Extended Release Local Anesthetic for Postsurgical Pain After Posterior Colporrhaphy and Perineorrhaphy: A Randomized Controlled Study
Phase: PHASE4
Conditions: Postoperative Pain
Sponsor: Wake Forest University Health Sciences

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Official Title: Extended Release Local Anesthetic for Postsurgical Pain After Posterior 
Colporrhaphy and Perineorrhaphy: A Randomized Controlled Study  
 
NCT number: 03875664 
 
Date of document: July 23, 2018 
 
Principal Investigator 
 
Sarah Evans, MD 
2001 Vail Avenue, Suite 360 
Charlotte, NC 28207 
609-408-1021 
 
Co-Investigators 
 
Megan Tarr, MD 
 
200 Medical Park Drive, Suite 250 
 
Concord, NC 28025 
 
704-403-6350 
 
 
Erinn Myers, MD 
 
2001 Vail Avenue, Suite 360 
 
Charlotte, NC 28207 
 
704-304-1160 
 
 
Bernard Taylor, MD 
 
200 Medical Park Drive, Suite 250 
 
Concord, NC 28025 
 
704-403-6350 
 
Kevin Stepp, MD 
 
2001 Vail Avenue, Suite 360 
 
Charlotte, NC 28207 
 
704-304-1160 
 
 
Dina Bastawros, MD 
 
2001 Vail Avenue, Suite 360 
 
Coharlotte, NC 28207 
 
STUDY OBJECTIVES 
 
Primary Objective  
 

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To evaluate the effect of intraoperative infiltration of liposomal bupivacaine at the time 
of posterior colporrhaphy and perineorrhaphy on postsurgical pain scores during the first 
72 hours after surgery as measured by visual analog scales (VAS).  
 
Secondary Objectives 
 
1. To evaluate total opioid consumption during the first 72 postoperative hours, 
measured in milligram morphine equivalents (MME). 
2. To evaluate patient satisfaction with postoperative analgesia as measured by Likert 
Scales. 
3. To evaluate median time to first opioid administration postoperatively. 
4. To evaluate hospital length of stay in hours. 
5. To evaluate length of stay in post-anesthesia care unit (PACU) in minutes.  
6. To evaluate total hospital costs. 
7. To evaluate time to first bowel movement postoperatively. 
8. To evaluate rate of postoperative nausea and vomiting by antiemetic requirements 
postoperatively.  
9. To evaluate time to successful voiding trial. 
10. To evaluate proportion of patients discharged home with a Foley catheter (i.e. failed 
voiding trials). 
 
BACKGROUND 
 
Liposomal bupivacaine (Exparel; Pacira Pharmaceuticals, San Diego, CA) is an extended 
release local anesthetic approved by the Food and Drug Administration since 2011 for 
the treatment of postsurgical pain1.  It is a multivesicular liposomal delivery system, 
consisting of a liquid bupivacaine core encapsulated by a phospholipid shell2. This 
delivery technology allows for the slow, sustained release of bupivacaine over at least 
72 hours compared to 7 hours with standard bupivacaine2,3 with plasma levels peaking 
between 24 and 48 hours2. Liposomal bupivacaine has been studied extensively in the 
general surgery and orthopedic surgery literature4,5. Specifically, infiltration of liposomal 
bupivacaine after excisional hemorrhoidectomy has been shown to significantly lower 
postsurgical pain scores, decrease total postoperative opioid consumption, increase the 
number of patients who do not require any opioids, meaningfully delay the median time 
to first opioid use, and improve patient satisfaction with overall perioperative 
analgesia6,7. In gynecologic surgery, transversus abdominis plane blocks with liposomal 
bupivacaine in patients undergoing robotic hysterectomy have demonstrated a greater 
than 50 percent reduction in total opioid use during the first 72 postsurgical hours, 
while decreasing maximum pain scores when compared to blocks with standard 
bupivacaine8. Studies investigating the use of liposomal bupivacaine in pelvic 
reconstructive surgery patients are lacking.  A randomized controlled trial involving over 
100 patients comparing infiltration of liposomal bupivacaine versus placebo after 
retropubic tension free vaginal tape midurethral sling placement revealed lower pain 
scores and reduced narcotic use during the first three postoperative days without an 

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increase in adverse events and with unaffected patient satisfaction3. As the female 
patient population ages, the number of women presenting for pelvic reconstructive 
surgery is estimated to increase by nearly 50 percent by the year 20509. In this setting, it 
becomes increasingly imperative to develop evidence-based perioperative care and 
analgesia regimens to help patients return to their baseline health and functional status 
after surgery. Posterior colporrhaphy and perineorrhaphy are pelvic reconstructive 
surgical procedures that are associated with significant postsurgical localized pain 
resulting from surgical incisions10. Similar to hemorrhoidectomy, this localized 
prolonged postsurgical pain seems particularly suited for the use of an extended release 
local anesthetic formulation.  Indeed, intraoperative infiltration of a standard local 
anesthetic during posterior repair and perineorrhaphy has been shown to improve early 
analgesia and facility early postoperative recovery - decreasing pain scores and the need 
for rescue-opioids during the first 4 hours after surgery, limiting the time spent in 
postsurgical recovery phase I, and accelerating the time to first ambulation after 
surgery11.These findings reiterate the need for studies investigating a slow-release, 
longer-acting local anesthetic formulation for patients undergoing posterior repair and 
perineorrhaphy.  One that ideally can be integrated into an evidence-based, opioid-
sparing postsurgical pain management regimen to improve perioperative care for the 
steadily growing pelvic reconstructive surgical patient population.  
 
STUDY DESIGN AND METHODS 
 
This is a randomized, placebo-controlled prospective trial offered to patients undergoing 
posterior colporrhaphy and/or perineorrhaphy for pelvic organ prolapse at our 
institution.  The study will be conducted at two clinical sites:  
1. Women’s Center for Pelvic Health (Mercy), Carolinas Health Care System, Charlotte, 
NC 
2. Women’s Center for Pelvic Health Northeast, Carolinas Health Care System, 
Concord, NC 
 
Human Subject Research and Informed Consent 
 
Each participant will be required to sign an Institutional Review Board (IRB) approved 
consent form prior to beginning any study-related interventions or assessments. The 
informed consent form will describe the study in detail. Additionally, the study consent 
form will disclose the planned uses of study data, as well as potential risks to the 
participants. Each prospective subject will have the objectives of the study explained to 
them prior to enrollment. The subject will be given an opportunity to ask questions and 
decide whether or not to participate. Copies of the signed informed consent form will be 
provided to the participants, and the originals will be stored with the research records for 
this study at the Mercy study center.  
 
Subjects have the right to: 
• Voluntarily participate in the study 

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• Withdraw or refuse participation in the study at any point without questioning 
• Understand the objectives of the study 
• Understand the risks and benefits of the study 
• Have their confidentiality maintained 
 
Participant Screening and Point of Enrollment 
Participants scheduled to undergo possible posterior repair and/or perineorrhaphy will be 
identified and screened against inclusion and exclusion criteria. If confirmed to meet the 
requirements for the study, they will be eligible to be invited to participate in the study.  
Participants will be consented for enrollment into the study by physicians, fellow 
physicians, nurse practitioners, physician’s assistants, and/or a research nurse prior to 
surgery. Participants will be randomized to one of the two treatment groups at the 
completion of the surgical procedure and prior to anesthesia reversal. 
Provider and Clinical Staff Training  
To ensure consistent infiltration technique, the principal investigator will provide in-
service education to all participating providers who will be performing surgery and 
incisional infiltration. Educational reviews will include medication pharmacology and 
specific infiltration protocol.  All clinical staff, including nursing and physicians, will 
receive in-service training about the study protocol and guidelines. 
Inclusion Criteria 
 
1. Females age 18 and greater 
2. Undergoing posterior repair and/or perineorrhaphy  
a. Concomitant surgical procedures allowed 
 
Exclusion Criteria  
 
1. Planned regional anesthesia 
2. Allergy or contraindication to bupivacaine 
a. Severe hepatic disease 
b. Pregnant/lactating  
3. Allergy or contraindication to opioids 
4. Allergy to contraindication to non-steroidal medications  
5. Non-English speaking 
6. Inability to provide consent/decisionally impaired  
7. Planned laparotomy 
8. Chronic pain diagnosis 
9. Chronic narcotic use (daily narcotic use for ³ 3 weeks before surgery) 
 
Study Withdrawal 

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Participants may withdraw from the study at any point in time. Documentation of the 
reason for withdrawal will be captured in the data collection forms. There will be no risk 
to participants that choose to withdraw from the study. 
Preoperative Period 
All consecutive patients planned to undergo posterior colporrhaphy and/or 
perineorrhaphy will be identified, screened, and approached for participation in the study.  
Concomitant pelvic reconstructive surgical procedures allowed.  Participants who do not 
meet the inclusion and exclusion criteria will be considered screen failures. Screen 
failures will be captured and the cause for screen failure will be documented.   
Perioperative and Surgery Period 
All participants will receive routine preoperative intravenous antibiotic prophylaxis based 
on standard hospital protocols.  All participants will receive standard of care induction 
and intraoperative analgesic medications as determined by anesthesia providers.  All 
patients will receive prophylactic antiemetic medications perioperatively as deemed 
necessary by anesthesia providers.  These medications will be documented in the 
patient’s medical record and available for chart review.  
Intervention: Eligible subjects will be randomized using a computer-generated 
randomization scheme, with patients assigned in a blinded 1:1 ratio, stratified by 
concurrent abdominal surgery, to either: 
Group 1: 20 mL liposomal bupivacaine expanded with 10 mL of injectable sterile 
normal saline solution (0.9%) for a total of 30 mL. 
Group 2: 30 mL of injectable sterile normal 0.9% saline solution (placebo). 
The allocation sequence will be in sealed, opaque envelopes. An envelope will be 
retrieved in the operating room.  The OR circulating nurse will assemble the appropriate 
intervention medication.  The envelope will then be disposed of while still in the 
operating room in a secure manner. 
Procedures will be performed by 4 fellowship trained, board-certified female pelvic 
reconstructive surgeons and 2 fellows in training.  Subjects will be positioned in dorsal 
lithotomy with the use of adjustable stirrups.  The patient will be prepped and draped as 
is standard of care at our institution, either for vaginal, or combined vaginal and 
abdominal surgery depending on planned concomitant surgery.  After surgical timeout, a 
Foley urinary catheter will be placed.  Concomitant procedures will be performed in the 
order that the surgeon deems necessary.  When attention is turned to the posterior repair 
and perineorrhaphy, as is standard of care in our institution, the posterior compartment 
vaginal epithelium and perineal body will be injected with 10 mL of a local anesthetic 
with epinephrine for tissue dissection and hemostasis prior to incision.  This local 
anesthetic may be diluted with normal saline to a final volume deemed appropriate by the 

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surgeon. All patients will receive the same amount of anesthetic in this dilution.  For 
purposes of this study, we will standardize all patients to receive  bupivacaine HCl with 
epinephrine prior to incision as bupivcaine HCl may be administered immediately before 
EXPAREL12 without affecting the sustained release of the study drug. The vaginal 
epithelium is then incised as far proximal as is indicated to correct the rectocele.  The 
vaginal epithelium is elevated and separated from the underlying connective tissue to 
expose the rectocele to the arcus tendineous rectovaginalis.  The endopelvic fascia is then 
plicated with a delayed absorbable barbed suture (2-0 V-Loc), a delayed absorbable non-
barbed suture (2-0 polydioxanone, PDS) or a polyglactin (Vicryl) suture in either a 
running or interrupted fashion.  The vaginal epithelium is trimmed as is deemed 
necessary by the surgeon.  The vaginal skin is closed with a 3-0 or 4-0 Vicryl or 
Monocryl suture down to the hymenal plate.  The bulbocavernosus and the transversus 
perineal muscles are reunited in the midline with inverted sutures of PDS or Vicryl.  The 
perineal epithelium is closed in a subcuticular fashion using 3-0 or 4-0 Vicryl or 
Monocryl suture. Knots are tied inside the hymeneal plane when possible to avoid pain 
caused by knots in the perineal body.  
At the completion of the procedure and prior to anesthesia reversal, the sequentially 
numbered opaque sealed envelope will be opened by the circulating nurse, revealing the 
study group allocation. The surgeons will proceed with infiltration of either liposomal 
bupivacaine (intervention) or normal saline (control) depending on randomization.  
Liposomal bupivacaine has an opaque white appearance that lessons with dilution but is 
still visible.  For this reason, surgeons injecting the study drug will not be blinded to 
allocation of study drug.  We feel this will not significantly impact our results as patients 
will remain blinded and study personnel collecting outcome data will also remain 
blinded.  Moreover, anesthesia will not observe the incision infiltration and will remain 
behind the patient drape. While the OR nursing and anesthesia team may see the 
difference in solution color, the subject and all other postoperative clinical staff (recovery 
nurses, floor nurses, and rounding physicians) will be blinded to study arm.  Furthermore, 
we anticipate collection of all data by the patient’s first postoperative visit, which is 
scheduled 1-2 weeks after surgery.  Therefore, data will be collected prior to patient 
receiving a bill for surgery so that if the bill is itemized to include the study drug, this 
will not interfere with study blinding.  
Intervention infiltration: Subjects randomized to liposomal bupivacaine group (Group 
1) will receive a single 20-mL dose of EXPAREL 266 mg expanded in volume with 10 
mL normal saline (0.9%) for a total volume of 30 mL, administered in a standardized 
manner in the vaginal skin and the perineal body.  This technique not only approximates 
what is currently standard of care of infiltration of local anesthetic for this procedure but 
was also the technique used in prior studies evaluating the efficacy of short acting local 
analgesia at the time of posterior repair and perineorrhaphy11.  Injections will be 
performed using a 1.5” 22-gauge needle, which is consistent with EXPAREL packaging 
insert use.  
Active control infiltration (placebo): Subjects randomized to the control group (Group 
2) will receive 30 mL of injectable preservative-free sterile normal saline (0.9%), 
administered in an identical fashion as described above.  A placebo was used to control 

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for anesthesia potentially induced from tissue distention3. Normal saline was chosen as 
placebo because pre-incisional bupivacaine HCl was injected, and we feel the addition of 
another common anesthetic would not likely add significant anesthesia compared to the 
pre-incisional bupivacaine.  This is a similar study design to a prior study evaluating the 
efficacy of liposomal bupivacaine at the time of retropubic midurethral sling placement3.   
Vaginal packing is placed at the conclusion of the procedure in the operating room at the 
surgeon’s discretion.  
Postoperative Period 
Following surgery patients receive a multimodal pain regimen, standardized by an order 
set.  This consists of ketorolac 15 or 30 mg every 4-6 hours; oxycodone with or without 
acetaminophen 5 mg/325 mg 1-2 pills every 4-6 hours as needed; or intravenous 
hydromorphone 0.5 mg or morphine 2 mg as needed if unable to tolerate oral 
medications.  Antiemetic medications will be administered as needed including 
ondansetron as first line, then metoclopramide if persistent nausea. These medications 
will all be documented in the patient’s medical record and available for chart review. 
 
Participants will undergo a postoperative retrograde fill voiding trial per our division’s 
standard protocol prior to discharge – on postoperative day zero for outpatient procedures 
or on the morning of postoperative day 1 for hospitalized participants. If vaginal packing 
was placed in the operating room, this is removed prior to voiding trial.  The bladder is 
backfilled with 300 mL sterile water and patients have 90 minutes to void.  Participants 
will pass the voiding trial if they void more than 200 mL with less than one-third post-
void residual based on ultrasound assessment of residual. If they fail, a 16 French Foley 
catheter will be reinserted.  All participants that fail the voiding trial will be discharged 
home with an indwelling Foley catheter. These participants will receive Foley 
maintenance education prior to discharge. They will be scheduled for a follow up voiding 
trial in the office in 1-5 days.  
 
Depending on concomitant surgical procedures performed, patients may be discharged on 
the same day of surgery or on the first postoperative day.  To be considered for discharge, 
patients must be able to ambulate independently, tolerate a diet, have adequate pain 
control with oral medications, and have had a voiding trial. Discharge criteria will not be 
altered by this study. 
 
All patients are discharged home with prescriptions for ibuprofen 600-800 mg every 6-8 
hours, oxycodone/acetaminophen 5mg/325 mg 1-2 pills every 4 hours as needed, and 
instructions to take Miralax, Colace, or another stool softener as needed.   
 
Patients are advised not to place anything inside the vagina and not to lift anything more 
than 10 lbs until their first postoperative visit. No other activity limitations are given.  
Week 2 Postoperative Visit (+/- 1 week): 

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Participants will be scheduled for a postoperative follow up visit, on average 1-2 weeks 
after surgery. They will be instructed to return their Patient Assessment Form including 
their pain medication diary, bowel movement diary, and VAS/NRS recordings at that 
visit.  Finally, they will complete a patient satisfaction questionnaire at this visit.  
Randomization: 
A Carolinas HealthCare System biostatistician will generate a randomization sequence 
using SAS Enterprise Guide 6.1 (SAS Institute Inc., Cary, NC, USA).  A permuted block 
randomization scheme will be used to assign patients in a 1:1 ratio to intervention or 
control.  Randomization will be stratified by presence or absence of concurrent 
abdominal surgery.  We feel this stratification of randomization sequence is necessary 
because we anticipate patients who undergo vaginal surgery alone versus vaginal and 
concurrent abdominal surgery experience a different quality and severity of postsurgical 
pain.  
The study will be blinded such that both study participants and investigators collecting 
postsurgical outcome data will be masked to treatment allocation and block size 
randomization.  The surgeon injecting the study drug will be unblinded.  The pharmacist 
and statistician will also not be blinded, and will have no contact with the patients.  
The commercial pharmacy will provide study medications - consisting of syringes 
containing either a 20-mL dose of EXPAREL 266 mg expanded in volume with 10 mL 
normal saline for a total volume of 30 mL or 30 mL of injectable normal saline solution 
(0.9%).  
The study medications will be released by the pharmacy to the operating room nurse.  At 
the completion of the procedure and prior to anesthesia reversal, the sequentially 
numbered opaque sealed envelope will be opened by the circulating nurse, revealing the 
study group allocation. 
DATA COLLECTION AND MANAGEMENT:  
Case report forms will be developed by the investigators.  Data will be collected 
prospectively per the schedule in Table 1. All study data will be recorded by research 
staff and securely maintained at the Mercy study site.  The data flow will consist of paper 
data collection for eligibility assessment, baseline data, randomization, intervention 
group, primary and secondary outcomes, adverse events, and protocol deviations.  
Data will be entered by study staff into REDCap database that will be stored on a secure 
server at Carolinas HealthCare System.  REDCap (Research Electronic Data Capture) is a 
secure, web-based application designed to support data capture for research studies, 
providing:  1) an intuitive interface for validated data entry; 2) audit trails for tracking 
data manipulation and export procedures; 3) automated export procedures for seamless 
data downloads to common statistical packages; and 4) procedures for importing data 
from external sources. [cite:  Harris PA, Thielke R, Payne J, Gonzalez N, Conde JG. 

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Research electronic data capture (REDCap) – a metadata-driven methodology and 
workflow process for providing translational research informatics support. J Biomed 
Inform. 2009 Apr;42(2):377-81.]  Data will be entered into REDCap within 30 business 
days of collection. 
Each patient will have a unique identification number to which only the principal and 
sub-investigators will have access. The data collection spreadsheet will not contain any 
patient identifiers and will be password protected. The master list that links the patients 
and their study identification number will be stored separately from the database. All 
collected information will be stored separately on a password protected hard drive. A 
back up copy of the file will be stored on a password protected hospital network 
drive.  All hard copies of study data will be stored in a locked cabinet in the office of the 
research nurse, which will also be locked. 
Table 1. Data Collection Schedule 
 
Prior to 
Surgery 
Surgery 
(Intraop) 
PACU 
(Immediately 
post-op) 
 
In Hospital 
Postoperative 
Period 
Postoperative 
Period After 
Discharge 
(£72 hours) 
2 Week 
Follow up 
30 day 
(Study 
Conclusion) 
Informed Consent 
X 
 
 
 
 
 
 
Medical History  
X 
 
 
 
 
 
 
Medication review  
X 
 
 
 
 
 
 
Other Demographics* 
X 
 
 
 
 
 
 
Surgery** 
 
X 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Pain scales (VAS, NRS) 
X 
 
X 
X 
X 
 
 
Total Inpatient 
Opioids (MME) 
 
X 
X 
X 
 
 
 
Pain medication diary 
 
 
 
 
X 
 
 
First opioid use (date, 
time) 
 
 
X 
X 
X 
 
 
First BM  
 
 
X 
X 
X 
 
 
Antiemetic use 
 
 
X 
X 
 
 
 
Failed voiding trial 
 
 
X 
X 
X 
X 
 
Adverse Events 
Screen 
 
 
 
 
 
X 
X 
Patient satisfaction 
(Likert) 
 
 
 
 
 
X 
 
Total Hospital Costs 
 
 
 
 
 
 
X 
*Other demographic data includes: Age, Race, Body Mass Index (BMI), American 
Society of Anesthesiologists (ASA) Physical Status classification score, Stage of 
posterior compartment prolapse (per pre-operative POP-Q exam), smoking status (packs 
per day), if sexually active (yes or no) 
**Surgery data includes: concurrent surgeries performed, type of suture used in posterior 
repair/perineorrhaphy, site specific versus midline repair, intraoperative morphine 

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equivalents received, if packing placed (yes/no), surgical duration (minutes), estimated 
blood loss 
Source of records to be reviewed:  
 
• Canopy EMR (electronic medical record) 
• Research nurse coordinator will identify charts to be reviewed based on addition of 
subject’s name and medical record number to a general data sheet 
• Patients will be discharged home with a Patient Assessment Form including a pain 
medication diary to complete for the first 3 postoperative days, a place to record 
bowel movements if this occurs during the first 3 postoperative days, and visual 
analog (VAS) and numerical rating scales (NRS) to record their pain intensity the 
evening of hospital discharge, as well as every morning and evening for the first 
three postoperative days.  
 
Confidentiality of data 
 
Electronic data will be stored to safe-guard confidentiality using a password protected 
computer.  Principal investigator, Co-investigator, Research Coordinator nurse, and 
statisticians will have access to harvested patient data.  Harvested patient data will be 
stored until final statistical analysis completed and manuscript accepted and published. 
 
OUTCOME MEASURES 
 
Primary Outcome Measure 
 
The primary outcome will be assessed using visual analog scales (VAS) as well as 
numerical rating scales (NRS) to describe the patient’s postsurgical pain intensity.  The 
VAS is a validated 100 mm scale with “no pain” on the left equating to 0 mm and “worst 
pain” on the right equating to 100 mm. Subjects are asked to draw a vertical line on the 
scale that corresponds to their level of pain.  The NRS is an 11-point scale with zero 
being “no pain” and ten being “worst pain”.  The VAS and NRS scores will be collected 
by blinded study personnel at multiple time points.  The initial scores will be collected 
prior to patient transfer from post anesthesia care unit (PACU), then on the evening of 
postoperative day 0, and in the mornings and evenings of postoperative days 1, 2 and 3 – 
regardless of if the patient is in the hospital or at home.  If the patient is in the hospital 
during these time points, their answers will be recorded by blinded study personnel.  If 
the patient has been discharged, they will fill out their scores in the Patient Assessment 
Form that will be given to them prior to hospital discharge.  A blinded research nurse or 
one of the study investigators will contact patients on the second postoperative day to 
remind patients to complete the Patient Assessment Form. We will also contact them 
prior to their postoperative appointment to remind them to return this to clinic.  The 
Patient Assessment Form will be explained to them at the time of study inclusion and 
again prior to hospital discharge.  See Figure 2.  
 
Secondary Outcome Measures 

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Patient satisfaction with pain control: This will be assessed using a Likert Scale. The 
Likert scale is a 5-point scale allowing patients to rate their overall level of satisfaction 
with pain control as “very unsatisfied”, “unsatisfied”, “neutral”, “satisfied”, and “very 
satisfied”. It will be collected at the patient’s 2-week postoperative visit.  If necessary, this 
can also be collected over the phone 2 weeks after surgery.  See Figure 5.  
 
Time to first opioid administration: This will be abstracted from the electronic medical 
record and recorded in minutes from the time patient arrives in the post anesthesia care unit 
(PACU) as measured by first vitals in PACU to the time of first opioid administration as 
recorded in the patient MAR.   
 
Total inpatient opioid administration: This will be abstracted from the electronic 
medical record and recorded in morphine milligram equivalents based on the MAR.  This 
calculation will include intraoperative morphine milligram equivalents, as well as all 
morphine equivalents received in the post anesthesia care unit and inpatient floor prior to 
hospital discharge.  
 
Medication diary: Patients will be given a medication diary to complete at home as part 
of their Patient Assessment Form described above.  Patients will be asked to record the 
date and time of all pain medications taken.  We will record total milligram morphine 
equivalents and milligram of NSAIDs consumed at home during each of the first 3 
postoperative days.  See Figure 3.  
 
Antiemetic requirements: This will be abstracted from the electronic medical record and 
recorded in total number of doses received as an inpatient.  
 
Hospital length of stay: The time from admission to discharge will be abstracted from the 
electronic medical record and recorded in hours. 
 
Time in PACU: This will be abstracted from the electronic medical record and recorded 
in minutes.  Admission to PACU will be the time of first vital signs in PACU.  Discharge 
from PACU will be time of transfer to inpatient floor or discharge home. 
 
First bowel movement: We will record the postoperative day during which the 
participant has her first bowel movement – as POD#0, 1, 2 or 3.  The first bowel 
movement will be patient-reported.  If the first bowel movement occurs during the 
patient’s hospitalization, this will be recorded by blinded study personnel.  Patients will 
record if bowel movements occur at home during the first 3 postoperative days after 
hospital discharge.  It is possible that patients will not yet have a bowel movement during 
this study time period. See figure 4.  
 
Failed Voiding Trial: This will be abstracted from the medical record (voiding trial passed 
– yes or no). We will also record the date of passed voiding trial to determine how many 
days postoperatively this occurs (up until the 1-2 week postoperative visit).  If the patient 

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is still not spontaneously voiding at the time of the 1-2 week postoperative visit we will 
record this as a voiding trial failure. 
 
Adverse events: Any adverse event related to drug administration will be reported. 
Adverse events not related to medication administration will not be collected. We will 
however collect information on if patients are re-admitted during the study time period 
(yes or no).  Please refer to section on Adverse Events for details of reportable criteria. 
 
Hospital Costs: We will record total direct and indirect hospital costs, including 
pharmacy costs for each patient in this study.  This data will come from Population 
Health department.  
 
STATISTACAL CONSIDERATIONS 
 
Statistical Methods 
 
The data will be analyzed as intent to treat.  Descriptive statistics for all variables will be 
calculated by study group (intervention v. control).  The primary analysis will compare 
VAS at different hours postoperatively between study groups using Student’s t test if 
normally distributed or the Wilcoxon rank sum test if not normally distributed.  
Secondary outcomes, demographics and other baseline variables will be compared 
between the two groups using the X2 test or Fisher’s exact test for categorical data, 
Student’s t test for normally distributed data, and the Wilcoxon rank sum test for ordinal 
data or continuous data that are not normally distributed.  Sensitivity analyses will be 
performed to assess how participants who withdrew affect the results.  SAS® Enterprise 
Guide 6.1 (SAS Institute, Cary, NC, USA) will be used for all analyses. A two-tailed p-
value of less than 0.05 will be considered statistically significant. 
 
Sample Size Calculation  
 
Based on prior studies and review of pain literature, a 20-30 mm difference on a 
continuous 100 mm VAS scale is considered clinically significant13,14,15.  To detect a 
20mm difference on VAS scores between groups, assuming a power of 80% with a 
standard deviation of 28 mm and an alpha of 0.05 for a two-tailed t test, it is 
determined that 32 subjects will be needed in each group for a total of 64 subjects.  SAS® 
Enterprise Guide 6.1 (SAS Institute Inc., Cary, NC, USA) was used to calculate sample 
size.   
 
Missing data may occur if subjects fail to return for follow-up. However, since study 
participants are undergoing surgery, they are more likely to return for their follow-up 
visits since these are a part of their standardized postoperative care. Therefore, this will 
decrease the rate of dropouts.  To account for a 10% drop-out rate, we will aim to enroll 
72 subjects with 36 in each group.  
 
STUDY DOCUMENTATION AND MONITORING  

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Site Documentation 
All study documents included in this protocol that will be presented to subjects will be 
submitted to the IRB for review. The Mercy site will maintain a study binder for all sites 
that will include the following:  
• Enrollment log of patients that have consented to be in the study 
(electronic version) 
• Protocol deviation log (electronic version) 
• Adverse event log (electronic version) 
• Investigator protocol and amendments 
• IRB submissions, modifications, and renewals 
• Data safety monitoring committee reports 
• IRB approved consent form 
• Data collection forms 
• Patient assessment forms 
Data Safety Monitoring 
The research coordinator will complete bimonthly reports detailing the study progress 
and subject status, any adverse events, and any protocol deviation.  The research 
coordinator will inform all study staff members of any unanticipated problems involving 
risks to study subjects or others.  The research coordinator will facilitate and participate 
in internal monitoring visits by staff of the Office of Clinical and Translational Research 
at Carolinas HealthCare System.  This will include a thorough review of research 
participant records, source documents, regulatory binders, and consent forms.  
The Principal Investigator will monitor the study and assess the need for amendments as 
the study progresses. The PI will review the progress of each subject on the study and 
will apprise the IRB of adverse events or unexpected problems that may influence the 
IRB’s decision to allow the trial to continue, in accordance with the IRB’s standard 
operating procedures and policies.  A protocol revision may be necessary for reasons 
including but not limited to rights, safety of participants, welfare of participants, and thus, 
an amendment will be required. Appropriate approvals (i.e., IRB) of the revised protocol 
must be obtained prior to implementation at each site.  
The biostatistical team will generate periodic reports to monitor screening, enrollment, 
completeness of data for intervention implementation and outcomes, adverse events, and 
protocol deviations. 
Data safety monitors will serve as an independent body to review the study data on a 
regular basis. The data safety monitors will include an external physician and an external 
research nurse. Data and safety monitoring responsibilities will consist of review of the 
research protocol and ongoing study activities, including review of data quality and 
completeness, review of fidelity to the study protocol, review of adequacy of participant 

14 
recruitment and retention, review of adverse events, and making recommendations to the 
study PI and to the IRB concerning trial continuation, modification, or conclusion.  Such 
monitoring helps to safeguard subject safety, ensure data quality, and provide ongoing 
training and support to ensure compliance.  The data safety monitors will first convene to 
approve the study protocol and determine the frequency of meetings.  After the first ten 
patients are enrolled and randomized, the study statisticians will generate a report for the 
data safety monitors to review.  Content and frequency of the reports will be agreed upon 
prior to implementation of the trial.  The PI (Sarah Evans, MD) will be responsible for 
ensuring that the study complies with the data safety monitors’ requests.  
Study Drug Information 
Medical Risks related to injection of local anesthetic, include but are not limited to, 
pain, bleeding, hematoma formation, infection, and/or lack of pain relief. In clinical trials, 
the most common adverse reactions (incidence ≥10%) following EXPAREL 
administration were nausea, constipation, and vomiting. Although these are common 
symptoms experienced by patients in the post-operative period, we will monitor for 
excessive reporting of these symptoms.  Non-bupivacaine-based local anesthetics, 
including lidocaine, may cause an immediate release of bupivacaine from EXPAREL if 
administered together locally. The administration of EXPAREL may follow the 
administration of lidocaine after a delay of 20 minutes or more.  Formulations of 
bupivacaine other than EXPAREL should not be administered within 96 hours following 
administration of EXPAREL. This is not applicable to our study, as we will be using 
bupivacaine HCl prior to EXPAREL and will not be using non-bupivacaine-based local 
anesthetics.  Although adverse effects with the use of EXPAREL are rare, more serious 
adverse reactions have been reported with the use of bupivacaine-containing products. 
There have been reports of adverse neurologic reactions with the use of local anesthetics. 
These include persistent anesthesia and paresthesias. CNS reactions are characterized by 
excitation and/or depression. Toxic blood concentrations depress cardiac conductivity 
and excitability which may lead to dysrhythmias sometimes leading to death. Allergic-
type reactions (e.g., anaphylaxis and angioedema) are rare and may occur as a result of 
hypersensitivity to the local anesthetic or to other formulation ingredients. The doses of 
medications in this study will be standardized and toxic doses of anesthetic therefore will 
be avoided to prevent the serious adverse reactions listed above.  
Medical Benefits related to injection of local anesthetic: Improved postoperative pain 
control, reduced narcotic pain medication use and its related side effects, improved 
postoperative ambulation, possible shorter hospital stay, greater patient satisfaction. 
Protocol Deviations 
Protocol deviations will be documented and logged on the Protocol Deviations log 
(electronic version). This will be done for every protocol related deviation related to any 
portion of the study timeline. Deviations will be reviewed and evaluated on an ongoing 
basis, and, as necessary, appropriate corrective and preventive actions (including 
notification, re-training, or discontinuation) will be put in place. 

15 
Data Safety Monitoring 
Data safety monitors will include an external physician and research nurse. They will be 
tasked to review all adverse events that occur. A semi-annual report of all adverse events 
will be generated and sent to the data safety monitors every 6 months. 
All Serious Adverse Events (SAEs) will be reported to the data safety monitors via email 
within 2 business days of site staff being informed of its occurrence. The PI and research 
nurse will be copied on all communications with the data safety monitors. Copies of de-
identified source documentation regarding the SAE will be included, as well as other 
clinically meaningful documentation. 
The PI (Evans) will be responsible for ensuring that the study complies with the data 
safety monitors’ requests. 
Reporting Adverse Events 
 
 
 
Adverse events (AE) will be recorded and reported per the criteria and timeline below.  
 
All AEs must be recorded and entered into the AE log and REDCap. An event number will 
be assigned by each site and recorded.  The DSMB will be tasked to review all adverse 
events that occur. A semi-annual report of all adverse events will be generated and sent to 
the DSMB every 6 months. 
 
All Serious Adverse Events (SAEs) will be reported to the DSMB via email within 2 
business days of site staff being informed of its occurrence. The PI and research nurse will 
be copied on all communications with the DSMB. Copies of de-identified source 
documentation regarding the SAE will be included, as well as other clinically meaningful 
documentation. 
 
Reportable AEs include those determined to be related to the study medication. AEs not 
related to the study medications will not be collected. Please note that underlying diseases 
are not reportable AEs unless there is an increase in severity or frequency during the 
course of the investigation. Death should not be recorded as an AE, but as an outcome of 
a specific SAE.  
 
Any participant that suffers an allergic reaction to the study medications will be 
unblinded. This will be a reported adverse event that will also be reported to the DSMB, 
as outlined above.  
 
Adverse Event Definitions 
 
Adverse Event: any untoward medical occurrence, unintended disease or injury, or any 
untoward clinical signs (including abnormal laboratory finding) in subjects, whether or 
not related to study medications 
 

16 
Serious Adverse Event: an adverse event that led to: 
• Death 
• Serious deterioration in the health of the subject that either resulted in 
o A life-threatening illness or injury 
o A permanent impairment of a body structure or a body function 
o Medical or surgical intervention to prevent life-threatening illness 
or injury or permanent impairment to a body structure or body 
function 
 
Unrelated: No evidence that the timing of the AE has a relationship to the time study 
medications were taken 
 
Possibly Related: The AE has a timely relationship to the study medications, however a 
potential alternative etiology may be responsible for the AE 
 
Probably Related: The AE has a timely relationship to the study medications and the 
causative relationship can clearly be established. No potential alternative etiology is 
apparent. 
 
Severity Definitions 
 
Mild: Awareness of signs or symptoms, but easily tolerated and are of minor irritant type 
causing no loss of time from normal activities. Symptoms do not require therapy or a 
medical evaluation; signs and symptoms are transient.  
 
Moderate: Events introduce a low level of inconvenience or concern to the participant 
and may interfere with daily activities, but are usually improved by simple therapeutic 
measures; moderate experiences may cause some interference with functioning.  
 
Severe: Events interrupt the participant’s normal daily activities and generally require 
systemic drug therapy or other treatment; they are usually incapacitating. 
 
REFERENCES: 
 
1. FDA Approved Drug Products. U.S. Food & Drug Administration. U.S. Department of 
Health and Human Services. 
https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&
ApplNo=022496. Accessed Oct 24, 2017. 
2. Candiotti K. Liposomal bupivacaine: an innovative nonopioid local analgesic for the 
management of postsurgical pain. Pharmacotherapy 2012;32(suppl9):19S-26S 
3. Mazloomdoost D, Pauls RN, Hennen EN, Yeung JY, Smith BC, Kleeman SD, Cristp CC. 
Liposomal bupivacaine decreases pain following retropubic sling placement: a 
randomized placebo-controlled trial. Am J Obstet Gynecol. 2017. 

17 
4. Hamilton TW, Athanassoglou V, Trivella M, Strickland LH, Mellon S, Murray D, Pandit 
HG. Liposomal bupivacaine peripheral nerve block for the management of postoperative 
pain (Review). Cochrane Database of Systematic Reviews. 2016. 8:CD011476. 
5. Hamilton TW, Athanassoglou V, Trivella M, Strickland LH, Mellon S, Murray D, Pandit 
HG. Liposomal bupivacaine infiltration at the surgical site for the management of 
postoperative pain. Cochrane Database of Systematic Reviews 2017. 2:CD011419. 
6. Haas E, Onel E, Miller H, Ragupathi M, White PF. A double-blind, randomized, 
activecontrolled study for post-hemorrhoidectomy pain management with liposome 
bupivacaine, a novel local analgesic formulation. Am Surg 2012;78:574-81. 
7. Gorfine SR, Onel E, Patou G, Krivokapic ZV. Bupivacaine extended-release liposome 
injection for prolonged postsurgical analgesia in patients undergoing 
hemorrhoidectomy: a multicenter, randomized, double-blind, placebo- controlled trial. 
Dis Colon Rectum 2011;54:1552-9. 
8. Hutchins J, Delaney D, Vogel RI, Ghebre RG, Downs LS, Carson L, Mullany S, Teoh D, 
Geller M. Ultrasound guided subcostal transversus abdominis plane (TAP) infiltration 
with liposomal bupivacaine for patients undergoing robotic assisted hysterectomy: A 
prospective randomized controlled study. Gynecol Oncol. 2015; 138(3):609-613.  
9. Wu JM, Kawasaki A, Hundley AF, Dieter AA, Myers ER, Sung VW. Predicting the number 
of women who will undergo incontinence and prolapse surgery, 2010 to 2050. Am J 
Obstet Gynecol 2011;205:230. 
10. Muir TW. Surgical Treatment of Rectocele and Perineal Defects. Walters MD, Karram 
MM. Urogynecology and Reconstructive Pelvic Surgery, Fourth Edition. Chapter 24, pp 
342-359. Elsevier Inc. 2015. 
11. Kristensen BB, Rasmussen YH, Agerlin M, Topp MW, Weincke MO, Kehlet H. Local 
infiltration analgesia in urogenital prolapse surgery: a prospective, randomized, double-
blind, placebo-controlled study. Acta Obstet Gynecol Scand. 2011; 90(10):1121-5.  
12. Toxicity thresholds for bupivacaine HCl. Pacira Pharmaceuticals, Inc. 
https://www.exparel.com/hcp/pharmacokinetics. Accessed Oct 24, 2017. 
13. Jensen MP, Chen C, Brugger AM (2003) Interpretation of visual analog scale ratings and 
change scores: a reanalysis of two clinical trials of postoperative pain. J Pain 4(7):407–
414 
14. Lee JS, Hobden E, Stiell IG, Wells GA (2003) Clinically important change in the visual 
analog scale after adequate pain control. Acad Emerg Med 10(10):1128–1130 
15. Dunivan GC, Parnell BA, Connolly A, Jannelli ML, Horton BJ, Geller EJ. Bupivacaine 
injection during mid urethral sling and postoperative pain: a randomized controlled trial. 
Int Urogynecol J 2011;22:433-8. 
16. Schulz K, Altman D, Moher D. CONSORT 2010 Statement: updated guidelines for 
reporting parallel group randomized trials. Ann Intern Med 2010;152:726-32. 
 
 
 

18 
FIGURE 1. Study Trial Flow16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Inpatient data collection by study personnel: 
• Visual analog scales (VAS) and Numerical rating scales (NRS) prior to patient discharge 
from PACU 
• VAS and NRS on evening of POD#0 and mornings and evenings of POD#1-3 if patient still 
admitted to hospital 
• Date and time of first bowel movement if this occurs while patient in the hospital 
• Date and time of first unassisted ambulation prior to hospital discharge 
 
**Patient Assessment Form: 
Assessed for eligibility and 
Consented 
Excluded  
¨   Not meeting inclusion criteria 
¨   Declined to participate  
¨   Other reasons  
Patient returns for 1st post-op visit 1-2 weeks later: returns Patient Assessment Form, completes satisfaction survey 
Total hospital costs calculated 
Chart review for remaining outcome data completed 
Inpatient data collection by blinded study personnel* 
After hospital discharge: participants complete Patient Assessment Form** for first 3 postoperative days 
Study personnel contact participants to remind them to complete Patient Assessment Form 
Allocated to intervention: liposomal bupivacaine 
¨ Received allocated intervention  
¨ Did not receive allocated intervention (give 
reasons) 
Allocated to placebo: normal saline 
¨ Received allocated intervention  
¨ Did not receive allocated intervention (give 
reasons)  
Allocation 
Analysis 
Follow-Up 
Randomized in OR 
Enrollment 

19 
• VAS and NRS for evening of POD#0, mornings and evenings of POD#1-3 (7 total) à 
Figure 2 
• Pain medication diary for POD#0-3 à Figure 3 
• Bowel movement diary for POD#0-3 à Figure 4 
 
Figure 2.  Visual Analog Scale (VAS) and Numerical Rating Scale (NRS) with example3 
 
 QUESTION 1:  
Please make a vertical mark on the line below that corresponds to your level of vaginal 
pain or discomfort now:  
                                                                                                           
 
 
 
 
QUESTION 2: 
Please circle the number that corresponds to your level of vaginal pain or discomfort now:    
      
 
 
 
 
 
 
 
No pain or 
discomfort 
Most pain or 
discomfort 
No pain or 
discomfort 
Worst 
possible pain 
or discomfort 
Moderate 
pain or 
discomfort 

20 
 
Figure 3. Medication Diary: Write down when you take pain medications and/or stool 
softeners today. The first line is an example. . 
 
Time 
Medication  
# of pills/tablets 
9 AM 
Motrin 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 4. Bowel Movement Diary – will be printed below pain medication diary for each 
postoperative day 
 
Did you have a bowel movement today? (circle one):   yes    no 
 
Figure 5. Likert Scale for patient satisfaction with postoperative analgesia 
 
 
Overall, how satisfied were you with your pain control after surgery? 
1
 Very unsatisfied 
2
 Unsatisfied 
3
 Neutral 
4
 Satisfied 
5
 Very satisfied 
 
How satisfied were you with your overall surgical experience? 
1
 Very unsatisfied 
2
 Unsatisfied 
3
 Neutral 
4
 Satisfied 
5
 Very satisfied 
 

21 
How would you rate this surgical experience compared to prior surgical experiences? 
1
 Very unsatisfied 
2
 Unsatisfied 
3
 Neutral, N/A 
4
 Satisfied 
5
 Very satisfied 
 
Figure 6. Additional Data to be Collected by Chart Review  
• Age 
• Race 
• Body Mass Index 
• Smoking status – yes, no 
• American Society of Anesthesiology (ASA) score 
• Sexually active – yes, no 
• Past medical history of anxiety or depression – yes, no 
• Past surgical history of prior pelvic reconstructive surgical procedures – yes, no  
• Mean number of medications preoperatively 
• Chronic narcotic use (daily narcotic use for >3 weeks prior to surgery) – yes, no  
• Stage of posterior pelvic organ prolapse on preoperative POP-Q (1, 2 or 3) 
• Procedure duration, minutes 
• Concurrent procedures performed 
• Site specific repair (if no then presume midline) – yes, no  
• Type of suture used 
• Packing placed – yes, no  
• Hospital admission time 
• Hospital discharge time 
• PACU admission time (time of first PACU vitals) 
• PACU transfer time (either to home or inpatient floor) 
• Total opioid consumption in milligram morphine equivalents 
o Intraoperative 
o PACU 
o Inpatient floor 
• Date and time of first opioid administration postoperatively 
• Number of doses of anti-emetics given postoperatively  
• Discharges home with Foley catheter (i.e. failed voiding trial) 
• Date and time of successful voiding trial 
• Total direct and indirect hospital costs 
• Total pharmacy costs 
• Adverse events