Clinical trial NCT03907033
Conditions: Vaginal Hysterectomy
Sponsor: Mayo Clinic
Start date: 2019-09-03; Completion date: 2021-07-23
Enrollment: 28 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The aim of this study is to compare the effects of preemptive analgesia using liposomal bupivacaine mixed with bupivacaine HCl, versus bupivacaine HCl alone for uterosacral ligament injection in patients undergoing vaginal hysterectomy. We hypothesize that the group receiving a combination of liposomal bupivacaine and bupivacaine HCl will report superior postoperative pain management. Enhancement in pain control should confer a decrease in opioid and other analgesic medication requirements, which may contribute to decreased nausea, vomiting, and higher overall patient satisfaction with pain control.

Detailed description:
Prior to surgery, patients are assigned by chance (like a coin toss) to receive either the bupivacaine HCl injection at the time of surgery or bupivacaine HCl plus liposomal bupivacaine. Patients and the Principal Investigator cannot choose the study group. Patients will have a 50% chance of being assigned to either group; however, regardless of which group they are assigned to, the medical record will show that they received liposomal bupivacaine. The injections will be given in the vaginal area when the patient is under anesthesia.

After surgery, patients will be asked to record their pain, medication use, pain scores and symptoms in a diary for each 12 hour interval up to 72 hours. Someone will also call twice a day during the 72 hours after surgery to ask about pain level and pain medication use.

Patients will also receive a phone call 7-10 days after the surgery to ask about their recovery and pain level.

Arms: arm 1: Patients in the control group will receive 0.25% bupivacaine hydrochloride (bupivacaine HCl). 10cc will be injected bilaterally into each uterosacral ligament prior to the colpotomy incision. After entry into the posterior cul-de-sac, an additional 10cc of will be injected bilaterally into the deeper uterosacral ligaments. arm 2: Patients in the study group will receive a mixture of 0.5% bupivacaine HCl and liposomal bupivacaine in 1:1 ratio. 10cc of the mixture will be injected bilaterally into each uterosacral ligament prior to the colpotomy incision. After entry into the posterior cul-de-sac, an additional 10cc will be injected bilaterally into the deeper uterosacral ligaments
Interventions: intervention 1: Liposomal bupivacaine intervention 2: Bupivacaine Hydrochloride
Intervention descriptions: intervention 1: Liposomal bupivacaine is a novel formulation of local bupivacaine and allows prolonged release of the medication, thereby providing longer lasting effects. It is approved by the FDA and has been shown to provide excellent pain control after surgery. intervention 2: We currently administer local plain bupivacaine during vaginal hysterectomy to decrease pain in the postoperative period. Bupivacaine is an anesthetic that works by blocking nerve conduction and producing a numbing effect.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Preemptive Local Analgesia 
with Liposomal Bupivacaine in 
Vaginal Hysterectomy: A 
Randomized Controlled Study 
 
NCT03907033 
 
September 27, 2019 


IRB #15-008413 – UPDATED Sept. 27, 2019 
Page 1 
 
Preemptive local analgesia with liposomal bupivacaine in vaginal hysterectomy: A 
randomized, blinded, controlled study 
 
 
 
Jeffrey L. Cornella, MD 
Principal Investigator 
April 25, 2018 
 
REVISED:   November 27, 2018 
May 2, 2019 
September 27, 2019 
 
 
 
 
 
 
Megan Wasson, DO 
Kristina Butler, MD 
Johnny Yi, MD 
Gynecology 
 
 
David Rosenfeld, MD 
Molly Kraus, MD 
Anesthesiology 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Page 2 
 
INTRODUCTION 
Reduction in immediate postsurgical pain is important as it results in less opioid requirements 
and fewer opioid-related adverse events such as central nervous system and respiratory 
depression, nausea, vomiting, ileus, and pruritus. Decreased postoperative pain may also result in 
shorter recovery room and hospital stays, and higher patient satisfaction.   
 
Preemptive analgesia in form of uterosacral ligament injection has been shown to be effective for 
patients undergoing vaginal hysterectomy. Injection of bupivacaine into the uterosacral 
ligaments has been associated with significantly reduced pain scores in the first three hours after 
surgery as well as lower total narcotic use within the first 24 hours following surgery (1). 
Preemptive analgesia with bupivacaine during vaginal hysterectomy is standard practice at our 
institution as part of a multi-modal pain management platform.  
 
Liposomal bupivacaine is a novel formation of local bupivacaine designed to provide prolonged 
postsurgical analgesia.  The drug is encapsulated in multivesicular liposomes, thereby allowing 
prolonged drug release for up to 72 hours. Its safety and side effect profile is similar to 
bupivacaine HCl and normal saline (2). In 2011, the FDA approved of its use for single-dose 
local administration into surgical sites.  
 
The efficacy of liposomal bupivacaine has been demonstrated in orthopedic procedures, hernia 
repairs, hemorrhoidectomy, and breast augmentation. When compared to bupivacaine HCl, 
studies suggest liposomal bupivacaine may be more efficacious in terms of lower pain scores, 
longer time to first rescue opioid dose, decreased total opioid consumption postoperatively, and 
shorter length of hospital stays (3).  
 
There are few studies evaluating liposomal bupivacaine in gynecologic surgery.  Hutchins et al 
demonstrated that patients who received transversus abdominis plane (TAP) blocks with 
liposomal bupivacaine required 50% less total opioid during the first 72 hours following robotic 
assisted hysterectomy than patients who received bupivacaine (4). While liposomal bupivacaine 
is promising for management of postoperative pain, it has not yet been studied in vaginal 
surgery.  
 
The aim of this study is to compare the effects of preemptive analgesia using liposomal 
bupivacaine mixed with bupivacaine HCl, versus bupivacaine HCl alone for uterosacral ligament 
injection in patients undergoing vaginal hysterectomy. We hypothesize that the group receiving a 
combination of liposomal bupivacaine and bupivacaine HCl will report superior postoperative 
pain management. Enhancement in pain control should confer a decrease in opioid and other 
analgesic medication requirements, which may contribute to decreased nausea, vomiting, and 
higher overall patient satisfaction with pain control. 
 


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Page 3 
 
OBJECTIVES 
The primary aim of this study is to compare total post-surgical analgesic medication use in the 
first 72 hours following surgery completion (all opioids in IV morphine equivalents and total mg 
use of ibuprofen and/or acetaminophen combined).   
 
Secondary outcome measures include mean PACU VAS (0-10) pain score, VAS pain score at 
24, 48, and 72 hours post-surgery completion, nausea and emesis at 24, 48, and 72 hours post-
surgery completion, urinary retention, and patient satisfaction with pain management at 72 hours 
and 7-10 days post op. 
 
 
DESIGN 
This is a prospective randomized, blinded, controlled clinical trial.   
 
 
STUDY MEDICATION 
Liposomal bupivacaine is being used per FDA indication (postsurgical analgesia) at an approved 
dose and route of administration (surgical site infiltration). It is also being given within the FDA 
labeled doses of the bupivacaine HCl given concomitantly, which recommends mg dose of 
bupivacaine HCl to liposomal not to exceed 1:2.  Safety and efficacy of concomitant use has 
been prospectively studied (5). This study does not intend to pursue change to labeling or 
advertising. This study will be carried out in accordance with the applicable United States 
government regulations and Mayo Clinic research policies and procedures. 
 
 
PARTICIPANTS 
We plan to enroll women 18-85 years old who will be undergoing outpatient vaginal 
hysterectomy with or without concurrent prolapse repair surgeries at the Mayo Clinic Hospital in 
Arizona. Participants will be recruited during the preoperative visit and consented with a written 
form.  
 
Exclusion criteria will include:  
• Known history of hepatic disease evidenced by AST or ALT greater than normal values 
• Known history of renal disease evidenced by serum Cr greater than normal values 
• Known history of prolonged QT (QTc > than 500 m/s) 
• Opiate tolerance noted by daily use of greater than 20 mg morphine daily oral equivalents 
per day for minimum one month prior to surgery    
• Allergy or contraindication to amide local anesthetics, celecoxib, ketorolac, NSAIDS, 
acetaminophen, gabapentin, sulfa drugs, or ondansetron.  Patients allergic to both 
oxycodone and hydromorphone 


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• Patients with acute GI bleed in < 6 months of study  
• Adults lacking capacity to consent 
   
 
MATERIALS AND METHODS  
 
Randomization and Blinding: 
 
Redcap software will generate a randomization list in one-to-one ratio to assign patients to either 
the study group (receiving both liposomal bupivacaine and bupivacaine HCl) or control group 
(receiving bupivacaine only). All subjects will be recruited and assigned according to their 
priority at admission. The pharmacist will use this randomization list and dispense the 
medication sequentially. Patients, care team in recovery, study team members collecting and 
recording data, and statisticians will be blinded to randomization assignment. The surgical team 
and pharmacy will be un-blinded. All patients will be documented in EMR as receiving 
liposomal bupivacaine to ensure the blind is maintained and to ensure that safety features in the 
EMR for all patients receiving liposomal bupivacaine are activated. 
 
 
TREATMENT GROUPS 
Patients in both groups will be given a total volume of 40ml and dose of 100 mg plain 
bupivacaine: 
 
• Patients in the study group will receive a mixture of 0.5% bupivacaine HCl and liposomal 
bupivacaine in 1:1 ratio. 10cc of the mixture will be injected bilaterally into each 
uterosacral ligament prior to the colpotomy incision. After entry into the posterior cul-de-
sac, an additional 10cc will be injected bilaterally into the deeper uterosacral ligaments 
(diagram attached as appendix 3).  
 
• Patients in the control group will receive 0.25% bupivacaine HCl. 10cc will be injected 
bilaterally into each uterosacral ligament prior to the colpotomy incision. After entry into 
the posterior cul-de-sac, an additional 10cc of will be injected bilaterally into the deeper 
uterosacral ligaments. 
 
We plan to standardize preoperative medication, intraoperative anesthetic regimen, medication, 
administration in the recovery area, and discharge medication treatment (see appendix 1). Care 
will include key elements of a validated enhanced recovery protocol (6). 
 
 
 


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DATA COLLECTION 
Demographic data including age, BMI, medical and surgical history, indication for surgery, and 
degree and type of pelvic organ prolapse will be collected.  
 
Intraoperative fentanyl use will be recorded from the anesthesia record.  Immediate postoperative 
opioid use will be retrieved from the EMR until discharge from PACU.  Immediate nausea and 
emesis will be determined by total dose of antiemetics in PACU.  Urinary retention will be 
determined as post void residual greater than 200 ml on catheterization or bladder scan.  Patients 
will be offered PO opioid analgesics as first line therapy in PACU.  Number and percentage of 
patients receiving intravenous opioids as second line therapy, thus failing PO as first line therapy 
in PACU will be recorded; however they will remain in the study. 
 
Other intraoperative and immediate postoperative data will include completed procedure, surgery 
time, estimated blood loss, final pathology, and presence of failed voiding trial, length of stay in 
recovery, and numbers and reason for any unplanned admissions.  Unplanned admission 
patients’ data will be excluded and be recorded as a treatment failure.   
 
All patients will be discharged home with a diary to record analgesic use, VAS pain scores, and 
presence of nausea and emesis through 72 hours post-surgery (POD 3).  Opioid use will be 
documented as total tablets of 5 mg oxycodone, hydromorphone 2mg, and non-opioid 
medication use as total tablets of acetaminophen 500 mg and/or ibuprofen 600 mg. VAS (0-10) 
pain scores will be logged at 6 hour intervals.  Nausea and emesis will be documented as how 
many times patients felt nauseated, how many times they vomited, and total tablets of anti-
emetic. Patients will be emailed twice a day with a link to record their documented scores. Those 
who prefer not to complete the surveys electronically will have the option to complete the paper 
questionnaire and diary. Those choosing the paper option will receive a daily phone call from 
study personnel blinded to study groups to remind them to complete their diary and 
questionnaire. Patient satisfaction for pain control will be assessed as a 0-10 scale question at the 
72 hour mark and again at 7 to 10 days postop via telephone.  
 
Allergic reaction to liposomal bupivacaine and local anesthesia toxicity will be assessed 
immediately on presentation to PACU, prior to discharge, and assessed by telephone and 
documented up to the 7 to 10th post-operative day.  All doses of liposomal bupivacaine are within 
manufacturer labeling, and this is an FDA “on label” use of the drug (surgical site tissue 
infiltration). Concomitant bupivacaine HCl with liposomal bupivacaine doses are within 
manufacturer “on label” recommended ratio of 1:2.  Intralipid 20% for local anesthetic toxicity 
treatment will be immediately available at all times prior to discharge.  All data will be entered 
into HIPAA-compliant REDCap software. 
 
 


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SAMPLE SIZE 
We plan to enroll and randomize 104 patients with the goal of obtaining complete data on at least 
96 (47 per group) assuming a 10% loss to follow up. With a sample of 96, we achieve 80% 
power to detect a 30% difference in total opioid use at the 72 hour mark corresponding to an 
effect size of 0.6 at an alpha 0.05. 
 
 
DATA ANALYSIS 
Statistical summary descriptives such as mean, median, standard deviation, first quartile, third 
quartile and range for quantitative data, and frequency and proportions for categorical data will 
be provided. The objectives of the study comprise the group comparisons between combination 
liposomal bupivacaine/bupivacaine HCl vs. bupivacaine HCl only for total opioid use in 
morphine equivalents, total non-opioid use, VAS pain scores, episodes of emesis, total 
antiemetic use, and patient satisfaction. The normality assumptions will be checked and the 
appropriate parametric tests such as the two independent sample t-test or non-parametric tests 
such as the Wilcoxon rank sum test will be used. Group associations with categorical variables 
will be tested using the Chi-square or Fishers’ exact test. The significance level is at 0.05. 
 
 
SAFETY MONITORING 
All patients will be continuously monitored for local anesthetic toxicity or other reaction to 
liposomal bupivacaine for the entire surgical scope of care.  During surgery standard ASA 
monitors will be in place and in recovery vital signs every 15 minutes with continuous telemetry 
and pulse ox, with a minimum 2:1 RN monitoring.  They will remain in recovery a minimum of 
4 hours post op.  Continuous surveillance for medication reaction or local anesthetic toxicity 
including but not limited to tinnitus, perioral numbness, mental status changes, cardiac 
arrhythmia, respiratory compromise, rash, or hives.  20% intralipid for treatment of toxicity will 
be available at all times.  Patients will also be discharged with specific education regarding signs 
and symptoms for local anesthetic toxicity and instructions to call the on call physician with mild 
symptoms and present to the ED if moderate or severe symptoms.   
 
 
ADVERSE EVENTS 
The investigator/study team will report to the Mayo IRB any UPIRTSOs and Non-UPIRTSOs 
according to the Mayo IRB Policy and Procedures. 
An adverse event is defined as an untoward or undesirable experience associated with the use of 
a medical product (i.e. drug, device, biologic) in a patient or research subject. All adverse events 
that are considered related to the direct use of liposomal bupivacaine will be defined, collected, 
and reported. 


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Page 7 
 
The principal investigator will be responsible for determining whether an event is related to the 
direct use of liposomal bupivacaine. An AE will be considered unexpected if the nature, severity, 
or frequency of the event is not consistent with the risk information previously described for the 
standard of care procedure or in the package insert for liposomal bupivacaine. 
All study-related AEs will be followed until stabilization or resolution. 
 
ADVERSE EVENT REPORTING PERIOD 
For this study, the study treatment follow-up period is defined as 7-10 days after the procedure 
when they are contacted by the study team.  
 
MEDICAL MONITORING 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her 
site.  This safety monitoring will include careful assessment and appropriate reporting of adverse 
events as noted above, as well as the construction and implementation of a site data and safety-
monitoring plan   Medical monitoring will include a regular assessment of the number and type 
of serious adverse events. 
 
FUNDING 
Pacira Pharmaceuticals, Inc. is funding the study.  Pacira Pharmaceuticals, Inc. will pay the 
institution to cover costs related to running the study; however, they will have no role in 
randomization, patient care, assessment of data, or development of conclusions. Attempts will be 
made to publish the results independent of outcome, even for a negative study.  
 
REFERENCES  
 
1. Long JB, Eiland RJ, Hentz JG, et al. Randomized trial of preemptive local analgesia in 
vaginal surgery. Int Urogynecol J. 2008; 20(1):5-10 
 
2. Ilfled BM, Biscusi ER, Hadzic A, et al. Safety and side effect profile of liposome 
bupivacaine (Exparel) in peripheral nerve blocks. Regional Anesthesia and Pain 
Medicine. 2015; 40 (5):572-582 
 
3. Bergese SD, Ramamoorthy S. Efficacy profile of liposome bupivacaine, a novel 
formation of bupivacaine for postsurgical analgesia. Journal of Pain Research. 2012; 
5:107-116 
 


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Page 8 
 
4.  Hutchins J, Delaney D, Isaksson Vogel R, et al. Ultrasound guided transversus 
abdominis plane (TAP) infiltration with liposomal bupivacaine for patients undergoing 
robotic assisted hysterectomy: A prospective randomized controlled study. Gynecologic 
Oncology. 2015; 138:609-613. 
 
5.   Mont MA, Beaver WB, Dysart SH, et al.  Local infiltration analgesia with liposomal 
bupivacaine improves pain scores and reduces opioid use after total knee arthroplasty: 
results of a randomized controlled trial.  The Journal of Athroplasty.  2018; 33:90-96 
 
6.   Kalogera E, Bakkum-Gamez JN, Jankowski CJ, et al.  Enhanced recovery in 
gynecologic surgery.  Obstet Gynecol. 2015; 122(2 0 1): 319–328. 
 
 
APPENDIX I 
 
DATA COLLECTION  
 
I. 
Demographic data 
a. Age/date of birth 
b. BMI 
 
II. 
Preoperative data 
a. Indication for surgery 
b. Medical history 
c. Surgical history 
 
III. 
Operative data 
a. Surgery performed 
b. Operative time  
c. Pathologic diagnosis 
d. Total fentanyl dose in mcg during surgery 
e. Complications during surgery; anesthetic and surgical 
 
IV. 
Immediate postoperative data (PACU until discharge) 
a. Total opioid use in mg morphine IV equivalents 
b. Antiemetic use as total doses IV antiemetics 
c. VAS pain scores: cumulative in PACU until discharge 
d. Urinary retention: determined as post void residual greater than 200 ml on 
catheterization or bladder scan.   
 


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V. 
Postoperative data to 72 hour (POD 3) 
a. Total opioid use in mg morphine IV equivalents 
b. Non-opioid medication use in total tablets of 600 mg ibuprofen and 500 mg 
acetaminophen 
c. VAS pain scores: mean of cumulative in PACU until discharge, day of discharge 
at home, 24 hours (POD 1), 48 hours (POD 2), 72 hours (POD 3).  Home VAS 
scores will be mean of 6 hour intervals each day 
d. Times patients felt nauseated: day of discharge at home, 24 hours (POD 1), 48 
hours (POD 2), 72 hours (POD 3).   
e. Episodes of emesis: day of discharge at home, 24 hours (POD 1), 48 hours (POD 
2), 72 hours (POD 3).   
f. Antiemetic medication use: day of discharge at home, 24 hours (POD 1), 48 hours 
(POD 2), 72 hours (POD 3).    
g. Indication for admission (if applicable) 
h. Patient satisfaction with postoperative pain control (0-10; 0=unsatisfied, 10=very 
satisfied) 
i. 72 hours  
ii. 7-10 days post op 
 
 
ANESTHESIA PROTOCOL 
 
I.       Preoperative: 
a. Up to 4 mg Midazolam at providers discretion on transport to OR 
b. Celecoxib 400mg PO (Gyn service order) 
i. For patients 18-64 years old 
c. Acetaminophen 1000mg PO (Gyn service order) 
d. Decadron 4mg (Gyn service order) 
e. Gabapentin 300-600mg PO (Gyn service order) 
i. For patients 18-59 years old, order 600mg 
ii. For patients 60-69 years old, order 300 mg 
iii. Do not give if >70 years old 
 
II.      Intraoperative: 
a. Study group: (OR nurse to retrieve, surgeon to inject) 
i. Mix 20cc 0.5% bupivacaine HCl and 20 cc liposomal bupivacaine in 1:1 
ratio 
ii. Inject 10c of mixture into each uterosacral ligament prior to colpotomy  
iii. After entry into posterior cul-de-sac, inject additional 10cc of mixture into 
deeper uterosacral ligaments  


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Page 10 
 
iv. Total injection = 40 ml 
b. Control group: (OR nurse to retrieve, surgeon to inject) 
i. Inject 10cc of 0.25% bupivacaine into each uterosacral ligament prior to 
colpotomy  
ii. After entry into posterior cul-de-sac, inject additional 10cc of 0.25% 
bupivacaine into deeper uterosacral ligaments bilaterally 
iii. Total injection = 40ml 
 
 
c. Anesthesia: 
i. All patients will receive general endotracheal anesthesia 
ii. Induction with Fentanyl 1-2 mcg/kg, Propofol/lidocaine, 
succinylcholine/rocuronium 
iii. Maintenance with Sevoflurane in air oxygen mixture, and fentanyl prn to a 
case maximum of 400 mcg, no additional opioids 
iv. Background propofol infusion (25-75 mcg/kg/min) 
v. No ketamine 
vi. Prophylactic antibiotic prior to incision 
vii. Reversal at provider’s discretion with glycopyrrolate/neostigmine, or 
sugammadex 
viii. Ketorolac 15mg IV during wound closure 
ix. Ondansetron 4mg IV during wound closure 
 
III. 
Recovery:  
a. PACU 
i. First line: IV Tylenol, PO Oxycodone 5-10 mg or PO hydromorphone 2 - 
4 mg mild (VAS 0-4), moderate (5-6), or severe (7-10) pain  (Gyn service 
order) 
ii. Second line: Fentanyl 25 mcg q 5 min prn to max of 200 mcg for severe 
pain (7-10) (Gyn service order) 
iii. Third line: hydromorphone 0.2 mg IV q 5 min to max of 2 mg for severe 
pain (7-10) refractory to fentanyl (Gyn service order) 
iv. Ondansetron 4 mg IV PRN up to 2 doses (Gyn service order) 
v. Promethazine 6.25 mg IV PRN one dose for refractory nausea up to 2 
doses (Gyn service order) 
vi. May give other anti-emetics as needed.  
 
b. Discharge Medications 
i. Acetaminophen 1000 (2 OTC 500 mg strength) mg Q8 hrs PRN mild (0-4) 
to moderate (5-6) pain 


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ii. Ibuprofen 600 (prescription 600 mg strength) mg Q8 hours PRN mild (0-
4) to moderate (5-6) pain 
iii. Oxycodone 5 or 10 mg Q4 hrs PRN for moderate (5-6) to severe (7-10) 
pain.  Patients will be discharged with two prescriptions: the first to be 
filled for 10 tablets, the second for additional 20 tablets if needed.    
iv. Hydromorphone 2 or 4 mg Q4 hrs PRN for moderate (5-6) to severe (7-
10) pain.  Patients will be discharged with two prescriptions: the first to be 
filled for 10 tablets, the second for additional 20 tablets if needed.    
v. Ondansetron 4 mg PO Q6 hours PRN for nausea 
vi. Prochlorperazine 10 mg PO Q8 hours PRN for nausea 
 
 
 
APPENDIX 2