A Double-Blind Randomized Placebo-Controlled Clinical Trial of Preoperative Gabapentin Prior to Vaginal Apical Suspension Prolapse Procedures
Phase: PHASE4
Conditions: Pelvic Organ Prolapse, Perioperative/Postoperative Complications
Sponsor: Joseph Kowalski

Manual of Procedures/Protocol 
 
Title: A Double-Blind Randomized Placebo-Controlled Clinical Trial of Preoperative 
Gabapentin Prior to Vaginal Apical Suspension Prolapse Procedures 
 
Fellow: Colin Johnson, MD PGY5 
Research Mentor: Joseph Kowalski, MD 
 
University of Iowa Hospitals and Clinics 
Department of Female Pelvic Medicine and Reconstructive Surgery 
Iowa City, IA 
July 2022 
 
NCT 05658887 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Specific Aims and Hypothesis 
 
Primary Aim: To compare the impact of preoperative gabapentin versus placebo on post-
operative opioid use.  
 
Hypothesis: Preoperative gabapentin is associated with reduced post-operative opioid use 
compared to placebo for patients undergoing vaginal apical support procedures for pelvic organ 
prolapse.  
 
Null Hypothesis: Preoperative gabapentin is not associated with reduced post-operative 
opioid use compared to placebo for patients undergoing vaginal apical support procedures for 
pelvic organ prolapse. 
 
Secondary Aims:  
1. To compare adverse events between groups. 
2. To compare subjective pain scores and anti-emetic use between groups. 
3. To compare time to discharge between groups. 
 
Introduction, Background, and Significance 
 
Enhanced Recovery after Surgery (ERAS) is an approach to perioperative care that 
focuses on evidence-based care protocols that emphasize minimizing stress as well as improving 
the body’s response to stress.1 Common elements to ERAS protocols include a multidisciplinary 
approach, preoperative optimization, emphasizing minimally invasive techniques, maintaining 
euvolemia, early mobilization, early postoperative oral intake, and multi-modal opioid-sparing 
pain control.1,2 ERAS protocols have resulted in a significant decrease in length of stay, 
complications, and cost in many different surgical specialties.1,2 The Enhanced Recovery After 
Surgery Society was founded in 2010 and publishes and updates evidence-based perioperative 
guidelines for many different surgical specialties and subspecialties.1 In gynecology, the ERAS 
Society has published ERAS guidelines for gynecologic oncology (updated in 2019)3 and for 
vaginal surgery (published 2020).4 There have been many other gynecology ERAS 
programs/guidelines published,5 and in 2019, Scheib et al. published a review of 50 gynecology 
ERAS programs.5 Our institution implemented a gynecologic ERAS protocol in 2020, and after 
the protocol was introduced, patients undergoing pelvic organ prolapse surgery received 
significantly fewer opioids.6 
Gabapentinoids (gabapentin and pregabalin) are anticonvulsant medications that are 
commonly used for chronic neuropathic pain and other chronic pain disorders but also have an 
anxiolytic effect.7 Several ERAS protocols use a preoperative or perioperative gabapentinoid 
2,3,5,6 as part of a multi-modal pain control approach in order to improve postoperative pain 
control and limit opioid use,3 including the ERAS protocol that we currently use at our 
institution.3,6 
The data regarding perioperative use of gabapentin is mixed. In 2015, Doleman et al. 
published a systematic review and meta-analysis of 133 randomized controlled trials (RCTs) of 
peri-operative gabapentin (ranging from 300 mg to 1200 mg) versus placebo and found that 
gabapentin was associated with reduced opioid consumption and pain scores during the first 24 
hours after surgery.8 They also found that it was associated with decreased preoperative anxiety, 

decreased postoperative nausea and vomiting (PONV), and increased sedation.8 Notably most of 
the trials were in non-gynecologic surgery8 with only one of the trials looking at gabapentin in 
vaginal surgery9 and none of the trials looking specifically at urogynecologic surgery.8 In 2017, 
Hah et al. published a study showing that perioperative administration of gabapentin had no 
effect on postoperative pain resolution but it did have an effect of promoting opioid cessation 
after surgery.10 In 2020, Verret et al. published a meta-analysis of 281 randomized controlled 
trials studying the use of perioperative gabapentinoids in adult patients and they found no 
clinically significant analgesic effect for the perioperative use of gabapentinoids and a greater 
risk of the adverse events of dizziness and visual disturbance.11 In the minimally invasive 
gynecologic literature, the results of peri-operative gabapentin are also mixed: one randomized 
controlled trial (75 patients) found that preoperative gabapentin reduced postoperative pain and 
PONV in patients undergoing vaginal hysterectomy,9 while another randomized controlled trial 
(129 patients) found that preoperative gabapentin does not reduce total opioid use 24 hours after 
surgery in patients undergoing minimally invasive hysterectomy.12  
Adverse events are common in patients taking gabapentinoids for chronic pain.7 
Dizziness, somnolence, and gait disturbance are the most common side effects.7 When used 
perioperatively it has been shown to be associated with sedation,8 respiratory depression,13 
dizziness,11 and visual disturbance11. Elderly patients may be more susceptible to these 
gabapentin-related adverse effects.10 Notably, in December of 2019, the U.S. Food and Drug 
Administration issued a warning that serious breathing difficulties may occur in patients using 
gabapentin or pregabalin in patients with respiratory risk factors and is now requiring that 
warnings about the risk of respiratory depression be added to the prescribing information of 
gabapentinoids.14 
Pelvic organ prolapse (POP) is a common benign condition with peak incidence of 
symptomatic prolapse occurring in women in their 70s.15 In the United States, surgery for pelvic 
organ prolapse is very common,15 with vaginal apical suspension being one of the most common 
surgeries for pelvic organ prolapse.16 The data regarding perioperative gabapentin in surgery for 
pelvic organ prolapse is very limited. In 2018, Li et al. published a small RCT (47 patients total) 
comparing preoperative gabapentin to placebo in patients undergoing vaginal hysterectomy with 
concomitant pelvic reconstruction; they did not find a significant difference in opioid 
requirements in the first 24 hours after surgery between the two groups.17 Other than this small 
study, to the best of our knowledge, the effects of perioperative gabapentin in patients 
undergoing vaginal apical suspension for pelvic organ prolapse are not well established. Due to 
the unclear benefits in this surgical population and the potential adverse effects of 
gabapentin,7,8,11,13 especially considering that many of the patients receiving surgery for POP are 
elderly,15 we think it is important to compare preoperative gabapentin to placebo for patients 
undergoing vaginal apical suspension for pelvic organ prolapse. 
 
Research Methods 
 
 
Study Design: Double-blind randomized placebo-controlled clinical trial 
 
 
Setting: University of Iowa Hospitals and Clinics in Iowa City, IA, USA 
 
 
Study Subjects:  

Inclusion Criteria: All patients scheduled for a vaginal apical support procedure 
(sacrospinous ligament fixation or vaginal uterosacral ligament suspension), female, age 
18 or higher 
 
Exclusion criteria: (1) non-English speaking, (2) incarcerated, (3) cognitive 
impairment precluding informed consent, (3) chronic opioid users, (4) chronic 
gabapentinoid users, (5) subjects with contraindications to acetaminophen (allergy, 
severe liver disease), celecoxib (allergy, glomerular filtration rate<50, history of 
cardiovascular disease or coronary artery disease, history of peptic ulcer disease/GI 
bleeding), or gabapentinoids (allergy, glomerular filtration rate<50), (6) concurrent 
laparoscopic or abdominal surgery, (7) males 
 
 
Detailed Procedure 
Recruitment: Potential subjects will be recruited from all University of Iowa 
urogynecology clinics. All patients scheduled for a vaginal apical support procedure will 
be assessed for eligibility. Those that meet inclusion criteria and no exclusion criteria will 
be approached about study recruitment at least 7 days before their surgery either at the 
time of their original surgical consultation visit or preoperative clinic appointment. A 
study team member will discuss the study with the potential subject and review and sign 
informed consent. The subject will be considered enrolled at that time. Note that we will 
assess renal function (via a creatinine lab draw) as part of routine pre-operative 
evaluation in patients with risk factors for kidney disease (diabetes mellitus, heart 
disease, history of kidney disease, age>65 years old) in patients who have not had a 
creatinine drawn in the year preceding surgery. We will exclude patients from the study 
who have GFR <50. 
A paper screening log will be maintained by the primary investigator that will 
include date of screening, name, medical record number, screening result (i.e. enrolled, 
not eligible, declined, not asked), and reason for ineligibility. This paper log will be kept 
in a locked file cabinet in the locked office of the primary investigator. Identifying 
information will be removed from the screening log at the close of patient enrollment. 
 
Randomization, blinding, placebo compounding, and dispensing: NuCara 
Pharmacy will be providing the randomization (including allocation sequence), blinding, 
compounding, and dispensing services. Seven to fourteen days prior to an enrolled 
subject’s planned procedure, a prescription for the capsule will be written to the 
compounding pharmacy. The patient will be considered enrolled and randomized at this 
point. The pharmacy will randomize the subject to the intervention group (active 
gabapentin 300 mg, preoperative celecoxib 400 mg, and preoperative acetaminophen 975 
mg) or the control group (identical appearing gabapentin placebo, preoperative celecoxib 
400 mg, and preoperative acetaminophen 975 mg) in a 1:1 ratio with blocks of 6 and 
stratified by surgery type (SSLF or ULS) and surgeon. A commercially available 300 mg 
gabapentin capsule will be over-encapsulated in an opaque capsule to provide blinding. 
The placebo capsule will contain microcrystalline cellulose and be placed in a matching 
opaque capsule. The medication will be mailed to the University of Iowa Investigational 
Pharmacy with the patient’s identifying information and labeled as “active vs placebo.” 
Therefore subjects, investigators, statisticians, and all other clinical staff (nurses, 

anesthesiology team, etc.) will be blinded to placebo vs active medication. The 
University of Iowa investigational pharmacy will build the order for the research 
compound into the electronic medical record. Prior to the procedure, the compound will 
be brought from the investigational pharmacy to the preoperative area and dispensed to 
the patient within 2 hours prior to surgery along with preoperative acetaminophen 975 
mg PO and preoperative celecoxib 400 mg PO. Notably, we considered gabapentin 600 
mg as recommended by ACOG,18 but we were concerned about it potentially causing a 
decrease in same day discharges, especially since many of our patients are elderly. 
 
 
Intervention: After receiving the preoperative acetaminophen, celecoxib, and 
study drug (placebo or gabapentin corresponding to which study arm the patient is in), 
the patient will undergo the planned vaginal apical support procedure. All procedures will 
be performed by one of three fellowship-trained Female Pelvic Medicine and 
Reconstructive surgeons. Surgical management and intraoperative pain control will be at 
the discretion of the surgical and anesthesia teams. Postoperative pain control will be 
scheduled acetaminophen and scheduled NSAIDs (either ibuprofen or ketorolac) with 
breakthrough opioids as needed.  
 
Data Collection: Baseline patient characteristics, demographics, and relevant 
histories will be obtained through the electronic medical record and stored in a secure 
database. Pain scores will be collected in the PACU and second stage recovery area by 
nurses per standard protocol. Opioid use while in the hospital will be recorded. Amounts 
of opioids used will be converted to morphine milligram equivalents (MME) using the 
CMS conversion chart.19 
 
At 24 hours after surgery (starting when the patient leaves the operating room), 
the subject will be asked whether they experienced any dizziness, sedation, visual 
changes, nausea, or vomiting within the first 24 hours after surgery. They will also be 
asked if their pain control in the first 24 hours was adequate or inadequate. If the subject 
has already been discharged from the hospital, they will be called sometime between 24 
and 36 hours postoperatively and asked the above questions as well as the amount of 
opiates they took between leaving the hospital and 24 hours after surgery ended. This list 
of questions and a table that allows them to keep track of opiates taken will be given to 
them when they are consented for the study. 
 
Subjects will only be informed of their assigned group upon request following 
completion of the entire study. 
 
 
 
Outcomes  
 
Primary Outcome: Total postoperative opioid use in the first 24 hours postop 
measured in MME (starting when the patient leaves the operating room).  
 

Secondary Outcomes: Mean postoperative pain score while admitted using the 
validated numerical rating scale20 (0-10), postoperative opioid use while admitted (max 
of 24 hours) measured in morphine milliequivalents per hour (MMEs/hr), time to 
discharge, anti-emetic use, adverse events, patient reported adverse events of dizziness, 
sedation, visual changes, nausea, and vomiting in the first 24 hours after surgery, patient 
reported adequacy of pain control in the first 24 hours. 
 
Other Covariates: Relevant medical and surgical histories (including history of 
pelvic radiation, inflammatory bowel disease, diabetes mellitus, history of chronic pain, 
prior hysterectomy, prior POP surgery, current smoking status, recent HbA1c), relevant 
medications (including insulin, immunosuppression, vaginal estrogen, OAB 
medications/treatment, and alpha blockers), and baseline patient characteristics and 
demographics including age, race, parity, BMI, and current exam (including POP-Q, 
cough stress test, pelvic muscle exam, PVR, and the presence or absence of vaginal 
atrophy). We will also record the surgical details including the type of surgery, suture 
used, number of suspension sutures, laterality, other concomitant procedures done 
(including hysterectomy and other prolapse or incontinence procedures). 
 
 
Design, Sample Size, Analyses: 
 
 
 
Trial Design: The trial will be designed as a superiority trial.21 The hypothesis is 
that the treatment arm will be statistically significantly more effective at reducing 
postoperative opioid use than the control arm and the null hypothesis is that the treatment 
arm will not be statistically significantly more efficacious than the control arm. 
The study done my Mehr et al.,6 which was done at our institution showed that in 
the pre-ERAS group the total postoperative opioid use was an average of 31.6 MME with 
a standard deviation of 28.3. The average admission time was 27 hours which means 
average postoperative time is about 20 hours.6 Extrapolating from this the average MME 
use would be roughly 50 MME in 24 hours with a standard deviation of roughly 30. We 
believe that a clinically relevant reduction in MME use would be 30% which would be 35 
MME in 24 hours. Standard deviation for the post ERAS group was 13 but accounting for 
the decreased time in the hospital standard deviation would be closer to 20. Using these 
numbers (mean MME of 50 with a reduction to 35 and standard deviations of 30 and 20), 
and an alpha of 0.05 and a beta of 0.2 (power 80%), sample size is 46 per group which is 
a total of 92 subjects. Adding 20% for loss to follow up (cannot contact them 24 hours 
after) and cancellations after randomization is 110.  
Analyses: Baseline patient characteristics and relevant histories will be analyzed 
and compared between the control and treatment groups. Study results will be analyzed 
with appropriate statistical tests of student’s t-test for continuous variables and c2 or 
Fischer’s exact tests for categorical variables. A stratified analysis or linear regression 
will be completed in order to control for key variables such as concurrent hysterectomy if 
these variables are unequal following randomization. The study will be registered with 
clinicaltrials.gov and results will be reported in accordance with the CONSORT 
guidelines.  
Volume: We anticipate a volume of approximately 100 vaginal apical support 
procedures yearly. Based on enrollment rates in other ongoing studies at our institution 

(roughly 75%), this volume should allow us to meet our recruitment goal of 110 subjects 
within a 1.5 year period.  
 
 
Adverse Events and Data Safety Monitoring 
 
Adverse events are unwanted medical occurrences associated with the use of drugs in 
humans, whether or not they are considered related to the drug.22 The Clavien-Dindo 
classification of surgical complications is a standardized tool used to assess postoperative 
complications.23 Adverse events of Clavien-Dindo grade II or higher (see below) that occur 
during the study period will be recorded and reported.   
 
Grade I 
Any deviation from the normal postoperative course without the need for 
pharmacological treatment or surgical, endoscopic, and radiological 
interventions. Allowed therapeutic regimens are: drugs as antiemetics, 
antipyretics, analgetics, diuretics, electrolytes, and physiotherapy. This grade 
also includes wound infections opened at the bedside 
Grade II 
Requiring pharmacological treatment with drugs other than such allowed for 
grade I complications. Blood transfusions and total parenteral nutrition are also 
included. 
Grade III 
Requiring surgical, endoscopic or radiological intervention 
Grade IV 
Life-threatening complication (including CNS complications) requiring IC/ICU 
management 
Grade V 
Death of a patient  
 
According to the FDA, an adverse event or suspected adverse reaction is considered “serious” if 
in the view of the investigator it results in death, a life-threatening adverse event, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or 
substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect.22 Notably a suspected adverse reaction is any adverse event for which there 
is reasonable possibility that the drug caused the adverse event.22 
 
Members of the study team including PI and co-investigators will meet monthly to review data 
security, protocol deviations, recruitment, and adverse events. Any adverse event that is serious 
or unexpected (as defined by the FDA Code of Federal Regulations22) and possibly related to the 
administration of gabapentin will be reported to the IRB within 24 hours of learning of the event. 
Data security breaches, protocol deviations, adverse event data, and subject recruitment data will 
also be reported to the IRB as required. 
 
Ethics and Patient Consent 
 
This study will be approved by the University of Iowa Institutional Review Board (IRB). 
The study will be discussed in detail and informed consent reviewed with potential subjects prior 
to enrollment. 
 
Risks of this study include loss of confidentiality of protected health information (PHI). 
We will maintain records on a secure password protected local server (REDCAP) in-order-to 
minimize this risk. In addition, data forms will not contain any patient names or other personal 

information. Each form will contain only a unique subject identifier. Any paper data 
(deidentified) will be kept in a locked file cabinet in a locked office. 
Other risks of this study include the risks of taking a one-time dose of 300 mg 
gabapentin. Notably in 2019, the U.S. Food and Drug Administration issued a warning that 
serious breathing difficulties may occur in patients using gabapentin or pregabalin in patients 
with respiratory risk factors and is now requiring that warnings about the risk of respiratory 
depression be added to the prescribing information of gabapentinoids. Respiratory depression has 
not been reported with a one-time low dose (300 mg) of gabapentin. Other rare risks include gait 
disturbance, somnolence, dizziness, and sedation. 
As described above, there is conflicting data regarding the use of preoperative 
gabapentin, and therefore randomization to either the control arm or the treatment arm is 
currently within standard of care. Patients randomized to the gabapentin group potentially stand 
to benefit from better postoperative pain control and less postoperative opioid use. Patients 
randomized to the placebo group may potentially benefit from fewer medication side effects. 
 
 
Project Timeline/Schedule 
October  2022: IRB Submission  
December 2022: Begin enrollment 
July 2024: End enrollment 
December 2024: Data analysis and manuscript preparation 
 
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