Liposomal Bupivacaine To Control Post-Operative Pain Following BMG

Pain following urethroplasty with buccal mucosal graft (BMG) harvesting is primarily related
to the oral graft harvest site. This pain results in significant increases in narcotic use,
patient morbidity, and limits nutritional intake following surgery. During BMG harvesting,
lidocaine with epinephrine is routinely injected for hydrodissection and to assist with
hemostasis. The analgesic benefits from this local anesthetic, however, have abated prior to
completion of the urethral reconstruction and contribute little to post-operative pain
control.

In an effort to alleviate pain following BMG harvesting, several centers have evaluated
technical aspects of the procedure to reduce post-operative pain. These have primarily
focused on location of the graft harvest and wound closure. A novel liposomal formulation of
bupivacaine has recently been introduced as a 96-hour delayed release formulation. It has
been safely used in multiple surgical wounds and results in significantly reduced
post-operative pain and narcotic usage. Given that patient reported pain from the BMG harvest
site is worst in the first 1-2 days following surgery, infiltration of this medication has
the potential to dramatically reduce post-operative pain in these patients.

Objectives:

Our objective is to evaluate post-operative pain and narcotic usage following BMG harvesting
with liposomal bupivacaine infiltration. Our hypothesis is that infiltrating the buccal graft
harvest surgical site with liposomal bupivacaine will decrease both post-operative pain and
narcotic usage and increase patient satisfaction.

Study Design:

The study will be a prospective, randomized, single blind controlled trial. Patients will be
recruited from the offices of Urology of Virginia, Devine-Jordan Center for reconstructive
surgery and pelvic health. Eligible patients will include all males 18 years of age or older
identified as requiring a urethroplasty with BMG harvesting. On the initial visit, eligible
patients will complete a research consent.

Patients will be randomized to receive either standard of care BMG harvesting or standard of
care plus buccal infusion of liposomal bupivacaine. Randomization will be determined with a
random number generator in the Urology of Virginia research office prior to surgery. Patient
randomization will be revealed to the operative surgeon on the day of surgery following
induction of general anesthesia. The remainder of the procedure will be performed as per
routine.

Post-operatively, a member of the research team who was not a member of the operative team
will monitor the patient's pain and narcotic usage. Pain will be assessed using a validated
10-point pain scale as well as a non-validated BMG harvest site morbidity questionnaire, an
evaluation technique that has been used previously. Inpatient narcotic usage will be
calculated post-op through cumulative morphine equivalents on a 24-hour basis on the day of
surgery as well as post-op days one, two and three. All patients are routinely discharged
home on post-op day two or three. The pain and morbidity questionnaire will be administered
in the pre-operative holding area, then daily for the first seven days followed by monthly
through 6 months of follow up. Studies have shown a return to baseline pain within six months
following BMG harvesting and assessments beyond that time are unnecessary. Responses to
questionnaires will be obtained either by a member of the Urology of Virginia research staff
through either a phone call or email message to the patients at each time point. Preferred
method of contact, including a preferred phone number and email address will be obtained
during the initial visit when study consent is obtained.

The primary endpoint will be reduction in post-op pain on the 10-point numerical rating
scale, post-operative narcotic requirements and oral morbidities. Secondary endpoints will be
return of eating a regular diet, perioral numbness, salivary changes and the ability to open
the mouth completely.

Power analysis shows that 40 patients would be required to attain 80% power to detect a > 1
point change in the numeric pain scale at a 2-sided level of 5%. Accounting for 10-20%
dropout rate, the study investigators plan to recruit 50 patients for randomization.

The Urology of Virginia research department will maintain all study data. Patients will be
identified by medical record number for the purpose of data collection. However, in the
database, patient information will be associated only with a non-identifying subject
identification number that will be assigned at study entry. A file linking patient medical
record numbers with subject identification numbers will be maintained separately from the
database. All files will be kept on an encrypted, password-protected external data drive for
additional security. All files will be destroyed no later than three years following the end
of the study.

Safety monitoring for this study will be done at each subject encounter and maintained within
the Urology of Virginia research office. Adverse effects will be queried during each
interaction with the patient and is also included in the questionnaire to be filled out
throughout the study period.

Rudimentary statistical analysis will be carried out using excel spreadsheets, which will
include mean/median values, percentages and data trends. Additionally, multivariate
regressions models will be created using the Statistical Package for the Social Sciences
(SPSS) software.

Risk to Subjects:

Liposomal bupivacaine has been used for several years in a variety of surgical settings
without significant adverse events compared to traditional bupivacaine. However, its specific
use in buccal infiltration for BMG harvesting has not previously been reported.

Liposomal bupivacaine has been studies in several clinical trials. The reported adverse
reactions related to its use include, but are not limited to:

- Most common

o Nausea, constipation, and vomiting.

- Common

o Fever, dizziness, peripheral swelling, anemia, hypotension, pruritus, tachycardia,
headache, insomnia, muscle spasms, back pain, somnolence, and procedural pain.

- Less common/rare

o Chills, erythema, bradycardia, anxiety, urinary retention, pain, edema, tremor,
dizziness postural, paresthesia, syncope, incision site edema, procedural hypertension,
procedural hypotension, procedural nausea, muscular weakness, neck pain, pruritus
generalized, rash pruritic, hyperhidrosis, cold sweat, urticaria, bradycardia,
palpitations, sinus bradycardia, supraventricular extrasystoles, ventricular
extrasystoles, ventricular tachycardia, hypertension, pallor, anxiety, confusional
state, depression, agitation, restlessness, hypoxia, laryngospasm, apnea, respiratory
depression, respiratory failure, body temperature increased, blood pressure increased,
blood pressure decreased, oxygen saturation decreased, urinary retention, urinary
incontinence, vision blurred, tinnitus, drug hypersensitivity, and hypersensitivity.

- Specific neurological and cardiac adverse reactions o Dizziness (6.2%), headache (3.8%),
somnolence (2.1%), hypoesthesia (1.5%), and lethargy (1.3%), tachycardia (3.9%) and
bradycardia (1.6%).

This study does involve data collection from medical records and depends upon patient
identifiers for data collection. HIPAA compliance in clinical data handling will ensure
protection of patient's right to privacy. Information in the database will be
non-identifiable. All collected data will be stored on an encrypted, password-protected
external data drive. No personal health information data will be released. Only investigators
listed within this Institutional review board proposal will have access to the data
collected. Despite these safeguards, there is always risk for incidental release of patient
personal health information. As outlined above, every effort will be made to limit these
risks.

Disposition of Results:

The results of this study will be communicated in presentations at society meetings (such as
the American Urologic Association national meeting). Final disposition of this study will be
submitted for publication in a peer-reviewed scientific journal. All information is
unidentified.

Inclusion Criteria:

- male adults with urethral stricture assessed to be requiring a urethroplasty with BMG
harvesting

Exclusion Criteria:

- female adult patient with urethral strictures

- prior diagnosis of chronic pain or systemic disease that would interfere with outcome
assessment or metabolism of the local anesthetics or narcotics.

- allergy to liposomal content or bupivacaine or any cross reaction to local anesthetics

- neurological disease with impaired communication or neurological deficit to pain

- with poor oral health with lesions

- urethroplasties with no requirement for BMG graft

- on daily narcotic requirement pre-operatively

- on daily analgesia medication required for other condition

- consented for other clinical trials which may interfere the outcome assessment

- unwilling for post-operative interview or survey involvement