Clinical trial NCT02703259
Conditions: Pain, Postoperative
Sponsor: Christiana Care Health Services
Start date: 2016-06-01; Completion date: 2017-07-01
Enrollment: 137 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the investigators' study is to assess the efficacy of a single dose of preoperative gabapentin within an enhanced recovery after surgery protocol in acute postoperative pain reduction for women undergoing a minimally invasive hysterectomy. Participants who consent to participate will be randomized to either a control group without gabapentin or to a study arm and receive gabapentin 600 mg prior to their planned surgery. The investigators will collect data on postoperative narcotic use, subjective pain as rated by a numeric pain scale, in addition to any adverse effects of single dose gabapentin use.

Detailed description:
Multimodal postoperative analgesia after a hysterectomy has been mainly based on a combination of nonsteroidal anti-inflammatory drugs and opioids. However, adverse effects including nausea, vomiting, sedation, and pruritus may limit use of opioids. As the side effects are dose related, minimizing opioid exposure may significantly reduce these risks. Thus, there has been an interest in evaluating preemptive as well as post-operative administration of non-opioids. Additional regimens have been suggested to minimize opioid use and its associated adverse effects including injection of local anesthetics, epidural analgesia, and anticonvulsants, such as gabapentin or pregabalin.

Gabapentin, a widely used anticonvulsant used for treatment of neuropathic pain, has recently been suggested to improve postoperative analgesia and reduce opioid requirements. Gabapentin is thought to modulate calcium channels on the presynaptic nociceptive neurons, which in turn modulate or inhibit the release of excitatory neurotransmitters from activated nociceptors. In addition to inhibiting pain transmission, gabapentin may exert an analgesic effect by activating descending inhibitory noradrenergic pathways.

Many studies have demonstrated the safety and efficacy of gabapentin for perioperative use in a variety of procedures across disciplines including thoracotomy, laparoscopic cholecystectomy, tonsillectomy, major orthopedic surgery, cesarean sections, and abdominal hysterectomy. Several randomized trials have evaluated the effects of gabapentin administered preoperatively only as well as given pre- and postoperatively for hysterectomy. In a systematic review of 14 studies conducted between 2004 and 2013, with samples ranging from 40 to 200, investigators identified 8 trials in which gabapentin was administered only preoperatively to reduce pain associated with abdominal hysterectomy surgery. Analysis of those data clearly demonstrates that preemptive gabapentin reduced the postoperative visual analog scale (VAS) pain score by approximately 50% and postoperative use of morphine by approximately 37%. The incidence of pruritus and dry mouth in those receiving preemptive gabapentin appeared similar to those receiving placebo, however there was a higher rate of reported dizziness (not statistically significant) associated with gabapentin. In contrast, multiple postoperative doses of gabapentin in addition to the preoperative dose was found to have no significant effect on VAS scores at 24 hours, thus favoring a single preoperative dose.

Although initial results have been encouraging, uptake of gabapentin in routine clinical use remains limited due to mixed results and variability between gabapentin protocols, including dosing and duration. Christiana Care Health System (CCHS) plans to implement the Enhanced Recovery After Surgery (ERAS) protocol which administers preoperative medications to reduce postoperative pain, including acetaminophen, celecoxib, dexamethasone, and gabapentin. Therefore the aim of this study is to assess the efficacy of a single dose of preoperative gabapentin protocol to reduce acute postoperative pain in women undergoing a minimally invasive hysterectomy.

Arms: arm 1: As per the enhanced recovery after surgery protocol at our health institution, subject will receive oral medications prior to surgery including acetaminophen, celecoxib, and gabapentin x 1 dose given preoperatively. The number of tablets and capsules will remain identical in both study arms. Medications given include:

Gabapentin 600 mg (two capsules of gabapetin 300 mg); Acetaminophen 975 mg (three tablets of acetaminophen 325 mg); Celecoxib 400 mg (two capsules of celecoxib 200 mg) = Total 3 tablets, 4 capsules arm 2: As per the enhanced recovery after surgery protocol at our health institution, subject will receive oral medications prior to surgery including acetaminophen and celecoxib x 1 dose given preoperatively. The number of tablets and capsules will remain identical in both study arms. Medications given include:

Acetaminophen 975 mg (three tablets of acetaminophen 325 mg); Celecoxib 400 mg (four capsules of celecoxib 100 mg) = Total total 3 tablets, 4 capsules
Interventions: intervention 1: Gabapentin intervention 2: Acetaminophen intervention 3: Celecoxib
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_SAP_000.pdf: 
NCT 02703259 
Date: February 12, 2016 
 
Research title:  Single dose preoperative gabapentin use in minimally invasive 
hysterectomy for acute pain management 
 
 
 
 


NCT 02703259 
Date: February 12, 2016 
 
 
Principal Investigators: Terri Huynh, MD 
 
Additional Investigators: Gretchen Makai, MD; Nima Patel, MD; Nancy Sloan, DrPH 
Objectives:  
 
The purpose of this study is to evaluate the efficacy of preoperative single dose 
gabapentin for subjects undergoing a minimally invasive hysterectomy in 
management of acute postoperative pain.  The study will compare the effectiveness, 
and side effects of preoperative provision of three non-opioid oral medications 
(acetaminophen, celecoxib, and gabapentin) compared with acetaminophen and 
celecoxib alone (without gabapentin).  As providing the least medication and lowest 
doses is consistent with best medical practices, we propose to assess whether 
provision of gabapentin does or does not provide significant reduction of post-
operative pain above and beyond oral acetaminophen and celecoxib. We aim to 
assess efficacy with dual primary outcomes of reduction in 24 hour numeric analog 
scale (NAS) and reduction in 24 hour narcotic use. 
 
Hypothesis: 
 
We hypothesize a single preoperative dose of gabapentin 600 mg in addition to oral 
acetaminophen and celecoxib will meaningfully reduce the reported 24 hour 
postoperative NAS score by at least 35% and reduce the 24 hour narcotic use by at 
least 25% compared with preoperative acetaminophen and celecoxib alone.  These 
effects are clinically meaningful, while conservatively lower than those found by 
Alayed et al (2014).   
 
Background: 
 
Multimodal postoperative analgesia after a hysterectomy has been mainly based on 
a combination of nonsteroidal anti-inflammatory drugs and opioids.  However, 
adverse effects including nausea, vomiting, sedation, and pruritus may limit use of 
opioids (Dolin 2005).  As the side effects are dose related, minimizing opioid 
exposure may significantly reduce these risks.  Thus, there has been an interest in 
evaluating preemptive as well as post-operative administration of non-opioids. 
Additional regimens have been suggested to minimize opioid use and its associated 
adverse effects including injection of local anesthetics, epidural analgesia, and 
anticonvulsants, such as gabapentin or pregabalin (Tiippana 2007). 
 
Gabapentin, a widely used anticonvulsant used for treatment of neuropathic pain, 
has recently been suggested to improve postoperative analgesia and reduce opioid 
requirements.  Gabapentin is thought to modulate calcium channels on the 
presynaptic nociceptive neurons, which in turn modulate or inhibit the release of 
excitatory neurotransmitters from activated nociceptors (Schmidt et al 2013).  In 


NCT 02703259 
Date: February 12, 2016 
 
addition to inhibiting pain transmission, gabapentin may exert an analgesic effect by 
activating descending inhibitory noradrenergic pathways (Schmidt et al. 2013). 
 
Many studies have demonstrated the safety and efficacy of gabapentin for 
perioperative use in a variety of procedures across disciplines including 
thoracotomy, laparoscopic cholecystectomy, tonsillectomy, major orthopedic 
surgery, cesarean sections, and abdominal hysterectomy (Tiippana 2007).  Several 
randomized trials have evaluated the effects of gabapentin administered 
preoperatively only as well as given pre- and postoperatively for hysterectomy.  In a 
systematic review of 14 studies conducted between 2004 and 2013, with samples 
ranging from 40 to 200, Alayed et al. (2014) identified 8 trials in which gabapentin 
was administered only preoperatively to reduce pain associated with abdominal 
hysterectomy surgery.  Analysis of those data clearly demonstrates that preemptive 
gabapentin reduced the postoperative visual analog scale (VAS) pain score by 
approximately 50% and postoperative use of morphine by approximately 37%.  The 
incidence of pruritus and dry mouth in those receiving preemptive gabapentin 
appeared similar to those receiving placebo, however there was a higher rate of 
reported dizziness (not statistically significant) associated with gabapentin.  In 
contrast, multiple postoperative doses of gabapentin in addition to the preoperative 
dose was found to have no significant effect on VAS scores at 24 hours, thus favoring 
a single preoperative dose.  
 
Although initial results have been encouraging, uptake of gabapentin in routine 
clinical use remains limited due to mixed results and variability between gabapentin 
protocols, including dosing and duration.  Christiana Care (CCHS) plans to 
implement the Enhanced Recovery After Surgery (ERAS) protocol which 
administers preoperative medications to reduce postoperative pain, including 
acetaminophen, celecoxib, dexamethasone, and gabapentin.  Therefore the aim of 
this study is to assess the efficacy of a single dose of preoperative gabapentin to 
reduce acute postoperative pain in women undergoing a minimally invasive 
hysterectomy. 
 
Study Design:  
 
This is a double-blind, randomized controlled trial with a balanced 1:1 ratio 
evaluating the efficacy of single dose perioperative gabapentin above and beyond 
the effects of preoperative acetaminophen and celecoxib for women undergoing a 
hysterectomy via a minimally invasive approach.   
 
Assuming a standard deviation equivalent to 50% of the average of both study 
groups (three medications including gabapentin compared to two medications 
excluding gabapentin), a sample of 51 women in each study group is needed using a 
two tailed test, α=0.05, 1-β=90%.  Assuming that the two primary outcomes are 
80% correlated, a Bonferroni adjustment for multiple comparisons increases the 
sample size by 2 people per group.  Therefore, in case of missing information and/or 


NCT 02703259 
Date: February 12, 2016 
 
attenuation of effect should analyses controlled for confounding be necessary, the 
study plans to enroll 67 women per study group.   
 
 
Study Participants:  
 
Our study population will include all females undergoing a minimally invasive 
hysterectomy with surgeons operating within the Christiana Care at the Newark 
location only.  Participants will be included if they are at least 18 years of age and 
undergoing hysterectomy for any indication via a minimally invasive approach – 
vaginal, laparoscopic, and/or robotic-assisted. 
 
Participants will be excluded if they decline to participate, have a known history of 
liver or renal failure, a history of gastric bypass, gastroparesis, recent or current 
regular gabapentin use, or a hypersensitivity to gabapentin, acetominophen, or 
celecoxib, or procedure is converted to laparotomy for any indication. Mini-
laparotomy for specimen removal alone will not be excluded. 
 
Consents will be requested from eligible subjects in the office setting at the time of 
scheduling their hysterectomy.  Consenting participants will then be randomized 
into the experimental or control study group stratified by surgeon, to eliminate bias 
associated with provider experience.   The preoperative medications will be 
administered 1-2 hours before surgery in the preoperative holding area.    Both 
groups will continue to receive the standard preoperative care and medications per 
protocol at Christiana Care. 
 
 
Study Protocol: 
 
1. Procedure 
Eligible participants will be approached and voluntary informed consent will 
be requested in the office setting at the time of their preoperative visit.  
Consenting subjects will then be randomized on the day of surgery to either 
the experimental or control group by the research coordinator.  The study 
will use concealed envelop random allocation in which each group will be 
identified by an anonymous letter (X or Y); the identity of the study group 
allocation will be maintained in a locked file by the Chief Epidemiologist of 
the CCHS Department of Obstetrics and Gynecology, Nancy Sloan, and will 
not be revealed except to and if directed by the institutional.  Randomization 
will be stratified by surgeon.  While in the preoperative preparation and hold 
area, subjects will complete a survey to assess a baseline pain score.  To 
support double-blind implementation, perioperative nurses will administer 
routine preoperative medications approximately 1-2 hours prior to surgery 
to ensure the study data collectors and data entry personnel are unaware of 
the study group allocation.  Although the study does not have the funding to 


NCT 02703259 
Date: February 12, 2016 
 
support purchase of visually identical placebos, the study will support the 
double blind design by providing the same number of capsules to both study 
groups. Subjects in the control arm will receive acetominophen 975 mg 
(three tablets of acetaminophen 325 mg) and celecoxib 400 mg (four 
capsules of celecoxib 100 mg) orally.  Subjects in the study arm will receive 
gabapentin 600 mg (two capsules of gabapentin 300mg), acetaminophen 975 
mg (three tablets of acetaminophen 325 mg), and celecoxib 400 mg (two 
capsules of celecoxib 200 mg) orally.  Thus, both the experimental and 
control groups will receive three tablets and four capsules for perioperative 
oral medications to support the double blind design.  Subjects will undergo 
their scheduled minimally invasive surgery as per routine by participating 
surgeons.  Surgeons will be encouraged to administer 20 cc local 0.25% 
Marcaine distributed equally among all incision sites. 
 
Postoperatively, subjects will continue to receive the standard of care as 
performed by the Christiana Care and the attending surgeon.  Recovery and 
floor nurses will continue to manage patient care as routine, including 
assessing for patient pain immediately post operatively and at routine time 
points postoperatively until discharge, using either the verbal numerical 
rating scale or the Wong-Baker FACES pain rating scale.  Subjects discharged 
prior to 24 hours will report their pain rating and narcotic medication use via 
telephone follow-up from a research coordinator.  Up to 3 telephone calls will 
be made to maximize follow-up. 
 
Subjects will also receive a phone call 2 weeks postoperatively to assess pain, 
postoperative narcotic use, and potential side effects. 
 
Study Arms: 
 Gabapentin group: Gabapentin 600 mg (two capsules of gabapetin 300 
mg) , acetominophen 975 mg (three tablets of acetaminophen 325 mg), 
Celecoxib 400 mg (two capsules of celecoxib 200 mg) = total 3 tablets, 4 
capsules 
 Control group: Acetominophen 975 mg (three tablets of acetaminophen 
325 mg), Celecoxib 400 mg (four capsules of celecoxib 100 mg) = total 
total 3 tablets, 4 capsules 
 
Administration: Medication given 1-2 hours prior to surgery by preop RN 
 
 
2. Confidentiality 
Voluntary informed consent for study participation will be requested from all 
eligible subjects.  To enable data collection, names and medical record 
numbers will be recorded on informed consent forms along with an assigned 
a study ID number to link these identifiers.  To protect confidentiality, all 
data will be entered into an encrypted, password protected electronic file 


NCT 02703259 
Date: February 12, 2016 
 
using REDCap software.  Hard copy informed consent forms will be 
maintained in locked files in the Principal Investigator's office and later 
destroyed in a manner compliant with CCHS data security.  Extracted data 
from REDCap and data analysis files will be maintained on secure CCHS 
media/secure flash drive.  When data collection is complete, all identifiers 
excepting the study ID number will be redacted from the data set to further 
protect confidentiality. 
 
3. Subject Compensation 
Participants will not be compensated for participating in this study. 
 
 
 
Drugs or Devices: 
 
Subjects will receive medications that are not investigational.  The study 
medications have been preapproved for routine use in the enhanced recovery after 
surgery protocol at CCHS. 
 
Data Collection Variables: 
 
1. Primary Outcome Variables 
 Narcotic use in the immediate 24 hour postoperative period is our co-
primary outcome.  Narcotic use postoperatively, both intravenous and oral, 
will be collected from subject charts and converted to standard equivalents 
of oral oxycodone using the equianalgesic table available at globalrph.com.  
Narcotic use after discharge will be assessed by telephone call and asking 
subjects to count pills remaining in prescribed medication bottles between 
24 hours. 
 Mean differences in pain scale rating from preoperative rating to rating 24 
hours after surgery is our other co-primary outcome; ratings within a subject 
will be compared to other study participants in the control and study group.  
Pain scale assessment using a verbal numerical rating scale or the Wong-
Baker FACES pain rating scale will be collected at four time points: prior to 
surgery, immediately on arrival to the PACU, arrival to the inpatient floor, 
and at 24 hours postoperatively. 
2. Secondary Outcome Variables 
 The study is not designed to test any hypotheses other than the primary 
outcomes. The study will, however, collect data on narcotic use over the 
entire 2 week postoperative period and assess pain at 2 weeks as well.  In 
addition, the study will collect data on and analyze and describe side effects 
that may be contributed to gabapentin use.  These variables include the 
presence or absence of postoperative nausea and vomiting, dizziness, 
somnolence, blurry vision, and tremulousness within the first 24 hours 
postoperatively.  Presence of symptoms will be noted as either a documented 
complaint of the patient, postoperative administration of medication to treat 


NCT 02703259 
Date: February 12, 2016 
 
symptom (such as antiemetic administration while inpatient), 
documentation of symptom in the chart (such as emesis volume recorded), 
and/or subject confirms symptoms within the past 24 hours at the 24 hour 
postoperative phone survey. 
 
Randomization criteria:  Provider 
Potential Confounding and Mediating Variables, Data Collection 
 Age 
 BMI 
 PMH:  
o chronic pain syndromes (fibromyalgia, chronic pelvic pain, 
chronic back pain, neuropathy) 
 PSH:  
o number of laparoscopic surgeries 
o number of open abdominal surgeries 
o total number of surgeries (including extra-abdominal 
surgeries) 
 Procedure details:  
o indication for surgery 
o surgical approach (i.e. vaginal, lsc, robotic) 
o procedure other than hysterectomy 
 salpingectomy 
 oophorectomy 
 lysis of adhesion 
 sacrocolpopexy 
 perineorrhaphy 
 sacrospinous ligament fixation 
 sling (transobturator, TVT) 
 +/- mesh 
 lymphadenectomy (pelvic, aortic) 
 omentectomy 
o EBL 
o Operating time 
o use of local anesthetic at incision 
o method to remove specimen (i.e. minilaparotomy vs 
colpotomy vs power morcellation) 
o Attending surgeon 
o Date of surgery 
 Surgical Complications:  
o Clavien-Dindo classification 
o infection 
o transfusion 
o wound separation 
o visceral injury 
 bowel 


NCT 02703259 
Date: February 12, 2016 
 
 bladder 
 ureter 
 blood vessel 
o Patient survey (phone call) 
 24 hours/2 weeks 
 pain scale 
 amount of oral pain narcotic used 
 experienced following symptoms 
o nausea 
o vomiting 
o dizziness 
o ataxia 
o tiredness/somnolence 
o blurred vision 
o Pain rating postop: define on arrival to PACU ( = 0 hours) 
 Arrival to PACU 
 Arrival to floor 
 24 hours postop 
 2 weeks postop 
 
 
Method of Analysis: 
The study data will be entered into an MS Access database that will be maintained 
on the protected CCHS computer system and approved encrypted thumb drives.  
Descriptive statistics using chi-square for categorical and Student's t-tests for 
continuous variables, with Fisher's continuity correction for analyses with fewer 
than 5 subjects in any cell will be reported.  Linear (for continuous outcome) and 
logistic (for categorical variables) regression analyses will be conducted to adjust 
for confounding factors and assess mediation of effect (for example, associated with 
surgical complications). 
 
Risks/Benefits: 
 
The Christiana Care Institutional Review Board will review this study protocol.  The 
study will be registered with ClinicalTrials.gov prior to enrollment of its first 
patient.  Voluntary informed consent for study participation will be requested of all 
eligible women undergoing a minimally invasive hysterectomy for any indication.  
This study carries a small risk regarding breech of confidentiality, as protected 
health information will be collected.  However information will be kept coded and 
secure in accordance with CCHS data security measures and REDCap software.   
 
There is a potential risk for side effects from gabapentin administration including 
temporary dizziness/drowsiness, fatigue, loss of balance, blurry vision, 
tremulousness, swelling, nausea, vomiting, diarrhea, and allergic reaction, however 
these side effects are rare.  Risks of side effects from gabapentin are also minimal as 


NCT 02703259 
Date: February 12, 2016 
 
the study will only administer a single dose.  Potential benefits include improved 
postoperative pain management, less narcotic use, and decreased postoperative 
nausea and vomiting. 
 
References: 
Alayed N, Alghanaim N, Tan X, Tulandi T. Preemptive use of gabapentin in 
abdominal hysterectomy: a systematic review and meta-analysis. Obstet Gynecol. 
2014 Jun;123(6):1221-9. doi: 10.1097/AOG.0000000000000289. 
 
Clarke H, Bonin R, Orser B et. al.  (2012) The prevention of chronic postsurgical pain 
using gabapentin and pregabalin: A combined systematic review and meta-analysis.  
Anesthesia and Analgesia, 115(2), 428-442.  doi: 10.1213/ANE.0b013e318249d36e 
 
Dolin SJ, Cashman JN. Tolerability of acute postoperative pain management: nausea, 
vomiting, sedation, pruritus, and urinary retention. Evidence from published data. 
Br J Anaesth. 2005 Nov;95(5):584-91. Epub 2005 Sep 16. 
 
Schmidt PC, Ruchelli G, Mackey SC, Carroll IR. Perioperative gabapentinoids: choice 
of agent, dose, timing, and effects on chronic postsurgical pain.  Anesthesiology. 
2013 Nov;119(5):1215-21. doi: 10.1097/ALN.0b013e3182a9a896. 
Straube, S., Derry, S., Ra, M., Pj, W., & Hj, M. (2013). Single dose oral gabapentin for 
established acute postoperative pain in adults ., 5(5), 20464764. 
http://doi.org/10.1002/14651858.CD008183.pub2.Single 
Tiippana EM, Hamunen K, Kontinen VK, Kalso E. Do surgical patients benefit from 
perioperative gabapentin/pregabalin? A systematic review of efficacy and safety. 
Anesth Analg. 2007 Jun;104(6):1545-56.