Clinical trial NCT04644796
Conditions: Lumbar Spine Degeneration
Sponsor: University of Missouri-Columbia
Start date: 2021-02-10; Completion date: 2022-06-13
Enrollment: 34 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to establish a relationship between liposomal bupivacaine surgical site injection and postop opioid utilization.

Detailed description:
Multiple studies have shown that people who are taking opioids for acute pain have a greater likelihood of long-term opioid use. Many efforts have been made to reduce postop pain and opioid use, including developments in incisional site injections of local anesthetics, continuous incisional site anesthetic pain pumps, as well as multimodal comprehensive pain management, yet patients undergoing lumbar spine surgeries continue to depend on opioids for relief. Liposomal bupivacaine (LB) (Exparel) is a novel formulation of long-acting bupivacaine, lasting for up to 72 hours following injection. LB has been shown to be efficacious in reducing postop pain and opioid utilization in several different surgical settings, however its utility in spine surgeries has still yet to be established. The goal of this study is to determine the efficacy of liposomal bupivacaine vs saline in lumbar spine surgeries in reducing opioid utilization as well as determine if there difference patient reported outcomes and length of hospital stay.

Arms: arm 1: Patients in this group will be given the placebo (sterile saline). arm 2: Patients in this group will be given the study drug (liposomal bupivacaine).
Interventions: intervention 1: saline 0.9% intervention 2: Liposomal bupivacaine
Intervention descriptions: intervention 1: Patients included in the placebo group will have their incisional site infused, targeting the paraspinal muscles with sterile saline at the end of their surgery. intervention 2: Patients included in the treatment group will have their incisional site infused, targeting the paraspinal muscles with liposomal bupivacaine at the end of their surgery.

Protocol documents:
Prot_SAP_000.pdf: 
Page 1 of 8 
BIOMEDICAL RESEARCH PROTOCOL  
UNIVERSITY OF MISSOURI 
 
Project Title: A randomized controlled trial of the effect liposomal bupivacaine (Exparel) when 
compared to saline control in reducing opioid utilization for pain management in postoperative 
lumbar spine surgeries.  
IRB Number: 2037544 
Version Number: 3 
Version Date: 04/25/2022 
Principal Investigator: Theodore Choma, MD 
Funding Source: TIGERS Grant – University of Missouri School of Medicine 
 
Clinical Trial Phase: Phase IV 
Clinicaltrials.gov Number: MCT04644796 
Study Drug/Study Device: Liposomal Bupivacaine (Exparel) 
 
 
 
 
1. Primary Objective:  
a. Establish a relationship between liposomal bupivacaine surgical site injection and 
postop opioid utilization. 
2. Secondary Objectives: 
a. How does self-reported pain (11 point visual analog pain scale) differ in patients 
given liposomal bupivacaine compared to patients in the control group? 
b. Is there a difference in length of hospital stay between the liposomal bupivacaine 
group compared to the control group. 
3. Background: 
a. Lumbar spine fusions utilizing a posterior approach are major surgeries that 
generally entail a significant amount dissection, even with minimally invasive 
spine techniques. Despite efforts to utilize multimodal approaches to combat 
postop spine pain, most patients will still require some form of opioid pain 
medication for a period of time.  
b. Multiple studies have shown that people who are taking opioids for acute pain 
have a greater likelihood of long-term opioid use. Furthermore, the greater the 
initial opioid exposure, the greater the risk of long-term use, abuse, and overdose. 
Studies have shown that patients who are given doses of opioids exceeding 90 
morphine milligram equivalents per day increases the risk of death from an 
overdose by 10-fold. 
c. Many efforts have been made to reduce postop pain and opioid use, including 
developments in incisional site injections of local anesthetics, continuous 
incisional site anesthetic pain pumps, as well as multimodal comprehensive pain 
management, yet patients undergoing lumbar spine surgeries continue to depend 
on opioids for relief.  
d. Liposomal bupivacaine (LB) is a novel formulation of long-acting bupivacaine, 
lasting for up to 72 hours following injection. LB has been shown to be 
I.
Research Objectives/Background


Page 2 of 8 
efficacious in reducing postop pain and opioid utilization in several different 
surgical settings, however its utility in spine surgeries has still yet to be 
established.  
e. For the past 5 years, one of our spine surgeons has been using liposomal 
bupivacaine for incisional site infusion, targeting the paraspinal muscles. 
Retrospective data was collected in a historic chart review between 2014 – 2019 
and analysis of this data showed clear benefit to using LB to reduce opioid use 
within the first 72 hours postop. 
f. Given our promising results from an observational study, it is our goal to advance 
our study to a double blind, randomized trial to determine the efficacy of 
liposomal bupivacaine in lumbar spine surgeries in reducing opioid utilization.  
 
 
 
 
1. Liposomal bupivacaine (Exparel) 266mg/20mL, Intramuscular, single dose 
intraoperatively. 
2. Liposomal bupivacaine is a long-acting local anesthetic, lasting for up to 72 hours, that 
has been FDA approved for the indication of surgical site local analgesia. We chose to 
use this product for this study because it has the benefit of providing long-acting 
analgesia, which especially beneficial in studying the immediate postoperative period for 
pain relief. 266mg/20mL is considered to be the maximum safe dose administered IM, 
without diluting the solution with saline.  
3. The standard reference therapy will be a saline placebo. There is currently no local 
anesthetic utilized upon surgical site closure as a standard of care for lumbar spine 
patients. For this reason, we want to determine if the use of liposomal bupivacaine is 
superior in reducing opioid utilization post-op compared to no liposomal bupivacaine. 
4. Include justification and safety information. 
5. Liposomal bupivacaine can be differentiated visually from normal saline. In order to 
blind the surgeons from treatment vs control, the syringes containing the medication or 
saline will be sheathed by the investigational drug study department.  
 
 
 
1. Patients will be recruited from The Missouri Orthopedic Institute (MOI) during routine 
outpatient clinic evaluations for lumbar spine procedures. Surgical procedures will be 
performed either at MOI or University of Missouri Hospital.  
2. Both male and female patients will be considered for this study. Any patient over the age 
of 18 years old and having an isolated lumbar spine procedure that requires a posterior 
surgical approach for therapeutic spine purposes will be considered.  
3. Standard safety precautions according to University of Missouri Hospital System 
guidelines will be taken by research staff. These precautions include wearing appropriate 
PPE (approved masks and eyewear) and social distancing 6 feet apart whenever possible. 
4. All patients will be screened for COVID-19 prior to surgery within 14 days of the day of 
surgery, in accordance with University of Missouri Guidelines. 
 
III.
Recruitment Process
IV.
Consent Process
II. 
Drugs/Biologics/Devices 


Page 3 of 8 
 
 
1. Patients will be given a short survey to determine eligibility for the study. 
2. For patients who are eligible to be enrolled in the study, consent will be obtained from 
the authorized clinical research staff.  
3. Recruitment is completely voluntary, and it is the patient’s right to revoke consent at any 
point in time during the study if they no longer wish to participate. 
 
 
 
 
1. Inclusion criteria: 
a. Patients undergoing isolated lumbar spine procedures using a posterior approach. 
b. Surgical spine procedures include: 
i. Single-level lumbar spine surgeries with or without fusion 
ii. Multi-level lumbar spine surgeries with or without fusion 
2. Exclusion criteria: 
a. Procedures involving intrathecal space 
b. Patients with documented allergy to local anesthetics (bupivacaine, lidocaine, 
procaine, benzocaine). 
c. Acute lumbar trauma that requires immediate spine stabilization 
d. Revision of failed back surgeries (including nonunion and malunion) 
e. Revision of wound or hardware 
f. Contraindication to regional anesthesia 
g. Patients with chronic use of opioid medications  
h. Liver dysfunction (INR > 1.5, albumin <2.8g/dl, bilirubin >2mg/dl) 
i. Renal dysfunction (eGFR < 60ml/min/1.73m2) 
j. Severe COPD requiring continuous oxygen supplementation 
k. Unable to give informed consent (including prisoners and mentally disabled) 
l. Pregnant patients 
 
 
 
 
1. Using data taken from Tomov et al 2018, a power analysis was conducted to test 
differences in mean total opioid use between the liposomal bupivacaine group and the 
control group at 72 hours post-op.  Equal group sizes were considered with power at least 
0.80, two-sided Type I error set at 0.05, and  equal variances between the two groups 
were assumed using a two-sample independent t-test framework.  Using a treatment mean 
total opioid use (in morphine equivalent mg) of 231.4mg and control mean of 273.9mg, 
with pooled standard deviation of 40.0mg, at least 15 subjects per treatment group are 
required (30 total).  As follow-up for this study is shortly after surgery (and all during 
LOS), an adjustments were made for study attrition to allow for enrollment up to 50 to 
account for those that may be consented but not have surgery or those that do not fill out 
the VAS and medication log post-op.    
 
V.
Inclusion/Exclusion Criteria
VI.
Number of Subjects
VII.
Study Procedures/ Design/Treatment Plan


Page 4 of 8 
 
 
1. Randomization of study group vs control group will be done independently by 
investigational drug study personnel. Vials of the medication vs sterile saline will be 
blinded with labels that are able to be scanned into the system so that only investigational 
drug study personnel know which patients belong to each arm. In order to blind the 
surgeon, the syringes will be shielded due to the ability to visually differentiate the two 
treatments.  
2. All patients will be screened for COVID-19 per University of Missouri Hospital and 
Clinic’s protocol (<14 days from day of surgery). 
3. All patients will undergo a standard induction and maintenance of general anesthesia 
balanced according to institutional protocols based on ASA guidelines: 
a. Anesthesia protocol (standard of care) – All surgery will be performed 
with standard general anesthesia. Induction will be achieved, and general 
anesthesia maintained based on the following protocol (Doses vary based 
on patient specifics such as age, weight and comorbid disease): 
i. Lidocaine 50 – 100mg 
ii. Fentanyl 50 – 100mcg 
iii. Propofol 100 – 200 mg 
iv. Rocuronium 50 – 100mg 
b. Intraoperative (standard of care) 
i. Sevoflurane 1 – 2% or desflurane 4 – 6% 
ii. Fentanyl, hydromorphone, ketorolac and / or ketamine IV as 
needed on suspicion of pain. 
iii. antibiotics were given intravenously 2g of cefazolin or 900mg of 
clindamycin. 
4. All patients will receive the standard of care for indicated lumbar spine procedures. 
5. Patients in the study group will receive liposomal bupivacaine at the end of the procedure 
(following fascial closure, but prior to superficial closure). LB should be injected slowly 
and deeply, infusing ~1-2 mL according to manufacture guidelines for infiltration. 
According to these guidelines, injection should utilize a moving needle technique (ie, 
inject while withdrawing the needle) at multiple locations surrounding the incision(s) to 
achieve maximal effect. Care will be taken to aspirate prior to injection to minimize the 
risk of intravascular injection of medication.  
6. Patients in the control group will utilize the same technique of injecting as the study 
group, however, with normal saline.  
7. If necessary, patients will be given additional pain medications to facilitate extubating 
following surgery. 
8. All patients will receive a standardized inpatient pain protocol based on ASA guidelines 
for acute pain management in the post-op period.  
a. MILD PAIN (score 1-4) 
i. Acetaminophen 1000mg PO q6hr PRN 
ii. Ibuprofen 800mg PO q4hr PRN 
iii. Acetaminophen-codeine 1 Tablet PO q4h PRN  
iv. Acetaminophen-Hydrocodone 325mg-5mg PO q4h PRN 
v. Acetaminophen-Oxycodone 325mg-5mg PO q4h PRN 


Page 5 of 8 
vi. Oxycodone IR 5mg PO q4hr PRN  
vii. Morphine 2mg IV q4h PRN mild breakthrough pain 
viii. Hydromorphone 0.5mg IV q4h PRN mild breakthrough pain 
b. MODERATE PAIN (5-7) 
i. Acetaminophen-codeine 2 Tablets PO q4h PRN  
ii. Acetaminophen-Hydrocodone 325mg-5mg PO, 2 tablets, q4h PRN 
iii. Acetaminophen-Oxycodone 325mg-5mg PO, 2 tablets, q4h PRN 
iv. Oxycodone IR 5mg PO, 2 tablets, q4hr PRN  
v. Ketorolac 15mg IV q8h PRN 
vi. Morphine 2mg IV q4h PRN moderate breakthrough pain 
vii. Hydromorphone 0.5mg IV q4h PRN moderate breakthrough pain 
c. SEVERE PAIN (8-10) 
i. Acetaminophen-Hydrocodone 325mg-5mg PO, 2 tablets, q4h PRN 
ii. Ketorolac 30mg IV q8hr PRN 
iii. Oxycodone IR 5mg PO, 2 tablets, q4hr PRN 
iv. Morphine 4mg IV q2h PRN severe breakthrough pain 
v. Hydromorphone 1mg IV q4h PRN severe breakthrough pain 
9. Data collection: 
a. Inpatient opioid utilization will be obtained from the patient chart from 
authorized research staff. Outpatient opioid utilization will be obtained by 
patient pain log. Patients who are discharged will be contacted by research 
personnel every other day to ensure adequate follow-up and compliance to 
study protocol. Opioids will be quantified by post-op day and converted to 
standard morphine milliequivalents (MME) for comparison.  
b. Visual analog pain scales will be collected from inpatients every hour for 
the first 6 hours postop, then every 4 hours for the duration of the hospital 
stay to determine appropriateness of PRN medications.  
c. Outpatient VAS  and pain medication log will be utilized each day until 
the first post-operative clinic visit, about 2 weeks post-op. Patients who 
are discharged will be contacted by research personnel every other day to 
ensure adequate follow-up and compliance to study protocol. 
d. Patient length of hospital stay will be obtained by authorized research staff 
from the patient chart.  
e. Additionally, data for time in the operating room, time spent in the PACU,  
intraoperative complications (fracture, vascular injury, and anesthesia-
related), acute postoperative complications (medical, nerve injury, 
dislocation, hematoma, and wound complications), opioid complications 
(nausea, hypoxia, increased O2 requirement, post-op ileus), and cost of 
local infiltrates will be collected from patient charts. 
10. Data analysis: 
a. Opiate consumption, pain scores, and hospital length of stay will be 
analyzed comparing the study and control groups. The study and control 
groups will then be subdivided based on the type of procedure (single-
level lumbar spine without fusion, single-level lumbar spine with fusion, 
multi-level lumbar spine without fusion, multi-level lumbar spine with 


Page 6 of 8 
fusion). Study and control patients will be analyzed using either unpaired 
t-test or Mann-Whitney U test depending on the data normality. 
b. Categorical data will be compared using chi-square test or Fisher’s Exact 
test.  
c. Data will be analyzed by our team of biostatisticians within the 
department of Orthopedic Surgery.  
d. Primary outcome: Opiate utilization 
e. Secondary outcomes: Visual analog pain score and hospital length of stay 
11. Patient removal criteria will include: 
a. Need to convert surgery to involve intradural space. 
b. Unintentional breach of intradural space.  
c. Patients with neurologic impairment following surgery, of which was not 
present prior to operation. 
d. Patient fails to comply with post-op instructions and limitations. 
12. The study will be ended prematurely if an obvious superiority of treatment group over 
control submerges during data analysis.  
 
 
 
1. Risks for surgery in both groups are no different from patients who are not enrolled in the 
study.  
2. General risks for lumbar spine surgery include the risk of bleeding, infection, wound 
dehiscence, injury to surrounding structures, and lower extremity paresthesia or paralysis.  
3. Foreseeable discomfort will be no different from patients undergoing the same procedure 
who are not enrolled in the study. There will be foreseeable discomfort in perioperative 
pain, which will be minimized based on techniques outlined in the study procedures. 
4. Risk to patients given liposomal bupivacaine include nausea, vomiting, constipation, 
unintentional intravascular injection which could result in dysrhythmias and depressed 
cardiac conductivity, in rare cases leading to death. Great care is taken during injection of 
the medication to aspirate the injection site to avoid intravascular infiltration. 
Methemoglobinemia has been reported with use of local anesthetic. It’s important to note, 
however, that these rare, yet potentially life-threatening, complications are not unique to 
liposomal bupivacaine, rather these are risks associated with the drug class as a whole. 
5. If serious complications occur (cardiac, respiratory, neurologic, hypoxemias, or other 
unanticipated serious complications), that are suspected by the physician to be related to 
the use of liposomal bupivacaine, these events will be reported to the PI within 24 hours 
of the event occurrence. The PI will then report this complication to the IRB within 5 
days of becoming aware of the event.  
 
 
 
1. Anticipated benefits to the patient will be potentially: 
a. less or equivalent post-operative pain  
b. Less need for opioid pain medications, decreasing individual risk of developing 
tolerance, chronic need for opioid pain medication, and risk of developing opioid 
use disorder.  
VIII.
Potential Risks/Adverse Events
IX.
Anticipated Benefits


Page 7 of 8 
2. Anticipated benefit to society: 
a. Providing a long-acting postoperative pain modality to potentially reduce patient 
need for opioids. 
b. Less need for providers to prescribe opioids for acute postop pain management 
will potentially lead to less opioid diversion on a societal level. 
c. Less post-operative pain leads to earlier time to ambulation and shorter hospital 
stays, ultimately moving lumbar spine procedures closer to the goal of moving 
toward same-day outpatient procedures. 
 
 
 
 
1. N/A 
 
 
 
 
1. Cost of liposomal bupivacaine and sterile normal saline 
2. Cost of research personnel  
3. Cost of statistician services 
4. Cost of investigational drug study services 
 
 
 
 
The PI will be responsible for maintaining safety of the data. The PI will monitor the data to 
ensure study protocol is being followed. Both the patient master list and coded data will be 
monitored by the PI.  
 
All procedures involved in this study will be conducted with the same degree of privacy 
consideration used for standard of care with these procedures. All data will be collected and 
stored in electronic format. Study data will be coded and stored separately from the patient 
master list. The electronic data will be stored on a secure MU network and password protected. 
Data will be monitored and curated by the involved approved research staff as designated by the 
IRB for this project. Data will be deidentified and analyzed via statistical software once the data 
has been gathered per the study protocol.  
 
The patient is at no greater than minimal risk due to the data being collected. To minimize the 
risk of the use of private records, only members of the research staff will have access to any of 
these records. The data will be stored for a minimum of 7 years per MU policy. Any electronic 
data will be stored on a secure server. They will be deleted appropriately at the end of the storage 
period. Any breach in data security will be immediately reported to the IRB within five days of 
detection.  
 
 
 
1. This study will be performed at a single site. 
X.
Compensation
XII.
Data Safety Monitoring Plan
XI.
Costs
XIII.
Multiple Sites


Page 8 of 8 
2. The University of Missouri Hospital and Missouri Orthopaedic Institute will be utilized 
according to attending physician schedule and availability 
3. Both institutions have all required approvals necessary to participate in the proposed 
study 
 
 
 
 
1. Postoperative Pain and Length of Stay Lowered by Use of Exparel in Immediate, 
Implant-Based Breast Reconstruction 
2. Daniel R Butz 1, Deana S Shenaq 1, Veronica L M Rundell 1, Brittany Kepler 1, Eric 
Liederbach 1, Jeff Thiel 1, Catherine Pesce 1, Glenn S Murphy 1, Mark Sisco 1, Michael 
A Howard 1 
3. Postoperative Pain Management after Spinal Fusion Surgery: An Analysis of the Efficacy 
of Continuous Infusion of Local Anesthetics. Richard A. K. Reynolds,1 Julie E. 
Legakis,1 Jillian Tweedie,2 YoungKey Chung,3 Emily J. Ren,4 Patricia A. BeVier,2 
Ronald L. Thomas,5 and Suresh T. Thomas2 
4. A Novel Liposomal Bupivacaine Formulation to Produce Ultralong-Acting Analgesia 
Gilbert J. Grant, M.D.,* Yechezkel Barenholz, Ph.D.,† Elijah M. Bolotin, Ph.D.,‡ 
Mylarrao Bansinath, Ph.D.,§ Herman Turndorf, M.D., Boris Piskoun, B.S.,# Elyad M. 
Davidson, M.D.** 
5. The Use of Exparel (Liposomal Bupivacaine) to Manage Postoperative Pain in Unilateral 
Total Knee Arthroplasty Patients Jonathan W. Surdam, MD, David J. Licini, MD , 
Nathan T. Baynes, PA-C, Britney R. Arce, BSN, RN, CRRN 
6. Practice Guidelines for Acute Pain Management in the Perioperative Setting: An Updated 
Report by the American Society of Anesthesiologists Task Force on Acute Pain 
Management. https://pubs.asahq.org/anesthesiology/article/116/2/248/12956/Practice-
Guidelines-for-Acute-Pain-Management-in  
7. https://www.cdc.gov/drugoverdose/epidemic/index.html 
8. https://www.exparel.com/hcp/about-exparel/dosing-and-administration 
XIV.
References/Appendices