Conditions: Cancer of Head and Neck Narcotic Use
Keywords: Gabapentin Narcotic Cancer Placebo
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 8
Healthy volunteers: no

Brief summary:
Patients undergoing head and neck cancer surgery often have a lot of pain after surgery, which can lead to a need for a lot of narcotic pain medication. These medications can have many side effects that can make recovery more difficult including nausea, vomiting, dizziness, being overly sleepy, itchiness, inability to urinate, confusion, inability to have a bowel movement, longer time before being able to start walking. These side effects can make the hospital stay longer. The use of gabapentin, which is a non narcotic pain medication that focuses on nerve pain, has been used in smaller head and neck surgeries including removal of tonsils, sinus surgery, thyroid surgery. Studies in patients needing orthopedic or OB/Gyn surgery have shown improved pain control with gabapentin. Potential benefits to future patients include improved pain control, less narcotic associated side effects and faster functional recovery.

Detailed description:
Patients undergoing head and neck cancer surgery frequently experience significant post surgical pain, which often necessitates the use of narcotic pain medication. However, opioids can have multiple side effects that can complicate the head and neck cancer surgery patients postoperative care including nausea, vomiting, dizziness, sedation, pruritis, urinary retention, delirium, constipation, and time to ambulation. This, in turn, may affect patient length and cost of hospital stay. Consequently, a multimodal approach to analgesia is often employed with a focus on use of scheduled acetaminophen +/- NSAIDs supplemented with narcotics.

The use of gabapentin in the head and neck surgery literature has largely been limited to outpatient surgeries, including tonsillectomy in children and adults, functional endoscopic sinus surgery, and thyroidectomy. Indeed, a recent systematic review examined RCT comparing multimodal analgesia with gabapentin to analgesia without gabapentin in the otolaryngology literature. The majority of these studies employed preoperative dosing only, with only 1 study providing a single postoperative dose as well. The control group pain regimen among these studies did vary and included a combination of acetaminophen, NSAIDs, dexmedetomidine, or clonidine supplemented with opioids. The studies focused on the impact of gabapentin on acute postoperative pain determined by subjective measurement of reduction in visual analog pain scale. Of note, these patients were not hospitalized for longer than 24 hours. The thyroid and sinus studies consistently demonstrated improved pain control with use of gabapentin compared to control. The data was slightly more variable across the tonsillectomy studies. Moreover, 7 studies also measured the need for breakthrough pain medication and supplemental analgesia; each of these studies demonstrated significantly less supplemental analgesia consumption in the gabapentin group.

The only study examining the utility of gabapentin in pain management in head and neck cancer patients (glossectomy with anterolateral thigh free flap) examined the utility of a single preoperative dose. The authors concluded that this led to a significant reduction in subjective postoperative pain scores, morphine requirement, and nausea and vomiting compared to controls. This study did not employ postoperative gabapentin.

Furthermore, a recent meta analysis (133 RCT) examining literature across multiple surgical specialties pertaining to the efficacy of perioperative gabapentin supplementation vs placebo. The meta analysis indicated both the efficacy of gabapentin supplementation in decreasing opioid requirement (measured via morphine equivalent units) in the experimental group during the first 24 hours (P\<0.001), as well as a good safety profile across a wide range of loading and maintenance doses (200 to 1200 mg) of gabapentin. The significant reduction in opioid requirement was independent of surgery type. Moreover, the gabapentin group demonstrated a significant decrease in VAS postoperative pain scores, nausea, vomiting and itching; however, sedation scores were increased. Only 8 of these 133 RCT examined the effect of gabapentin outside the immediate 24 hour period, and all 8 trials demonstrated improvement in chronic pain scores at 3 months post-operatively. Finally, patient satisfaction scores and preoperative anxiety were also significantly improved with the use of gabapentin compared to controls.

Here, the investigators propose, for the first time, a superiority double blind randomized controlled placebo trial examining the effect of perioperative supplementation with gabapentin in head and neck cancer patients undergoing surgery. The primary purpose of this study is to determine the difference in morphine equivalent units between the experimental (i.e. perioperative gabapentin) and control group (i.e. no perioperative gabapentin). The secondary purpose of this study is to determine differences across the two groups in relation to the following: visual analog pain scores, cost and length of stay, medication side effects, and incidence of postoperative complications. Of note, in order to maximize reliability of the visual analog scale (VAS), prior studies have employed the Jadad scoring system, which the investigators will also implement in the study.

Arms:
arm 1: Standard of care use of perioperative analgesia with acetaminophen and opioids that is supplemented with placebo solution. Participants will then be discharged after surgery with postoperative acetaminophen, opioids, and placebo. arm 2: Interventional use of perioperative analgesia with acetaminophen and opioids that is supplemented with gabapentin solution. Participants will then be discharged after surgery with postoperative acetaminophen, opioids, and gabapentin.

Interventions: intervention 1: Gabapentin intervention 2: Placebo - Concentrate
Intervention descriptions: intervention 1: Use of Gabapentin peri- and post-operatively. intervention 2: Use of sugar-free Placebo peri- and post-operatively.

Protocol document:
Prot_SAP_000.pdf: 
Perioperative Analgesia using Gabapentin in Head and Neck Free Flap Reconstruction Surgery: A Randomized Controlled 
Trial  
 
Clinical Study Protocol CCOL026 
 
 
Version 7.0 (08.26.2019) 
 
 
Page 1 of 37 
PERIOPERATIVE ANALGESIA USING GABAPENTIN IN HEAD AND NECK FREE 
FLAP RECONSTRUCTION SURGERY: A RANDOMIZED CONTROLLED 
TRIAL  
 
Protocol Number: 
CCOL026 
Indication: 
 
Phase: 
N/A, Interventional 
Funding Source: 
Departmental 
Agent: 
Gabapentin 
Principal Investigator: 
Arnaud Bewley, MD 
University of California, Davis  
Department of Otolaryngology  
2521 Stockton Blvd, Suite 7200 
Sacramento, CA 95817 
Telephone: 916-734-2831   
Fax: 916-703-5011 
Email: abewley@ucdavis.edu 
Co-Investigator(s): 
Jeffrey Uppington, MBBS 
University of California, Davis  
4150 V Street Suite 1200  
Sacramento, CA 95817 
Telephone: 916-734-5028 
Fax: 916-734-7980 
Email: juppington@ucdavis.edu  
Statistician: 
Shuai Chen 
Division of Biostatistics 
University of California, Davis 
One Shields Avenue  
Davis, CA 95616 
Telephone:  (530) 752-9758 
Email: shschen@ucdavis.edu 
Protocol History: 
11/26/2019 
 
 
 
 
 
 
 


Perioperative Analgesia using Gabapentin in Head and Neck Free Flap Reconstruction Surgery: A Randomized Controlled 
Trial  
 
Clinical Study Protocol CCOL026 
 
 
Version 7.0 (08.26.2019) 
 
 
Page 2 of 37 
PROTOCOL SIGNATURE PAGE 
Protocol Number: CCOL026 
Protocol Title: Perioperative analgesia using gabapentin in head and neck free flap reconstructive 
surgery: A randomized controlled trial 
I have read this protocol and agree that it contains all necessary details for carrying out this 
study. I will conduct the study as outlined herein and will complete the study within the time 
designated, in accordance with all stipulations of the protocol and in accordance with Good 
Clinical Practices, local regulatory requirements, and the Declaration of Helsinki.  
I will provide copies of the protocol and all pertinent information to all individuals responsible to 
me who assist in the conduct of this study. I will discuss this material with them to ensure that 
they are fully informed regarding the study agent(s) and the conduct of the study. 
 
 
__________________________________ 
Investigator Name (print)                          
 
__________________________________ 
Investigator Signature  
 
__________________ 
Date  
 
 
 


Perioperative Analgesia using Gabapentin in Head and Neck Free Flap Reconstruction Surgery: A Randomized Controlled 
Trial  
 
Clinical Study Protocol CCOL026 
 
 
Version 7.0 (08.26.2019) 
 
 
Page 3 of 37 
PROTOCOL SYNOPSIS 
Protocol Title: Perioperative analgesia using gabapentin in head and neck free flap reconstructive 
surgery: A randomized controlled trial 
Protocol Number: CCOL026 
Phase of Development: N/A 
Investigational Product, Dosage Form, Route, and Dose Regimen:  
Gabapentin: 900 mg of oral/enteral, 1 hour before surgery and 300mg TID, 37 days post-
operatively. 
Primary Objective: Determine differences in morphine equivalent units between experimental 
and control group from the immediate perioperative setting to 30 days post operatively  
Secondary Objectives: To evaluate for possible associations between pain control and history of 
opioid use, functional outcomes, location of tumor, presence and type of flap reconstruction 
Study Design and Investigational Plan / Methodology: A superiority double blind randomized 
controlled placebo trial examining the effect of perioperative supplementation with gabapentin in 
head and neck patients undergoing free flap reconstructive surgery 
Study Population and Sample Size: Patients undergoing head and neck surgery with concomitant 
free flap reconstruction at UCDMC, N=100 
Eligibility Criteria: Adult patients naïve to gabapentin undergoing head and neck surgery with 
concomitant free flap reconstruction at UCDMC 
Endpoints: Daily morphine equivalent units, Pain score assessed via visual analog scales (VAS), 
Difference in length of stay and cost, Difference in narcotic related side effects, Difference in 
narcotic related, and incidence of postoperative complications. 
Duration of Study and Follow-up: Patients will be enrolled to the study for 37 days starting the 
day of the surgery. Patients will be discharged from the hospital with a 37-day supply of 
gabapentin. Subjects will routinely follow up in clinic 1 week after discharge and 4 weeks post-
surgery for wound check and routine postoperative care 
Enrollment period: 24 months 
Statistical Considerations: Intention-to-treat analysis will be performed to the data. ANOVA test 
will be used to evaluate the effect of the intervention on daily morphine equivalent units over the 
1st week to address the primary objective  
 


Perioperative Analgesia using Gabapentin in Head and Neck Free Flap Reconstruction Surgery: A Randomized Controlled 
Trial  
 
Clinical Study Protocol CCOL026 
 
 
Version 7.0 (08.26.2019) 
 
 
Page 4 of 37 
STUDY SCHEMA 
 
  
 
 
Randomization 
Subject Identification 
Patients undergoing head and neck surgery 
with concomitant free flap reconstruction at 
UCDMC  
There will be two groups- Group 1: Boney 
free flap only. Group 2: Non-Boney free 
flaps  
 
Informed Consent 
Intervention, perioperative (n=50) 
Subjects receive standard of care multimodal 
analgesia with acetaminophen and opioids 
that is supplemented with gabapentin, 
provided 1 hour preoperatively. Anesthesia 
regimen standardized across both groups 
(Appendix 13.2). 
Control, perioperative (n=50) 
Subjects receive standard of care multimodal 
analgesia with acetaminophen and opioids 
that is supplemented with placebo solution 
drug, provided 1 hour preoperatively. 
Anesthesia regimen standardized across both 
groups (Appendix 13.2).  
Control, postoperative (n=50) 
Subjects receive standard post-operative care 
with multimodal analgesia composed of 
acetaminophen, opioids, and placebo.  
Intervention, postoperative (n=50) 
Subjects receive standard post-operative care 
with multimodal analgesia composed of 
acetaminophen, opioids, and gabapentin.  


Perioperative Analgesia using Gabapentin in Head and Neck Free Flap Reconstruction Surgery: A Randomized Controlled 
Trial  
 
Clinical Study Protocol CCOL026 
 
 
Version 7.0 (08.26.2019) 
 
 
Page 5 of 37 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Post-Operative Monitor and Follow-Up for Data Collection (n=100) 
Subjects will be provided study medication 300mg TID for 30-day with a 7 day taper. This will be given 
during their hospital stay and they will be discharged with the remaining medication. 
 
POD 1-7 (while inpatient):  
- 
Pain level will be assessed by research assistant/resident daily between 9 and 11 am via Visual 
Analog Scale (VAS) 
- 
Calculation of daily morphine equivalents 
- 
The following information will be obtained from chart review for each day of hospitalization: 
nausea, vomiting, bowel movement [BM], physical therapy assessment (time to graduation), 
delirium/altered mental status (AMS), incidence of sedation requiring holding of medication 
If discharged prior to POD 7 (earliest discharge will be POD 2): all patients will receive daily 
questionnaires as seen in Appendix 13.1. 
• 
nausea (yes/no) 
• 
vomiting (yes/no) 
• 
BM (yes/no) 
• 
Amount of narcotic taken in 24 hours (# of pills and dose in mg) 
• 
Activity scale [“how would you rate your activity today] (0-4) 
• 
Pain score (VAS) 
 
Provider assessment at 1-week post discharge and 4-week postoperative outpatient clinic follow up: 
• 
Obtain pain scores (VAS) 
• 
Calculate daily morphine equivalent units based on residual narcotic requirement as well as 
number of remaining pills in the bottle, taking into account any refills 
• 
Review patient’s questionnaires 
• 
Measure home study medications 
 
30-Day Follow-Up Phone Call: 
• 
Obtain pain scores (VAS) 
• 
Finalize Adverse Event reporting 
• 
Review final pain medication reporting 
 
After 30 days post-surgery, the patient will taper off the study medication to 300mg BID for 3 days and 
then 300mg once a day for 4 days. The study will then be completed.  


Perioperative Analgesia using Gabapentin in Head and Neck Free Flap Reconstruction Surgery: A Randomized Controlled 
Trial  
 
Clinical Study Protocol CCOL026 
 
 
Version 7.0 (08.26.2019) 
 
 
Page 6 of 37 
LIST OF ABBREVIATIONS AND TERMS 
Abbreviation/Term 
Definition 
ACS 
Acute coronary syndrome 
AE 
adverse event 
AMS 
Altered mental status 
BM 
Bowel movement 
CAD 
Coronary artery disease 
CR 
complete response 
CRC 
clinical research coordinator 
CRF 
case report form 
CT 
computed tomography 
CTCAE 
(NCI) Common Terminology Criteria for Adverse Events 
DBP 
Diastolic blood pressure 
DLT 
dose-limiting toxicity 
DVT 
Deep vein thrombosis 
ENT 
Otolaryngology (Ear, Nose, Throat) 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GT 
Gastrostomy tube 
IDS 
Investigational Drug Services 
IEC 
independent ethics committee 
IND 
Investigational New Drug 
IRB 
institutional review board 
IV 
intravenous 
MI 
Myocardial infarction 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NG 
NasoGastric 
NSAID 
Nonsteroidal anti-inflammatory drug 
OCR 
Office of Clinical Research 
OS 
overall survival 
PAD 
Peripheral artery disease 
PD 
progressive disease 
PE 
Pulmonary embolism 
PET 
positron emission tomography 
PI 
principal investigator 
PO 
Per oral 
POD 
Postoperative date 
PR 
partial response 
RASS 
Richmond Agitation-Sedation Scale 
RCT 
Randomized Controlled Trial 
SAE 
serious adverse event 
SBP 
Systolic blood pressure 
SRC 
Scientific Review Committee 
TID 
ter in die, three times a day 
UCDCCC 
UC Davis Comprehensive Cancer Center 
UCDMC 
University of California, Davis Medical Center 
UTI 
Urinary tract infection 
VAS 
Visual Analog Scale 
 
 


Perioperative Analgesia using Gabapentin in Head and Neck Free Flap Reconstruction Surgery: A Randomized Controlled 
Trial  
 
Clinical Study Protocol CCOL026 
 
 
Version 7.0 (08.26.2019) 
 
 
Page 7 of 37 
TABLE OF CONTENTS 
PERIOPERATIVE ANALGESIA USING GABAPENTIN IN HEAD AND NECK FREE FLAP 
RECONSTRUCTION SURGERY: A RANDOMIZED CONTROLLED TRIAL ......................... 1 
PROTOCOL SIGNATURE PAGE .............................................................................................................. 2 
PROTOCOL SYNOPSIS .............................................................................................................................. 3 
STUDY SCHEMA........................................................................................................................................ 4 
LIST OF ABBREVIATIONS AND TERMS ............................................................................................... 6 
TABLE OF CONTENTS .............................................................................................................................. 7 
1. 
INTRODUCTION ........................................................................................................................... 9 
1.1 
Background and Study Rationale........................................................................................ 9 
2. 
STUDY OBJECTIVES AND ENDPOINTS ............................................................................... 100 
2.1 
Primary Objective ........................................................................................................... 100 
2.2 
Secondary Objectives ..................................................................................................... 100 
2.3 
Study Endpoints .............................................................................................................. 111 
3. 
STUDY DESIGN ........................................................................................................................ 122 
3.1 
Method ............................................................................................................................ 122 
3.2 
Procedures Involved ....................................................................................................... 155 
4. 
SUBJECT SELECTION .............................................................................................................. 176 
4.1 
Inclusion Criteria ............................................................................................................ 176 
4.2 
Exclusion Criteria ........................................................................................................... 176 
4.3 
Inclusion of Women, Minorities, and Other Underrepresented Populations .................. 177 
5. 
CONCOMITANT MEDICATION .............................................................................................. 177 
5.1 
Termination of Treatment and/or Study Participation .................................................... 177 
6. 
STUDY EVALUATIONS ............................................................................................................. 18 
6.1 
Treatment Phase ................................................................................................................ 18 
6.2 
End of Treatment Visit ..................................................................................................... 18 
6.3 
Follow-up Phase ............................................................................................................... 19 
6.4 
Efficacy and Safety ........................................................................................................... 19 
7. 
DRUG INFORMATION ............................................................................................................... 19 
7.1 
Gabapentin ........................................................................................................................ 19 
 
7.1.1 Formulation, Packaging, and Handling ................................................................... 19 
7.1.2 Disposal and Destruction ......................................................................................... 19 
8. 
STUDY CALENDAR ................................................................................................................... 19 
9. 
SAFETY AND REPORTING REQUIREMENTS ........................................................................ 19 
9.1 
Adverse Event Definition ................................................................................................. 19 
9.2 
Adverse Event Documentation ......................................................................................... 20 
9.3 
Serious Adverse Event Definition .................................................................................... 20 
9.4 
Procedures for Reporting Serious Adverse Events (SAEs) ............................................ 211 
9.4.1 
Reporting to the Institutional Review Board ................................................ 211 
9.4.2 
Follow-up of Adverse Events and Serious Adverse Events ......................... 211 
10. 
RISKS TO SUBJECTS ................................................................................................................ 221 
10.1 
Risk of loss of Confidentiality ........................................................................................ 221 


Perioperative Analgesia using Gabapentin in Head and Neck Free Flap Reconstruction Surgery: A Randomized Controlled 
Trial  
 
Clinical Study Protocol CCOL026 
 
 
Version 7.0 (08.26.2019) 
 
 
Page 8 of 37 
10.2 
Risk of Gabapentin ......................................................................................................... 221 
10.3 
Placebo Risk ................................................................................................................... 232 
10.4 
Unknown Risks to Women of Child Bearing Potential and Pregnant Women ............... 232 
10.5 
Risk Associated with Randomizaton .............................................................................. 232 
10.6 
Mitigating Potential AE: Post-op Prerenal Disease .......................................................... 22 
11. 
STATISTICAL CONSIDERATIONS ......................................................................................... 243 
11.1 
Study Design and Overview of Primary and Secondary Endpoints ............................... 243 
11.2 
Sample Size Estimation /Accrual Rate ........................................................................... 243 
11.3 
Evaluation of Efficacy .................................................................................................... 254 
11.4 
Evaluation of Safety ........................................................................................................ 254 
12. 
ADMINISTRATIVE REQUIREMENTS ..................................................................................... 24 
12.1 
Good Clinical Practice ...................................................................................................... 24 
12.2 
Ethical Considerations ...................................................................................................... 24 
12.3 
Study Registration ............................................................................................................. 25 
12.4 
Patient Information and Informed Consent ....................................................................... 25 
12.5 
Patient Confidentiality ...................................................................................................... 25 
12.6 
Protocol Compliance and Deviations ................................................................................ 25 
12.7 
Premature Closure of the Study ........................................................................................ 26 
12.8 
Record Retention .............................................................................................................. 26 
12.9 
Quality Assurance and Control ......................................................................................... 26 
12.10 Provisions to Monitor the Data to Ensure the Safety of Subjects ..................................... 26 
12.11 Data Banking .................................................................................................................... 27 
13. 
REFERENCES .............................................................................................................................. 27 
14. 
APPENDICES ............................................................................................................................... 29 
14.1 
HOME DATA COLLECTION SHEET ........................................................................... 29 
14.2 
INTRA OP DATA COLLECTION SHEET ................................................................... 331 
14.3 
RESEARCH DOSE DIARY............................................................................................ .32  
14.4 
STUDY DISCHARGE INSTRUCTIONS ....................................................................... 34 
 
 
 
 
 
 
 
 
 
 
 


Perioperative Analgesia using Gabapentin in Head and Neck Free Flap Reconstruction Surgery: A Randomized Controlled 
Trial  
 
Clinical Study Protocol CCOL026 
 
 
Version 7.0 (08.26.2019) 
 
 
Page 9 of 37 
1.0 
INTRODUCTION  
1.1 
Background and Study Rationale 
Patients undergoing head and neck surgery requiring concomitant free flap reconstruction 
frequently experience significant post surgical pain, which often necessitates the use of narcotic 
pain medication. However, opioids can have multiple side effects that can complicate the 
postoperative care including nausea, vomiting, dizziness, sedation, pruritis, urinary retention, 
delirium, constipation, and time to ambulation of patients undergoing head and neck surgery 
with concomitant free flap reconstruction. This, in turn, may affect patient length and cost of 
hospital stay. Consequently, a multimodal approach to analgesia is often employed with a focus 
on use of scheduled acetaminophen +/- NSAIDs supplemented with narcotics 1,2 3 
The use of gabapentin in the head and neck surgery literature has largely been limited to 
outpatient surgeries, including tonsillectomy in children and adults, functional endoscopic sinus 
surgery, and thyroidectomy 4-15 Indeed, a recent systematic review by Sanders et al examined 15 
RCT comparing multimodal analgesia with gabapentin to analgesia without gabapentin in the 
otolaryngology literature 4. The majority of these studies employed preoperative dosing only, 
with only 1 study providing a single postoperative dose as well. The control group pain regimen 
among these studies did vary and included a combination of acetaminophen, NSAIDs, 
dexmedetomidine, or clonidine supplemented with opioids. The studies focused on the impact of 
gabapentin on acute postoperative pain determined by subjective measurement of reduction in 
visual analog pain scale.  Of note, these patients were not hospitalized for longer than 24 hours. 
The thyroid and sinus studies consistently demonstrated improved pain control with use of 
gabapentin compared to control. The data was slightly more variable across the tonsillectomy 
studies. Moreover, 7 studies also measured the need for breakthrough pain medication and 
supplemental analgesia; each of these studies demonstrated significantly less supplemental 
analgesia consumption in the gabapentin group.  
The only study examining the utility of gabapentin in pain management in head and neck cancer 
patients (glossectomy with anterolateral thigh free flap) examined the utility of a single 
preoperative dose.16 The authors concluded that this led to a significant reduction in subjective 
postoperative pain scores, morphine requirement, and nausea and vomiting compared to controls. 
This study did not employ postoperative gabapentin.  
Furthermore, Doleman et al17 performed  a recent meta analysis (133 RCT) examining literature 
across multiple surgical specialties pertaining to the efficacy of perioperative gabapentin 
supplementation vs placebo. The meta analysis indicated both the efficacy of gabapentin 
supplementation in decreasing opioid requirement (measured via morphine equivalent units) in 
the experimental group during the first 24 hours (P<0.001), as well as a good safety profile 
across a wide range of loading and maintenance doses (200 to 1200 mg) of gabapentin. The 
significant reduction in opioid requirement was independent of surgery type. Moreover, the 


Perioperative Analgesia using Gabapentin in Head and Neck Free Flap Reconstruction Surgery: A Randomized Controlled 
Trial  
 
Clinical Study Protocol CCOL026 
 
 
Version 7.0 (08.26.2019) 
 
 
Page 10 of 37 
gabapentin group demonstrated a significant decrease in VAS postoperative pain scores, nausea, 
vomiting and itching; however, sedation scores were increased. Only 8 of these 133 RCT 
examined the effect of gabapentin outside the immediate 24 hour period, and all 8 trials 
demonstrated improvement in chronic pain scores at 3 months post operatively. Finally, patient 
satisfaction scores and preoperative anxiety were also significantly improved with the use of 
gabapentin compared to controls. 
 
Here, we propose, for the first time, a superiority double blind randomized controlled placebo 
trial examining the effect of perioperative supplementation with gabapentin in head and neck 
patients undergoing surgery requiring free flap reconstruction. The primary purpose of this study 
is to determine the difference in morphine equivalent units between the experimental (i.e. 
perioperative gabapentin) and control group (i.e. no perioperative gabapentin). The secondary 
purpose of this study is to determine differences across the two groups in relation to the 
following: visual analog pain scores, cost and length of stay, medication side effects, and 
incidence of postoperative complications. Of note, in order to maximize reliability of the visual 
analog scale (VAS), prior studies have employed the Jadad scoring system, which we will also 
implement in our study.18 
2.0 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objective 
o Determine differences in morphine equivalent units between experimental and control 
group from the immediate perioperative setting to 30 days post operatively  
o The morphine equivalent units will be recorded every day; we will examine 
the daily average amount received at POD 7 and then again at the 4-week 
post operative visit for each patient. 
2.2 
Secondary Objectives  
o Obtain pain scores (Visual analog score filled by patient) on a standardized 1-10 
scale once daily between 9 am and 11 am by the same research coordinator while 
inpatient among each group on weekdays. On weekends, same standardized scale 
will be given between the same hours by the ENT resident on call.  
o If patient discharged home prior to POD 7, will go home with a Questionnaire 
Log (Appendix A) to fill out daily. Each patient will receive a phone call from the 
research coordinator between 9 and 11 am to remind them to fill out the log 


Perioperative Analgesia using Gabapentin in Head and Neck Free Flap Reconstruction Surgery: A Randomized Controlled 
Trial  
 
Clinical Study Protocol CCOL026 
 
 
Version 7.0 (08.26.2019) 
 
 
Page 11 of 37 
▪ One set of below questions for each day until POD 7: 
▪ nausea (yes/no), vomiting (yes/no), BM (yes/no), activity scale [“how 
would you rate your activity today] (0-4), number of opioid doses today 
(1, 2, 3, 4, 5, 6, 7, 8), rate your pain according to VAS (0-10 likert scale) 
• activity scale:  
o 0 - did not make it out of bed 
o 1 - out of bed to bathroom or chair 
o 2 - ambulated around house 
o 3 - ambulated outside of house 
o 4 - return to baseline activity  
▪ Patients will also be reminded to bring in their gabapentin and narcotic 
pill/liquid bottle (i.e. oxycodone or hydrocodone-acetaminophen) to each 
post operative appointment (i.e. at 1 week post discharge and 4 week post 
surgery) and not to obtain pain prescriptions from any physician not part 
of the UCDMC Otolaryngology staff during the first 30 days after surgery, 
as this will provide another means by which to calculate morphine 
equivalent units  
o At post operative appointments: Obtain pain scores (Visual analog score filled by 
patient) & morphine equivalent units (ie how much oxycodone still requiring/how 
many pills left in the bottle taking into account any refills/review of home log 
when applicable) at the 1 week post discharge visit and again at the 4 week post 
surgery visit (will be obtained by the physician/NP) 
o Calculate total cost of inpatient stay among the two groups 
o Record narcotic related complications among the two groups (determined from 
chart review, recorded by ancillary staff including physical therapist and nurses): 
time to “discharge from physical therapy,” time to reach goal enteral bolus/oral 
feeds, occurrence of hypotension as defined by SBP < 90 or DBP <60 , incidence 
of delirium, time to first BM, incidence of nausea, dizziness, vomiting, 
constipation, urinary retention 
o Incidence of common postoperative complications: pneumonia, UTI, DVT, PE, 
ACS 
o We plan to evaluate for possible associations between pain control and history of 
opioid use, functional outcomes, location of tumor, presence and type of flap 
reconstruction 
2.3 
Study Endpoints 
All subjects will complete a 1-month follow up course and will be examined for: 
Outcome measures:  
o Daily morphine equivalent units during the first week, at 1 week post discharge, and 
at 4 weeks post operation  
o Pain score assessed via visual analog scales (VAS) at following intervals: daily 
morning VAS questionnaire during the first week, at 1 week post discharge, and at 4 
weeks post operation  
o Difference in length of stay and cost 


Perioperative Analgesia using Gabapentin in Head and Neck Free Flap Reconstruction Surgery: A Randomized Controlled 
Trial  
 
Clinical Study Protocol CCOL026 
 
 
Version 7.0 (08.26.2019) 
 
 
Page 12 of 37 
o Difference in narcotic related side effects: nausea, vomiting, dizziness, sedation, 
pruritis, urinary retention, delirium 
▪ 
We will use RASS score to evaluate sedation. Will hold opioid and/or 
gabapentin if RASS sedation score between -2 and -5 which will be 
recorded prior to administration of each dose of opioid/gabapentin. This is 
the current UCDMC Pain Pharmacy Department standard of practice. 
▪ 
RASS -1 indicates a drowsy state where patient is able to maintain > 10 
seconds of eye contact to voice 25 
▪ 
RASS -2 indicates light sedation where patient awakens to voice with eye 
contact but holds it for less than 10 seconds before closing eyes again25 
▪ 
RASS -3 indicates moderate sedation where patient demonstrates 
movement to voice but does not awaken25 
▪ 
RASS -4 indicates deep sedation where patient does not demonstrate any 
movement to voice but does move to physical stimulation25 
▪ 
RASS -5 indicates unarousable state where there is no response to voice or 
stimulation25 
▪ 
Per standard UCDMC protocol, we will also hold opioid and/or 
gabapentin for respiratory rate less than 10 
▪ 
Based on discussion with the UCDCM Pain Pharmacy team and per the 
standard UCDMC policy, during the inpatient stay, every patient on 
Gabapentin will have the following nursing order to ensure safety and 
prevent falls: “Monitor for sedation and dizziness. Out of bed with 
assistance only.” 
▪ 
If patient becomes symptomatic we will reduce Gabapentin to 100 mg 
TID immediately and place a pain pharmacy consult to reassess dosing.  
o Difference in narcotic related complications including days to mobilization (measured 
by physical therapy phase 4), days to tolerating oral or enteral feeding, hemodynamic 
instability, delirium, nausea 
o Incidence of postoperative complications: pneumonia, wound infection, wound 
dehiscence, wound fistula, UTI 
o Demographic information 
o Gender, age, history of cigarette smoking, history of alcohol use, history of 
diabetes, CAD, PAD, MI, PE, history of prior radiation, history of prior 
chemotherapy  
3.0 
STUDY DESIGN 
3.1 
Method 
The current otolaryngology and general surgery literature has demonstrated the safety of 
administering a single perioperative dose of gabapentin across a wide range (i.e. 100 mg to 1200 
mg) 4,17 with no clear efficacy advantage of one dose over another. Moreover, in the orthopedic 
literature, safety for gabapentin daily dosing of up to 1200 mg has been established.19 Moreover, 
Peng et al19 demonstrated significant improvement in pain occurring with doses >/= 900 mg once 


Perioperative Analgesia using Gabapentin in Head and Neck Free Flap Reconstruction Surgery: A Randomized Controlled 
Trial  
 
Clinical Study Protocol CCOL026 
 
 
Version 7.0 (08.26.2019) 
 
 
Page 13 of 37 
daily but not <900 mg once daily. Thus, our experimental group will receive a single 
perioperative dose of 900 mg of oral/enteral gabapentin 1 hour before surgery, while the control 
group will receive the same amount of placebo syrup 1 hour before surgery. Per the current 
standard of practice by the UCDMC Pain Pharmacy department, we will initiate study dose at 
300 mg TID on the AM of POD 1.17 Patients in the study will continue the study drug for 30 
days postoperatively at which time it will be weaned off by decreasing to 300 mg BID for 3 days 
after which the dose will be reduced to 300 mg once daily for 4 days. At the end of the 7-day 
tapering, the study medication will be completely stopped. At the start of the study, we will 
create a 37-day supply of gabapentin (concentration of 250 mg/5ml) or placebo syrup for each 
patient. A total of 18 mls of 50 mg/ml would be required for a 900mg daily dose. Thus, a 30-day 
supply which would be 540 mls. Including the tapering doses, this amount would bring the total 
per patient study medication to 600mL. With a 1:1 randomization, 50 patients would require a 
total of 30,000 ml of gabapentin and another 50 patients will require 30,000 ml of the placebo 
syrup.  
 
Our study proposes a protocol in which all patients will receive standardized postoperative pain 
regimen which includes scheduled 24 hours total of 3000 mg acetaminophen daily that is 
supplemented by 5-10 mg of oxycodone liquid via per oral (PO) (if tolerated) or enteral route via 
NasoGastric(NG) or Gastrostomy Tube (GT) as needed for breakthrough pain every 3 hours. 
Nursing will be advised to provide 5 mg for moderate breakthrough pain (VAS 4-6) and 10 mg 
for severe breakthrough pain (VAS 7-10) at these 3 hours intervals. In addition, for pain not 
controlled by liquid acetaminophen and liquid oxycodone, we will prescribe intravenous (IV) 
hydromorphone. Nursing will have orders to provide a single dose of 0.3 mg IV hydromorphone 
at least 30min after their last dose of oral oxycodone, only as needed for breakthrough pain rated 
as moderate (VAS 4-6) that is not controlled by the combination of acetaminophen, 
gabapentin/placebo and oxycodone. For severe breakthrough pain (VAS 7-10) not controlled 
with the acetaminophen, gabapentin/placebo and oxycodone, nursing will have orders to provide 
0.6 mg of IV hydromorphone at least 30min after their last dose of oral oxycodone. If pain is still 
not well controlled (ie VAS is > 4), the nurse will call the on call resident who can then prescribe 
any additional opioid medication and consult pain pharmacy, as needed. Prn IV pain medication 
may be provided until they day of discharge. If pain not well controlled on this regimen, as 
indicated by inability to work with physical therapy due to pain, the pain pharmacy team will be 
consulted.  
There is a documented interaction between opioid medication and gabapentin. Specifically, the 
co-administration with hydrocodone can reduce the exposure to the hydrocodone, whereas co-
administration with morphine can increase the effect of gabapentin.27(Pfizer 2017) The majority 
of head and neck patients undergoing free flap reconstruction surgery require baseline opioid 
post-operatively. For this reason, as mentioned above, we will be implementing the RASS score 


Perioperative Analgesia using Gabapentin in Head and Neck Free Flap Reconstruction Surgery: A Randomized Controlled 
Trial  
 
Clinical Study Protocol CCOL026 
 
 
Version 7.0 (08.26.2019) 
 
 
Page 14 of 37 
as well as nursing orders to “Monitor for sedation and dizziness. Out of bed with assistance 
only.” This is in accordance with the current UCDMC Pain Pharmacy Department standard of 
practice. In this way, the dose of gabapentin will be safely titrated while inpatient under these 
monitoring procedures prior to discharge on this titrated dose with continued instructions to stop 
medication if experiencing sedation, dizziness or other distressing side effects. Finally, the use of 
Maalox antacid can also decrease bioavailablity of Gabapentin; since this is a decrease and not 
increase in the bioavailablity of gabapentin, it should not increase risk of gabapentin related 
sedation and dizziness side effects compared to taking gabapentin by itself. 
As mentioned briefly, perioperative gabapentin supplementation has also been studied in other 
surgical subspecialties, such as thoracic surgery, orthopedics surgery, and obstetrics/gynecology, 
often via RCT 20-24 
Indeed, several RCT in the orthopedics and obstetrics literature assess efficacy of the gabapentin 
group compared to control by measurement of morphine equivalent units, which is the same 
proposed primary outcome of our study. For this similarity in outcome measure, and the overall 
lack of similar otolaryngology literature, we used the following two studies to perform our power 
analysis. Paul et al23 examined patients undergoing primary total hip arthroplasty. He compared 
an experimental group receiving preoperative gabapentin followed by two days of postoperative 
dosing to the placebo group. The authors demonstrated no statistically significant difference in 
morphine equivalent units across these two randomized groups. Reagan et al20 examined patients 
undergoing reconstructive pelvic surgery. He similarly compared morphine equivalent units 
across the same two randomized groups (gabapentin vs placebo) and demonstrated that the 
gabapentin group had less need for opioid at time of discharge, as well as decreased overall need 
for opioid analgesia.  
 
Finally, after discussion with the UCDMC Department of Anesthesia a standardized anesthetic 
plan was adopted to be used during all study enrolled head and neck surgeries with concomitant 
free flap reconstruction (please see Appendix B). Of note, post operatively, study patients will be 
transitioned to oral/enteral acetaminophen as soon as medically safe, at a dose of 1000 mg every 
8 hours. Will plan for IV acetaminophen the first night after surgery with initiation of oral/enteral 
acetaminophen on the morning of POD 1 in most cases. This scheduled acetaminophen will thus 
be timed and scheduled with the study drug on a q8hr basis. 
 
We think that perioperative administration of gabapentin in addition to a standardized 
postoperative pain regimen will help improve postoperative analgesia and reduce narcotic pain 
medication requirements when compared to patients randomized to the non-gabapentin pain 
regimen as evidence by an overall decrease in morphine equivalents. Moreover, we propose that 
the gabapentin group will have improved time to mobilization and tolerance of bolus enteral 


Perioperative Analgesia using Gabapentin in Head and Neck Free Flap Reconstruction Surgery: A Randomized Controlled 
Trial  
 
Clinical Study Protocol CCOL026 
 
 
Version 7.0 (08.26.2019) 
 
 
Page 15 of 37 
feeds, in addition to a reduction in occurrence of pneumonia, DVT and PE (opioid 
complications).  
For morphine equivalent comparison, the following exchanges will be used: 
o oral hydrocodone = 1:1.5, oral oxycodone = 1:1.5, and oral hydromorphone = 1:4 
o IV hydromorphone: oral hydromorphone = 1.5:7.5  
 
3.2 
Procedures Involved 
Randomization 
The study is a superiority, blinded, randomized controlled trial. Randomization will be done by 
the UCDMC Investigational Drug Services (IDS) as simple block randomization via electronic 
randomizer. All research and surgical staff involved including nursing, surgeons, pain 
management, patients, and PI will be masked. The IDS team will remain the sole unmasked 
group.  
 
Study Medication 
IDS will purchase, prepare, and dispense both study solutions for oral or enteral route 
administration. At the start of the study, we will create a 37-day supply of gabapentin 
(concentration of 250 mg/5ml) or placebo syrup for each patient. Inpatient dispensing will 
remove medication from the patient specific bottle stored in IDS. Once the patient is ready for 
discharge, they will be given the remaining solution, a study diary (Appendix C), and a study 
discharge handout (Appendix D) to take home.  
Recruitment 
Patients will be head and neck patients at UCDMC Otolaryngology who will undergo surgery 
requiring free flap reconstruction requiring at least 2 days of inpatient stay. Indications for head 
and neck surgery with concomitant free flap reconstruction include, but are not limited to, 
cutaneous and mucosal malignancies, soft tissue (muscle, fat, bone, nerve, vascular) 
malignancies, including all malignancies involving cranial skull base; additional indications for 
free flap reconstruction include osteoradionecrosis of the head and neck, as well as functional 
laryngectomy. All patients will be screened based on the inclusion and exclusion criteria. 
Patients meeting study criteria will be approached at their pre-op visit by the primary investigator 
and approved research staff to obtain informed consent. Once informed consent is signed, each 
subject will be assigned a numeric code. This code and patient information will be provided to 


Perioperative Analgesia using Gabapentin in Head and Neck Free Flap Reconstruction Surgery: A Randomized Controlled 
Trial  
 
Clinical Study Protocol CCOL026 
 
 
Version 7.0 (08.26.2019) 
 
 
Page 16 of 37 
IDS for treatment randomization. Study data that is collected will be reference under this code. 
Informed consent will be obtained prior to any study related procedures. 
 
Pre-operation 
 
Upon the completed of informed consent, the following information will be extracted from the 
patient’s medical charts: 
Name, DOB, MRN, demographics, pertinent history of present illness, medical history, surgical 
history, current medications, allergies, social history, substance use, pertinent imaging (CT, MRI, 
PET, Angiography), physical examination findings, endoscopy videos. In addition, relevant 
medical and surgical history will be collected and confirmed with the patient. Confidentiality 
will be maintained as explained in Section 11.5: Patient Confidentiality.  
 
Inpatient 
The patient will arrive on the day of surgery and given oral or enteral 900mg study treatment 1 
hour prior to surgery. The patient will begin the 300mg TID regiment starting the morning of 
post-op day 1.  IDS will individually dispense three times a day to the nursing staff. Nurses will 
follow the breakthrough pain protocol outlined in the Methods section. All relative medication 
(including surgery anesthesia) will be collected and converted to morphine equivalent units 
during pre-operation, perioperation, and post-operation. Patient vitals, hematology and 
biochemistry lab draws, and VAS pain levels are routinely checked daily as part of inpatient 
care. This information will only be collected if it is available. No additional orders will be placed 
to collect this information.  
 
Discharge Outpatient Follow up 
Patients will be discharged with a research dose diary (Appendix C), study discharge instructions 
(Appendix D), and study medication. If the patient is discharged early, they will be given an 
additional questionnaire to complete until Day 7 postop (Appendix A).    
The patient will continue the 300mg TID regiment until a total of 30 days has passed since the 
surgery. After 30 days, the patient will taper off the medication by taking 300mg BID for 3 days 
(Day 31-33) and 300mg QD for 4 days (Day 34-37). At the point of discharge, the patient will be 
asked to return to clinic at 1 week and 4 weeks post-surgery for standard assessments. During 
these visits, the patient will return with their diary, bottle of study medication, and their post-
operative narcotics. Copies will be made of the diary, the study bottle amounts will be recorded, 
and any pills will be counted at each office visit. Within 2-3 days after the patient has completed 
their 30-day study regiment they will receive a phone call from a study researcher. The 
researcher will follow up on any outstanding adverse events, pain medication use, and VAS pain. 
This phone call will also provide the patient an opportunity to ask final research questions, 
review tapering instruction, and how to dispose of extra medication.  


Perioperative Analgesia using Gabapentin in Head and Neck Free Flap Reconstruction Surgery: A Randomized Controlled 
Trial  
 
Clinical Study Protocol CCOL026 
 
 
Version 7.0 (08.26.2019) 
 
 
Page 17 of 37 
4.0 
SUBJECT SELECTION 
4.1 
Inclusion Criteria 
Patients must meet all of the following criteria to be eligible for study entry. 
a) 
Patients undergoing head and neck surgery with concomitant free flap reconstruction 
surgery at UCDMC. There will be two groups; group 1 will include reconstruction 
with boney free flap only. Group 2 will include any non-boney free flap 
reconstruction. 
b) 
Patients naïve to gabapentin 
c) 
Adult patients >18 years of age and able to consent 
4.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry.  
 
a) 
Patients who are already taking scheduled gabapentin 
b) 
Patients allergic to gabapentin 
c) 
Chronic opioid use not from active head and neck disease 
d) 
Illicit drug use (per report) 
e) 
Patients with known renal compromise, such that Creatinine clearance is < 30 
f) 
Patient with known hepatic insufficiency or cirrhosis   
g) 
Adults unable to consent 
h) 
Individuals < 18 yo 
i) 
Pregnant women 
j) 
Prisoners 
4.3 
Inclusion of Women, Minorities, and Other Underrepresented Populations 
Recruitment is open to all minorities and both genders.   
5.0 
CONCOMITANT MEDICATION 
Because there is a potential for interaction of gabapentin with other concomitantly administered 
drugs through the cytochrome P450 system, the case report form must capture the concurrent use 
of all other drugs, over-the-counter medications, or alternative therapies. The Principal 
Investigator (or Protocol Chair) should be alerted if the participant is taking any agent known to 
affect or with the potential to affect selected CYP450 isoenzymes. 
5.1 
Termination of Treatment and/or Study Participation 
Patients will be informed that they have the right to withdraw from the study at any time for any 
reason, without prejudice to their medical care. They will be given two options:  
1) Removal from the study entirely (no medication and no follow up); or 
2) Removal from taking the study medication and remain in the study for follow up only.  


Perioperative Analgesia using Gabapentin in Head and Neck Free Flap Reconstruction Surgery: A Randomized Controlled 
Trial  
 
Clinical Study Protocol CCOL026 
 
 
Version 7.0 (08.26.2019) 
 
 
Page 18 of 37 
Patients who wish to stop taking the study medication will have the opportunity to remain in the 
study for long-term follow-up. The study will continue to monitor these patients for safety and to 
ensure that their pain is appropriately monitored and documented.  
The investigator also has the right to withdraw patients from the study for safety, behavioral or 
administrative reasons. The reason(s) for discontinuation will be documented and may include: 
• Patient voluntarily withdraws from treatment (follow-up permitted); 
• Patient withdraws consent (termination of treatment and follow-up); 
• Patient demonstrates disease progression; 
• Patient experiences unacceptable toxicity; 
• Start of a new treatment cycle is delayed for > 28 days as a result of toxicities at least 
possibly related to study treatment; 
• Patient becomes pregnant; 
• Patient is lost to follow-up; 
• The study is terminated. 
The Investigator will make every reasonable effort to keep each patient in the study unless it is in 
the patient’s best interests to discontinue participation.  If a patient is removed from the study or 
declines further participation, all End of Treatment evaluations should be performed if the patient 
is willing and able to be assessed.  A description of the reason(s) for withdrawal from the study 
must be recorded on the case report form (CRF).  The Investigator should also ensure that all 
patients are followed up for survival status after the Final Visit. 
Patients who discontinue following entry will have relevant information completed and recorded 
on the CRF.  All patients who discontinue because of adverse events or clinically significant 
laboratory abnormalities should be followed up until they recover or stabilize, and the 
subsequent outcome will be recorded.  If any patient should die during the trial or within 30 days 
of stopping study treatment, the Investigator will inform the IRB The cause of death should be 
recorded in detail, within 24 hours, on a serious adverse event (SAE) form and reported to 
institutional, federal and any other appropriate committees and/or sponsors. 
6.0 
STUDY EVALUATIONS 
6.1 
Treatment Phase 
• Treatment will consist of daily gabapentin or placebo during the first 30 days post 
operatively from head and neck free flap surgery 
6.2 
End of Treatment Visit 
• Treatment will end on post-operative day 30 after which the drug (gabapentin or placebo) 
will be weaned over the next 7 days 


Perioperative Analgesia using Gabapentin in Head and Neck Free Flap Reconstruction Surgery: A Randomized Controlled 
Trial  
 
Clinical Study Protocol CCOL026 
 
 
Version 7.0 (08.26.2019) 
 
 
Page 19 of 37 
6.3 
Follow-up Phase 
• Patients will have daily in-person follow-up while admitted (usually POD 1-7). Patients 
that are discharged prior to POD 7 will receive daily questionnaires as seen in appendix 
A. Patients will also follow up in clinic 1 week after discharge and 4 weeks post 
operatively from surgery. 
6.4 
Efficacy and Safety 
• Gabapentin is a commercially available medical drug that has been shown to be safe and 
effective in the clinical setting, including in the Otolaryngology patient population.  
7.0 
DRUG INFORMATION 
7.1 
Gabapentin 
7.1.1 
Formulation, Packaging, and Handling 
The investigational product will be prepared, stored and dispensed by the Investigational Drug 
Service (IDS) Pharmacy.  The contents of each dose will be blinded by IDS and the unblinding 
key stored in IDS. 
7.1.2 
Disposal and Destruction 
Drug supply will be disposed of according to institutional standard operating procedure. 
Accurate records of all investigational product received at and dispensed from the study site 
should be recorded on the Drug Log.  
8.0 
STUDY CALENDAR 
Evaluation 
Pre-
operative 
Peri-
operative 
POD 1-7 
(daily)1 
1 week after 
discharge 
4 weeks after 
surgery 
30 days post-op  
(Phone Call) 
Inclusion/exclusion criteria 
X 
  
  
± 4 days 
± 4 days 
 
Demographics 
X 
 
 
 
 
 
Medical History 
X 
  
  
  
  
 
Physical Exam3 
X 
X 
X 
X  
X  
 
Vital signs 
X 
X 
X 
X 
X 
 
Basic Metabolic Panel lab 
X 
  
X2 
X6 
  
 
Visual Analog Scale for Pain Assessment 
X 
X  
X 
X 
X  
X 
Daily morphine equivalents5 
X 
X 
X 
X 
X 
X 
Narcotics-related complications4 
X 
  
X 
X 
X 
X 
Study Medication Compliance 
 
 
 
X 
X 
X 
Post-operative complications 
  
  
X 
X  
X  
X 
Adverse Events 
  
X  
X 
X  
X  
X 
Concomitant Medications  
 
X  
X 
X  
X  
X 


Perioperative Analgesia using Gabapentin in Head and Neck Free Flap Reconstruction Surgery: A Randomized Controlled 
Trial  
 
Clinical Study Protocol CCOL026 
 
 
Version 7.0 (08.26.2019) 
 
 
Page 20 of 37 
Evaluation 
Pre-
operative 
Peri-
operative 
POD 1-7 
(daily)1 
1 week after 
discharge 
4 weeks after 
surgery 
30 days post-op  
(Phone Call) 
1: If discharged before Post-Operative Date 7, patients will keep track of narcotics-related complications with a home data collection form 
(Appendix A). Patients must remain inpatient at least 2 days.  
2: Lab data will be required during pre-operative and on the day of discharge.  
3: Physical Exam includes height, weight, performance status, clinical tumor measurements (if applicable). 
4: Narcotic-related complications includes nausea, hypotension, delirium, and syncope. 
5: Daily morphine equivalents extracted from medication provided during pre-operation, surgery (APPENDIX B), and post-operation. 
6: Only patients who experience a clinically significant change in creatinine that leads to a study dose adjustment will be required to have a 1 
week post-discharge follow up lab draw to review creatinine stability.   
9.0 
SAFETY AND REPORTING REQUIREMENTS 
9.1 
Adverse Event Definition 
Adverse event (AE) means any untoward medical occurrence in a patient or subject administered 
a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product whether or not it is related to the medicinal product.  
This includes any newly occurring event, or a previous condition that has increased in severity or 
frequency since the administration of study drug.  
For this protocol, an abnormal laboratory value will not be assessed as an AE unless that value 
leads to discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline.  
Any other AE not listed as an expected event in the Investigator’s Brochure or in this protocol 
will be considered unexpected. 
9.2 
Adverse Event Documentation 
Any patient enrolled in the trial who signed the consent form and received at least one dose of 
Gabapentin will be eligible for adverse event reporting.  
All AEs must be recorded on case report forms (CRFs). Documentation must be supported by an 
entry in the subject’s file. Each event should be described in detail along with start and stop 
dates, severity, action taken and outcome. 
9.3 
Serious Adverse Event Definition 
Serious adverse event (SAE) means any untoward medical occurrence that at any dose: 
• Results in death. 
• Is life-threatening (Note: the term “life-threatening” refers to an event/reaction in which 
the patient was at risk of death at the time of the event/reaction.  It does not refer to an 
event/reaction, which hypothetically might have caused death if it were more severe). 


Perioperative Analgesia using Gabapentin in Head and Neck Free Flap Reconstruction Surgery: A Randomized Controlled 
Trial  
 
Clinical Study Protocol CCOL026 
 
 
Version 7.0 (08.26.2019) 
 
 
Page 21 of 37 
• Requires inpatient hospitalization or prolongation of an existing hospitalization  
• Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions). 
• Is a congenital anomaly/birth defect. 
• Is a medically important event or reaction. Medical and scientific judgment should be 
exercised in deciding whether other situations should be considered serious, such as 
important medical events that might not be immediately life-threatening or result in death 
or hospitalization, but might jeopardize the patient or might require intervention to 
prevent one of the other outcomes listed in the definition above. 
 
Clarification should be made between the terms serious and severe because they ARE NOT the 
same.  The term severe is often used to describe the intensity (severity) of a specific event (as in 
mild, moderate, or severe myocardial infarction); the event itself, however, may be of relatively 
minor medical significance (such as a severe headache).  This is NOT the same as serious, which 
is based on patient/event outcome or action criteria described above and is usually associated 
with events that pose a threat to a patient’s life or functioning.  A severe AE does not necessarily 
need to be considered serious.  For example, persistent nausea of several hours duration may be 
considered severe nausea but may not be considered an SAE.  On the other hand, a stroke 
resulting in only a minor degree of disability may be considered mild but would be defined as an 
SAE based on the above noted criteria.  Seriousness (not severity) serves as a guide for defining 
regulatory reporting obligations. 
9.4 
Procedures for Reporting Serious Adverse Events (SAEs)  
9.4.1 
Reporting to the Institutional Review Board 
Both serious and non-serious adverse events will be reported in accordance with UCD IRB 
Administration and UCD Office of Clinical Research (OCR) policies. The UC Davis IRB can be 
reached at (916) 703-9151.  
Participating site(s) will report adverse events per institution’s IRB guidelines.  
9.4.2 
Follow-up of Adverse Events and Serious Adverse Events 
The investigator shall provide follow-up information as and when available in a new follow-up 
SAE form. All SAEs must be followed until resolved, become chronic, or stable unless the 
subject is lost to follow up. Resolution status of such an event should be documented on the CRF.  
In addition, any known untoward event of any severity that occurs subsequent to the AE 
reporting period that the Investigator assesses as at least possibly related to the study therapy 
(i.e., the relationship cannot be ruled out) should also be reported as an AE. 


Perioperative Analgesia using Gabapentin in Head and Neck Free Flap Reconstruction Surgery: A Randomized Controlled 
Trial  
 
Clinical Study Protocol CCOL026 
 
 
Version 7.0 (08.26.2019) 
 
 
Page 22 of 37 
10.0 
RISKS TO SUBJECTS 
10.1 
Risk of loss of Confidentiality 
The study poses the risk of loss of confidentiality. The risk will be minimized through the data 
collection and banking processes described in Section 12.  
10.2 
Risk of Gabapentin 
Gabapentin Drug related risks include: 26(Kaye 2017) 
• Somnolence (15.2%) 
• Dizziness (10.9%) 
• Asthenia (6.0%) 
• Headache (4.8%) 
• Nausea (3.2%) 
• Ataxia (2.6%) 
• Weight gain (2.6%) 
• Amblyopia (2.1%) 
Additionally, rare and serious side effects of gabapentin include 27(Pfizer 2017) 
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS),  
• Anaphylaxis and angioedema,  
• Withdrawal-precipitated seizure,  
• Suicidal ideation,  
• Increased risk of pancreatic tumors (rats only), and  
• Sudden and unexplained death (in epileptic patients) 
Patients taking gabapentin are advised against driving or operating heavy machinery until they 
have sufficiently assessed the individual effects of the medication impairing their ability to 
drive.27(Pfizer 2017) 
Addiction 
Gabapentin abuse is considered low due to its low potential for addition compared to opioids. 
However, there is a new trend of gabapentin abuse in group of patients who are already abusing 
opioids. The abuse not been clinically validated, but spikes in gabapentin-related fatalities have 
led several states to register Gabapentin as a controlled substance (Virginia, Ohio, Kentucky, and 
West Virginia). A meta-analysis study by Bonnet and Scherbaum (2017) examined the addictive 
potential of gabapentin through evaluating several dimension and concluded that current 
literature does not offer strong evidence to support the addictive effects of gabapentin.28 
Although recent health care policy has reclassified gabapentin as a controlled substance in 
certain states, this reclassification is based on its potential for abuse.29 Potential for abuse does 
not reflect potential for addiction. The medication has been deemed an opportunistic drug for 


Perioperative Analgesia using Gabapentin in Head and Neck Free Flap Reconstruction Surgery: A Randomized Controlled 
Trial  
 
Clinical Study Protocol CCOL026 
 
 
Version 7.0 (08.26.2019) 
 
 
Page 23 of 37 
abuse due factors such as low cost, national classification as a non-controlled substance, and 
increasing rates of on- and off-label prescribing, and not necessarily due to addictive potential.29 
10.3 
Placebo Risk 
 
During this study, there is a 50% chance that a subject will receive a placebo. There is 
no anticipated risk associated with placebo treatment, as both groups of study participants 
will receive standard anesthesia and pain management plan post-surgery. The patients in 
placebo group may take higher amount of narcotic pain medication compared to those in the 
gabapentin group. This is not proven yet, and the narcotic medication intake amount is the 
primary outcome measure of the study. The researchers will carefully monitor the pain score 
reported by the participants. Study participants may withdraw from the study if the pain is not 
managed.  
10.4 
Unknown Risks to Women of Child Bearing Potential and Pregnant Women 
There are/may be risks to a fetus if a participant become pregnant while participating in 
this study.    
A patient will not be a surgery candidate if she is pregnant, and therefore pregnant 
patients will not be eligible for the study. 
10.5 
Risk Associated with Randomization 
 
The patient will be assigned to a study group at random (by chance) in order to avoid 
any bias in data collection or data analysis. The treatment group a subject is assigned to might 
not be the group the subject would prefer to be in. It might also prove to be less effective or 
have more side effects than the other study groups(s), or standard treatments available for your 
condition. 
 
10.6 
Mitigating Potential AE: Post-op Prerenal Disease 
In the event that a patient develops increased serum creatinine levels during their inpatient stay, 
they will be allowed to remain in the study at the discretion of the PI and placed on a pharmacy 
adjusted at-home dose.  Serum creatinine will be routinely screened pre-operatively and prior 
to discharge. If the patient develops a clinically significant increase in serum creatinine, the IDS 
will be informed and will provide a dose adjustment for the at-home patient dosing (See Table 
2). Patients who have clinically significant changes in their inpatient labs will routinely require 
follow-up labs to be reviewed during their outpatient appointments. The study will review the 1-
week post-discharge routine basic metabolic panel lab draws for patients that experience post-op 
prerenal disease. Further dose adjustments or patient withdrawal will be required if the creatinine 
level have worsened at the 1-week post-discharge office visit. Patient withdrawal will occur at 
the PI’s discretion. The underlined sections in the Patient Discharge Instructions (Appendix D) 
will be corrected based on PI discretion using the following dose adjustment guidelines: 
 
Table 2: Dose adjustment guidelines 
 


Perioperative Analgesia using Gabapentin in Head and Neck Free Flap Reconstruction Surgery: A Randomized Controlled 
Trial  
 
Clinical Study Protocol CCOL026 
 
 
Version 7.0 (08.26.2019) 
 
 
Page 24 of 37 
Creatinine Clearance 
(mL/minute) 
Normal Titration 
Schedule 
Tapering Schedule 
30–59 
300mg TID 
300mg BID 3 days, 
300mg QD 4 days 
15–29 
300mg BID 
300mg QD 7 days 
<15 not on hemodialysis 
300mg QD 
100mg QD 7 days 
 
10.7 
Mitigating Suicidal Ideation 
Patients will be routinely evaluated for suicidal ideation during their office visits. Standard of 
care evaluations will be used to identify and manage treatment options for study patients. 
Patients will be removed from the study at the discretion of the PI.  
11.0 
STATISTICAL CONSIDERATIONS  
11.1 
Study Design and Overview of Primary and Secondary Endpoints 
The subjects will be randomly assigned to control group and intervention group. Intention-to-
treat analysis will be performed to the data. The intervention and control groups will be 
compared for similarity of age, sex, weight, prior therapy, type of surgery, and the presence or 
absence of pre-operative opioid use to ensure adequate randomization.  
• Primary outcome: daily morphine equivalent units measured repeatedly over the 1st 
week 
• Exploratory outcome: total morphine equivalent units accumulated over 1 month 
• Secondary outcomes for side effects: 
a. Pain score (measured as 0-10) measured daily over 1 month. 
b. Binary outcomes measured daily over 1 month (including nausea, vomiting, 
dizziness, sedation, pruritis, urinary retention, and delirium). 
c. Length of stay and costs over 1-month (readmission is not included). 
We expect to have about 15% attrition during the 1-month follow-up time, and most dropouts 
will occur after 1 week due to discharge at Day 7. To handle the dropouts, longitudinal analyses 
will be performed to explore the effects and association with covariates, using likelihood-based 
method based on missing-at-random (MAR) assumption. In addition, imputation methods will be 
performed whenever necessary, and sensitivity analysis will be conducted.  
11.2 
Sample Size Estimation /Accrual Rate 
The primary outcome measure is the daily morphine equivalent units measured repeatedly over 
the 1st week. Each subject is measured 7 times at consecutive 7 days after surgery. Assume the 
null hypothesis is that the difference of daily morphine equivalent means between two groups is 
0 over the 1st week. Based on previous studies, we expect that the intervention will reduce 50% 


Perioperative Analgesia using Gabapentin in Head and Neck Free Flap Reconstruction Surgery: A Randomized Controlled 
Trial  
 
Clinical Study Protocol CCOL026 
 
 
Version 7.0 (08.26.2019) 
 
 
Page 25 of 37 
daily morphine equivalents from 40mg/day in control group (ie, 20mg/day in intervention 
group). Due to the fact that previous studies did not have data for the repeated measures over the 
1st week, we assume that the means of daily morphine equivalent at the consecutive 7 days are 
constantly 20mg/day in intervention group, and constantly 40mg/day in control group under 
alternative hypothesis. We assume the standard deviation is 30 for both groups, and the 
correlation between repeated measures is 0.9. Therefore, sample sizes of 45 patients per group 
(total 90) achieve power of 91% to detect the above difference of means between two groups, 
with a significance level (alpha) of 0.05. This is based on a two-sided repeated-measure ANOVA 
test. Considering 5-10% attrition over the 1st week, we will need additional 5 patients per group, 
resulting total 50 patients per group (total 100). We will plan an interim analysis after enrollment 
and data collection of the first 50 total patients (25 in each group) to assess statistical 
significance.  
Due to no precise data from previous studies, the above sample size justification is based on 
some assumptions. After 50 patients have been enrolled, we will further refine the sample size 
calculation with the obtained data.  
11.3 
Evaluation of Efficacy 
For the primary outcome, repeated-measure ANOVA test will be used to evaluate the effect of 
the intervention on daily morphine equivalent units over the 1st week. Exploratory longitudinal 
analysis will also be conducted, using linear mixed-effect model to explore the treatment effect 
change over time and association with covariates. 
For total morphine equivalent units accumulated over 1 month, Wilcoxon rank sum test will be 
performed to test the effect of intervention. Additionally, multivariate linear regression analysis 
adjusted with covariates will be conducted.  
11.4 
Evaluation of Safety 
Daily pain score over 1 month will be tested using repeated-measure ANOVA test. Linear 
mixed-effect model will also be performed to explore the change of pain score over time and 
association with covariates. 
Daily binary outcomes over 1 month (including nausea, vomiting, dizziness, sedation, pruritis, 
urinary retention, and delirium) will be analyzed used mixed-effect logistic regression to 
evaluate the side effect of intervention over time and the association with covariates. 
Length of stay and costs over 1-month will be compared between two groups using Wilcoxon 
rank sum test. Additionally, multivariate linear regression analysis adjusted with covariates will 
be conducted as exploratory analysis. 


Perioperative Analgesia using Gabapentin in Head and Neck Free Flap Reconstruction Surgery: A Randomized Controlled 
Trial  
 
Clinical Study Protocol CCOL026 
 
 
Version 7.0 (08.26.2019) 
 
 
Page 26 of 37 
12.0 
ADMINISTRATIVE REQUIREMENTS  
12.1 Good Clinical Practice 
The study will be conducted in accordance with the International Conference on Harmonisation 
(ICH) for Good Clinical Practice (GCP) and the appropriate regulatory requirement(s).  The 
investigator will be thoroughly familiar with the appropriate use of the drug as described in the 
protocol and Investigator’s Brochure.  Essential clinical documents will be maintained to 
demonstrate the validity of the study and the integrity of the data collected.  Master files should 
be established at the beginning of the study, maintained for the duration of the study and retained 
according to the appropriate regulations. 
12.2 Ethical Considerations  
The study will be conducted in accordance with ethical principles founded in the Declaration of 
Helsinki.  The IRB will review all appropriate study documentation in order to safeguard the 
rights, safety and well-being of the patients.  The protocol, Investigator’s Brochure, informed 
consent, advertisements, written information given to the patients, safety updates, annual 
progress reports, and any revisions to these documents will be provided to the IRB by the 
investigator.   
12.3 Study Registration 
Once signed, informed consent has been obtained and all pretreatment evaluations have been 
performed, patients will be entered on study according to UCD Office of Clinical Research 
(OCR) policy. To register a patient, the data manager or designee must complete the Patient 
Registration Form.   
12.4 Patient Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from the 
patient prior to study participation.  The method of obtaining and documenting the informed 
consent and the contents of the consent will comply with ICH-GCP and all applicable regulatory 
requirement(s).  In accordance with UCD OCR policy an original signed and dated participant 
Informed Consent document will reside in a secured location within the UCD OCR.  Copies of 
the signed and dated Informed Consent document will be provided to the study participant and 
UCD Health System Information Management for inclusion in the participant’s UCD Health 
System Medical Record. 
12.5 Patient Confidentiality 
In order to maintain patient privacy, all study reports and communications will identify the 
patient by initials and the assigned patient number.  Data capture records and drug accountability 
records will be stored in secure cabinets in the Glassrock building.  Medical records of patients 


Perioperative Analgesia using Gabapentin in Head and Neck Free Flap Reconstruction Surgery: A Randomized Controlled 
Trial  
 
Clinical Study Protocol CCOL026 
 
 
Version 7.0 (08.26.2019) 
 
 
Page 27 of 37 
will be maintained in strict confidence according to legal requirements.  The investigator will 
grant monitor(s) and auditor(s) from UC Davis Office of Research or its designees and 
regulatory authority(ies) access to the patient’s original medical records for verification of data 
gathered on the data capture records and to audit the data collection process.  The patient’s 
confidentiality will be maintained and will not be made publicly available to the extent permitted 
by the applicable laws and regulations. 
12.6 Protocol Compliance and Deviations 
The investigator will conduct the study in compliance with the protocol given approval/favorable 
opinion by the IRB and the appropriate regulatory authority(ies).   
All protocol deviations will be reported in accordance with UCD IRB Administration and UCD 
Cancer Center OCR policies. Any departures from the protocol must be fully documented in the 
source documents.   
12.7 Premature Closure of the Study 
This study may be prematurely terminated, if in the opinion of the there is sufficient reasonable 
cause.  Written notification documenting the reason for study termination will be provided to the 
investigator by the terminating party.   
Circumstances that may warrant termination include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to patients 
• Failure to enter patients at an acceptable rate 
• Insufficient adherence to protocol requirements 
• Insufficient complete and/or evaluable data 
• Plans to modify, suspend, or discontinue the development of the drug 
12.8 Record Retention 
The investigator will maintain all study records according to ICH-GCP and applicable regulatory 
requirement(s).  
12.9 Quality Assurance and Control 
Quality assurance audits of select patients and source documents may be conducted by the UC 
Davis Comprehensive Cancer Center Quality Assurance Committee as outlined in the UC Davis 
Cancer Center Data and Safety Monitoring plan. Quality control will be maintained by the OCR 
Quality Assurance team according to OCR policy. 


Perioperative Analgesia using Gabapentin in Head and Neck Free Flap Reconstruction Surgery: A Randomized Controlled 
Trial  
 
Clinical Study Protocol CCOL026 
 
 
Version 7.0 (08.26.2019) 
 
 
Page 28 of 37 
12.10 Provisions to Monitor the Data to Ensure the Safety of Subjects 
a) The PI will be responsible that the following are carried out: 
o Ensure that the protocol is being followed 
o Ensure that informed consent is documented  
o Ensure that changes to the protocol are approved by the UC Davis IRB 
o Ensure that accurate and complete records are being maintained by the site 
o Ensure that accurate and complete reports are being made to UC Davis IRB 
o Ensure that the information in the investigator’s report is complete, accurate, and 
legible 
o Ensure that there are no omissions in the reports of data that may be directly or 
indirectly relevant to the study 
o Ensure that missing examinations are noted in the reports 
o Ensure that subjects failing to complete the study are noted along with the reason for 
such failure 
o Follow IRB policies for reporting of Adverse Events/Serious Adverse Events 
 
12.11 Data Banking 
Data sheets used in the collection of PHI and generation of the recruitment database will be 
destroyed upon completion of the recruitment process. No data will be disclosed from the 
study. We assure that the protected health information will not be reused or disclosed to 
any other person or entity, except as required by law, for authorized oversight of the 
research study, or for other research for which the use or disclosure of protected health 
information for which an authorization or opportunity to agree or object is not required by 
45 CFR 164.512. 
13.0 
REFERENCES 
1. 
Kurd MF, Kreitz T, Schroeder G, Vaccaro AR. The Role of Multimodal Analgesia in 
Spine Surgery. J Am Acad Orthop Surg 2017; 25:260-268. 
2. 
Halawi MJ, Grant SA, Bolognesi MP. Multimodal Analgesia for Total Joint Arthroplasty. 
Orthopedics 2015; 38:e616-625. 
3. 
Dort JC, Farwell DG, Findlay Met al. Optimal Perioperative Care in Major Head and 
Neck Cancer Surgery With Free Flap Reconstruction: A Consensus Review and 
Recommendations From the Enhanced Recovery After Surgery Society. JAMA 
Otolaryngol Head Neck Surg 2017; 143:292-303. 
4. 
Sanders JG, Dawes PJ. Gabapentin for Perioperative Analgesia in Otorhinolaryngology-
Head and Neck Surgery: Systematic Review. Otolaryngol Head Neck Surg 2016; 
155:893-903. 
5. 
Mikkelsen S, Hilsted KL, Andersen PJet al. The effect of gabapentin on post-operative 
pain following tonsillectomy in adults. Acta Anaesthesiol Scand 2006; 50:809-815. 
6. 
Jeon EJ, Park YS, Park SS, Lee SK, Kim DH. The effectiveness of gabapentin on post-
tonsillectomy pain control. Eur Arch Otorhinolaryngol 2009; 266:1605-1609. 


Perioperative Analgesia using Gabapentin in Head and Neck Free Flap Reconstruction Surgery: A Randomized Controlled 
Trial  
 
Clinical Study Protocol CCOL026 
 
 
Version 7.0 (08.26.2019) 
 
 
Page 29 of 37 
7. 
Amani S, Abedinzadeh MR. Effects of Oral Gabapentin, Local Bupivacaine and 
Intravenous Pethidine on Post Tonsillectomy Pain. Iran J Otorhinolaryngol 2015; 27:343-
348. 
8. 
Amin SM, Amr YM. Comparison between preemptive gabapentin and paracetamol for 
pain control after adenotonsillectomy in children. Anesth Essays Res 2011; 5:167-170. 
9. 
Yeganeh Mogadam A, Fazel MR, Parviz S. Comparison of analgesic effect between 
gabapentin and diclofenac on post-operative pain in patients undergoing tonsillectomy. 
Arch Trauma Res 2012; 1:108-111. 
10. 
Amr YM, Yousef AA. Evaluation of efficacy of the perioperative administration of 
Venlafaxine or gabapentin on acute and chronic postmastectomy pain. Clin J Pain 2010; 
26:381-385. 
11. 
Kazak Z, Meltem Mortimer N, Sekerci S. Single dose of preoperative analgesia with 
gabapentin (600 mg) is safe and effective in monitored anesthesia care for nasal surgery. 
Eur Arch Otorhinolaryngol 2010; 267:731-736. 
12. 
Turan A, White PF, Karamanlioglu Bet al. Gabapentin: an alternative to the 
cyclooxygenase-2 inhibitors for perioperative pain management. Anesth Analg 2006; 
102:175-181. 
13. 
Brogly N, Wattier JM, Andrieu Get al. Gabapentin attenuates late but not early 
postoperative pain after thyroidectomy with superficial cervical plexus block. Anesth 
Analg 2008; 107:1720-1725. 
14. 
Lee JH, Lee HK, Chun NH, So Y, Lim CY. The prophylactic effects of gabapentin on 
postoperative sore throat after thyroid surgery. Korean J Anesthesiol 2013; 64:138-142. 
15. 
Al-Mujadi H, AR AR, Katzarov MG, Dehrab NA, Batra YK, Al-Qattan AR. Preemptive 
gabapentin reduces postoperative pain and opioid demand following thyroid surgery. Can 
J Anaesth 2006; 53:268-273. 
16. 
Chiu TW, Leung CC, Lau EY, Burd A. Analgesic effects of preoperative gabapentin after 
tongue reconstruction with the anterolateral thigh flap. Hong Kong Med J 2012; 18:30-
34. 
17. 
Doleman B, Heinink TP, Read DJ, Faleiro RJ, Lund JN, Williams JP. A systematic 
review and meta-regression analysis of prophylactic gabapentin for postoperative pain. 
Anaesthesia 2015; 70:1186-1204. 
18. 
Jadad AR, Moore RA, Carroll Det al. Assessing the quality of reports of randomized 
clinical trials: is blinding necessary? Control Clin Trials 1996; 17:1-12. 
19. 
Peng C, Li C, Qu J, Wu D. Gabapentin can decrease acute pain and morphine 
consumption in spinal surgery patients: A meta-analysis of randomized controlled trials. 
Medicine (Baltimore) 2017; 96:e6463. 
20. 
Reagan KML, O'Sullivan DM, Gannon R, Steinberg AC. Decreasing postoperative 
narcotics in reconstructive pelvic surgery: a randomized controlled trial. Am J Obstet 
Gynecol 2017; 217:325 e321-325 e310. 
21. 
Grosen K, Drewes AM, Hojsgaard A, Pfeiffer-Jensen M, Hjortdal VE, Pilegaard HK. 
Perioperative gabapentin for the prevention of persistent pain after thoracotomy: a 
randomized controlled trial. Eur J Cardiothorac Surg 2014; 46:76-85. 
22. 
Clarke HA, Katz J, McCartney CJet al. Perioperative gabapentin reduces 24 h opioid 
consumption and improves in-hospital rehabilitation but not post-discharge outcomes 


Perioperative Analgesia using Gabapentin in Head and Neck Free Flap Reconstruction Surgery: A Randomized Controlled 
Trial  
 
Clinical Study Protocol CCOL026 
 
 
Version 7.0 (08.26.2019) 
 
 
Page 30 of 37 
after total knee arthroplasty with peripheral nerve block. Br J Anaesth 2014; 113:855-
864. 
23. 
Paul JE, Nantha-Aree M, Buckley Net al. Randomized controlled trial of gabapentin as 
an adjunct to perioperative analgesia in total hip arthroplasty patients. Can J Anaesth 
2015; 62:476-484. 
24. 
Monks DT, Hoppe DW, Downey K, Shah V, Bernstein P, Carvalho JC. A Perioperative 
Course of Gabapentin Does Not Produce a Clinically Meaningful Improvement in 
Analgesia after Cesarean Delivery: A Randomized Controlled Trial. Anesthesiology 
2015; 123:320-326. 
25. 
Sessler CN, Gosnell MS, Grap MJet al. The Richmond Agitation-Sedation Scale: validity 
and reliability in adult intensive care unit patients. Am J Respir Crit Care Med 2002; 
166:1338-1344. 
26. 
Kaye AD, Cornett EM, Helander Eet al. An Update on Nonopioids: Intravenous or Oral 
Analgesics for Perioperative Pain Management. Anesthesiol Clin 2017; 35:e55-e71. 
27. 
Neurotin (gabapentin) [package insert]. Reference ID: 4168942 Pfizer, NY; 2017 
28.  
Bonnet U, Scherbaum N. How addictive are gabapentin and pregabalin? A systematic 
review. Eur Neuropsychopharmacol. 2017 Dec;27(12):1185-1215. 
29.  
Peckham AM, Ananickal MJ, Sclar DA. Gabapentin use, abuse, and the US opioid 
epidemic: the case for reclassification as a controlled substance and the need for 
pharmacovigilance. Risk Manag Healthc Policy. 2018;11:109-116. 
14.0 
APPENDICES 
14.1 
APPENDIX A:  
HOME DATA COLLECTION SHEET 
TO BE FILLED OUT BY THE PATIENT IF DISCHARGED EARLY UNTIL POD 7 
Patient Name: 
Patient MRN:   
1st day after discharge 


Perioperative Analgesia using Gabapentin in Head and Neck Free Flap Reconstruction Surgery: A Randomized Controlled 
Trial  
 
Clinical Study Protocol CCOL026 
 
 
Version 7.0 (08.26.2019) 
 
 
Page 31 of 37 
1. Did you have nausea over the last 24 hours? (yes or no) 
2. Did you vomit over the last 24 hours? (yes or no) 
3. Did you have a bowel movement over the last 24 hours? (yes or no) 
4. How would you rate your activity over the last 24 hours?  (please circle only 1) 
a. 0 - did not make it out of bed 
b. 1 - out of bed to bathroom or chair 
c. 2 - ambulated around house 
d. 3 - ambulated outside of house 
e. 4 - return to baseline activity  
5. How many times did you take narcotic medication over the last 24 hours? ____ 
6. How many mg total of narcotic did you take over the last 24 hours? ___  
7. Please rate your pain right now on a scale of 1-10 ___ 
 
Patient Name: 
Patient MRN:   
2nd day after discharge 
1. Did you have nausea over the last 24 hours? (yes or no) 
2. Did you vomit over the last 24 hours? (yes or no) 
3. Did you have a bowel movement over the last 24 hours? (yes or no) 
4. How would you rate your activity over the last 24 hours?  (please circle only 1) 
o 0 - did not make it out of bed 
o 1 - out of bed to bathroom or chair 
o 2 - ambulated around house 
o 3 - ambulated outside of house 
o 4 - return to baseline activity  
5. How many times did you take narcotic medication over the last 24 hours? ____ 
6. How many mg total of narcotic did you take over the last 24 hours? ___  
7. Please rate your pain right now on a scale of 1-10 ___ 
 
Patient Name: 
Patient MRN:   
3rd day after discharge 


Perioperative Analgesia using Gabapentin in Head and Neck Free Flap Reconstruction Surgery: A Randomized Controlled 
Trial  
 
Clinical Study Protocol CCOL026 
 
 
Version 7.0 (08.26.2019) 
 
 
Page 32 of 37 
 
1. Did you have nausea over the last 24 hours? (yes or no) 
2. Did you vomit over the last 24 hours? (yes or no) 
3. Did you have a bowel movement over the last 24 hours? (yes or no) 
4. How would you rate your activity over the last 24 hours?  (please circle only 1) 
o 0 - did not make it out of bed 
o 1 - out of bed to bathroom or chair 
o 2 - ambulated around house 
o 3 - ambulated outside of house 
o 4 - return to baseline activity  
5. How many times did you take narcotic medication over the last 24 hours? ____ 
6. How many mg total of narcotic did you take over the last 24 hours? ___  
7. Please rate your pain right now on a scale of 1-10 ___ 
 
Patient Name: 
Patient MRN:   
4th day after discharge 
1. Did you have nausea over the last 24 hours? (yes or no) 
2. Did you vomit over the last 24 hours? (yes or no) 
3. Did you have a bowel movement over the last 24 hours? (yes or no) 
4. How would you rate your activity over the last 24 hours?  (please circle only 1) 
o 0 - did not make it out of bed 
o 1 - out of bed to bathroom or chair 
o 2 - ambulated around house 
o 3 - ambulated outside of house 
o 4 - return to baseline activity  
5. How many times did you take narcotic medication over the last 24 hours? ____ 
6. How many mg total of narcotic did you take over the last 24 hours? ___  
7. Please rate your pain right now on a scale of 1-10 ___ 
 
Patient Name: 
Patient MRN:   
5th day after discharge 


Perioperative Analgesia using Gabapentin in Head and Neck Free Flap Reconstruction Surgery: A Randomized Controlled 
Trial  
 
Clinical Study Protocol CCOL026 
 
 
Version 7.0 (08.26.2019) 
 
 
Page 33 of 37 
1. Did you have nausea over the last 24 hours? (yes or no) 
2. Did you vomit over the last 24 hours? (yes or no) 
3. Did you have a bowel movement over the last 24 hours? (yes or no) 
4. How would you rate your activity over the last 24 hours?  (please circle only 1) 
o 0 - did not make it out of bed 
o 1 - out of bed to bathroom or chair 
o 2 - ambulated around house 
o 3 - ambulated outside of house 
o 4 - return to baseline activity  
5. How many times did you take narcotic medication over the last 24 hours? ____ 
6. How many mg total of narcotic did you take over the last 24 hours? ___  
7. Please rate your pain right now on a scale of 1-10 ___ 
 
 
14.2 
APPENDIX B: 
INTRA OP DATA COLLECTION SHEET 
TO BE FILLED OUT BY THE ANESTHESIA PROVIDER AT THE END OF SURGERY 
PLACE IN STUDY ENVELOPE WHEN COMPLETE 
 
Anesthesia Provider(s):   
Anesthetic agents used: 
• Request standard anesthetic to include Inhalational anesthetics (sevoflurane/desflurane), 
+/- propofol drip, and IV narcotic infusion of choice (remifentanyl, fentanyl, sufentanil).  
Please specifically avoid nitrous oxide and as an anesthetic agent and ketorolac as pain 
adjunct.   
• Request that anesthetic adjuncts such as IV ketamine (drip or bolus) and IV 
Dexmedetomidine (drip or bolus) be withheld by the anesthesia team, unless deemed 
medically necessary.   
• Request that 1000 mg of IV Tylenol be provided as first dose 1 hour prior to surgery and 
then be dosed at a dose of 1000 mg every 8 hours intra operatively for surgery lasting > 8 
hours  
 
Induction: 
Versed IV dose:  ______ 
Fentanyl IV dose:  _______ 
Propofol IV dose:  ________ 


Perioperative Analgesia using Gabapentin in Head and Neck Free Flap Reconstruction Surgery: A Randomized Controlled 
Trial  
 
Clinical Study Protocol CCOL026 
 
 
Version 7.0 (08.26.2019) 
 
 
Page 34 of 37 
Neuromuscular blocking agent:  agent:________   dose:  ___________ 
Maintenance: 
Inhalational anesthesia: 
       Agent:  _____            %:  ________ 
Propofol drip:  Total dose:__________ 
IV narcotic:  
    Remifentanyl: Total dose:  __________ 
    Sufentanil:  Total dose  __________ 
Adjuncts (if used)  
Agent 1  _______     
Dose and timing (from incision start):  ________ 
Reason?  ________ 
 
Agent 2  _______     
Dose and timing (from incision start):  ________ 
Reason?  ________ 
 
Agent 3  _______     
Dose and timing (from incision start):  ________ 
Reason?  ________ 
 
14.3 
APPENDIX C: 
RESEARCH DOSE DIARY 
TO BE FILLED OUT BY PATIENTS AFTER DISCHARGE 
 
Did you take 
all three doses? 
If no, please check which dose 
you missed 
Did you take any medications 
other than your discharge 
medications? 
If Yes, please list what you took: Drug Name, 
Amount taken (mg or mL), and why 
Day 1 
Yes            No 
Morning  □ Afternoon □ Night □   
Yes              No 
 
Day 2 
Yes            No 
Morning  □ Afternoon □ Night □   
Yes              No 
 


Perioperative Analgesia using Gabapentin in Head and Neck Free Flap Reconstruction Surgery: A Randomized Controlled 
Trial  
 
Clinical Study Protocol CCOL026 
 
 
Version 7.0 (08.26.2019) 
 
 
Page 35 of 37 
Day 3 
Yes            No 
Morning  □ Afternoon □ Night □   
Yes              No 
 
Day 4 
Yes            No 
Morning  □ Afternoon □ Night □   
Yes              No 
 
Day 5 
Yes            No 
Morning  □ Afternoon □ Night □   
Yes              No 
 
Day 6 
Yes            No 
Morning  □ Afternoon □ Night □   
Yes              No 
 
Day 7  
Yes            No 
Morning  □ Afternoon □ Night □   
Yes              No 
 
Day 8 
Yes            No 
Morning  □ Afternoon □ Night □   
Yes              No 
 
Day 9  
Yes            No 
Morning  □ Afternoon □ Night □   
Yes              No 
 
Day 10  
Yes            No 
Morning  □ Afternoon □ Night □   
Yes              No 
 
Day 11  
Yes            No 
Morning  □ Afternoon □ Night □   
Yes              No 
 
Day 12 
Yes            No 
Morning  □ Afternoon □ Night □   
Yes              No 
 
Day 13 
Yes            No 
Morning  □ Afternoon □ Night □   
Yes              No 
 
Day 14 
Yes            No 
Morning  □ Afternoon □ Night □   
Yes              No 
 
Day 15 
Yes            No 
Morning  □ Afternoon □ Night □   
Yes              No 
 
Day 16 
Yes            No 
Morning  □ Afternoon □ Night □   
Yes              No 
 
Day 17 
Yes            No 
Morning  □ Afternoon □ Night □   
Yes              No 
 
Day 18 
Yes            No 
Morning  □ Afternoon □ Night □   
Yes              No 
 
Day 19 
Yes            No 
Morning  □ Afternoon □ Night □   
Yes              No 
 
Day 20 
Yes            No 
Morning  □ Afternoon □ Night □   
Yes              No 
 
Day 21 
Yes            No 
Morning  □ Afternoon □ Night □   
Yes              No 
 
Day 22 
Yes            No 
Morning  □ Afternoon □ Night □   
Yes              No 
 
Day 23 
Yes            No 
Morning  □ Afternoon □ Night □   
Yes              No 
 
Day 24 
Yes            No 
Morning  □ Afternoon □ Night □   
Yes              No 
 
Day 25 
Yes            No 
Morning  □ Afternoon □ Night □   
Yes              No 
 
Day 26 
Yes            No 
Morning  □ Afternoon □ Night □   
Yes              No 
 
Day 27 
Yes            No 
Morning  □ Afternoon □ Night □   
Yes              No 
 
Day 28 
Yes            No 
Morning  □ Afternoon □ Night □   
Yes              No 
 
Day 29 
Yes            No 
Morning  □ Afternoon □ Night □   
Yes              No 
 
Day 30 
Yes            No 
Morning  □ Afternoon □ Night □   
Yes              No 
 
You have completed your 30-day regiment and you can begin to wean off the medication. For the next 3 days, please take the medication 300mg 
Twice a Day (Morning and Night). After 3 days, lower the dose again to 300mg Once a day for 4 days.  After this, you will be done with the study 
medication.  
If you have any questions, Call Angela (Study Coordinator) at 916-734-2704 
If you miss a dose, wait and take your normal next dose. Do not double up your doses. 
 


Perioperative Analgesia using Gabapentin in Head and Neck Free Flap Reconstruction Surgery: A Randomized Controlled 
Trial  
 
Clinical Study Protocol CCOL026 
 
 
Version 7.0 (08.26.2019) 
 
 
Page 36 of 37 
14.4 
APPENDIX D: 
STUDY DISCHARGE INSTRUCTIONS 
TO BE PROVIDED TO PATIENT PRIOR TO DISCHARGE 
 
STUDY DISCHARGE INSTRUCTIONS 
You are participating in a randomized research study that requires you to take 
medication at home. You have been provided a bottle of the study medication and a 
home diary. Please avoid driving until after at least 7 days post-op. 
Instructions for Medication Use 
Your study medication bottle holds enough liquid for _____days.  
Since you have been in the hospital, you have been given 300mg three times per day. 
Continue this medication routine while you are at home. Most patients will take it in the 
morning, afternoon, and at night. This medication can be taken with or without food. 
Below are instructions on how to measure the correct volume of medication.  
 
• Ensure that you fill the syringe until the 6mL mark for the full 300mg dose. 
• Once you have finish taking your oral dose, clean the syringe by flushing it with 
water.  
If you missed a dose, document it in your dose diary. Skip the missed dose if it is almost 
time for your next scheduled dose. Do not take extra medicine to make up the missed 
dose. 
Do not stop taking this medication without first talking to your Study Doctor.  
After 30 days, we will ask you to wean yourself off the medication. For 3 days (Day 31-
33), take 300mg twice a day. You will then take 300mg once for 4 days (Day 34-37).  


Perioperative Analgesia using Gabapentin in Head and Neck Free Flap Reconstruction Surgery: A Randomized Controlled 
Trial  
 
Clinical Study Protocol CCOL026 
 
 
Version 7.0 (08.26.2019) 
 
 
Page 37 of 37 
Follow up 
Your next scheduled appointment with Dr. _________________ is  
_____________________ 
**Please bring all your discharge and study medications to this visit.  
Diary 
You have been provided a Research Dose Diary to help you keep track of your 
compliance. Complete this form once a day while taking this medication at home.  
**Please bring your diary to your next office visit.  
Contact 
If you start to feel any of the following unnatural side effect, please contact the Clinical 
Trials team at 916-734-2704: Lack of coordination, unusual changes in mood or 
behavior, or seizures.   
 
Non-emergent medical problems or questions, please call the Otolaryngology-HNS 
clinic at 916-734-5400 during the daytime on weekdays. For emergent issues, please 
proceed immediately to the ER.   

ICF_001.pdf: 







 !!"
#$

%&'!()*+,

(!'-

.

.$

$

!!!!$

!'$

/!
!$

!!$

$

0$

0$

0!$

$

0 $

1!

1!$

1 !
!23#45#675$$
8#!9::;/%23#45#67,/
/+#$1
!2!$
 !
!+-6667
 
APPROVED by the Institutional Review
Board at the University of California, Davis
Protocol
APPROVED
1166778
January 13, 2020



6
.1+%<1+=,$1!
#->>$$$>!>#
!>$0!1+!!%23,74#2?#!@$626
((577+!562(!:2?A-

0 !!$

0!$

0!!$

0 )$

0!$


!$.!!
!!!""
!!!
$.!$.
#!!
!$(
/>B!$
!
$

'5?$

'77$

1!
C> 
!$0 $.
!$!
!.!'1D
$1477!!
!$0
47!477!4
477!5$
 !
!+-6667
 
APPROVED by the Institutional Review
Board at the University of California, Davis
Protocol
APPROVED
1166778
January 13, 2020



4
!$47#
!$0
#527#
$0
!!&E.!$1
 
$047#
!$
1!#!
 !$.  -
FE%>,
FD!%>,
F!%>,
FE!!65
FG<=H%7#5,
F%D(,
/!$
E!$0 
!$E!$
1!!
!$

1-
$ !!!!
$1!#!
IJ$I-

%>,!%>,!!%>,
G<H%7#5,!

6$ 0!9:&E.!
47$
4$ 0 !+!
!$
5$ > #!$
 !
!+-6667
 
APPROVED by the Institutional Review
Board at the University of California, Davis
Protocol
APPROVED
1166778
January 13, 2020



5

0!$0
$

0!$0
!!
$
1
!$
0! $

.$.!!"
)!$
"#-
(
""

;
E
'-!!!

J"
+&(!(!!%+&((,
$
.
!!!!%
!,)$
'!-$
#$
("!B
(
1!%,
('%,
!!
$.)
 !
!+-6667
 
APPROVED by the Institutional Review
Board at the University of California, Davis
Protocol
APPROVED
1166778
January 13, 2020



?
!$/
'""$
.'$
0!!!
$
$%
B!$$!
%!,
!$ $
% &'!&
.>!!$.
$
1$0
!!!
$
1!$.!!
!$
 0!%,$
0!%,!!
$.!$1
!!%,
!$
?7K$.

!!$1!!!!
!$
#.!
!$!
$1
!$1
!!!$
 !
!+-6667
 
APPROVED by the Institutional Review
Board at the University of California, Davis
Protocol
APPROVED
1166778
January 13, 2020



3

!!$;
!
!
$

&!!!
!!$!!
$/"!!1+
9:!!$
!$;!
!$
->>$:.$ 9$($
J$.!$!
!!$0!$
1!%$$!,
!!$
8!!$
.9:;(!E
%->>$!$$>>>,!$
 !
.!!
$

0!$
.!!!!"$
0'#!
$/'!
$
8!!!$.!
9:9E#&!&!%1AA4,
!((!$
 !
!+-6667
 
APPROVED by the Institutional Review
Board at the University of California, Davis
Protocol
APPROVED
1166778
January 13, 2020




1!!
)$1)
9:!!$!
!!9!
!)!$.9!
!!)$8!!!!
1+!%23,74#2?!;(#1+!@$$
0!$
$!'
0!!$
()

!)
(

!
 !
!+-6667
 
APPROVED by the Institutional Review
Board at the University of California, Davis
Protocol
APPROVED
1166778
January 13, 2020