Clinical trial NCT03922620
Conditions: Pain, Acute Surgery Anesthesia Opioid Use
Sponsor: Geisinger Clinic
Start date: 2020-01-23; Completion date: 2021-06-30
Enrollment: 1 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Liposomal bupivacaine has gained interest in recent literature for its potential to be an effective adjunct to other pain control modalities in a multi-modal approach to post-operative pain control. The goal of this investigation is to compare the efficacy of local administration of liposomal bupivacaine versus the efficacy of a peripheral nerve block in terms of post-operative pain scores after elective ankle and hindfoot surgery. The investigators hypothesize that there will not be a significant difference in the pain scores of these two groups in opioid naïve patients.

Detailed description:
Liposomal bupivacaine has gained interest in recent literature for its potential to be an effective adjunct to other pain control modalities in a multi-modal approach to post-operative pain control. Liposomal bupivacaine is an analgesic that is suspended in lipids to allow for gradual release of the analgesic over a 72-hour period (NAMDARI). From prior literature, the utilization of local analgesics infiltrated into surgical sites have been shown to reduce pain in the immediate post-operative period in foot and ankle surgery (GADEK). However, the evaluation of liposomal bupivacaine in foot and ankle surgery is limited. One prospective study found that the addition to liposomal bupivacaine to a multi-modal pain management protocol for forefoot surgery resulted in decreased pain scores during the first four post-operative days as well as fewer refills of opioid pain medication prescriptions, although both findings were not statically significant (ROBBINS). As the general medical community and public policy makers continue to focus on decreasing the amount of opioid pain medications prescribed and available in the community due to the opioid epidemic, liposomal bupivacaine has the potential to be a useful adjunct in the management of post-operative pain without reliance on opioid prescriptions. The goal of this investigation is to compare the efficacy of local administration of liposomal bupivacaine versus the efficacy of a peripheral nerve block in terms of post-operative pain scores after elective ankle and hindfoot surgery. The investigators hypothesize that there will not be a significant difference in the pain scores of these two groups in opioid naïve patients. Furthermore, this study aims to determine if there are differences in the amount of opioid medications utilized for post-operative pain control, patient satisfaction scores, functional outcomes, complications, and unscheduled healthcare contact between the two groups. In order to accomplish these aims, a randomized, controlled investigation will be conducted.

Arms: arm 1: No peripheral nerve block will be given. Local infiltration of 20cc of Liposomal Bupivacaine infiltrated to the surgical area. arm 2: Peripheral Nerve Block performed by anesthesia team (blocks will be given by same anesthesia provider utilizing same technique every time in order to reduce variations in delivery of peripheral nerve block). No local analgesic agent infiltration
Interventions: intervention 1: Liposomal bupivacaine intervention 2: Peripheral Nerve Block
Intervention descriptions: intervention 1: Local infiltration of 20cc of Liposomal Bupivacaine infiltrated to the surgical area intervention 2: Peripheral Nerve Block performed by anesthesia team (blocks will be given by same anesthesia provider utilizing same technique every time in order to reduce variations in delivery of peripheral nerve block).

Protocol documents:
Prot_001.pdf: 
IRB NUMBER: 2018-0486
IRB Approved:  08/12/2019
PI: Gerard Cush, MD 
IRB# 2018-0486 
Version 1.1 (07/23/2019)
NCT03922620
Liposomal Bupivacaine vs Peripheral Nerve Block
Principal Investigator: 
Gerard Cush, MD
100 N. Academy Ave
Danville, PA 17822-2130
570-271-6541


IRB NUMBER: 2018-0486
IRB Approved:  08/12/2019
PI: Gerard Cush, MD
IRB# 2018-0486
Version 1.1 (07/23/2019)
Abstract:
Liposomal bupivacaine has gained interest in recent literature for its potential to be an effective adjunct 
to other pain control modalities in a multi-modal approach to post-operative pain control. Liposomal 
bupivacaine is an analgesic that is suspended in lipids to allow for gradual release of the analgesic over a 
72-hour period (NAMDARI). From prior literature, the utilization of local analgesics infiltrated into 
surgical sites have been shown to reduce pain in the immediate post-operative period in foot and ankle 
surgery (GADEK). However, the evaluation of liposomal bupivacaine in foot and ankle surgery is limited. 
One prospective study found that the addition to liposomal bupivacaine to a multi-modal pain 
management protocol for forefoot surgery resulted in decreased pain scores during the first four post-
operative days as well as fewer refills of opioid pain medication prescriptions, although both findings 
were not statically significant (ROBBINS). As the general medical community and public policy makers 
continue to focus on decreasing the amount of opioid pain medications prescribed and available in the 
community due to the opioid epidemic, liposomal bupivacaine has the potential to be a useful adjunct in 
the management of post-operative pain without reliance on opioid prescriptions. The goal of our 
investigation is to compare the efficacy of local administration of liposomal bupivacaine versus the 
efficacy of a peripheral nerve block in terms of post-operative pain scores after elective ankle and 
hindfoot surgery. We hypothesize that there will not be a significant difference in the pain scores of 
these two groups in opioid naïve patients. Furthermore, we aim to determine if there are differences in 
the amount of opioid medications utilized for post-operative pain control, patient satisfaction scores, 
functional outcomes, complications, and unscheduled healthcare contact between the two groups.  In 
order to accomplish our goal and aims, we plan to conduct a randomized, controlled investigation.
Background and Significance:
Liposomal bupivacaine has gained interest in the orthopaedic community for its potential to be a useful 
adjunct in the control of post-operative pain. Especially with the recent focus on decreasing the number 
of opioids prescribed and available to the general public due to the opioid epidemic, liposomal 
bupivacaine is being investigated in numerous orthopaedic sub-specialties as a promising way to control 
post-operative pain, maintain high patient satisfaction, all the while decreasing dependence on opioids 
for pain control. The arthroplasty arena has led the way in the investigation of liposomal bupivacaine in 
the management of post-operative pain. Sabesan, et al. demonstrated excellent pain relief for patients 
undergoing shoulder arthroplasty who received a local liposomal bupivacaine injection in addition to a 
single-bolus interscalene block compared to patients who received continuous interscalene nerve block 
(SABESAN). Yu, et al. demonstrated that patients who received a local liposomal bupivacaine injection 
after total knee arthroplasty consumed slightly less morphine equivalents of opioids than patients who 
received a femoral nerve block (YU). Given these findings, the utilization of liposomal bupivacaine in foot 
and ankle surgery is of interest as well.
From prior literature, the utilization of local analgesics infiltrated into surgical sites have been shown to 
reduce pain in the immediate post-operative period in foot and ankle surgery (GADEK). However, the 
evaluation of liposomal bupivacaine in foot and ankle surgery is limited. One prospective study found 
that the addition to liposomal bupivacaine to a multi-modal pain management protocol for forefoot 
surgery resulted in decreased pain scores during the first four post-operative days as well as fewer refills 
of opioid pain medication prescriptions, although both findings were not statically significant (ROBBINS).


IRB NUMBER: 2018-0486
IRB Approved:  08/12/2019
PI: Gerard Cush, MD
IRB# 2018-0486
Version 1.1 (07/23/2019)
The goal of our investigation is to compare the efficacy of local administration of liposomal bupivacaine 
versus the efficacy of a peripheral nerve block in terms of post-operative pain scores after elective ankle 
and hindfoot surgery. We hypothesize that there will not be a significant difference in the pain scores of 
these two groups in opioid naïve patients. Furthermore, we aim to determine if there are differences in 
the amount of opioid medications utilized for post-operative pain control, patient satisfaction scores, 
functional outcomes, complications, and unscheduled healthcare contact between the two groups.  In 
order to accomplish our goal and aims, we plan to conduct a randomized, controlled investigation.
Hypothesis and Aims:
Hypothesis:
We hypothesize that there will not be a significant difference in the pain scores of patients randomized 
into the liposomal bupivacaine group and the peripheral nerve block group in opioid naïve patients.
Specific Aim 1: 
To compare post-operative pain scores after elective ankle and hindfoot surgery in patients who receive 
a local infiltration of liposomal bupivacaine versus a peripheral nerve block.
Specific Aim 2: 
To compare opioid consumption in morphine equivalents after elective ankle and hindfoot surgery in 
the two groups.
Specific Aim 3: 
To compare patient satisfaction scores after elective ankle and hindfoot surgery in the two groups.
Specific Aim 4: 
To compare functional outcomes after elective ankle and hindfoot surgery in the two groups.
Specific Aim 5: 
To compare complication rates after elective ankle and hindfoot surgery in the two groups.
Specific Aim 6: 
To compare rates of unscheduled healthcare contact after elective ankle and hindfoot surgery in the two 
groups.
Study Design:
This is a prospective, randomized trial to investigate whether there is a difference in pain score, opioid 
consumption, patient satisfaction, functional outcomes, complication rates, and unscheduled healthcare 
contact associated with local liposomal bupivacaine infiltration versus peripheral nerve block in patient 
undergoing elective ankle and hindfoot surgery. Approximately 50 patients will be randomized. 
Study Population:
Approximate Number of Subjects:


IRB NUMBER: 2018-0486
IRB Approved:  08/12/2019
PI: Gerard Cush, MD
IRB# 2018-0486
Version 1.1 (07/23/2019)
Approximately 50 total Geisinger patients will participate in the study.
Inclusion Criteria:
1.
Patients 18 years of age or older
2.
Patients undergoing elective primary ankle or hindfoot surgery (ankle arthrodesis, subtalar 
arthrodesis, triple arthrodesis, total ankle arthroplasty, peroneal tendon 
debridement/transfer, Cavus Reconstruction, Medial Displacement Calcaneal Osteotomy, 
Dwyer Osteotomy)
Exclusion Criteria:
1.
Patients who are undergoing revision surgical procedure
2.
Patients who have taken opioid pain medications in the past 3 months prior to surgical 
procedure
3.
Patients who have allergies to any of the medications or components of medications 
investigated in the study
4.
Patients currently incarcerated
5.
Patients who cannot read and speak English
Study Recruitment:
The study investigators will identify potential study participants in the outpatient clinic. The patients 
that meet inclusion criteria will be approached by the physician investigator, research coordinator(s), 
and/or research assistant(s) during their orthopaedic clinic visit and will be asked to participate in the 
study. After hearing the study explanation, if the patient is interested in participating, the physician 
investigators, research coordinator(s) and/or research assistant(s) will review, with the patient, the 
informed consent form asking authorization to access/use their PHI.  The patient will sign and date the 
form after all questions have been satisfactorily answered by the study team.  Recruitment materials will 
consist of the informed consent form.
Study Duration:
Approximate Duration of Subject Participation:
Patients will participate in the study for approximately 3 months – from initial recruitment to 
end of participation.
Approximate Duration of Study:
The study will be completed in approximately 12 months. The end of the study is the last visit of 
the last subject, or end of collection of data from the patient’s electronic health record.
Procedures:
Patients who meet inclusion criteria will undergo a selection process, and if they choose to participate 
will be randomized into one of two groups. The randomization scheme will be created with the use of an 
internet based randomization website (https://www.randomizer.org).  Qualifying subjects will be 
randomized into one of two groups prior to their surgery:


IRB NUMBER: 2018-0486
IRB Approved:  08/12/2019
PI: Gerard Cush, MD
IRB# 2018-0486
Version 1.1 (07/23/2019)
 
1. Liposomal Bupivacaine Group
a. Pre-operative
i. No peripheral nerve block will be given
b. Intraoperative
i. Local infiltration of 20cc of Liposomal Bupivacaine infiltrated to the 
surgical area
c.
Post-operative (At Discharge)
i. Oxycodone 5mg every 6 hours as needed for pain (30 tablets)
ii. Acetaminophen 500mg every 6 hours scheduled
2. Peripheral Nerve Block Group
a. Preoperative 
i. Peripheral Nerve Block performed by anesthesia team (blocks will be 
given by same anesthesia provider utilizing same technique every time in 
order to reduce variations in delivery of peripheral nerve block).
b. Intraoperative
i. No local analgesic agent infiltration
c.
Post-operative (At Discharge)
i. Oxycodone 5mg every 6 hours as needed for pain (30 tablets)
ii. Acetaminophen 500mg every 6 hours scheduled
Patients will be randomized as to which analgesia regimen they will receive.  The surgeon will not be 
blinded. 
On the day that the patient is consented for the study, they will complete the following standard of care 
assessments in clinic: 
1.
VAS Pain Scale
2.
Pain Catastrophizing Scale 
3.
PROMIS Self-Efficacy of Managing Symptoms
On the day of surgery, all qualifying patients will undergo their elective ankle or hindfoot surgery under 
standard practices.  Randomized patients will receive pre-operative peripheral nerve block prior to the 
procedure. The participating surgeon will perform the procedure in accordance with their standard 
practice.  Liposomal Bupivacaine will be injected prior to incision and after wound closure. Patients will 


IRB NUMBER: 2018-0486
IRB Approved:  08/12/2019
PI: Gerard Cush, MD
IRB# 2018-0486
Version 1.1 (07/23/2019)
be placed in sterile dressings and a post-operative splint in accordance with the surgeon’s standard 
practice.  All patients will receive discharge instructions based on the surgeons standard practice.  All 
patients will receive the same post-operative opioid pain regimen. 
  
Patients will keep a pain journal, documenting their pain from postoperative days 1-7.  It will include 
pain score as well as pain medication utilization documentation starting from immediately in the Post-
Anesthesia Care Unit, 6 hours post-op, and 12 hours post-op. Afterwards, participants will be asked to 
document pain score and pain medication utilization daily from post-operative days 1-7. They will bring 
their pain journal with them to their first postoperative visit.  
Patients will be seen at 2 weeks and 6 weeks postoperatively. During these visits, a routine wound check 
will be performed.  The patient’s range of motion and pain will be assessed.  Any complications will be 
recorded.  All postoperative care other than the medications prescribed at the time of discharge will be 
in accordance with each surgeon’s standard practice.  At each of these two visits, patients will complete 
the following assessments: 
1.
VAS Pain Scale
2.
Pain Medication Utilization Questionnaire
3.
Pain journal collection
At the conclusion of the 6-week post-operative period, the EMR will be reviewed an any instances of 
unscheduled healthcare contact (email, MyGeisinger messages, telephone calls, unscheduled clinic 
visits, ED visits) will be recorded and analyzed for cause.  
All surgeons participating in the study will adhere to the randomization, treatment and follow-up 
protocol.   There will be 2 participating sites within the Geisinger system (GMC and GMC Woodbine) 
whom will participate in this research project.  


IRB NUMBER: 2018-0486
IRB Approved:  08/12/2019
PI: Gerard Cush, MD
IRB# 2018-0486
Version 1.1 (07/23/2019)
  Study Time and Events Table  
Study Procedures
Visit ~pre-
surgery
Visit
Day of
Surgery
0, 6, & 12 
Hours Post 
Op
Visit
2 week
follow-up
Visit
6 week
Follow-up
Office Visit
X
X
X
Prescreen
X
Provide Info Sheet
X
Review
Inclusion/
Exclusion
X
X
Demographics,
medical history,
habits,
historical
diagnoses
X
Consent of Patient
X
Randomization
X
Outcome measures 
/ examination 
assessment 
recorded
X
X
X
X
Analgesia 
administration
X
Surgery
X
AE / Complication 
Reporting
X
X
X
X
Primary Endpoints:
The primary endpoint is to determine if there is a statistically significant difference in pain scores (VAS 
Pain Scale) for patients undergoing elective ankle and hindfoot surgery randomized to a group receiving 
intra-operative liposomal bupivacaine infiltration versus a group receiving a peripheral nerve block. 
Secondary Endpoints:
1.
Differences in morphine equivalents consumed for post-operative pain control
2.
Difference in patient satisfaction score 
3.
Differences in functional outcomes
4.
Difference in complications
5.
Differences in unscheduled healthcare contact
Statistics:


IRB NUMBER: 2018-0486
IRB Approved:  08/12/2019
PI: Gerard Cush, MD
IRB# 2018-0486
Version 1.1 (07/23/2019)
Statistical analysis will be performed by Les Kirchner
Data Management
Data to be Collected:
The following data will be collected from the EMR:

PHI elements (will not be included in final dataset)

Medical Record Number (MRN)

Name

Date of Birth

Patient Demographics (Age, gender, weight, height, Body Mass Index (BMI))

Medical History 

Narcotic use history 

Inflammatory or Rheumatoid Arthritis 

Complications / AE

Wound Hematoma 

Superficial wound infection (defined as any prescription for post-op antibiotics)

Wound complications 

Deep infection (defined as need for surgical irrigation and debridement)

Crossover

Number of patients randomized to liposomal bupivacaine group that request peripheral nerve 
block

Unscheduled healthcare contact and reason for contact

Phone calls

Emails

MyGeisinger Messages

Unscheduled clinic visits

ED visits 

Dates 

Date(s) and information related to of admission, surgery, and discharge

Date(s) and information related to clinic visits
The following data will be collected during the patient clinic visits:

VAS Pain Scale (0-10)

Pain journal from post-operative days 0-7 including pain medication utilization and pain scores
Data Collection and Storage
The data points outlined above will be reviewed and collected from the EMR by the study 
coordinator(s), project coordinator(s) and/or co-investigators.  A data request will be submitted to the 
BC Data Broker, an independent person from the study team. 
A member of the IRB-approved Geisinger study team will perform a manual chart review for data points 
not captured during the BC data pull. A member of the IRB approved study team will randomly assign 


IRB NUMBER: 2018-0486
IRB Approved:  08/12/2019
PI: Gerard Cush, MD
IRB# 2018-0486
Version 1.1 (07/23/2019)
study ID numbers in order to protect the identity of the subject.  After the dataset has been de-
identified, an IRB-approved study team member will forward the completed dataset to Les Kirchner for 
analysis.  All study data will be kept in GHS maintained username/password-protected computer files 
and hard copy data will be double locked and accessible only to the study investigators in the locked 
office of the Study Coordinator.  Only group-level information without personal identifiers will be 
included when presenting results or submitting manuscripts for publication.
Personal or sensitive information that could be potentially damaging to participants (e.g. relating to 
illegal behaviors, alcohol or drug use, sexual attitudes, mental health, etc.) will not be collected.  With 
concerns to HIV/AIDS status, if the status is already in the participant’s medical record it will be reported 
into the CRF as a “yes” or “no,” otherwise it will be reported in the CRF as “not assessed.”  Regarding 
collected mental health information that could be potentially damaging to participants, participants 
indicating that they are very depressed, thus raising concern regarding their mental state, will be 
referred to their primary care physician.
No PHI will be shared outside of the IRB approved study staff.
Records Retention
Records of data generated in the course of the study will be kept indefinitely and may be used for future 
research purposes.
Adverse Event Reporting
Clinical adverse events (AEs) will be monitored throughout the study.  All AEs will be reported to the 
institutional review board (IRB) according to IRB policy.  The date and time of onset and outcome, 
course, intensity, action taken, and causality to study treatment will be assessed by the study PI.  
Definitions
An adverse event (AE) is any untoward, undesired, or unplanned event in the form of signs, symptoms, 
disease, or laboratory or physiologic observations occurring in a person given a test article or in a clinical 
study. The event does not need to be causally related to the test article or clinical study. 
Adverse Events related to Elective Ankle and Hindfoot Surgery:

Infection

Wound healing issues

Persistent pain

Peripheral nerve injury

Arterial injury 

Wound complications
A protocol-related adverse event is an AE occurring during a clinical study that is not related to the test 
article, but is considered by the investigator or the medical monitor (or designee) to be related to the 
research conditions, i.e., related to the fact that a subject is participating in the study. For example, a 


IRB NUMBER: 2018-0486
IRB Approved:  08/12/2019
PI: Gerard Cush, MD
IRB# 2018-0486
Version 1.1 (07/23/2019)
protocol-related AE may be an untoward event occurring during a washout period or an event related to 
a medical procedure required by the protocol.


IRB NUMBER: 2018-0486
IRB Approved:  08/12/2019
PI: Gerard Cush, MD
IRB# 2018-0486
Version 1.1 (07/23/2019)
Recording and Reporting
A subject’s AEs will be recorded and reported from the signing of the informed consent form to end of 
study period. 
Protection of human subjects
Informed Consent
The investigator will provide for the protection of the subjects by following all applicable regulations.  
The informed consent form will be submitted to the IRB for review and approval.  Prior to having any 
study procedures performed, the patient will be asked to read and then sign the informed consent form 
if they agree to participate in the study.  The subject will receive a copy of the signed/dated informed 
consent form for their records.  The original copy of the informed consent form will be scanned into the 
subject’s EMR and the hardcopy will be filed in the subject’s study binder.  The rights and welfare of the 
subjects will not be affected.  We are requesting to observe and record variables that are normally 
collected and entered into the patient’s EMR in the course of standard clinical care.  The purpose of 
recording data for this prospective study (in addition to the EMR) is simply to ensure that discrete, 
standardized format (since some variables, while stored in the EMR, may appear in physician notes as 
free text).
There is very little to no risk associated with this study.  The risk to study participants is related to 
accidental disclosure of PHI (i.e. MRNs, dates).  Any time information is collected for a study there is a 
small risk of breach confidentiality.  However, this risk is not greater than the risk that already exists in 
clinical settings when handling medical data.  
A partial waiver of HIPAA authorization is being requested for this study.  A waiver is necessary for the 
research to be practically conducted because the research team much review the patient’s PHI to 
determine eligibility.  The research team would be unaware of potential eligible patients without 
reviewing that patient’s relevant medical information.  If the patient does not meet eligibility criteria, 
they will not be approached to partake in the study.  While PHI is being requested, it is the minimal 
amount necessary to ensure patients are eligible based on the inclusion criteria.
Protection of Human Subjects Against Risks
The investigator will provide for the protection of the subjects by following all applicable 
regulations.  Anticipated risks in this study are minimal.  This study will not affect patient care or access 
to care.  The major risk to human subjects in this study is the accidental disclosure of PHI.    In this 
regard, the assignment of a coded test ID number to each individual participant and the protocol of 
providing only the necessary associated clinical information to the remainder of the research team 
mitigate this risk.  
All study data will be kept in Geisinger Health System maintained username/password-
protected computer files and hard copy data will be double locked and accessible only to the study 
investigators.  Only group-level information without personal identifiers will be included when 
presenting results or submitting manuscripts for publication.


IRB NUMBER: 2018-0486
IRB Approved:  08/12/2019
PI: Gerard Cush, MD
IRB# 2018-0486
Version 1.1 (07/23/2019)
Publication Plan:
We plan to prepare and submit the results of this study for presentation at national meetings and in 
peer-reviewed journals.