Efficacy of Extended-Release Liposomal Bupivacaine for Post-Partum Pain Management Following Obstetrical Laceration

All pregnant female subjects over the age of 18 eligible to deliver vaginally at WRNMMC will
be screened for potential recruitment in our long-acting liposomal bupivacaine (Exparel®)
postpartum pain medicine trial prior to admission for active labor or induction of labor. At
the 36 or 38 week visit, all pregnant patients will receive an information sheet describing
the study participation and they will be asked to consider participating in the study. At the
time of admission, patients will be asked if they were provided the study information sheet
and if they would like to consent to study participation. Discussion of the study will occur
after the delivery consent form for obstetric services has been signed and when discussion of
postpartum pain management is addressed. Those subjects who meet inclusion criteria for the
study will be randomized to either the plain bupivacaine group or exparel group after vaginal
delivery and identification of a second, third, or fourth degree laceration.

Potential study subjects will be informed that the purpose of the study is to evaluate the
efficacy of two different formulations of bupivacaine, 0.25% plain bupivacaine and liposomal
bupivacaine (Exparel®) on postpartum pain following repair of a second, third, or fourth
degree laceration sustained during vaginal delivery. This medication is FDA (Food and Drug
Administration) approved and is currently being used in our hospital by other surgical
sub-specialties as part of a multi-modal approach to post-operative pain control.

If a potential subject chooses to participate, she will be randomized to one of two groups,
either a 0.25% bupivacaine injection of total 20 ml or an injection of total 20 ml
long-active liposomal bupivacaine that will be injected in the subject's perineum (the tissue
between the opening of the anus and the vagina) at the completion of the case in the delivery
room. Regardless of the decision to participate in the study or which treatment group
assignment, all subjects will have the same options for partum pain medications. There is no
monetary payment for joining the study and subjects may choose to leave the study at any
point during the study without consequence. They will still receive the same high standard of
care from our Service.

The study is designed as a single blind, randomized study. This means the subject will not
know which group a subject is assigned to until completion of the study. Subjects may choose
to have their allocated study arm disclosed at this time. Randomization will occur using a
computer-generated randomization program carried out in the Investigational Pharmacy by Dr.
Moussavian. Subjects will be randomly assigned to either receive the study medication or
bupivacaine.

The primary goal of the study is to assess how effective the study medication is in providing
adequate pain control following repair of a second, third, or fourth degree laceration;
therefore, the subjects' post-partum pain will be assessed at various intervals following the
repair. On post-partum day one, subjects will be asked questions regarding their pain level
in the vaginal area according to an 11-point visual pain scale. Subjects will also be asked
about their bowel movements and any associated pain, again, using the same visual pain scale.
Subjects will also be asked to the impact the pain has on 4 quality of life measures using an
11-point visual pain scale. Subjects will also be called or contacted via email thru Relay
Health on post-op day three and on post-op day seven to assess pain on those days. Part of
the study's goal is to assess whether the study medication provides pain control for longer
than the acute (24 hour) period. Subjects will be given a visual pain scale to go home with
so that they can reference it during their post-operative phone or email follow ups.
Additionally, subjects will be asked to gather their pain medication bottles in order to
count out the remaining pills in each bottle. This will allow us to determine the amount of
oral pain medication used since discharge from the hospital.

Study participants will review the study consent form in detail with a provider, also an
Associate Investigator in the study. The subject will be given a copy of the signed consent
and a copy will remain on file in the patient's hospital record. The data sheet with
non-identifiable subject number will be the only identifying information on the sheet. The
subject's demographic data (gravida/parity, age, BMI, past medical history, allergies,
current medications, history of significant drug or alcohol dependence) will be annotated on
this data sheet along with the postpartum pain medications she receives. The data sheets will
be kept in a locked cabinet within the resident library on the Labor and Delivery Unit, in a
room locked during all-hours. A master list of subjects' full names and sponsor's last four
of the social security number will be kept in the same location to reference the subjects'
identification code. The dates of enrollment will be annotated on the master list as well.
Follow-up phone call dates/email replies will be collected as well. Subjects will be
re-assured that her participation in the study will be completely confidential and her
identifying information will be double-locked when not being reviewed.

Following review of the study and obtaining of a consent form, the pain scale on the visual
analog pain scale will be reviewed with the subject. Subjects must be willing to speak with a
member of the study team on post-delivery day one, three, and seven regarding their
post-operative pain, medications and bowel movements. Completion of day one data will occur
in the hospital, prior to hospital discharge. The subject will be asked to indicate whether
they prefer contact via phone or by email, using the Relay Health Network for day three and
seven. A maximum of three attempts will be made to contact the subject on their designated
follow up date, between the hours of 0800 and 2000. At the conclusion of the admission
process, the subject will be reassured that if they desire removal from the study at any
time, there will be no change in their customary post-delivery care.

At completion of the repair of the vaginal laceration, the consenting physician will enter
the appropriate information on the data sheet, including the prescribed medications and
quantities. A randomization envelope will be opened, assigning the patient to either the
bupivacaine group or the Exparel group. The appropriate study medication will be obtained
from the study refrigerator in the resident library and brought to the delivery room. Dr.
Moussavian will randomize each subject to either Exparel or bupivacaine group, via pre-sealed
opaque envelopes, and blind three 10mL syringes containing a total of 20 mL of either normal
saline or liposomal bupivacaine (increments of 9mL, 9mL and 2mL). Syringe barrels will be
covered with solid white labels to mask syringe contents. She will also print out a label to
accompany the syringe to the Operating Room on the day of surgery stating:

"This subject is enrolled in study protocol #_______ and is to receive no additional
bupivacaine post-operatively for 96 hours. "

This label will be placed on a wristband, following randomization, and will be worn during
the entire hospital stay. It will assure that those subjects who receive liposomal
bupivacaine will not receive additional bupivacaine but will still maintain blinding of all
involved in the protocol.

On the day of admission for delivery, a member of the research team will, consent interested
subjects for study participation. Any last minute questions can be answered and the subject
will be advised that they can withdraw from the study at any time.

In the delivery room, the delivery team will identify the laceration and perform a repair,
using standard technique. The use of 1% lidocaine with epinephrine may be used as a
distention media to assist with pain relief during the repair so long as a minimum of 20
minutes elapses prior to injection of the study medication or bupivacaine. Once a laceration
has been identified, a research team member will leave the room and obtain a randomization
envelope from the locked study medication refrigerator in the residents' office. The envelope
will be opened; identifying which treatment arm the patient will be assigned. The team member
will come back to the room and tell the delivery nurse to leave the room and draw up the
study medication into 20ml blinded-syringe. Once all surgical procedures have been completed,
the circulating room nurse will verify the subject's name and date of birth and hand the 20mL
blinded syringe to the delivering provider, who will attach an injection needle to the
syringe. The surgeon will identify the bilateral perineal areas to be injected, approximated
1-2 cm below the opening of the vagina and 1-2 cm on either side of midline. 9 mL of the
syringe solution will be injected into each bilateral location and then 2 mL at edge of
vaginal opening (see figure1 below). The injection of the solution will occur at the
completion of the surgical case. Following administration of the injection, the team will
resume normal post-procedure care. The operating surgeon will verify the study protocol
identification sticker has been placed in the subject's paper chart.

Post-delivery, the subject will recover in the delivery room per WRNMMC protocol and be
transferred to either the postpartum unit as per routine post-operative criteria. Postpartum
pain control will be managed by the obstetric team. Further injections of pain medications
will not be given in the perineal area outside of the operating room.

On postpartum day one, a member of the obstetric team will visit the subject in order to
obtain a pain and quality of life rating (0-10) based on the visual analog pain and quality
of life scales. This will be documented as Day one data. Upon discharge postpartum care
instructions will be reviewed and the subject will be reminded to expect her follow-up phone
call or email via Relay Health on day three and seven.

During postpartum follow up on day 3 and day 7, subjects will be asked to get out their
visual analog pain scale and rate the pain on their abdomen and the pain in the vagina on a
0-10 scale. The subject will also be asked if they have had a bowel movement and whether or
not it was painful, based on the same pain scale 0-10. Subjects will be sent home with a copy
of the pain scale with the hospital post-operative discharge paperwork. At postpartum phone
or email contacts, subjects will be asked to count their remaining pain pills and these
numbers will be documented in the data collection sheet.

All data sheets will be collected at the completion of each postpartum day and placed in the
locked cabinet. Obstetric team members will have access to sheets to record data as it is
collected. The data sheets will be shredded and disposed in a HIPAA compliant receptacle per
WRNMMC protocol at the completion of the study. All consents and HIPAA authorizations will be
maintained for six years after the study is closed. The Principal Investigator, Dr.
Christopher Strauchon, will be available for debriefing of any subject after the study is
completed if the subject desires.

Inclusion Criteria:

- Pregnant females >18 years of age who sustained a second, third, or fourth degree
laceration during a vaginal delivery, or operative vaginal delivery (forceps-assisted
or vacuum-assisted) at Walter Reed National Military Medical Center

Exclusion Criteria:

- Known allergy to amide local anesthetics

- Unstable cardiac arrhythmia

- Hepatic impairment

- Regular use of narcotic pain medication, defined as use on most days of week at any
time in the three months prior to surgery

- Significant history of opioid or alcohol abuse or addiction (requiring treatment)

- Delivery of a fetal demise