAS will be obtained but no study 
medication given. This last VAS concludes participation in the study.  Discharge surveys will be 
administered at this point if they have not been already (ie if the patient remained an inpatient for longer 
than 2 days postop).   
The investigational pharmacist will have delivered the medication dose in a properly labeled container to 
the 6200 inpatient floor prior to scheduled doses, and the medications will be stored in patient labeled 
bins in the locked medication refrigerator.  All VAS scores will be obtained with subject privacy optimized, 
including drawing the curtain in subject room to separate the sides of the room from any potential 
roommate.  Also, the research team member will not vocalize a subject’s status as a study patient.  VAS 
scores will be obtained at rest, with cough and following a swallowing gesture.  Scores are captured by 
providing the subject with a pen and asking the subject to mark the location of their pain on a line 
measuring 10cm during each phase of the VAS.   The scale is a validated tool that measures 10cm in 
size and is marked “no pain” on the far left and “worst pain” on the far right.  The subject marks their pain 
level on the scale and the study team member will measure with a ruler and record the resulting number 
in the study database.    
Subjects will fill out a discharge survey before they are discharged or at the completion of their 
participation to rate their satisfaction with their inpatient pain control.  This survey will be a hard copy 
labeled with study ID and the data will be entered into the study database.  All hard copy data will be 
stored in a locked cabinet accessible only to the study team.  At the end of the study, all hard copy data 
will be properly destroyed.   
 
Subjects will have 24/7 access to members of the study team should questions or concerns arise while 
they are actively participating in the study as well as up to 30 days after completion of the study.   
 
Note that study medication wrappers have patient names on them as a safety mechanism to make sure 
medications are given to the proper patient.  These wrappers and labels will be saved in the patient 
folders which are secured in a locked cabinet where only study team members have access.  Empty and 
unlabeled medication syringes will be discarded in the red biohazard bins inside patient rooms.  
3.2 Primary Study Endpoints 
The primary study endpoint is postoperative narcotic consumption.  Average daily narcotic use from 
postoperative admission to the last dose of pain medication on POD 2, or the day of discharge, whichever 
comes sooner, will be calculated. Total amount of narcotic use in morphine equivalents will be divided by 
the total hours of inpatient hospitalization, multiplied by 24 hours, to obtain the average daily narcotic 
consumption. 
3.3 Secondary Study Endpoints 
The secondary endpoints include (a) subject satisfaction with pain control, (b) VAS pain scores, (c) 
patient baseline pain perceptions (d) hospital length of stay, and (e) potential side effects of the 
medication.  
 
(a) Subject satisfaction with pain control will be captured in a survey administered at POD 2 after the 
AM dose administration, or after the AM dose administration on the day of discharge, whichever 
comes sooner.  Two of the survey questions will mirror those on the HCAPHS surveys, listed as 
followed (see attached “post-treatment questionnaire”): 
 
1. How often was your pain well controlled? 


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0) Never 
1) Sometimes 
2) Usually 
3) Always 
 
2. How often did the hospital staff do everything they could to help you with your pain? 
0) Never 
1) Sometimes 
2) Usually 
3) Always 
 
3. How satisfied are you with your overall pain control? 
0) Very dissatisfied 
1) Somewhat dissatisfied 
2) Neutral 
3) Somewhat satisfied 
4) Very satisfied 
 
4. Was there anything else that we could have done to make your pain control better during your 
inpatient stay? 
A point system is created with the sum of the numeric values assigned to questions 1-3 on a scale of 
0 to 10, with a score of 0-3 indicates overall dissatisfaction, 4 indicates neutrality, and 5-10 suggests 
overall satisfaction.  This will be analyzed as an ordinal variable. 
 
(b) VAS pain scores will be assessed 45min to 1 hour after surgery and then three times a day on 
POD 1-2 and once on POD 3, or until day of discharge, whichever comes sooner. A standardized 
VAS form will be given to subjects with verbal instruction to first “mark on the line the point that 
you feel represents your current pain level when you’re resting.”  This is followed by asking the 
subject to gesture swallowing and “mark another point on the line that represents your pain level 
when you swallow.”  Lastly, the subject will be asked to cough and to “mark the final point on the 
line that represents your pain when you cough.”  The study team member administering the test 
will annotate what each mark represents (rest, swallow, and cough).  The scale contains a 10-cm 
line from “no pain” on the left to “extreme pain” on the right (see “VAS form”).  The distance in 
centimeters from the left of the line to the center of the patient’s three marks will be recorded.  
The results from all available VAS scores for each subject will be averaged and included in the 
final analysis.  
 
(c) The subject’s belief in pain medication efficacy and pain tolerance will be assessed from a short 
survey obtained preoperatively during the office visit (see “pre-treatment questionnaire”). This 
includes the following questions: 
 
1. In the past, how effective are narcotic pain medications (such as morphine, Vicodin, Norco, 
Percocet, oxycodone, Dilaudid) at controlling your pain? 
0) Very ineffective 
1) Somewhat ineffective 
2) Somewhat effective 
3) Very effective 
 
2. In the past, how has your pain tolerance been? 
0) Very poor 
1) Somewhat poor 
2) Somewhat tolerant 
3) Very tolerant 


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3. Do you experience a significant amount of pain on a daily basis aside from the pain due to 
your current head and neck condition? 
1) Yes I do 
2) No I do not 
The results of these questions will be reported separately in the final analyses. 
 
(d) Hospital length of stay will be calculated for each subject. 
 
(e) During the VAS scores, study team members will also collect information about potential 
medication side effects, including those that are commonly associated with gabapentin or with 
narcotic medications.  
3.4 Primary Safety Endpoints 
The primary safety endpoints are the rate and severity of drug-related adverse events.  Adverse events 
will be monitored and recorded by study team members during subject inpatient stay.  These events will 
be reviewed by the principal investigator and categorized into “drug-related”, “likely drug-related”, and 
“unlikely drug-related.”  Any significant adverse events determined to be likely drug related will be 
reported to the OHRP within a 24 hour time period and stopping the study for the subject will be 
discussed. A project safety review will be conducted by a third party safety officer approximately half way 
through the study, or sooner if necessary.  
 
4 Subject Selection and Withdrawal 
4.1 Inclusion Criteria 
 
Subjects undergoing definitive mucosal head and neck resection including oral cavity, 
oropharynx, larynx, and hypopharynx 
 
At least 1 night of planned inpatient stay 
4.2 Exclusion Criteria 
 
Incapable of giving informed consent 
 
Age < 18 
 
GFR < 30 
 
Allergy to gabapentin  
 
Baseline gabapentin or lyrica use 
 
Chronic opioid use for over 6 months 
4.3 Subject Recruitment and Screening 
Subjects will be recruited either in the outpatient head and neck clinic prior to their planned surgeries or 
over the phone after this clinic appointment by designated study team members.  Potentially eligible 
patients will be identified by study team members prior to their scheduled appointments via the outpatient 
medical records system.  Patient recruited by phone will be able to sign the informed consent prior to 
surgery either at a subsequent surgical planning visit or in the pre-op holding are on the day of surgery.  
Eligible subjects will be consented in a private setting and the study outline explained to the patient. 
Written informed consent will be obtained from those patients who wish to participate.  Patients may 
choose to think about study participation but will need to decide and provide written consent prior to the 
day of surgery, either at their subsequent preoperative anesthesia clinic appointment or medical 
oncology/radiation oncology appointments.  Study team members will be properly trained in the informed 
consent process.  
 


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4.4 Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
Subjects may be withdrawn from the study prior to the expected completion if they develop 
hypersensitivity reactions to the study drug, are unable to swallow all study drugs in the study period, or 
choose to withdrawal for other reasons.  They will also be withdrawn if they remain sedated or intubated 
after the surgery or are placed on alcohol withdrawal medication protocols, which also cause significant 
sedation.  Subjects without a feeding tube who are unable, or unwilling, to swallow medications after 
surgery will not be given a feeding tube to remain in the study.  A 20% dropout rate was anticipated and 
accounted for in the sample size calculation.  Subjects will be able to withdraw on a continual basis 
throughout their participation.  Withdraw can be requested either by the subject or by any team member if 
medical significant adverse reactions are observed.  All withdraws will be reviewed by the principle 
investigator.  No subject will be denied the ability to withdraw. The withdraw process will begin 
immediately when deemed necessary or when desired by the subject, and documentation of the reason 
and time of withdraw will be performed.   
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
Withdrawn subjects will be excluded in the final data analysis. The reasons for withdrawal will be 
recorded and reported separately in the study data outcomes. 
 
4.4.3 Definitions 
Subject withdraw: Withdraw is defined as a subject who signed the informed consent document and for 
whatever reason dropped out of the study before completion, whether by choice or by exclusion criteria 
(ie- staying intubated the night after surgery). 
 
Subject screen fail: A screen fail is defined as a subject who has been recruited to participate and 
approached but does not meet all inclusion criteria.  
 
5 Study Drug  
5.1 Description 
300mg of liquid gabapentin or an equal volume of placebo will be pre-packaged by the investigational 
pharmacist in a labeled medication syringe or in a marked bag with a capsule.  An unblinded study team 
member in charge of the randomization process will indicate to the pharmacy which subjects are to 
receive what medication.  The blinded study team members will not know which medication contains 
placebo or gabapentin.  
5.2 Treatment Regimen 
Subjects will receive either placebo or gabapentin 300 mg PO the preoperative holding area 
approximately 1 hour before their procedure is scheduled to begin.  This first dose will designate the day 
of their procedure as POD 0.  If the procedure ends late in the evening (ie not extubated before 5pm), and 
the subject is not able to receive the second POD 0 dose by 7 PM, then this second POD 0 dose will be 
skipped.   Participants will then receive either placebo or 300 mg of gabapentin BID POD 1- POD 2.  
Dosing will end either on POD 2 after the PM dose or on day of discharge after the AM dose, whichever 
comes first.  VAS scores will be collected 45 minutes- 1 hour post extubation on POD as well as TID on 
POD 1-2 and one time at 7am on POD 3 (see above protocol flowsheet).  


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5.3 Method for Assigning Subjects to Treatment Groups 
After a subject consents to study, the unblinded data manager will randomize the subject into active or 
placebo group and assign a subject study number.  The subject study number will be used to identify 
which subjects are to receive which medication.  
5.4 Preparation and Administration of Study Drug 
The Investigational Pharmacist will mix and prepare the study medications necessary for each subject.  A 
pharmacist will deliver the medication to the preop holding unit or the floor and a designated study team 
member will administer it.  Please see section 5.7 below for mixing and packaging details. Contact 
information for the pharmacy for this project is pharmacist Kathryn Vehe at 314-795-7286. 
 
Inpatient pharmacists will be responsible for delivering the medication to the floor prior to the AM dose 
and to the PM dose, as well as will deliver the medication to the pre-op holding area prior to a subject’s 
procedure. Formal training for all study team members who will be administering the study drug or 
obtaining the VAS pain scores is required prior to subject interaction. 
5.5 Subject Compliance Monitoring 
The study team members will directly administer each study medication dosage during the study period 
and record adherence to study protocol.  If a dose is missed during this period, the subject will remain in 
the study through the completion of the protocol.  The decision to include data from subjects with missed 
doses will be made at the discretion of the principle investigator and statistician at the conclusion of the 
study.   Data integrity will be maintained such that subjects who are excluded for missed doses will be 
consistent among cases.  
5.6 Prior and Concomitant Therapy 
Every subject will have standard postoperative narcotic medications made available: 
 IV Dilaudid 0.25-0.5mg q2h PRN breakthrough pain (pain equal to or less than 5/10 will get 
0.25mg and pain >5/10 will get 0.5mg).  
 PO/PT oxycodone 5-10mg q4h PRN pain (pain equal to or less than 5/10 will get 5mg, and pain 
greater than 5/10 will get 10mg).  
 PO/PT acetaminophen 1000mg q6h for pain in non-cirrhotic patients, and 1000mg q12h in 
cirrhotic patients 
 Morphine IV and PO liquid equivalents will be substituted in cases of oxycode or dilaudid 
allergies. 1-2mg IV morphine Q2 hours PRN will be substituted for 0.25-0.5mg dilaudid for 
breakthrough pain (pain equal to or less than 5/10 will get 1mg and pain >5/10 will get 2mg).   
PRN liquid IR morphine 7.5-15mg will be substituted Q4 hours for oxycodone PRN for pain (pain 
equal to or less than 5/10 will get 7.5mg, and pain greater than 5/10 will get 15mg) 
 Study team members will place an order in compass for study investigation drug administration 
as per BJC protocol for investigational drug use.   
 
These medications can be up-titrated as needed at the discretion of the physicians managing the 
patient’s care as part of the routine postoperative management. 
5.7 Packaging 
 Study medications will be in liquid or capsule form.  Gabapentin comes as a standard liquid form 
of 250mg/5ml. Capsules will be used for the pre-operative dose, and will come as single capsules 
in bags labeled with study ID and name.  For post-operative doses, 6ml of either gabapentin or 
placebo will be packaged into a brown 20ml plastic syringe.  Each syringe will have the subject 
name and study ID on it.  The pharmacy will be made aware of all upcoming study subjects and 
will prepare the medications approximately 24 hours prior to administration, and will store these at 
4 degrees Celsius.  The medications will be stored prior to dosing on the floor in a locked fridge in 
patient specific compartments, as per the floor medication protocol.  


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5.8 Blinding of Study Drug 
The study team members administering the medications will be blinded towards whether a subject 
receives the study drug or the placebo.  The data manager who does not participate in data collection or 
have direct subject interaction, as well as the pharmacist preparing the medications, will be unblinded. 
5.9 Receiving, Storage, Dispensing and Return 
5.9.1 Receipt of Drug Supplies 
Investigational pharmacists will be responsible for medication delivery prior to planned doses.  They will 
be alerted to upcoming procedures that involve study subjects.  They will be responsible for delivering the 
medication to the inpatient floor and in the preoperative holding area.  Any damaged or unusable study 
drug in a given shipment will be documented in the study files and discarded. 
5.9.2 Storage 
Medications will be stored by the investigational pharmacy in a designated, locked area at 4 degrees 
Celsius. They will be stored on the inpatient floor in a locked, 4 degree fridge in patient specific 
compartments per the floor medication storage protocols.  
5.9.3 Dispensing of Study Drug 
The study team members administering the medications will receive the medication from the 
investigational pharmacist.  They will then administer the medication and record the time of administration 
and the subject identification number in the subject’s study flow sheet (“Gaba project subject study flow 
chart” attached). 
5.9.4 Return or Destruction of Study Drug 
At the completion of the study, there will be a final reconciliation of medications consumed.  This 
reconciliation will be logged on the drug reconciliation form, signed and dated.  Any discrepancies noted 
will be investigated, resolved, and documented.  Medication syringes will be discarded in the red 
biohazard containers in accordance with hospital policy and documented in the study files. Any labels or 
bags with patient names will be discarded in the shred bins on the 6200 floor or in the preop holding unit.  
 
6 Study Procedures 
The study procedures are outlined below and represented in the attached “Gaba project subject study 
flow chart”.  
 
Clinic Visit 
 
Consent. 
 
Pre-treatment questionnaire. 
 
Randomization group will be assigned by the study data manager after she is notified of subject 
agreement to participate. 
Day of Surgery 
 
One dose of study drug will be administered preoperatively according to subject’s randomization 
group approximately 1 hour prior to procedure start time.  The coordinator administering the 
medication will tape a study reminder sheet for anesthesia to the chart and will place an order in 
the chart that allows the participant to take the preop medication dose, and the RN to chart this 
dose as a study medication.  


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 
Standard pain medications orders will be provided. Morphine will be used as a substitute for 
dilaudid or oxycodone allergies or intolerances. These will be up-titrated as needed per discretion 
of service residents and attending physicians. 
 
One VAS score will be obtained 45 minutes to 1 hour postoperatively regardless of extubation 
time. 
 
One postoperative dose of study drug and VAS will be administered at 7pm if subjects are 
extubated by 5PM 
Post-Operative Day (POD) 1-2 
 
TID VAS scores will be obtained, two of which will be prior to drug administrations. 
 
BID study drug administration will be conducted according to subject’s randomization groups. 
POD 3  
 
POD 3 VAS at 7am will be obtained.  
POD 3 or Day of Discharge 
 
Post-treatment pain satisfaction questionnaire will be conducted either after the AM dose on POD 
3 or on date of discharge, whichever comes sooner. 
7 Statistical Plan 
7.1 Sample Size Determination 
Sample size calculations were performed based on prior studies with gabapentin use in otolaryngology 
patients undergoing thyroidectomy21.  A study by Al-Mujadid et al in a population of patients undergoing 
elective thyroidectomy reported that total morphine consumption in the placebo group in the first 24 hours 
post surgery required a mean of 29.5mg of morphine with a standard deviation of 9.9mg.  Assuming that 
this magnitude of effect variability will hold true in this project population, it is estimated that 46 subjects 
per group (total n=92) will be needed to detect with an 80% power at the 2-sided alpha level of 0.05 a 
difference of 20% or greater in average morphine dose (effect size d=0.6) between the placebo and 
gabapentin groups.  Assuming a 20% drop out rate, 116 subjects will be enrolled in this study.  The 
volume of eligible subjects for this study is predicted to meet the calculated sample size within two years 
of study start time. A review of surgical procedures meeting inclusion criteria performed over a sample 
three month time frame ranged from 12 to 17 procedures a month.  
7.2 Statistical Methods 
Descriptive statistics will be used to describe distribution of demographics. Bivariate analysis using 
independent samples t-test for continuous variables and chi square test for categorical variables will be 
used to compare distribution of characteristics between treatment groups to ensure successful 
randomization. 
 
The primary and secondary outcome measures will be compared between the two treatment groups via 
bivariate analyses.  In addition, a General Linear Model (GLM) approach will be used to explore the 
impact of gabapentin as compared to placebo on each of the outcomes of interest after controlling for 
potential cofounders that were unevenly distributed between the two groups.  The estimated mean 
difference and 95% confidence interval will be reported. 
7.3 Subject Population(s) for Analysis 
Protocol-compliant subjects who received all study drugs up to the conduction of post-treatment 
questionnaire will be included for analysis.  Subjects with missed medication doses will go on to complete 
the protocol, and per the discretion of the principle investigator and statistician may or may not be 


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included in the data analysis.  Data integrity will be maintained such that subjects who are excluded for 
missed doses will be consistent among cases. 
 
8 Safety and Adverse Events 
8.1 Definitions 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
 Unexpected in nature, severity, or frequency  (i.e. not described in study-related documents such 
as the IRB-approved protocol or consent form, the investigators brochure, etc) 
 Related or possibly related to participation in the research (i.e. possibly related means there is a 
reasonable possibility that the incident experience, or outcome may have been caused by the 
procedures involved in the research) 
 Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm). 
 
 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study.  Intercurrent illnesses or injuries will be regarded as adverse events.  
Abnormal results of diagnostic procedures are considered to be adverse events if the abnormality: 
 results in study withdrawal 
 is associated with a serious adverse event 
 is associated with clinical signs or symptoms 
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
 fatal 
 life-threatening 
 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event 
 
 
Mild and Moderate adverse events: 
A moderate adverse event is one that requires a medical intervention such as medication for 
nausea, but that does not cause permanent clinical harm and that does resolve in a reasonable 
amount of time. 
A mild adverse event is one that causes mild clinical effect and may or may not require medical 
intervention. It is expected to resolve completely with observation or medical treatment.  
 
Adverse Event Reporting Period 
The study period during which adverse events must be reported will be the period from the day of surgery 
to the end of the study treatment follow-up.  For this study, the study follow-up is defined as 30 days 
following the last administration of study drug.  Subjects will be provided with contact information for the 
study member that is in charge of adverse event follow up (Melanie Townsend, PI).  They will be 
instructed to contact this person with questions related to the study, adverse events or side effects 
experienced.  
For all severe adverse events, an IRB event form will be submitted. For mild or moderate events, and 
event form will be submitted if the event is one that is likely related to the medication and is an event that 


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is not considered an expected side effect of gabapentin. Mild or moderate events that do not resolve 
within an appropriate time frame will also be reported to the IRB.  Mild and moderate events will be 
reviewed by the PI and deemed appropriate for reporting.   
 
 
Post-study Adverse Event 
All unresolved adverse events will be followed by the investigator until the events are resolved, the 
subject is lost to follow-up, or the adverse event is otherwise explained.  At the last scheduled visit, the 
investigator will instruct each subject to report any subsequent event(s) that the subject, or the subject’s 
personal physician, believes might reasonably be related to participation in this study.   
8.2 Recording of Adverse Events 
At each interaction with the subject, the investigator will seek information on adverse events by specific 
questioning and, as appropriate, by examination.  Information on all adverse events will be recorded 
immediately in the source document.  All clearly related signs, symptoms, and abnormal diagnostic 
procedures results will be recorded in the source document. Specific side effects that will be elicited at 
each interaction include nausea, vomiting, dizziness and sedation.   
 
The clinical course of any adverse event will be followed until resolution, stabilization, or until it has been 
determined that the study treatment or participation is not the cause.  Serious adverse events that are still 
ongoing at the end of the study period will be followed up to determine the final outcome.  Any serious 
adverse event that occurs after the study period and is considered to be possibly related to the study drug 
or study participation will be recorded and reported immediately to the IRB. 
 
8.3 Unblinding Procedures 
For this study only the data manager and pharmacy will be unblinded to the study drug and placebo 
assignments.  Unblinding of the rest of the study investigators will occur after assurance that data 
collection has completed.  If any subject data is intentionally or unintentionally unblinded, the event will be 
documented in detail in the study documents within 48 hours.  Any unblinding that occurs during the study 
period for an individual participant will result in exclusion of that participant’s data from final analysis.  
Study investigators must report unblinding to the PI within a 24 hour time period and must document the 
event.  Subjects will immediately be made aware of the unblinding and will be withdrawn from completing 
the protocol.  
Stopping Rules  
The study will be terminated prematurely if 50% or more of the subjects receiving study drug (gabapentin 
or placebo) experience significant adverse events as defined above in section 8.1.  The study will not be 
prematurely stopped if subjects experience less significant medication side effects, specifically nausea, 
vomiting, dizziness and sedation.  A review of adverse events will be conducted at 25% and 50% 
enrollment to ensure that they are properly tracked.  
8.4 Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study.  This safety 
monitoring will include careful assessment and appropriate reporting of adverse events as noted above, 
as well as the construction and implementation of a site data and safety-monitoring plan (see section 10 
Monitoring).  Medical monitoring will include a regular assessment of the number and type of serious 
adverse events.  A designated, third party safety officer will review the study approximately half way 
through to ensure that subjects are not being harmed by this study.  


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9 Data Handling and Record Keeping 
9.1 Confidentiality 
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).   
Source data will be kept primarily in the electronic forms using REDCap for data collection.  Paper forms 
including the original consents, questionnaires, VAS pain score sheets, adverse event reporting forms 
etc. will be kept in a locked cabinet that only study team members have access to.  At the conclusion of 
the study, after data has been entered into a password protected spread sheet, these records will be 
destroyed in the proper manner in shred it bins where patient information is normally placed.  The official 
source document and case report form for this study will be the REDCap database. 
 
 
All research records will be maintained in the Outcomes Office, 8th floor McMillan for 7 years after study 
completion per WU record retention policy.  
 
10 Study Monitoring 
10.1 Study Monitoring Plan 
This study will be monitored in real time for each subject by the PI and study team.  At minimum, with 
25% accrual goal all adverse events and data collection forms will be reviewed by the PI and discussed 
among the study team. A designated, third party safety officer will review the study approximately half 
way through to ensure that subjects are not being harmed by this study.  
 
 
11 References 
1. Chang C.Y., Challa C.K., Shah J., Eloy J.D. Gabapentin in acute postoperative pain management.  
BioMed Research International Vol. 2014.  2014.  
2. Rafiq, Sulman, et al. "Multimodal analgesia versus traditional opiate based analgesia after cardiac 
surgery, a randomized controlled trial." J. Cardiothorac. Surg 10 (2014): 1749-8090. 
3. Kehlet H, Jensen TS, Woolf CJ: Persistent postsurgical pain: risk factors and prevention.  Lancet 
2006 May 13, 367(9522):1618-1625.  
4. Kehlet H: Multimodal approach to postoperative recovery. Curr Opin Crit Care 2009 Aug, 15(4):355-
358.  
5. Kong VK, Irwin MG: Gabapentin: a multimodal perioperative drug? Br J Anaesth 2007 Dec, 
99(6):775-786.  
6. Tiippana EM, Hamunen K, Vesa KK, Kalso E. Do surgical patients benefit from perioperative 
gabapentin/pregabalin? A systematic review of ef fi cacy and safety. Anesth Analg. 2007;104(6): 
1545–56. 
7. Clarke H, Bonin RP, Orser BA, Englesakis M, Wijeysundera DN, Katz J. The prevention of chronic 
postsurgical pain using gabapentin and pregabalin: A combined systematic review and meta-analysis. 
Anesth Analg. 2012;115:428–42 
8. Levine, Adam I., Satish Govindaraj, and Samuel DeMaria, eds. Anesthesiology and Otolaryngology. 
Springer, 2013. 
9. Lee J.H., Lee H.K., Chun N.H., So Y., Lim C.Y.  The prophylactic effects of gabapentin on 
postoperative sore throat after thyroid surgery.   Korean Journal of Anesthesiology 2013 64:2 (138-
142). 
10. Mohammed M.H., Fahmy A.M., Hakim K.Y.K. Preoperative gabapentin augments intraoperative 
hypotension and reduces postoperative opioid requirements with functional endoscopic sinus surgery. 
Egyptian Journal of Anaesthesia 2012 28:3 (189-192). 


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11. Ahn S.H., Lee J.H., Min K.T. The prophylactic effects of gabapentin on postoperative sore throat after 
thyroid surgery.  European Journal of Anaesthesiology 2012 29 SUPPL. 50 (202). 
12. Chiu T.W., Leung C.C.H., Lau E.Y.K., Burd A. Analgesic effects of preoperative gabapentin after 
tongue reconstruction with the anterolateral thigh flap. Hong Kong Medical Journal 2012 18:1 (30-34)  
13. Kazak Z., Mortimer N., Mekerci S. Single dose of preoperative analgesia with gabapentin (600 mg) is 
safe and effective in monitored anesthesia care for nasal surgery. European Archives of Oto-Rhino-
Laryngology 2010 267:5 (731-736).  
14. Jeon E.-J., Park Y.-S., Park S.S., Lee S.-K., Kim D.-H. The effectiveness of gabapentin on post-
tonsillectomy pain control. European Archives of Oto-Rhino-Laryngology 2009 266:10 (1605-1609). 
15. Turan A., Memi; D., Karamanlio;lu B., Yaiz R., Pamuk; Z., Yavuz E. The analgesic effects of 
gabapentin in monitored anesthesia care for ear-nose-throat surgery.  Anesthesia and Analgesia 
2004 99:2 (375-378). 
16. Hurley RW, Cohen SP, Williams KA, Rowlingson AJ, Wu CL. The analgesic effects of perioperative 
gabapentin on postoperative pain: A meta-analysis. Reg Anesth Pain Med. 2006;31:237–47. 
17. Peng PW, Wijeysundera DN, Li CC. Use of gabapentin for perioperative pain control—A meta-
analysis. Pain Res Manag. 2007;12:85–92. 
18. Seib RK, Paul JE. Preoperative gabapentin for postoperative analgesia: A meta-analysis. Can J 
Anaesth. 2006;53:461–9. 
19. Clivatti J., Sakata R.K., Issy A.M. Review of the use of gabapentin in the control of postoperative 
pain.  Revista Brasileira de Anestesiologia 2009 59:1 (87-98). 
20. Schmidt, Peter C., et al. "Perioperative Gabapentinoids: Choice of Agent, Dose, Timing, and Effects 
on Chronic Postsurgical Pain." Survey of Anesthesiology 58.2 (2014): 96-97. 
21. Al-Mujadid, Hussain, et al. Preemptive gabapentin reduces postoperative pain and opioid demand 
following thyroid surgery. Canadian Journal of Anesthesia. March 2006, Volume 53, Issue 3, pp 268-
273. 
22. Sally L. Collins, R. Andrew Moore, Henry J. McQuay.  The Visual Analogue Scale: what is moderate 
pain in millimeters? Pain (Impact Factor: 5.21). 09/1997; 72(1-2):95-7. 
23. Accessfda.gov. Keyword “gabapentin”. PDF title: Neurontin. Parke-Davis Division of Pfizer Inc, NY, 
NY 10017.  April 2009.   
  


The effect of gabapentin on perioperative pain control among head and 
neck surgery patients 
 
NCT# NCT02926573 
 
 
Document Version Date:  07/31/2016 
 
IRB Approval Date:  08/04/2016 


 
CONFIDENTIAL 
 
CLINICAL RESEARCH PROTOCOL 
 
 
 
 
 
 
 
 
THE EFFECT OF GABAPENTIN ON PERIOPERATIVE PAIN 
CONTROL AMONG HEAD AND NECK SURGERY PATIENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Initial version: 3/31/2016 
Amended: 
[7/31/2016] 
Amended: 
[ ] 


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Table of Contents 
 
STUDY SUMMARY ...................................................................................................................................... 1 
1 
INTRODUCTION .................................................................................................................................. 2 
1.1 
BACKGROUND ................................................................................................................................ 2 
1.2 
INVESTIGATIONAL AGENT ................................................................................................................ 2 
1.3 
CLINICAL DATA .............................................................................................................................. 2 
1.4 
DOSE RATIONALE AND RISK/BENEFITS ............................................................................................ 3 
2 
STUDY OBJECTIVES ......................................................................................................................... 3 
3 
STUDY DESIGN ................................................................................................................................... 3 
3.1 
GENERAL DESIGN .......................................................................................................................... 3 
3.2 
PRIMARY STUDY ENDPOINTS .......................................................................................................... 6 
3.3 
SECONDARY STUDY ENDPOINTS ..................................................................................................... 6 
3.4 
PRIMARY SAFETY ENDPOINTS ......................................................................................................... 8 
4 
SUBJECT SELECTION AND WITHDRAWAL .................................................................................... 8 
4.1 
INCLUSION CRITERIA ...................................................................................................................... 8 
4.2 
EXCLUSION CRITERIA ..................................................................................................................... 8 
4.3 
SUBJECT RECRUITMENT AND SCREENING ....................................................................................... 8 
4.4 
EARLY WITHDRAWAL OF SUBJECTS................................................................................................. 9 
4.4.1 
When and How to Withdraw Subjects ..................................................................................... 9 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects .......................................................... 9 
5 
STUDY DRUG ...................................................................................................................................... 9 
5.1 
DESCRIPTION ................................................................................................................................. 9 
5.2 
TREATMENT REGIMEN .................................................................................................................... 9 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ......................................................... 9 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ..................................................................... 9 
5.5 
SUBJECT COMPLIANCE MONITORING ............................................................................................. 10 
5.6 
PRIOR AND CONCOMITANT THERAPY ............................................................................................. 10 
5.7 
PACKAGING ................................................................................................................................. 10 
5.8 
BLINDING OF STUDY DRUG ........................................................................................................... 10 
5.9 
RECEIVING, STORAGE, DISPENSING AND RETURN .......................................................................... 10 
5.9.1 
Receipt of Drug Supplies ....................................................................................................... 10 
5.9.2 
Storage .................................................................................................................................. 11 
5.9.3 
Dispensing of Study Drug ...................................................................................................... 11 
5.9.4 
Return or Destruction of Study Drug ..................................................................................... 11 
6 
STUDY PROCEDURES ..................................................................................................................... 11 
7 
STATISTICAL PLAN ......................................................................................................................... 12 
7.1 
SAMPLE SIZE DETERMINATION ...................................................................................................... 12 
7.2 
STATISTICAL METHODS ................................................................................................................ 12 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ....................................................................................... 12 
8 
SAFETY AND ADVERSE EVENTS ................................................................................................... 12 
8.1 
DEFINITIONS ................................................................................................................................ 12 
8.2 
RECORDING OF ADVERSE EVENTS ................................................................................................ 13 
8.3 
UNBLINDING PROCEDURES ........................................................................................................... 14 
8.4 
MEDICAL MONITORING ................................................................................................................. 14 
9 
DATA HANDLING AND RECORD KEEPING ................................................................................... 14 
 


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10 
STUDY MONITORING ....................................................................................................................... 14 
10.1 
STUDY MONITORING PLAN ............................................................................................................ 14 
 
13 
REFERENCES ................................................................................................................................... 15 
 
 


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List of Abbreviations 
 
 
HCAHPS- Hospital Consumer Assessment of Healthcare Providers and Systems 
 
PRC-Professional Research Consultants  
 
FDA – Food and Drug Administration 
 
VAS – Visual Analog Scale 
 
POD – post-operative day 
 
 
 
 
 
 
 
 


[Insert short name of protocol here] 
 
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Study Summary 
Title 
The effect of gabapentin on perioperative pain control among head and neck 
surgery patients 
Short Title 
Gaba RCT 
Protocol Number 
1.1 (first amended version) 
Phase 
Phase 4 
Methodology 
Prospective randomized double-blind controlled trial followed by observational 
follow up study 
Study Duration 
2 years 
Study Center(s) 
Barnes Jewish Hospital 
Objectives 
Determine the effectiveness of gabapentin for reducing narcotic requirements 
and subjective pain scores in postoperative head and neck mucosal cancer 
patients.  Determine the ability of gabapentin to improve patient satisfaction 
with pain management. Track inpatient length of stay. Observation of post op 
swallow function.  
Number of Subjects 
120 
Diagnosis and Main 
Inclusion Criteria 
Adult head and neck patients undergoing oral cavity, oropharynx, larynx and 
hypopharynx resection (mucosal head and neck surgeries) 
Study Product, Dose, 
Route, Regimen 
Gabapentin liquid by mouth or Per Tube 300mg BID vs placebo 
Duration 
of 
administration 
Day of surgery and up to three days post operatively depending on the hospital 
stay.   
Reference therapy 
Placebo 
Statistical 
Methodology 
Bivariate analysis using independent samples t-test for continuous variables 
and chi square test for categorical variables will be used to compare between 
treatment groups 
 


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1 Introduction 
This document is a protocol for a human research study to be conducted according to US and 
international standards of Good Clinical Practice compliant to all associated Federal and applicable local 
and University research requirements, approved by the Institutional Review Board.  
1.1 Background 
High-quality healthcare is accessible, safe, efficient, patient-centered and imperative for good treatment 
outcomes.  In this era of healthcare reform, patient satisfaction has increasingly become an important 
metric of hospital performance.  The Medicare Hospital Value Based Purchasing Program utilizes patient 
reported satisfaction scores as a reflection of the quality of care delivered by hospital systems and 
clinician teams.  The scores resulting from these reports are integrated into the formula with which 
hospitals are reimbursed for Medicare patients. 
 
An important patient-physician interface in quality healthcare is the treatment of pain, and the treatment of 
acute postoperative pain is particularly relevant for surgical specialties.  Effective management of 
postoperative pain increases patient satisfaction, reduces hospital costs, reduces postoperative morbidity 
and shortens hospitalizations8.  HCAHP and PRC data from the Barnes Jewish Hospital otolaryngology 
inpatient unit reveals that postoperative otolaryngology patient satisfaction with pain control is routinely 
lower than the 75th percentile of all hospitals nationally surveyed.  Traditionally, pain regimens rely heavily 
on the use of narcotics, which are associated with nausea, vomiting, delirium, and decreased bowel 
motility.  These side effects have the potential to increase length of hospitalization and decrease patient 
satisfaction.  Moreover, otolaryngology patients often undergo very painful and functionally debilitating 
surgeries of the head and neck and are at increased risk for postoperative pain due to both the 
neuroanatomy of this region and the need to swallow postoperatively8.   Postoperative pain control in this 
population is critical for patient satisfaction and an expedited return to a functional swallowing status. 
 
Within the field of pain management is the practice of multimodal pain therapy.  This strategy employs 
non-narcotic medications working synergistically to improve pain control, decreasing narcotic medication 
requirements and narcotic-associated side effects8.  Studies utilizing multimodal pain regimens 
demonstrate such benefits in acute postoperative pain management2-5.  Gabapentin is a non-narcotic 
pain medication often used in multimodal pain regimens that has been shown to reduce acute 
postoperative pain.  
1.2 Investigational Agent 
Gabapentin is a non-narcotic medication developed to target neuropathic pain1.  It is an amino acid 1-
(aminomethyl)cyclohexaneacetic acid that is structurally related to the inhibitory neurotransmitter GABA 
(gamma-aminobutyric acid), without modifying the binding, metabolism, or elimination of GABA.  In vitro 
studies have demonstrated gabapentin binding sites in the rat brain, but the functional implication and the 
mechanism of its analgesic and anticonvulsant activity remains unknown in humans.  The oral 
bioavailability of gabapentin decreases as dose increases.  Its half-life is 5-7 hours, and it is eliminated by 
renal excretion without chemical alteration.  Dose adjustments are recommended for creatinine clearance 
less than 30 mL/min.  It is FDA approved since 1993 for post-herpetic neuralgia and epilepsy, and has 
been widely applied in neuropathic pain management.  It is also frequently used for acute postoperative 
pain, and meta-analysis of randomized controlled trials shows it to be an effective pain management 
strategy in postoperative patients.  The major adverse reactions reported were, in descending frequency, 
dizziness, sedation, asthenia, diarrhea, dry mouth, constipation, nausea, and vomiting 23. 
1.3 Clinical Data to Date 
Numerous randomized controlled trials demonstrated that gabapentin effectively reduced narcotic use 
and improved subjective pain in various surgical populations, such as gynecology-oncology and 
orthopedic surgery9-15.  Meta-analyses of these pooled trials reported an overall trend toward improved 
pain control and decreased postoperative narcotic use with gabapentin, despite the heterogeneity of the 
included studies6,16-19.  A small number of studies have examined the use of gabapentin in postoperative 


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otolaryngology patients and suggest a potential benefit in improving postoperative pain control after 
thyroidectomy, endoscopic sinus surgery, oral cavity resection with reconstruction, and tonsillectomy9-15. 
Most of the studies demonstrated an improvement with only one preoperative dose.  To date, no 
randomized control trials have been conducted with gabapentin use in adult otolaryngology patients 
undergoing all types of head and neck mucosal surgeries, which is an at-risk population for high levels of 
postsurgical pain. 
1.4 Dose Rationale and Risk/Benefits 
Dosing regimen of gabapentin will be 300 mg PO preoperatively, followed by 300 mg BID until POD 2 or 
the day of discharge, whichever comes first. Note that on the morning of POD3 at 7am, a VAS will be 
obtained to reflect the POD 2 7pm dose.  The liquid formulation will be used postoperatively given the 
possibility of dysphagia or postoperative NPO status potentially requiring a feeding tube.  The optimal 
dosage for gabapentin in acute postoperative pain is unknown.  Recommended gabapentin regimen for 
treatment of post-herpetic neuralgia is a 300 mg/day on day 1, 300 mg BID on day 2, 300 mg TID on day 
3, and subsequently up-titrated as needed to 600 mg TID23.  Prior studies using gabapentin for 
postoperative pain control in otolaryngology patients have primarily administered a single preoperative 
dose ranging from 100 mg to 1200 mg9-15. Data was inconsistent as some studies showed efficacy at low 
dosages and some showed no difference at high dosages, and an optimal dose regimen remains to be 
determined.  For this study a relatively low dosage was chosen to minimize sedation side effects, as 
included participants are likely to be gabapentin-naïve.  The perioperative BID dosing period was chosen 
to better elucidate the effects of gabapentin in the acute, postoperative period, as many head and neck 
mucosal resections cause significant pain for several days after the procedure.  The majority of head and 
neck inpatient stays are between 2-3 days, with some staying as short as 1 day and some as long as a 
few weeks.  At this dose and schedule, gabapentin side effects are minimized so that subject risk is also 
minimized without compromising medication analgesic abilities.  Collaboration with the inpatient pain 
management team also supports the expectation that this dose and time regimen will be effective and will 
minimize side effects.  
 
Post-operative swallow results will be collected from the medical record on those patients receiving post 
op swallow therapy per routine care.  The post-operative swallow evaluation will be observational, based 
solely on the discretion of the surgeon and is not required per the research protocol.  
2 Study Objectives 
This investigation is a quality improvement initiative designed to elucidate the benefit of gabapentin in 
pain management in subjects undergoing surgical resection of head and neck mucosal surfaces. 
 
Primary Objective 
To assess the efficacy of gabapentin on decreasing narcotic requirements for treatment of acute 
postoperative pain in head and neck patients undergoing surgical resection of mucosal surfaces. 
 
Secondary Objectives 
To assess subjective pain scores and participant satisfaction with pain control.  
 
Observational outcomes 
Hospital length of stay and post-operative swallow function if assessed.  
3 Study Design 
3.1 General Design 
This is a prospective, randomized, double-blind, placebo-controlled study with the intent of providing high 
quality and reproducible data.  The study subjects include adult otolaryngology patients over the age of 
18 years undergoing open or endoscopic/robotic resection involving the mucosal surfaces of the oral 
cavity, oropharynx, hypopharynx and larynx in a single tertiary academic center.  Participants are 
recruited from the otolaryngology head and neck cancer clinic during their preoperative visits.  The 


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duration of subject participation includes the subsequent inpatient hospitalization following definitive 
cancer resection up to two days after surgery.   Subjects will be given the placebo or gabapentin for up to 
two days post op or until discharge, whichever comes first.   
 
Potential subjects will be recruited from the patient population in the head and neck surgery clinic, 11th 
floor CAM, the center for outpatient health or at other outpatient or inpatient sites related to their pre-
surgical planning visits.  Eligible patients will be identified before their scheduled appointments via review 
of medical records in Allscripts by a study team member and approached either in the exam room during 
their scheduled appointment with the head and neck surgeons or afterwards via telephone call.  The 
study will be explained to them and a copy of the consent form will be provided after it has been signed.  
Patients will be reminded that participation is voluntary and will in no way affect their current or future care 
related to their head and neck health needs. Patients will be given time to ask questions and will have the 
option to consider participation and enroll at a subsequent appointment before their planned procedure. 
The consent process will take place in a private room.  Steps to avoid coercion include proper training in 
informed consent, private discussion rooms in which the surgeon is not present, and patients will be 
reassured that their care from their head and neck surgeon will not be affected by their decision to 
participate or to not participate.  Patients will be made aware that their postoperative care will not be 
limited by participation in this study, meaning that they will not be denied needed and appropriate narcotic 
pain medications simply because they are enrolled.  Written informed consent will be obtained prior to the 
start of research related procedures. 
 
 
 


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**Note that IV and PO or per tube morphine will be used in amounts equivalent to the dilaudid and oxycodone medications 
above if an allergy or intolerance to dilaudid or oxycodone exist. 
 
Subjects will present for their planned procedures to the pre-op surgery office and will be taken to the pre-
op holding area as per usual hospital procedure.  A study team member will meet the subject in the pre-
op holding area and will administer the pre-op medication approximately 1 hour prior to surgery start time. 
Patients will not be excluded if surgery start time is delayed past 1 hour.  An investigational pharmacist 
will deliver the medication appropriately labeled with patient name and study number to the pre-op 
holding area.  This oral administration is safe per consultation with the anesthesia faculty member of this 
project.  Additionally, on the day of surgery a study member will place pain medication orders in compass 
on hold for post op care.  These orders will be 1000mg of Tylenol PO or per tube Q6 hours (or Q12 hours 
if the patient has hepatic insufficiency), oxycodone 5-10mg Q4 hours PRN pain (5mg if pain less than or 
equal to 5/10, 10mg if greater than 5/10), and dilaudid 0.25-0.5mg Q2 hours PRN breakthrough pain 
(0.25mg if pain less than or equal to 5/10, 0.5mg if greater than 5/10).  Alternatives to these medications 
in case of allergy or intolerance is 1-2mg IV morphine Q2 hours PRN pain (1mg if pain less than or equal 
to 5/10, 2mg if greater than 5/10) and 7.5-15mg PO/PT liquid IR morphine Q4 hours PRN pain (7.5mg if 
pain less than or equal to 5/10, 15mg if greater than 5/10).  Additionally, the study team member will 
place the appropriate investigational drug order in compass.  The subject will be able to receive increases 
in pain medications as deemed appropriate by the inpatient treating physicians.  They will not have any 
limitations set on pain medications simply because they are involved in the study.  The subject will then 
proceed with surgery as planned. No alterations to intraoperative medications or anesthetic agents will be 
made based on study participation. 
 
The subject will return to the PACU after extubation.  If the subject had to remain intubated, he or she will 
be withdrawn from the study as he or she cannot complete pain scores while sedated. Additionally, if the 
subject is at any point during the study placed on alcohol withdrawal medication protocols, he or she will 
be withdrawn from the study.  The study team member administering the preoperative dose will remind 
anesthesia to use the same post-operative initial pain management options in the PACU at least initially, 
again with no restrictions on dose escalations that are needed.  The PACU can increase the dose of 
postoperative pain medications based on patient need and MD approval as per the usual PACU protocol 
without restriction based on a subject’s study participation.  Subjects will remain in the PACU per the 
usual protocol until the required level of alertness and clinical stability are reached for transfer.  The VAS 
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Note that subjects must have completed surgery (extubated) by 5PM in order to receive the 7PM dose 
after their surgery.  Otherwise, this dose is to be skipped and the next dose administered will be at 7AM 
the next day.  VAS scores can still be obtained at 45 minutes to 1 hour postoperatively, however, even if 
the case finishes later than 5pm. On POD 1-2, subjects will be given BID medications at 7am and 7pm 
per the study protocol and VAS scores will be obtained prior to medication administration   A separate 
VAS will be obtained at 10am on POD1 and POD 2.  ON POD 3 a 7am VAS will be obtained but no study 
medication given. This last VAS concludes participation in the study.  Discharge surveys will be 
administered at this point if they have not been already (ie if the patient remained an inpatient for longer 
than 2 days postop).   
The investigational pharmacist will have delivered the medication dose in a properly labeled container to 
the 6200 inpatient floor prior to scheduled doses, and the medications will be stored in patient labeled 
bins in the locked medication refrigerator.  All VAS scores will be obtained with subject privacy optimized, 
including drawing the curtain in subject room to separate the sides of the room from any potential 
roommate.  Also, the research team member will not vocalize a subject’s status as a study patient.  VAS 
scores will be obtained at rest, with cough and following a swallowing gesture.  Scores are captured by 
providing the subject with a pen and asking the subject to mark the location of their pain on a line 
measuring 10cm during each phase of the VAS.   The scale is a validated tool that measures 10cm in 
size and is marked “no pain” on the far left and “worst pain” on the far right.  The subject marks their pain 
level on the scale and the study team member will measure with a ruler and record the resulting number 
in the study database.    
Subjects will fill out a discharge survey before they are discharged or at the completion of their 
participation to rate their satisfaction with their inpatient pain control.  This survey will be a hard copy 
labeled with study ID and the data will be entered into the study database.  All hard copy data will be 
stored in a locked cabinet accessible only to the study team.  At the end of the study, all hard copy data 
will be properly destroyed.   
 
Subjects will have 24/7 access to members of the study team should questions or concerns arise while 
they are actively participating in the study as well as up to 30 days after completion of the study.   
 
Note that study medication wrappers have patient names on them as a safety mechanism to make sure 
medications are given to the proper patient.  These wrappers and labels will be saved in the patient 
folders which are secured in a locked cabinet where only study team members have access.  Empty and 
unlabeled medication syringes will be discarded in the red biohazard bins inside patient rooms.  
3.2 Primary Study Endpoints 
The primary study endpoint is postoperative narcotic consumption.  Average daily narcotic use from 
postoperative admission to the last dose of pain medication on POD 2, or the day of discharge, whichever 
comes sooner, will be calculated. Total amount of narcotic use in morphine equivalents will be divided by 
the total hours of inpatient hospitalization, multiplied by 24 hours, to obtain the average daily narcotic 
consumption. 
3.3 Secondary Study Endpoints 
The secondary endpoints include (a) subject satisfaction with pain control, (b) VAS pain scores, (c) 
patient baseline pain perceptions (d) hospital length of stay, and (e) potential side effects of the 
medication.  
 
(a) Subject satisfaction with pain control will be captured in a survey administered at POD 2 after the 
AM dose administration, or after the AM dose administration on the day of discharge, whichever 
comes sooner.  Two of the survey questions will mirror those on the HCAPHS surveys, listed as 
followed (see attached “post-treatment questionnaire”): 
 
1. How often was your pain well controlled? 
0) Never 
1) Sometimes 


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2) Usually 
3) Always 
 
2. How often did the hospital staff do everything they could to help you with your pain? 
0) Never 
1) Sometimes 
2) Usually 
3) Always 
 
3. How satisfied are you with your overall pain control? 
0) Very dissatisfied 
1) Somewhat dissatisfied 
2) Neutral 
3) Somewhat satisfied 
4) Very satisfied 
 
4. Was there anything else that we could have done to make your pain control better during your 
inpatient stay? 
A point system is created with the sum of the numeric values assigned to questions 1-3 on a scale of 
0 to 10, with a score of 0-3 indicates overall dissatisfaction, 4 indicates neutrality, and 5-10 suggests 
overall satisfaction.  This will be analyzed as an ordinal variable. 
 
(b) VAS pain scores will be assessed 45min to 1 hour after surgery and then three times a day on 
POD 1-2 and once on POD 3, or until day of discharge, whichever comes sooner. A standardized 
VAS form will be given to subjects with verbal instruction to first “mark on the line the point that 
you feel represents your current pain level when you’re resting.”  This is followed by asking the 
subject to gesture swallowing and “mark another point on the line that represents your pain level 
when you swallow.”  Lastly, the subject will be asked to cough and to “mark the final point on the 
line that represents your pain when you cough.”  The study team member administering the test 
will annotate what each mark represents (rest, swallow, and cough).  The scale contains a 10-cm 
line from “no pain” on the left to “extreme pain” on the right (see “VAS form”).  The distance in 
centimeters from the left of the line to the center of the patient’s three marks will be recorded.  
The results from all available VAS scores for each subject will be averaged and included in the 
final analysis.  
 
(c) The subject’s belief in pain medication efficacy and pain tolerance will be assessed from a short 
survey obtained preoperatively during the office visit (see “pre-treatment questionnaire”). This 
includes the following questions: 
 
1. In the past, how effective are narcotic pain medications (such as morphine, Vicodin, Norco, 
Percocet, oxycodone, Dilaudid) at controlling your pain? 
0) Very ineffective 
1) Somewhat ineffective 
2) Somewhat effective 
3) Very effective 
 
2. In the past, how has your pain tolerance been? 
0) Very poor 
1) Somewhat poor 
2) Somewhat tolerant 
3) Very tolerant 
 


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3. Do you experience a significant amount of pain on a daily basis aside from the pain due to 
your current head and neck condition? 
1) Yes I do 
2) No I do not 
The results of these questions will be reported separately in the final analyses. 
 
(d) Hospital length of stay will be calculated for each subject. 
 
(e) During the VAS scores, study team members will also collect information about potential 
medication side effects, including those that are commonly associated with gabapentin or with 
narcotic medications.  
3.4 Primary Safety Endpoints 
The primary safety endpoints are the rate and severity of drug-related adverse events.  Adverse events 
will be monitored and recorded by study team members during subject inpatient stay.  These events will 
be reviewed by the principal investigator and categorized into “drug-related”, “likely drug-related”, and 
“unlikely drug-related.”  Any significant adverse events determined to be likely drug related will be 
reported to the OHRP within a 24 hour time period and stopping the study for the subject will be 
discussed. A project safety review will be conducted by a third party safety officer approximately half way 
through the study, or sooner if necessary.  
 
4 Subject Selection and Withdrawal 
4.1 Inclusion Criteria 
 
Subjects undergoing definitive mucosal head and neck resection including oral cavity, 
oropharynx, larynx, and hypopharynx 
 
At least 1 night of planned inpatient stay 
4.2 Exclusion Criteria 
 
Incapable of giving informed consent 
 
Age < 18 
 
GFR < 30 
 
Allergy to gabapentin  
 
Baseline gabapentin or lyrica use 
 
Chronic opioid use for over 6 months 
4.3 Subject Recruitment and Screening 
Subjects will be recruited either in the outpatient head and neck clinic prior to their planned surgeries or 
over the phone after this clinic appointment by designated study team members.  Potentially eligible 
patients will be identified by study team members prior to their scheduled appointments via the outpatient 
medical records system.  Patient recruited by phone will be able to sign the informed consent prior to 
surgery either at a subsequent surgical planning visit or in the pre-op holding are on the day of surgery.  
Eligible subjects will be consented in a private setting and the study outline explained to the patient. 
Written informed consent will be obtained from those patients who wish to participate.  Patients may 
choose to think about study participation but will need to decide and provide written consent prior to the 
day of surgery, either at their subsequent preoperative anesthesia clinic appointment or medical 
oncology/radiation oncology appointments.  Study team members will be properly trained in the informed 
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4.4 Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
Subjects may be withdrawn from the study prior to the expected completion if they develop 
hypersensitivity reactions to the study drug, are unable to swallow all study drugs in the study period, or 
choose to withdrawal for other reasons.  They will also be withdrawn if they remain sedated or intubated 
after the surgery or are placed on alcohol withdrawal medication protocols, which also cause significant 
sedation.  Subjects without a feeding tube who are unable, or unwilling, to swallow medications after 
surgery will not be given a feeding tube to remain in the study.  A 20% dropout rate was anticipated and 
accounted for in the sample size calculation.  Subjects will be able to withdraw on a continual basis 
throughout their participation.  Withdraw can be requested either by the subject or by any team member if 
medical significant adverse reactions are observed.  All withdraws will be reviewed by the principle 
investigator.  No subject will be denied the ability to withdraw. The withdraw process will begin 
immediately when deemed necessary or when desired by the subject, and documentation of the reason 
and time of withdraw will be performed.   
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
Withdrawn subjects will be excluded in the final data analysis. The reasons for withdrawal will be 
recorded and reported separately in the study data outcomes. 
 
5 Study Drug  
5.1 Description 
300mg of liquid gabapentin or an equal volume of placebo will be pre-packaged by the investigational 
pharmacist in a labeled medication syringe or in a marked bag with a capsule.  An unblinded study team 
member in charge of the randomization process will indicate to the pharmacy which subjects are to 
receive what medication.  The blinded study team members will not know which medication contains 
placebo or gabapentin.  
5.2 Treatment Regimen 
Subjects will receive either placebo or gabapentin 300 mg PO the preoperative holding area 
approximately 1 hour before their procedure is scheduled to begin.  This first dose will designate the day 
of their procedure as POD 0.  If the procedure ends late in the evening (ie not extubated before 5pm), and 
the subject is not able to receive the second POD 0 dose by 7 PM, then this second POD 0 dose will be 
skipped.   Participants will then receive either placebo or 300 mg of gabapentin BID POD 1- POD 2.  
Dosing will end either on POD 2 after the PM dose or on day of discharge after the AM dose, whichever 
comes first.  VAS scores will be collected 45 minutes- 1 hour post extubation on POD as well as TID on 
POD 1-2 and one time at 7am on POD 3 (see above protocol flowsheet).  
5.3 Method for Assigning Subjects to Treatment Groups 
After a subject consents to study, the unblinded data manager will randomize the subject into active or 
placebo group and assign a subject study number.  The subject study number will be used to identify 
which subjects are to receive which medication.  
5.4 Preparation and Administration of Study Drug 
The Investigational Pharmacist will mix and prepare the study medications necessary for each subject.  A 
pharmacist will deliver the medication to the preop holding unit or the floor and a designated study team 
member will administer it.  Please see section 5.7 below for mixing and packaging details. Contact 
information for the pharmacy for this project is pharmacist Kathryn Vehe at 314-795-7286. 
 


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Inpatient pharmacists will be responsible for delivering the medication to the floor prior to the AM dose 
and to the PM dose, as well as will deliver the medication to the pre-op holding area prior to a subject’s 
procedure. Formal training for all study team members who will be administering the study drug or 
obtaining the VAS pain scores is required prior to subject interaction. 
5.5 Subject Compliance Monitoring 
The study team members will directly administer each study medication dosage during the study period 
and record adherence to study protocol.  If a dose is missed during this period, the subject will remain in 
the study through the completion of the protocol.  The decision to include data from subjects with missed 
doses will be made at the discretion of the principle investigator and statistician at the conclusion of the 
study.   Data integrity will be maintained such that subjects who are excluded for missed doses will be 
consistent among cases.  
5.6 Prior and Concomitant Therapy 
Every subject will have standard postoperative narcotic medications made available: 
 IV Dilaudid 0.25-0.5mg q2h PRN breakthrough pain (pain equal to or less than 5/10 will get 
0.25mg and pain >5/10 will get 0.5mg).  
 PO/PT oxycodone 5-10mg q4h PRN pain (pain equal to or less than 5/10 will get 5mg, and pain 
greater than 5/10 will get 10mg).  
 PO/PT acetaminophen 1000mg q6h for pain in non-cirrhotic patients, and 1000mg q12h in 
cirrhotic patients 
 Morphine IV and PO liquid equivalents will be substituted in cases of oxycode or dilaudid 
allergies. 1-2mg IV morphine Q2 hours PRN will be substituted for 0.25-0.5mg dilaudid for 
breakthrough pain (pain equal to or less than 5/10 will get 1mg and pain >5/10 will get 2mg).   
PRN liquid IR morphine 7.5-15mg will be substituted Q4 hours for oxycodone PRN for pain (pain 
equal to or less than 5/10 will get 7.5mg, and pain greater than 5/10 will get 15mg) 
 Study team members will place an order in compass for study investigation drug administration 
as per BJC protocol for investigational drug use.   
 
These medications can be up-titrated as needed at the discretion of the physicians managing the 
patient’s care as part of the routine postoperative management. 
5.7 Packaging 
 Study medications will be in liquid or capsule form.  Gabapentin comes as a standard liquid form 
of 250mg/5ml. Capsules will be used for the pre-operative dose, and will come as single capsules 
in bags labeled with study ID and name.  For post-operative doses, 6ml of either gabapentin or 
placebo will be packaged into a brown 20ml plastic syringe.  Each syringe will have the subject 
name and study ID on it.  The pharmacy will be made aware of all upcoming study subjects and 
will prepare the medications approximately 24 hours prior to administration, and will store these at 
4 degrees Celsius.  The medications will be stored prior to dosing on the floor in a locked fridge in 
patient specific compartments, as per the floor medication protocol.  
5.8 Blinding of Study Drug 
The study team members administering the medications will be blinded towards whether a subject 
receives the study drug or the placebo.  The data manager who does not participate in data collection or 
have direct subject interaction, as well as the pharmacist preparing the medications, will be unblinded. 
5.9 Receiving, Storage, Dispensing and Return 
5.9.1 Receipt of Drug Supplies 
Investigational pharmacists will be responsible for medication delivery prior to planned doses.  They will 
be alerted to upcoming procedures that involve study subjects.  They will be responsible for delivering the 


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medication to the inpatient floor and in the preoperative holding area.  Any damaged or unusable study 
drug in a given shipment will be documented in the study files and discarded. 
5.9.2 Storage 
Medications will be stored by the investigational pharmacy in a designated, locked area at 4 degrees 
Celsius. They will be stored on the inpatient floor in a locked, 4 degree fridge in patient specific 
compartments per the floor medication storage protocols.  
5.9.3 Dispensing of Study Drug 
The study team members administering the medications will receive the medication from the 
investigational pharmacist.  They will then administer the medication and record the time of administration 
and the subject identification number in the subject’s study flow sheet (“Gaba project subject study flow 
chart” attached). 
5.9.4 Return or Destruction of Study Drug 
At the completion of the study, there will be a final reconciliation of medications consumed.  This 
reconciliation will be logged on the drug reconciliation form, signed and dated.  Any discrepancies noted 
will be investigated, resolved, and documented.  Medication syringes will be discarded in the red 
biohazard containers in accordance with hospital policy and documented in the study files. Any labels or 
bags with patient names will be discarded in the shred bins on the 6200 floor or in the preop holding unit.  
 
6 Study Procedures 
The study procedures are outlined below and represented in the attached “Gaba project subject study 
flow chart”.  
 
Clinic Visit 
 
Consent. 
 
Pre-treatment questionnaire. 
 
Randomization group will be assigned by the study data manager after she is notified of subject 
agreement to participate. 
Day of Surgery 
 
One dose of study drug will be administered preoperatively according to subject’s randomization 
group approximately 1 hour prior to procedure start time.  The coordinator administering the 
medication will tape a study reminder sheet for anesthesia to the chart and will place an order in 
the chart that allows the participant to take the preop medication dose, and the RN to chart this 
dose as a study medication.  
 
Standard pain medications orders will be provided. Morphine will be used as a substitute for 
dilaudid or oxycodone allergies or intolerances. These will be up-titrated as needed per discretion 
of service residents and attending physicians. 
 
One VAS score will be obtained 45 minutes to 1 hour postoperatively regardless of extubation 
time. 
 
One postoperative dose of study drug and VAS will be administered at 7pm if subjects are 
extubated by 5PM 
Post-Operative Day (POD) 1-2 
 
TID VAS scores will be obtained, two of which will be prior to drug administrations. 
 
BID study drug administration will be conducted according to subject’s randomization groups. 


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POD 3  
 
POD 3 VAS at 7am will be obtained.  
POD 3 or Day of Discharge 
 
Post-treatment pain satisfaction questionnaire will be conducted either after the AM dose on POD 
3 or on date of discharge, whichever comes sooner. 
7 Statistical Plan 
7.1 Sample Size Determination 
Sample size calculations were performed based on prior studies with gabapentin use in otolaryngology 
patients undergoing thyroidectomy21.  A study by Al-Mujadid et al in a population of patients undergoing 
elective thyroidectomy reported that total morphine consumption in the placebo group in the first 24 hours 
post surgery required a mean of 29.5mg of morphine with a standard deviation of 9.9mg.  Assuming that 
this magnitude of effect variability will hold true in this project population, it is estimated that 46 subjects 
per group (total n=92) will be needed to detect with an 80% power at the 2-sided alpha level of 0.05 a 
difference of 20% or greater in average morphine dose (effect size d=0.6) between the placebo and 
gabapentin groups.  Assuming a 20% drop out rate, 116 subjects will be enrolled in this study.  The 
volume of eligible subjects for this study is predicted to meet the calculated sample size within two years 
of study start time. A review of surgical procedures meeting inclusion criteria performed over a sample 
three month time frame ranged from 12 to 17 procedures a month.  
7.2 Statistical Methods 
Descriptive statistics will be used to describe distribution of demographics. Bivariate analysis using 
independent samples t-test for continuous variables and chi square test for categorical variables will be 
used to compare distribution of characteristics between treatment groups to ensure successful 
randomization. 
 
The primary and secondary outcome measures will be compared between the two treatment groups via 
bivariate analyses.  In addition, a General Linear Model (GLM) approach will be used to explore the 
impact of gabapentin as compared to placebo on each of the outcomes of interest after controlling for 
potential cofounders that were unevenly distributed between the two groups.  The estimated mean 
difference and 95% confidence interval will be reported. 
7.3 Subject Population(s) for Analysis 
Protocol-compliant subjects who received all study drugs up to the conduction of post-treatment 
questionnaire will be included for analysis.  Subjects with missed medication doses will go on to complete 
the protocol, and per the discretion of the principle investigator and statistician may or may not be 
included in the data analysis.  Data integrity will be maintained such that subjects who are excluded for 
missed doses will be consistent among cases. 
 
8 Safety and Adverse Events 
8.1 Definitions 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
 Unexpected in nature, severity, or frequency  (i.e. not described in study-related documents such 
as the IRB-approved protocol or consent form, the investigators brochure, etc) 


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 Related or possibly related to participation in the research (i.e. possibly related means there is a 
reasonable possibility that the incident experience, or outcome may have been caused by the 
procedures involved in the research) 
 Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm). 
 
 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study.  Intercurrent illnesses or injuries will be regarded as adverse events.  
Abnormal results of diagnostic procedures are considered to be adverse events if the abnormality: 
 results in study withdrawal 
 is associated with a serious adverse event 
 is associated with clinical signs or symptoms 
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
 fatal 
 life-threatening 
 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event 
 
 
Adverse Event Reporting Period 
The study period during which adverse events must be reported will be the period from the day of surgery 
to the end of the study treatment follow-up.  For this study, the study follow-up is defined as 30 days 
following the last administration of study drug.  Subjects will be provided with contact information for the 
study member that is in charge of adverse event follow up (Melanie Townsend, PI).  They will be 
instructed to contact this person with questions related to the study, adverse events or side effects 
experienced.  
 
 
Post-study Adverse Event 
All unresolved adverse events will be followed by the investigator until the events are resolved, the 
subject is lost to follow-up, or the adverse event is otherwise explained.  At the last scheduled visit, the 
investigator will instruct each subject to report any subsequent event(s) that the subject, or the subject’s 
personal physician, believes might reasonably be related to participation in this study.   
8.2 Recording of Adverse Events 
At each interaction with the subject, the investigator will seek information on adverse events by specific 
questioning and, as appropriate, by examination.  Information on all adverse events will be recorded 
immediately in the source document.  All clearly related signs, symptoms, and abnormal diagnostic 
procedures results will be recorded in the source document. Specific side effects that will be elicited at 
each interaction include nausea, vomiting, dizziness and sedation.   
 
The clinical course of any adverse event will be followed until resolution, stabilization, or until it has been 
determined that the study treatment or participation is not the cause.  Serious adverse events that are still 
ongoing at the end of the study period will be followed up to determine the final outcome.  Any serious 
adverse event that occurs after the study period and is considered to be possibly related to the study drug 
or study participation will be recorded and reported immediately to the IRB. 
 


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8.3 Unblinding Procedures 
For this study only the data manager and pharmacy will be unblinded to the study drug and placebo 
assignments.  Unblinding of the rest of the study investigators will occur after assurance that data 
collection has completed.  If any subject data is intentionally or unintentionally unblinded, the event will be 
documented in detail in the study documents within 48 hours.  Any unblinding that occurs during the study 
period for an individual participant will result in exclusion of that participant’s data from final analysis.  
Study investigators must report unblinding to the PI within a 24 hour time period and must document the 
event.  Subjects will immediately be made aware of the unblinding and will be withdrawn from completing 
the protocol.  
Stopping Rules  
The study will be terminated prematurely if 50% or more of the subjects receiving study drug (gabapentin 
or placebo) experience significant adverse events as defined above in section 8.1.  The study will not be 
prematurely stopped if subjects experience less significant medication side effects, specifically nausea, 
vomiting, dizziness and sedation.  A review of adverse events will be conducted at 25% and 50% 
enrollment to ensure that they are properly tracked.  
8.4 Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study.  This safety 
monitoring will include careful assessment and appropriate reporting of adverse events as noted above, 
as well as the construction and implementation of a site data and safety-monitoring plan (see section 10 
Monitoring).  Medical monitoring will include a regular assessment of the number and type of serious 
adverse events.  A designated, third party safety officer will review the study approximately half way 
through to ensure that subjects are not being harmed by this study.  
9 Data Handling and Record Keeping 
9.1 Confidentiality 
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).   
Source data will be kept primarily in the electronic forms using REDCap for data collection.  Paper forms 
including the original consents, questionnaires, VAS pain score sheets, adverse event reporting forms 
etc. will be kept in a locked cabinet that only study team members have access to.  At the conclusion of 
the study, after data has been entered into a password protected spread sheet, these records will be 
destroyed in the proper manner in shred it bins where patient information is normally placed.  The official 
source document and case report form for this study will be the REDCap database. 
 
 
All research records will be maintained in the Outcomes Office, 8th floor McMillan for 7 years after study 
completion per WU record retention policy.  
 
10 Study Monitoring 
10.1 Study Monitoring Plan 
This study will be monitored in real time for each subject by the PI and study team.  At minimum, with 
25% accrual goal all adverse events and data collection forms will be reviewed by the PI and discussed 
among the study team. A designated, third party safety officer will review the study approximately half 
way through to ensure that subjects are not being harmed by this study.  
 
 


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11 References 
1. Chang C.Y., Challa C.K., Shah J., Eloy J.D. Gabapentin in acute postoperative pain management.  
BioMed Research International Vol. 2014.  2014.  
2. Rafiq, Sulman, et al. "Multimodal analgesia versus traditional opiate based analgesia after cardiac 
surgery, a randomized controlled trial." J. Cardiothorac. Surg 10 (2014): 1749-8090. 
3. Kehlet H, Jensen TS, Woolf CJ: Persistent postsurgical pain: risk factors and prevention.  Lancet 
2006 May 13, 367(9522):1618-1625.  
4. Kehlet H: Multimodal approach to postoperative recovery. Curr Opin Crit Care 2009 Aug, 15(4):355-
358.  
5. Kong VK, Irwin MG: Gabapentin: a multimodal perioperative drug? Br J Anaesth 2007 Dec, 
99(6):775-786.  
6. Tiippana EM, Hamunen K, Vesa KK, Kalso E. Do surgical patients benefit from perioperative 
gabapentin/pregabalin? A systematic review of ef fi cacy and safety. Anesth Analg. 2007;104(6): 
1545–56. 
7. Clarke H, Bonin RP, Orser BA, Englesakis M, Wijeysundera DN, Katz J. The prevention of chronic 
postsurgical pain using gabapentin and pregabalin: A combined systematic review and meta-analysis. 
Anesth Analg. 2012;115:428–42 
8. Levine, Adam I., Satish Govindaraj, and Samuel DeMaria, eds. Anesthesiology and Otolaryngology. 
Springer, 2013. 
9. Lee J.H., Lee H.K., Chun N.H., So Y., Lim C.Y.  The prophylactic effects of gabapentin on 
postoperative sore throat after thyroid surgery.   Korean Journal of Anesthesiology 2013 64:2 (138-
142). 
10. Mohammed M.H., Fahmy A.M., Hakim K.Y.K. Preoperative gabapentin augments intraoperative 
hypotension and reduces postoperative opioid requirements with functional endoscopic sinus surgery. 
Egyptian Journal of Anaesthesia 2012 28:3 (189-192). 
11. Ahn S.H., Lee J.H., Min K.T. The prophylactic effects of gabapentin on postoperative sore throat after 
thyroid surgery.  European Journal of Anaesthesiology 2012 29 SUPPL. 50 (202). 
12. Chiu T.W., Leung C.C.H., Lau E.Y.K., Burd A. Analgesic effects of preoperative gabapentin after 
tongue reconstruction with the anterolateral thigh flap. Hong Kong Medical Journal 2012 18:1 (30-34)  
13. Kazak Z., Mortimer N., Mekerci S. Single dose of preoperative analgesia with gabapentin (600 mg) is 
safe and effective in monitored anesthesia care for nasal surgery. European Archives of Oto-Rhino-
Laryngology 2010 267:5 (731-736).  
14. Jeon E.-J., Park Y.-S., Park S.S., Lee S.-K., Kim D.-H. The effectiveness of gabapentin on post-
tonsillectomy pain control. European Archives of Oto-Rhino-Laryngology 2009 266:10 (1605-1609). 
15. Turan A., Memi; D., Karamanlio;lu B., Yaiz R., Pamuk; Z., Yavuz E. The analgesic effects of 
gabapentin in monitored anesthesia care for ear-nose-throat surgery.  Anesthesia and Analgesia 
2004 99:2 (375-378). 
16. Hurley RW, Cohen SP, Williams KA, Rowlingson AJ, Wu CL. The analgesic effects of perioperative 
gabapentin on postoperative pain: A meta-analysis. Reg Anesth Pain Med. 2006;31:237–47. 
17. Peng PW, Wijeysundera DN, Li CC. Use of gabapentin for perioperative pain control—A meta-
analysis. Pain Res Manag. 2007;12:85–92. 
18. Seib RK, Paul JE. Preoperative gabapentin for postoperative analgesia: A meta-analysis. Can J 
Anaesth. 2006;53:461–9. 
19. Clivatti J., Sakata R.K., Issy A.M. Review of the use of gabapentin in the control of postoperative 
pain.  Revista Brasileira de Anestesiologia 2009 59:1 (87-98). 
20. Schmidt, Peter C., et al. "Perioperative Gabapentinoids: Choice of Agent, Dose, Timing, and Effects 
on Chronic Postsurgical Pain." Survey of Anesthesiology 58.2 (2014): 96-97. 
21. Al-Mujadid, Hussain, et al. Preemptive gabapentin reduces postoperative pain and opioid demand 
following thyroid surgery. Canadian Journal of Anesthesia. March 2006, Volume 53, Issue 3, pp 268-
273. 
22. Sally L. Collins, R. Andrew Moore, Henry J. McQuay.  The Visual Analogue Scale: what is moderate 
pain in millimeters? Pain (Impact Factor: 5.21). 09/1997; 72(1-2):95-7. 
23. Accessfda.gov. Keyword “gabapentin”. PDF title: Neurontin. Parke-Davis Division of Pfizer Inc, NY, 
NY 10017.  April 2009.   
  


The effect of gabapentin on perioperative pain control among head and 
neck surgery patients 
 
NCT# NCT02926573 
 
 
Document Version Date:  03/31/2016 
 
IRB Approval Date:  06/24/2016 


 
CONFIDENTIAL 
 
CLINICAL RESEARCH PROTOCOL 
 
 
 
 
 
 
 
 
A PROSPECTIVE RANDOMIZED CONTROLLED TRIAL ON 
THE EFFECT OF GABAPENTIN ON POSTOPERATIVE PAIN 
CONTROL AMONG HEAD AND NECK CANCER PATIENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Initial version: 3/31/2016 
Amended: 
[date] 
Amended: 
[date] 


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Table of Contents 
 
STUDY SUMMARY ...................................................................................................................................... 1 
1 
INTRODUCTION .................................................................................................................................. 2 
1.1 
BACKGROUND ................................................................................................................................ 2 
1.2 
INVESTIGATIONAL AGENT ................................................................................................................ 2 
1.3 
CLINICAL DATA .............................................................................................................................. 2 
1.4 
DOSE RATIONALE AND RISK/BENEFITS ............................................................................................ 3 
2 
STUDY OBJECTIVES ......................................................................................................................... 3 
3 
STUDY DESIGN ................................................................................................................................... 3 
3.1 
GENERAL DESIGN .......................................................................................................................... 3 
3.2 
PRIMARY STUDY ENDPOINTS .......................................................................................................... 6 
3.3 
SECONDARY STUDY ENDPOINTS ..................................................................................................... 6 
3.4 
PRIMARY SAFETY ENDPOINTS ......................................................................................................... 8 
4 
SUBJECT SELECTION AND WITHDRAWAL .................................................................................... 8 
4.1 
INCLUSION CRITERIA ...................................................................................................................... 8 
4.2 
EXCLUSION CRITERIA ..................................................................................................................... 8 
4.3 
SUBJECT RECRUITMENT AND SCREENING ....................................................................................... 8 
4.4 
EARLY WITHDRAWAL OF SUBJECTS................................................................................................. 8 
4.4.1 
When and How to Withdraw Subjects ..................................................................................... 8 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects .......................................................... 9 
5 
STUDY DRUG ...................................................................................................................................... 9 
5.1 
DESCRIPTION ................................................................................................................................. 9 
5.2 
TREATMENT REGIMEN .................................................................................................................... 9 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ......................................................... 9 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ..................................................................... 9 
5.5 
SUBJECT COMPLIANCE MONITORING ............................................................................................... 9 
5.6 
PRIOR AND CONCOMITANT THERAPY ............................................................................................... 9 
5.7 
PACKAGING ................................................................................................................................. 10 
5.8 
BLINDING OF STUDY DRUG ........................................................................................................... 10 
5.9 
RECEIVING, STORAGE, DISPENSING AND RETURN .......................................................................... 10 
5.9.1 
Receipt of Drug Supplies ....................................................................................................... 10 
5.9.2 
Storage .................................................................................................................................. 10 
5.9.3 
Dispensing of Study Drug ...................................................................................................... 10 
5.9.4 
Return or Destruction of Study Drug ..................................................................................... 10 
6 
STUDY PROCEDURES ..................................................................................................................... 10 
7 
STATISTICAL PLAN ......................................................................................................................... 11 
7.1 
SAMPLE SIZE DETERMINATION ...................................................................................................... 11 
7.2 
STATISTICAL METHODS ................................................................................................................ 11 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ....................................................................................... 11 
8 
SAFETY AND ADVERSE EVENTS ................................................................................................... 12 
8.1 
DEFINITIONS ................................................................................................................................ 12 
8.2 
RECORDING OF ADVERSE EVENTS ................................................................................................ 13 
8.3 
UNBLINDING PROCEDURES ........................................................................................................... 13 
8.4 
MEDICAL MONITORING ................................................................................................................. 13 
9 
DATA HANDLING AND RECORD KEEPING ................................................................................... 14 
 


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10 
STUDY MONITORING ....................................................................................................................... 14 
10.1 
STUDY MONITORING PLAN ............................................................................................................ 14 
 
13 
REFERENCES ................................................................................................................................... 14 
 
 


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List of Abbreviations 
 
 
HCAHPS- Hospital Consumer Assessment of Healthcare Providers and Systems 
 
PRC-Professional Research Consultants  
 
FDA – Food and Drug Administration 
 
VAS – Visual Analog Scale 
 
POD – post-operative day 
 
 
 
 
 
 
 
 


[Insert short name of protocol here] 
 
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Study Summary 
Title 
A prospective randomized controlled trial on the effect of gabapentin on 
postoperative pain control among head and neck cancer patients 
Short Title 
Gaba RCT 
Protocol Number 
1.0 
Phase 
Phase 4 
Methodology 
Prospective randomized double-blind controlled trial followed by observational 
follow up study 
Study Duration 
2 years 
Study Center(s) 
Barnes Jewish Hospital 
Objectives 
Determine the effectiveness of gabapentin for reducing narcotic requirements 
and subjective pain scores in postoperative head and neck mucosal cancer 
patients.  Determine the ability of gabapentin to improve patient satisfaction 
with pain management. Track inpatient length of stay. Observation of post op 
swallow function.  
Number of Subjects 
120 
Diagnosis and Main 
Inclusion Criteria 
Adult head and neck mucosal cancer patients undergoing oral cavity, 
oropharynx, larynx and hypopharynx resection 
Study Product, Dose, 
Route, Regimen 
Gabapentin liquid by mouth or Per Tube 300mg BID vs placebo 
Duration 
of 
administration 
Day of surgery and up to three days post operatively depending on the hospital 
stay.   
Reference therapy 
Placebo 
Statistical 
Methodology 
Bivariate analysis using independent samples t-test for continuous variables 
and chi square test for categorical variables will be used to compare between 
treatment groups 
 


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1 Introduction 
This document is a protocol for a human research study to be conducted according to US and 
international standards of Good Clinical Practice compliant to all associated Federal and applicable local 
and University research requirements, approved by the Institutional Review Board.  
1.1 Background 
High-quality healthcare is accessible, safe, efficient, patient-centered and imperative for good treatment 
outcomes.  In this era of healthcare reform, patient satisfaction has increasingly become an important 
metric of hospital performance.  The Medicare Hospital Value Based Purchasing Program utilizes patient 
reported satisfaction scores as a reflection of the quality of care delivered by hospital systems and 
clinician teams.  The scores resulting from these reports are integrated into the formula with which 
hospitals are reimbursed for Medicare patients. 
 
An important patient-physician interface in quality healthcare is the treatment of pain, and the treatment of 
acute postoperative pain is particularly relevant for surgical specialties.  Effective management of 
postoperative pain increases patient satisfaction, reduces hospital costs, reduces postoperative morbidity 
and shortens hospitalizations8.  HCAHP and PRC data from the Barnes Jewish Hospital otolaryngology 
inpatient unit reveals that postoperative otolaryngology patient satisfaction with pain control is routinely 
lower than the 75th percentile of all hospitals nationally surveyed.  Traditionally, pain regimens rely heavily 
on the use of narcotics, which are associated with nausea, vomiting, delirium, and decreased bowel 
motility.  These side effects have the potential to increase length of hospitalization and decrease patient 
satisfaction.  Moreover, otolaryngology patients often undergo very painful and functionally debilitating 
surgeries of the head and neck and are at increased risk for postoperative pain due to both the 
neuroanatomy of this region and the need to swallow postoperatively8.   Postoperative pain control in this 
population is critical for patient satisfaction and an expedited return to a functional swallowing status. 
 
Within the field of pain management is the practice of multimodal pain therapy.  This strategy employs 
non-narcotic medications working synergistically to improve pain control, decreasing narcotic medication 
requirements and narcotic-associated side effects8.  Studies utilizing multimodal pain regimens 
demonstrate such benefits in acute postoperative pain management2-5.  Gabapentin is a non-narcotic 
pain medication often used in multimodal pain regimens that has been shown to reduce acute 
postoperative pain.  
1.2 Investigational Agent 
Gabapentin is a non-narcotic medication developed to target neuropathic pain1.  It is an amino acid 1-
(aminomethyl)cyclohexaneacetic acid that is structurally related to the inhibitory neurotransmitter GABA 
(gamma-aminobutyric acid), without modifying the binding, metabolism, or elimination of GABA.  In vitro 
studies have demonstrated gabapentin binding sites in the rat brain, but the functional implication and the 
mechanism of its analgesic and anticonvulsant activity remains unknown in humans.  The oral 
bioavailability of gabapentin decreases as dose increases.  Its half-life is 5-7 hours, and it is eliminated by 
renal excretion without chemical alteration.  Dose adjustments are recommended for creatinine clearance 
less than 30 mL/min.  It is FDA approved since 1993 for post-herpetic neuralgia and epilepsy, and has 
been widely applied in neuropathic pain management.  It is also frequently used for acute postoperative 
pain, and meta-analysis of randomized controlled trials shows it to be an effective pain management 
strategy in postoperative patients.  The major adverse reactions reported were, in descending frequency, 
dizziness, sedation, asthenia, diarrhea, dry mouth, constipation, nausea, and vomiting 23. 
1.3 Clinical Data to Date 
Numerous randomized controlled trials demonstrated that gabapentin effectively reduced narcotic use 
and improved subjective pain in various surgical populations, such as gynecology-oncology and 
orthopedic surgery9-15.  Meta-analyses of these pooled trials reported an overall trend toward improved 
pain control and decreased postoperative narcotic use with gabapentin, despite the heterogeneity of the 
included studies6,16-19.  A small number of studies have examined the use of gabapentin in postoperative 


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otolaryngology patients and suggest a potential benefit in improving postoperative pain control after 
thyroidectomy, endoscopic sinus surgery, oral cavity resection with reconstruction, and tonsillectomy9-15. 
Most of the studies demonstrated an improvement with only one preoperative dose.  To date, no 
randomized control trials have been conducted with gabapentin use in adult otolaryngology patients 
undergoing head and neck mucosal surgeries, which is an at-risk population for high levels of 
postsurgical pain. 
1.4 Dose Rationale and Risk/Benefits 
Dosing regimen of gabapentin will be 300 mg PO preoperatively, followed by 300 mg BID until POD 3 or 
the day of discharge, whichever comes first.  The liquid formulation will be used postoperatively given the 
possibility of dysphagia or postoperative NPO status potentially requiring a feeding tube.  The optimal 
dosage for gabapentin in acute postoperative pain is unknown.  Recommended gabapentin regimen for 
treatment of post-herpetic neuralgia is a 300 mg/day on day 1, 300 mg BID on day 2, 300 mg TID on day 
3, and subsequently up-titrated as needed to 600 mg TID23.  Prior studies using gabapentin for 
postoperative pain control in otolaryngology patients have primarily administered a single preoperative 
dose ranging from 100 mg to 1200 mg9-15. Data was inconsistent as some studies showed efficacy at low 
dosages and some showed no difference at high dosages, and an optimal dose regimen remains to be 
determined.  For this study a relatively low dosage was chosen to minimize sedation side effects, as 
included participants are likely to be gabapentin-naïve.  The postoperative 3-day BID dosing period was 
chosen to better elucidate the effects of gabapentin in the acute, postoperative period, as many head and 
neck mucosal resections cause significant pain for several days after the procedure.  The majority of 
head and neck inpatient stays are between 2-3 days, with some staying as short as 1 day and some as 
long as a few weeks.  At this dose and schedule, gabapentin side effects are minimized so that subject 
risk is also minimized without compromising medication analgesic abilities.  Collaboration with the 
inpatient pain management team also supports the expectation that this dose and time regimen will be 
effective and will minimize side effects.  
 
Post-operative swallow results will be collected from the medical record on those patients receiving post 
op swallow therapy per routine care.The post-operative swallow evaluation will be based solely on the 
discretion of the surgeon and is not required per the research protocol.  
2 Study Objectives 
This investigation is a quality improvement initiative designed to elucidate the benefit of gabapentin in 
pain management in subjects undergoing definitive surgical resection of head and neck mucosal 
malignancies. 
 
Primary Objective 
To assess the efficacy of gabapentin on decreasing narcotic requirements for treatment of acute 
postoperative pain in head and neck cancer patients undergoing definitive surgical resection of mucosal 
surfaces. 
 
Secondary Objectives 
To assess subjective pain scores and participant satisfaction with pain control.  
 
Observational outcomes 
Hospital length of stay and post-operative swallow function if assessed.  
3 Study Design 
3.1 General Design 
This is a prospective, randomized, double-blind, placebo-controlled study with the intent of providing high 
quality and reproducible data.  The study subjects include adult otolaryngology patients over the age of 
18 years undergoing open or endoscopic/robotic tumor resection involving the mucosal surfaces of the 
oral cavity, oropharynx, hypopharynx and larynx in a single tertiary academic center.  Participants are 


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recruited from the otolaryngology head and neck cancer clinic during their preoperative visits.  The 
duration of subject participation includes the subsequent inpatient hospitalization following definitive 
cancer resection up to three days after surgery.   Subjects will be given the placebo or gabapentin for up 
to three days post op or until discharge, whichever comes first.   
 
Potential subjects will be recruited from the patient population in the head and neck surgery clinic, 11th 
floor CAM.  Eligible patients will be identified before their scheduled appointments via review of medical 
records in Allscripts by a study team member  and approached in the exam room during their scheduled 
appointment with the head and neck surgeons.  The study will be explained to them and a copy of the 
consent form will be provided.  Patients will be reminded that participation is voluntary and will in no way 
affect their current or future care related to their disease. Patients will be given time to ask questions and 
will have the option to consider participation and enroll at a subsequent appointment before their planned 
procedure. The consent process will take place in private clinical exam room.  Patients will be able to 
choose to participate up to 24 hours prior to their scheduled procedure, as this will give the study team 
enough time to alert the pharmacy and the study coordinators of their case.  Steps to avoid coercion 
include proper training in informed consent, private discussion rooms in which the surgeon is not present, 
and no involvement of the surgeon will occur to ensure that patients do not feel as though their care from 
that surgeon will be affected by their decision to participate or to not participate.  Patients will be made 
aware that their postoperative care will not be limited by participation in this study, meaning that they will 
not be denied needed and appropriate narcotic pain medications simply because they are enrolled.  
Written informed consent will be obtained prior to the start of research related procedures. 
 
 
 


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Subjects will present for their planned procedures to the pre-op surgery office and will be taken to the pre-
op holding area as per usual hospital procedure.  A study team member will meet the subject in the pre-
op holding area and will administer the pre-op medication at 6AM and no later than 630AM.  An 
investigational pharmacist will deliver the medication appropriately labeled with patient name and study 
number to the pre-op holding area.  This oral administration is safe per consultation with the anesthesia 
faculty member of this project.  Additionally, on the day of surgery a study Sub-Investigator will place pain 
medication orders in compass on hold for post op care.  These orders will be 1000mg of Tylenol PO or 
per tube Q6 hours (or Q12 hours if the patient has hepatic insufficiency), oxycodone 5-10mg Q4 hours 
PRN pain, and dilaudid 0.25-0.5mg Q2 hours PRN pain >5/10 or pain not controlled with maximal 
oxycodone dose.  The subject will be able to receive increases in pain medications as deemed 
appropriate by the inpatient treating physicians.  They will not have any limitations set on pain 
medications simply because they are involved in the study.  The subject will then proceed with surgery as 
planned. No alterations to intraoperative medications or anesthetic agents will be made based on study 
participation. 
 
The subject will return to the PACU after extubation.  If the subject had to remain intubated, he or she will 
be withdrawn from the study as he or she cannot complete pain scores while sedated.  The study team 
member administering the preoperative dose will have provided a postoperative order sheet in the 
inpatient chart signed by an MD on the study team with postoperative pain orders for the nurses in PACU, 
so that all subjects will start with the same amount of medications available.  This order will be written for 
2mg morphine IV q2 hours PRN pain.  The PACU can increase the dose of postoperative pain 
medications based on patient need and MD approval as per the usual PACU protocol without restriction 
based on a subject’s study participation.  Subjects will remain in the PACU per the usual protocol until the 
required level of alertness and clinical stability are reached for transfer.  The VAS score obtained after 
surgery will be completed two hours after emergence. This is an approximate time:  the post op VAS can 
be obtained sooner than two hours if the subject is alert and awake.  If should not be obtained before one 
hour after anesthesia emergence. Thus it can be obtained one to two hours after the subject has 
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Subjects will be given BID medications per the study protocol and VAS scores will be obtained prior to 
medication administration.   The doses will be scheduled at 7AM and at 7PM.   The investigational 
pharmacist will have delivered the medication dose in a properly labeled container to the 6200 inpatient 
floor prior to each dose.  Note that subjects must have completed surgery by 5PM in order to receive the 
7PM dose after their surgery.  Otherwise, this dose is to be skipped and the next dose administered will 
be at 7AM the next day.  VAS score will still be obtained two hours post operatively and will count as the 
7PM VAS score (see above).  A midday VAS score at 12PM will be obtained, pending the availability of 
the study team.   All VAS scores will be obtained with subject privacy optimized, including drawing the 
curtain in subject room to separate the sides of the room from any potential roommate.  Also, the 
research team member will not vocalize a subject’s status as a study patient.  VAS scores will be 
obtained at rest, with cough and following a swallowing gesture.  Scores are captured by providing the 
subject with a pen and asking the subject to mark the location of their pain on a scale of 0-10 during each 
phase of the VAS.   The scale is a validated tool that measures 10cm in size and is marked “no pain” at 0 
and “worst pain” at 10.  The subject marks their pain level on the scale and the study team member will 
measure with a ruler and record the resulting number in the study database.    
Subjects will fill out a discharge survey before they are discharged or at the completion of their 
participation to rate their satisfaction with their inpatient pain control.  This survey will be a hard copy 
labeled with study ID and the data will be entered into the study database.All hard copy data will be 
stored in a locked cabinet accessible only to the study team.  At the end of the study, all hard copy data 
will be properly destroyed.   
 
Subjects will have 24/7 access to members of the study team should questions or concerns arise while 
they are actively participating in the study as well as up to 30 days after completion of the study.   
3.2 Primary Study Endpoints 
The primary study endpoint is postoperative narcotic consumption.  Average daily narcotic use from 
postoperative admission to the last dose of pain medication on POD 3, or the day of discharge, whichever 
comes sooner, will be calculated. Total amount of narcotic use in morphine equivalents will be divided by 
the total hours of inpatient hospitalization, multiplied by 24 hours, to obtain the average daily narcotic 
consumption. 
3.3 Secondary Study Endpoints 
The secondary endpoints include (a) subject satisfaction with pain control, (b) VAS pain scores, (c) 
subject’s baseline pain tolerance, and (d) hospital length of stay. 
 
(a) Subject satisfaction with pain control will be captured in a survey administered at POD 3 after the 
AM dose administration, or after the AM dose administration on the day of discharge, whichever 
comes sooner.  Two of the survey questions will mirror those on the HCAPHS surveys, listed as 
followed (see attached “post-treatment questionnaire”): 
 
1. How often was your pain well controlled? 
0) Never 
1) Sometimes 
2) Usually 
3) Always 
 
2. How often did the hospital staff do everything they could to help you with your pain? 
0) Never 
1) Sometimes 
2) Usually 
3) Always 
 
3. How satisfied are you with your overall pain control? 
0) Very dissatisfied 


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1) Somewhat dissatisfied 
2) Neutral 
3) Somewhat satisfied 
4) Very satisfied 
 
4. Was there anything else that we could have done to make your pain control better during your 
inpatient stay? 
A point system is created with the sum of the numeric values assigned to questions 1-3 on a scale of 
0 to 10, with a score of 0-3 indicates overall dissatisfaction, 4 indicates neutrality, and 5-10 suggests 
overall satisfaction.  This will be analyzed as an ordinal variable. 
 
(b) VAS pain scores will be assessed 1-2 hours after surgery and then three times a day on POD 1-3 
or until day of discharge, whichever comes sooner.  Two of these scores will occur prior to study 
drug administration.  A standardized photo-copy of the VAS form will be given to subjects with 
verbal instruction to first “mark on the line the point that you feel represents your current pain 
level when you’re resting.”  This is followed by asking the subject to gesture swallowing and 
“mark another point on the line that represents your pain level when you swallow.”  Lastly, the 
subject will be asked to cough and to “mark the final point on the line that represents your pain 
when you cough.”  The study team member administering the test will annotate what each mark 
represents (rest, swallow, and cough).  The scale contains a 10-cm line from “no pain” on the left 
to “extreme pain” on the right (see “VAS form”).  The distance in millimeters from the left of the 
line to the center of the patient’s three marks will be recorded.  The results from all available VAS 
scores for each subject will be averaged and included in the final analysis. 
 
(c) The subject’s belief in pain medication efficacy and pain tolerance will be assessed from a short 
survey obtained preoperatively during the office visit (see “pre-treatment questionnaire”). This 
includes the following questions: 
 
1. In the past, how effective are narcotic pain medications (such as morphine, Vicodin, Norco, 
Percocet, oxycodone, Dilaudid) at controlling your pain? 
0) Very ineffective 
1) Somewhat ineffective 
2) Somewhat effective 
3) Very effective 
 
2. In the past, how has your pain tolerance been? 
0) Very poor 
1) Somewhat poor 
2) Somewhat tolerant 
3) Very tolerant 
 
3. Do you experience a significant amount of pain on a daily basis aside from the pain due to 
your current head and neck condition? 
1) Yes I do 
2) No I do not 
The results of these questions will be reported separately in the final analyses. 
 
(d) Hospital length of stay will be calculated for each subject. 


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3.4 Primary Safety Endpoints 
The primary safety endpoints are the rate and severity of drug-related adverse events.  Adverse events 
will be monitored and recorded by study team members during subject inpatient stay.  These events will 
be reviewed by the principal investigator and categorized into “drug-related”, “likely drug-related”, and 
“unlikely drug-related.”  Any significant adverse events determined to be likely drug related will be 
reported to the OHRP within a 24 hour time period and stopping the study for the subjectwill be 
discussed.  
 
4 Subject Selection and Withdrawal 
4.1 Inclusion Criteria 
 
Subjects undergoing definitive mucosal head and neck tumor resection including oral cavity, 
oropharynx, larynx, and hypopharynx 
 
At least 1 night of planned inpatient stay 
4.2 Exclusion Criteria 
 
Incapable of giving informed consent 
 
Age < 18 
 
GFR < 30 
 
Allergy to gabapentin 
 
Baseline gabapentin use 
 
Chronic opioid use for over 6 months 
4.3 Subject Recruitment and Screening 
Subjects will be recruited in the outpatient head and neck clinic prior to their planned surgeries by 
designated study team members.  Potentially eligible patients will be identified by study team members 
prior to their scheduled appointments via the outpatient medical records system.  Eligible subjects will be 
approached after their scheduled appointment in a private setting and the study outline explained to the 
patient. Written informed consent will be obtained from those patients who wish to participate.  Patients 
may choose to think about study participation but will need to decide and provide written consent prior to 
the day of surgery, either at their subsequent preoperative anesthesia clinic appointment or medical 
oncology/radiation oncology appointments.  Study team members will be properly trained in the informed 
consent process.  
 
4.4 Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
Subjects may be withdrawn from the study prior to the expected completion if they develop 
hypersensitivity reactions to the study drug, are unable to swallow all study drugs in the study period, or 
choose to withdrawal for other reasons.  Subjects without a feeding tube who are unable, or unwilling, to 
swallow medications after surgery will not be given a feeding tube to remain in the study.  A 20% dropout 
rate was anticipated and accounted for in the sample size calculation.  Subjects will be able to withdraw 
on a continual basis throughout their participation.  Withdraw can be requested either by the subject or by 
any team member if medical significant adverse reactions are observed.  All withdraws will be reviewed 
by the principle investigator.  No subject will be denied the ability to withdraw. The withdraw process will 
begin immediately when deemed necessary or when desired by the subject, and documentation of the 
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4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
Withdrawn subjects will be excluded in the final data analysis. The reasons for withdrawal will be 
recorded and reported separately in the study data outcomes. 
 
5 Study Drug  
5.1 Description 
300mg of liquid gabapentin or an equal volume of placebo will be pre-packaged by the investigational 
pharmacist in a labeled medication cup.  An unblinded study team member in charge of the 
randomization process will indicate to the pharmacy which subjects are to receive what medication.  The 
blinded study team members will not know which medication cup contains placebo or gabapentin.  
5.2 Treatment Regimen 
Subjects will receive either placebo or gabapentin 300 mg PO the preoperative holding area an hour 
before their procedure is scheduled to begin.  This first dose will designate the day of their procedure as 
POD 0.  If the procedure ends late in the evening, and the subject is not able to receive the second POD 
0 dose by 7 PM, then this second POD 0 dose will be skipped.   The subject must be completed with 
surgery and awake enough to give a VAS score.  Thus any subject not done with the procedure by 5 PM 
will not receive a 7PM dose on POD 0.  Participants will then receive either placebo or 300 mg of 
gabapentin BID POD 1- POD 3.  Dosing will end either on POD 3 after the PM dose or on day of 
discharge after the AM dose, whichever comes first.  
5.3 Method for Assigning Subjects to Treatment Groups 
After a subject consents to study, the unblinded data manager will randomize the subject into active or 
placebo group and assign a subject study number.  The subject study number will be used to identify 
which  are to receive which medication.  
5.4 Preparation and Administration of Study Drug 
The Investigational Pharmacist will mix and prepare the study medications necessary for each subject.  A 
pharmacist will deliver the medication to the floor and a designated study team member will administer it.  
Please see section 5.7 below for mixing and packaging details. Contact information for the pharmacy for 
this project is pharmacist Kathryn Vehe at 314-795-7286. 
 
Inpatient pharmacists will be responsible for delivering the medication to the floor prior to the AM dose 
and to the PM dose, as well as will deliver the medication to the pre-op holding area prior to a subject’s 
procedure.    Formal training for all study team members who will be administering the study drug or 
obtaining the VAS pain scores is required prior to subject interaction. 
5.5 Subject Compliance Monitoring 
The study team members will directly administer each study medication dosage during the study period 
and record adherence to study protocol.  If a dose is missed during this period, the subject will remain in 
the study through the completion of the protocol.  The decision to include data from subjects with missed 
doses will be made at the discretion of the principle investigator and statistician at the conclusion of the 
study.   Data integrity will be maintained such that subjects who are excluded for missed doses will be 
consistent among cases.  
5.6 Prior and Concomitant Therapy 
Every subject will have standard postoperative narcotic medications made available: 
 IV Dilaudid 0.25-0.5mg q2h PRN pain greater than 5/10 not improved by oral or per tube 
medications 
 PO/PT oxycodone 5-10mg q4h PRN pain  


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 PO/PT acetaminophen 1000mg q6h for pain in non-cirrhotic patients, and 1000mg q12h in 
cirrhotic patients 
 
These medications can be up-titrated as needed at the discretion of the physicians managing the 
patient’s care as part of the routine postoperative management. 
5.7 Packaging 
 Study medications will be in liquid form.  Gabapentin comes as a standard liquid form of 
250mg/5ml.  6ml of either gabapentin or placebo will be packaged into a brown 20ml plastic cup 
with a sealed aluminum top.  Each cup will have the subject name and study ID on it.  The 
pharmacy will be made aware of all upcoming study subjects and will prepare the medications 
approximately 24 hours prior to administration, and will store these at 4 degrees Celsius.   
 Individual doses will be delivered before each scheduled dose by an investigational pharmacist to 
the inpatient floor.  
5.8 Blinding of Study Drug 
The study team members administering the medications will be blinded towards whether a subject 
receives the study drug or the placebo.  The data manager who does not participate in data collection or 
have direct subject interaction, as well as the pharmacist preparing the medication cups, will be 
unblinded. 
5.9 Receiving, Storage, Dispensing and Return 
5.9.1 Receipt of Drug Supplies 
Investigational pharmacists will be responsible for medication delivery prior to each planned dose.  They 
will be alerted to upcoming procedures that involve study Subjects.  They will be responsible for directly 
delivering the medication to the study team members prior to administration both on the inpatient floor 
and in the preoperative holding area.  Any damaged or unusable study drug in a given shipment will be 
documented in the study files and discarded. 
5.9.2 Storage 
Medications will be stored by the investigational pharmacy in a designated, locked area at 4 degrees 
Celsius.  
5.9.3 Dispensing of Study Drug 
The study team members administering the medications will receive the medication from the 
investigational pharmacist.  They will then administer the medication and record the time of administration 
and the subject identification number in the subject’s study flow sheet (“Gaba project subject study flow 
chart” attached). 
5.9.4 Return or Destruction of Study Drug 
At the completion of the study, there will be a final reconciliation of medications consumed.  This 
reconciliation will be logged on the drug reconciliation form, signed and dated.  Any discrepancies noted 
will be investigated, resolved, and documented.  Medication cups and packaging will be discarded in the 
red biohazard containers in accordance with hospital policy and documented in the study files. 
 
6 Study Procedures 
The study procedures are outlined below and represented in the attached “Gaba project subject study 
flow chart”.  
 
Clinic Visit 


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 
Consent. 
 
Pre-treatment questionnaire. 
 
Randomization group will be assigned by the study data manager after she is notified of subject 
agreement to participate. 
Day of Surgery 
 
One dose of study drug will be administered preoperatively according to subject’s randomization 
group. 
 
Standard pain medications orders will be provided. These will be up-titrated as needed per 
discretion of service residents and attending physicians. 
o 
IV Dilaudid 0.25-0.5mg q2 PRN pain > 5/10 not controlled on PO/PT medications 
o 
PO/PT oxycodone 5-10mg q4h PRN  
o 
PO/PT acetaminophen 1000mg q6h for pain in non-cirrhotic patients, 100mg q12h in 
cirrhotic patients 
 
One VAS score will be obtained 1-2 hours postoperatively. 
 
One postoperative dose of study drug will be administered if subjects arrived to inpatient floor 
prior to 7 PM. 
Post-Operative Day (POD) 1-3 
 
TID VAS scores will be obtained, two of which will be prior to drug administrations. 
 
BID study drug administration will be conducted according to subject’s randomization groups. 
POD  3 or Day of Discharge 
 
Post-treatment pain satisfaction questionnaire will be conducted either after the AM dosing on 
POD 3 or on date of discharge, whichever comes sooner. 
7 Statistical Plan 
7.1 Sample Size Determination 
Sample size calculations were performed based on prior studies with gabapentin use in otolaryngology 
patients undergoing thyroidectomy21.  A study by Al-Mujadi et al in a population of patients undergoing 
elective thyroidectomy reported that total morphine consumption in the placebo group in the first 24 hours 
post surgery required a mean of 29.5mg of morphine with a standard deviation of 9.9mg.  Assuming that 
this magnitude of effect variability will hold true in this project population, it is estimated that 46 subjects 
per group (total n=92) will be needed to detect with an 80% power at the 2-sided alpha level of 0.05 a 
difference of 20% or greater in average morphine dose (effect size d=0.6) between the placebo and 
gabapentin groups.  Assuming a 20% drop out rate, 116 subjects will be enrolled in this study.  The 
volume of eligible subjects for this study is predicted to meet the calculated sample size within two years 
of study start time. A review of surgical procedures meeting inclusion criteria performed over a sample 
three month time frame ranged from 12 to 17 procedures a month.  
7.2 Statistical Methods 
Descriptive statistics will be used to describe distribution of demographics. Bivariate analysis using 
independent samples t-test for continuous variables and chi square test for categorical variables will be 
used to compare distribution of characteristics between treatment groups to ensure successful 
randomization. 
 
The primary and secondary outcome measures will be compared between the two treatment groups via 
bivariate analyses.  In addition, a General Linear Model (GLM) approach will be used to explore the 
impact of gabapentin as compared to placebo on each of the outcomes of interest after controlling for 


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potential cofounders that were unevenly distributed between the two groups.  The estimated mean 
difference and 95% confidence interval will be reported. 
7.3 Subject Population(s) for Analysis 
Protocol-compliant subjects who received all study drugs up to the conduction of post-treatment 
questionnaire will be included for analysis.  Subjects with missed medication doses will go on to complete 
the protocol, and per the discretion of the principle investigator and statistician may or may not be 
included in the data analysis.  Data integrity will be maintained such that subjects who are excluded for 
missed doses will be consistent among cases. 
 
8 Safety and Adverse Events 
8.1 Definitions 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
 Unexpected in nature, severity, or frequency  (i.e. not described in study-related documents such 
as the IRB-approved protocol or consent form, the investigators brochure, etc) 
 Related or possibly related to participation in the research (i.e. possibly related means there is a 
reasonable possibility that the incident experience, or outcome may have been caused by the 
procedures involved in the research) 
 Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm). 
 
 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study.  Intercurrent illnesses or injuries will be regarded as adverse events.  
Abnormal results of diagnostic procedures are considered to be adverse events if the abnormality: 
 results in study withdrawal 
 is associated with a serious adverse event 
 is associated with clinical signs or symptoms 
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
 fatal 
 life-threatening 
 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event 
 
 
Adverse Event Reporting Period 
The study period during which adverse events must be reported will be the period from the day of surgery 
to the end of the study treatment follow-up.  For this study, the study follow-up is defined as 30 days 
following the last administration of study drug.  Subjects will be provided with contact information for the 
study member that is in charge of adverse event follow up (Melanie Townsend, PI).  They will be 
instructed to contact this person with questions related to the study, adverse events or side effects 
experienced.  
 
 


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Post-study Adverse Event 
All unresolved adverse events will be followed by the investigator until the events are resolved, the 
subject is lost to follow-up, or the adverse event is otherwise explained.  At the last scheduled visit, the 
investigator will instruct each subject to report any subsequent event(s) that the subject, or the subject’s 
personal physician, believes might reasonably be related to participation in this study.   
8.2 Recording of Adverse Events 
At each interaction with the subject, the investigator will seek information on adverse events by specific 
questioning and, as appropriate, by examination.  Information on all adverse events will be recorded 
immediately in the source document.  All clearly related signs, symptoms, and abnormal diagnostic 
procedures results will be recorded in the source document. Specific side effects that will be elicited at 
each interaction include nausea, vomiting, dizziness and sedation.   
 
The clinical course of any adverse event will be followed until resolution, stabilization, or until it has been 
determined that the study treatment or participation is not the cause.  Serious adverse events that are still 
ongoing at the end of the study period will be followed up to determine the final outcome.  Any serious 
adverse event that occurs after the study period and is considered to be possibly related to the study drug 
or study participation will be recorded and reported immediately to the IRB. 
 
8.3 Unblinding Procedures 
For this study only the data manager and pharmacy will be unblinded to the study drug and placebo 
assignments.  Unblinding of the rest of the study investigators will occur after assurance that data 
collection has completed.  If any subject data is intentionally or unintentionally unblinded, the event will be 
documented in detail in the study documents within 48 hours.  Any unblinding that occurs during the study 
period for an individual participant will result in exclusion of that participant’s data from final analysis.  
Study investigators must report unblinding to the PI within a 24 hour time period and must document the 
event.  Subjects will immediately be made aware of the unblinding and will be withdrawn from completing 
the protocol.  
Stopping Rules  
The study will be terminated prematurely if 50% or more of the subjects receiving study drug (gabapentin 
or placebo) experience significant adverse events as defined above in section 8.1.  The study will not be 
prematurely stopped if subjects experience less significant medication side effects, specifically nausea, 
vomiting, dizziness and sedation.  A review of adverse events will be conducted at 25% and 50% 
enrollment to ensure that they are properly tracked.  
8.4 Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study.  This safety 
monitoring will include careful assessment and appropriate reporting of adverse events as noted above, 
as well as the construction and implementation of a site data and safety-monitoring plan (see section 10 
Monitoring).  Medical monitoring will include a regular assessment of the number and type of serious 
adverse events. 


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9 Data Handling and Record Keeping 
9.1 Confidentiality 
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).  Assigned study numbers will be 
used on all hard copy data collection instruments in place of subject name.Source Documents/Case 
Report Forms. 
Source data will be kept primarily in the electronic forms using REDCap for data collection.  Paper 
formsincluding the original consents, questionnaires, VAS pain score sheets, adverse event reporting 
forms etc. will be kept in a locked cabinet that only study team members have access to.  At the 
conclusion of the study, after data has been entered into a password protected spread sheet, will be 
destroyed in the proper manner.  The official source document and case report form for this study will be 
the REDCap database.  
 
All research records will be maintained in the Outcomes Office, 8th floor McMillan for 7 years after study 
completion per WU record retention policy.  
 
10 Study Monitoring 
10.1 Study Monitoring Plan 
This study will be monitored in real time for each subject by the PI and study team.  At minimum, with 
25% accrual goal all adverse events and data collection forms will be reviewed by the PI and discussed 
among the study team.  
 
11 References 
1. Chang C.Y., Challa C.K., Shah J., Eloy J.D. Gabapentin in acute postoperative pain management.  
BioMed Research International Vol. 2014.  2014.  
2. Rafiq, Sulman, et al. "Multimodal analgesia versus traditional opiate based analgesia after cardiac 
surgery, a randomized controlled trial." J. Cardiothorac. Surg 10 (2014): 1749-8090. 
3. Kehlet H, Jensen TS, Woolf CJ: Persistent postsurgical pain: risk factors and prevention.  Lancet 
2006 May 13, 367(9522):1618-1625.  
4. Kehlet H: Multimodal approach to postoperative recovery. Curr Opin Crit Care 2009 Aug, 15(4):355-
358.  
5. Kong VK, Irwin MG: Gabapentin: a multimodal perioperative drug? Br J Anaesth 2007 Dec, 
99(6):775-786.  
6. Tiippana EM, Hamunen K, Vesa KK, Kalso E. Do surgical patients benefit from perioperative 
gabapentin/pregabalin? A systematic review of ef fi cacy and safety. Anesth Analg. 2007;104(6): 
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7. Clarke H, Bonin RP, Orser BA, Englesakis M, Wijeysundera DN, Katz J. The prevention of chronic 
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Anesth Analg. 2012;115:428–42 
8. Levine, Adam I., Satish Govindaraj, and Samuel DeMaria, eds. Anesthesiology and Otolaryngology. 
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9. Lee J.H., Lee H.K., Chun N.H., So Y., Lim C.Y.  The prophylactic effects of gabapentin on 
postoperative sore throat after thyroid surgery.   Korean Journal of Anesthesiology 2013 64:2 (138-
142). 
10. Mohammed M.H., Fahmy A.M., Hakim K.Y.K. Preoperative gabapentin augments intraoperative 
hypotension and reduces postoperative opioid requirements with functional endoscopic sinus surgery. 
Egyptian Journal of Anaesthesia 2012 28:3 (189-192). 


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11. Ahn S.H., Lee J.H., Min K.T. The prophylactic effects of gabapentin on postoperative sore throat after 
thyroid surgery.  European Journal of Anaesthesiology 2012 29 SUPPL. 50 (202). 
12. Chiu T.W., Leung C.C.H., Lau E.Y.K., Burd A. Analgesic effects of preoperative gabapentin after 
tongue reconstruction with the anterolateral thigh flap. Hong Kong Medical Journal 2012 18:1 (30-34)  
13. Kazak Z., Mortimer N., Mekerci S. Single dose of preoperative analgesia with gabapentin (600 mg) is 
safe and effective in monitored anesthesia care for nasal surgery. European Archives of Oto-Rhino-
Laryngology 2010 267:5 (731-736).  
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tonsillectomy pain control. European Archives of Oto-Rhino-Laryngology 2009 266:10 (1605-1609). 
15. Turan A., Memi; D., Karamanlio;lu B., Yaiz R., Pamuk; Z., Yavuz E. The analgesic effects of 
gabapentin in monitored anesthesia care for ear-nose-throat surgery.  Anesthesia and Analgesia 
2004 99:2 (375-378). 
16. Hurley RW, Cohen SP, Williams KA, Rowlingson AJ, Wu CL. The analgesic effects of perioperative 
gabapentin on postoperative pain: A meta-analysis. Reg Anesth Pain Med. 2006;31:237–47. 
17. Peng PW, Wijeysundera DN, Li CC. Use of gabapentin for perioperative pain control—A meta-
analysis. Pain Res Manag. 2007;12:85–92. 
18. Seib RK, Paul JE. Preoperative gabapentin for postoperative analgesia: A meta-analysis. Can J 
Anaesth. 2006;53:461–9. 
19. Clivatti J., Sakata R.K., Issy A.M. Review of the use of gabapentin in the control of postoperative 
pain.  Revista Brasileira de Anestesiologia 2009 59:1 (87-98). 
20. Schmidt, Peter C., et al. "Perioperative Gabapentinoids: Choice of Agent, Dose, Timing, and Effects 
on Chronic Postsurgical Pain." Survey of Anesthesiology 58.2 (2014): 96-97. 
21. Al-Mujadi, Hussain, et al. Canadian Journal of Anesthesia. March 2006, Volume 53, Issue 3, pp 268-
273. 
22. Sally L. Collins, R. Andrew Moore, Henry J. McQuay.  The Visual Analogue Scale: what is moderate 
pain in millimeters? Pain (Impact Factor: 5.21). 09/1997; 72(1-2):95-7. 
23. Accessfda.gov. Keyword “gabapentin”. PDF title: Neurontin. Parke-Davis Division of Pfizer Inc, NY, 
NY 10017.  April 2009.