Does Liposomal Bupivacaine Improve Postoperative Pain Control After One Level Posterior Spinal Fusion With Instrumentation
Phase: PHASE4
Conditions: Lumbar Spinal Stenosis, Lumbar Disc Herniation, Lumbar Disc Disease, Lumbar Spondylolisthesis
Sponsor: Allina Health System

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Does liposomal bupivacaine improve postoperative pain control 
after one level posterior spinal fusion with instrumentation? 
 
Christopher Alcala-Marquez, MD 
Principal Investigator 
 
Manuel R. Pinto, MD 
Co-Investigator 
 
Twin Cities Spine Surgeons and Allina Health 
 
Study Synopsis 
This study will describe postoperative pain management for spine surgery patients receiving 
Exparel® (liposomal bupivacaine) compared to patients not receiving the drug. It is a prospective, 
randomized Phase 4 (post-market) clinical trial with two cohorts: Group A: standard of care (SOC) 
plus Exparel (n=30) and Group B: SOC (n=30).  All subjects will undergo open single-level 
posterior decompression and instrumented fusion for degenerative spondylolisthesis. The surgery 
is not an experimental procedure. Prior to closing the surgical wound, Exparel will be 
administered to Group A. The administration of the drug is a study procedure. Postoperatively, 
subjects will be assessed for pain and opioid consumption. The study is funded by the John H. 
Moe Research Fund of Twin Cities Spine Center. Study procedures occur at Twin Cities Spine 
Center and Allina Health facilities. Subjects incur no costs. 
 
Background 
Postoperative Pain Management 
Good pain control after surgery is associated with higher satisfaction rates.1 On the other hand, 
inadequate postoperative pain management is associated with patient dissatisfaction with medical 
care.2 It has been shown that Patient Controlled Analgesia (PCA) reduces postoperative pain but 
the opioids delivered can provoke adverse effects such as respiratory depression leading to 
hypoxemia (decreased blood oxygen saturation). Such adverse effects may prolong 
hospitalization.3,4 The Joint Commission recommends that surgical-site specific local anesthetic 
infiltration be considered for acute postoperative pain management for those procedures when 

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evidence indicates efficacy.5 Locally-injected analgesic drugs can significantly reduce PCA, 
increase patient satisfaction, and decrease length of stay.1 
 
Liposomal Bupivacaine for Postoperative Pain  
Liposomal bupivacaine (Exparel) may be injected locally to achieve postoperative pain control 
for 72-96 hours.6 Exparel was first approved by the US FDA for analgesia following 
bunionectomy and hemorrhoidectomy. Subsequently, the drug has been approved more broadly 
for post-surgical pain. Table 1 outlines a number of clinical trials conducted on patients 
undergoing total knee arthroplasty and total hip arthroplasty. Overall, patients receiving 
liposomal bupivacaine experienced less postoperative pain, used less opioid, and had shorter 
hospital stays. These and other studies also demonstrated that common instrumentation materials 
are unaffected by the drug and none have an adverse effect on the drug.13 
 
Investigator 
Patient Population 
Study Design 
Outcome 
Barrington7 
Total Joint 
Arthroplasty 
(Knee and Hip) 
Liposomal 
bupivacaine injection 
(LBUP) (n=1124) 
versus multimodal 
anal-gesia including 
periarticular injection 
(n=1124) 
Pain scores were significantly 
lower in the LBUP group for both 
hip and knee procedures. There 
was an increased number of pain-
free patients, a decreased LOS, 
trends toward decreased falls, and 
a decreased overall cost for the 
LBUP cohort. 
Cheridan8 
Total Hip 
Arthroplasty 
Liposomal bupi-
vacaine  (LBUP) 
suspension (n=5267) 
versus standard 
analgesic regimens 
(n=54,604) 
Length of stay for the LBUP 
cohort was shorter compared to 
no injection cohort. Numbers 
patients being discharged to home 
compared to a short-term nursing 
facility or a rehab facility were 
higher in the LBUP cohort.  
Chughtai9 
Total Knee 
Arthroplasty 
Liposomal 
bupivacaine (LBUP) 
suspension 
(n=14,668) versus no 
injection (n=80,160) 
Length of hospital stay was 
shorter for the LBUP cohort. 
Patients being discharged to home 
compared with short-term nursing 
facility or rehabilitation was high-
er in the LBUP cohort co-pared 
with the no injection cohort 
Emerson10 
Total Hip 
Arthroplasty 
Routine wound 
infiltration (RWI) 
(n=36) versus 
liposomal 
bupivacaine 
Pain scores were significantly 
higher for RWI patients overall 
and trended higher for each day 
after surgery up to day 5. The 
average number of opioid doses 

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infiltration injection 
(LBUP) (n=36) 
was 2.6x greater for the RWI 
group compared the LBUP group. 
The total opioid dosage consumed 
was greater in the RWI group. 
Emerson11 
Total Knee 
Arthroplasty 
Continuous femoral 
nerve block (FNB) 
(n=36) versus 
liposomal 
bupivacaine 
infiltration injection 
(LBUP) (n=36) 
The average number of narcotic 
doses and the total number of 
narcotics consumed was greater 
in the FNB group. Average visual 
analog scale pain scores trended 
higher for FNB patients overall 
and for each day postoperatively 
up to day 5, although the overall 
difference was not significant in 
this study sample.  
Yu12 
Total Hip 
Arthroplasty 
Intraoperative 
liposomal 
bupivacaine injection 
(LBUP) (n=586) 
versus standard pain 
management protocol 
(n=686) 
Pain scores were similar between 
cohorts; LBUP cohort had de-
creased total narcotic use up to 
postoperative day 2 and physical 
therapy milestones were better 
achieved. OR time and hospital 
cost were unaffected. LB cohort 
exhibited a decrease in length of 
stay by 0.31 days and improve-
ment in discharge disposition to 
home. 
 
Liposomal Bupivacaine for Postoperative Pain in Spine Patients 
Kim et al. compared lidocaine HCL to saline control in patients undergoing one-level lumbar 
laminectomy and discectomy.14 The investigators intravenously administered lidocaine HCl 
preoperatively and throughout the spine surgery. Lydocaine HCL significantly reduced PCA 
consumption and decreased length of stay compared to the control. Because lydocaine HCL 
typically has an elimination half-life of 1.5 to 2 hours,15 it must be administered repeatedly or 
continuously for post-surgical pain management. In contrast, liposomal bupivacaine is 
formulated for delayed release and has an effective duration of up to 96 hours. For this reason, 
liposomal bupivacaine is now being tested for postoperative pain management in patients who 
have undergone spine surgery (Table 2). While the results are encouraging, medical evidence is 
presently insufficient to recommend adopting the routine the use of Exparel in spine surgery 
patients. There have been no published prospective randomized control (Level I evidence) 
clinical trials to evaluate its efficacy and potential complications in spine surgery. 
 
 

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Investigator 
Patient Population 
Study Design 
Outcome 
Grieff16 
Posterior cervical 
de-compression 
and fusion or 
lumbar fusion for 
spondylolisthesis 
and/or stenosis 
Consecutive 
prospective case 
series (n=52 cervical 
and n=64 lumbar), 
bupivacaine HCL 
(Marcaine™) (n=65) 
versus liposomal 
bupivacaine (n=51) 
A trend toward decreased 
PCA use with liposomal 
bupivacaine in comparison with 
bupivacaine hydrochloride was 
observed. The study suffered 
from low statistical power. 
Kim17 
Transforaminal 
Lumbar Interbody 
Fusion (TLIF) 
Liposomal 
bupivacaine (n=38) 
versus non-liposomal 
local anesthetic 
(n=38) 
Significantly lower pain scores, 
significantly fewer narcotic 
equivalents consumed, and 
significantly shorter lengths of 
stay for the LBUP group 
compared to the control group. 
Puffer18 
Single-level 
microsdiscectomy 
Prospective case 
series (n=40) versus 
historical control 
(n=40) 
Significant decrease in length of 
time for narcotic pain medication 
for study group compared to 
control. No significant differences 
between cohorts in VAS pain in 
the postoperative period, in total 
injectable morphine equivalent 
doses, or in 30-day emergency 
room visits for pain 
Tomov19 
Single-level TLIF 
Retrospective case-
control series (n=16 
intervention cohort, 
n=14 control cohort) 
Significantly less morphine 
equivalents of intravenous 
narcotic use postoperatively in the 
intervention cohort from day of 
surgery to postoperative day 3 
compared to control. 
Wang20 
Endoscopic single-
level MIS TLIF 
without general 
anesthesia 
Consecutive 
retrospective case 
series (n=10)  
Length of hospital stay was 
reduced from typical 2 days to 1 
day; Functional scores were 
statistically improved from 
preoperative values. 
 
Objectives 
Opioids have demonstrated efficacy and often are drugs of choice for postoperative pain 
management. However, they are also associated with adverse effects including vomiting, 
pruritus, dizziness, somnolence, nausea, and constipation.21 There are additional severe risks 
such as respiratory depression, bradycardia, and hypotension.22 Long term adverse effects 
include iatrogenic addiction and opioid-induced hyperalgesia. Such complications have been 
shown to increase length of stay, costs, and mortality.23,24 Prescribing liposomal bupivacaine for 

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postoperative pain management may reduce a patient’s need for opioids and thereby decrease his 
or her pain scores and reduce his or her risk of adverse events; costs to ANW Hospital will be 
potentially reduced as the incidence of adverse events would be less. 
 
Study Design 
This is a prospective randomized clinical trial with two cohorts: one experimental and one 
control. Our hypothesis for statistical analysis is that there will be a 30% decrease in pain 
medication requirement for the experimental group (Group A: Exparel) versus the control group 
(Group B: No Exparel). Based upon the data of others,14 this would be a large effect (Cohen’s 
d=1.4, Effect size (r) = 0.6). For this anticipated effect size, a power level of 90% and a 
probability level of 5%, the minimum sample size per group is 9 for a one-tailed hypothesis. This 
study is designed for 30 subjects per cohort. We expect drop out to be low, so we also expect 30 
per group to be sufficient.  
 
The power analysis was based on a two-sample t-test. In the absence of data on the primary 
outcome variable (area under the curve (AUC) of the VAS pain intensity scores) to perform a 
power analysis, the decrease in analgesic use for the experimental group was used as a surrogate 
variable. Information on this substitute variable was gleaned from Grieff 2016, Yu 2016, and 
Chughtai 2016 (references cited in the protocol). We note that the proposed sample size is 
similar to that of other published studies cited in the protocol. 
 
Test Article 
Name 
Exparel® (liposomal bupivacaine). 
 
Dosage 
Exparel® (bupivacaine liposome injectable suspension) 20 mL single use vial, 1.3% (13.3 
mg/mL), Maximum dose of 266 mg (20 mL). 
 
Method/route of administration 
Inject Exparel® slowly into soft tissue via infiltration. 
 

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Mechanism of action 
Local anesthetics block the generation and the conduction of nerve impulses presumably by 
increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the 
nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression 
of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve 
fibers. Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, 
(3) touch, (4) proprioception, and (5) skeletal muscle tone. 
 
Known Drug Interactions 
Exparel® should not be admixed with lidocaine or other non-bupivacaine-based local anesthetics, 
Exparel® may be administered after at least 20 minutes or more have elapsed following local 
administration of lidocaine, Bupivacaine HCl, when injected immediately before or admixed 
with Exparel®, may impact the pharmacokinetic and/or physicochemical properties of the drugs.  
 
Known side effects 
Adverse reactions reported with an incidence greater than or equal to 10% following Exparel® 
administration were nausea, constipation, and vomiting. 
 
Manufacturer/Sponsor 
Pacira Pharmaceuticals, Inc. 
 
Name of Supplier 
Pacira Pharmaceuticals, Inc. 
 
Location of Supply 
Abbott Northwestern Hospital Pharmacy, United Hospital Pharmacy. 
 
IND Exemption 
The test drug is liposomal bupivacaine (Exparel®). Per the “Guidance for Clinical Investigators, 
Sponsors, and IRBs Investigational New Drug Applications (INDs) — Determining Whether 
Human Research Studies Can Be Conducted Without an IND,” clinical investigation of a 

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marketed drug is exempt from the IND requirements if all of the criteria for an exemption in § 
312.2(b) are met:  
• 
The drug product is lawfully marketed in the United States.  
 
This drug is lawfully marketed in the US. 
• 
The investigation is not intended to be reported to FDA as a well-controlled study in support 
of a new indication and there is no intent to use it to support any other significant change in 
the labeling of the drug.  
 
This drug will be used according to its current indications for use; there is no intent to use it 
to support a change in labeling. 
• In the case of a prescription drug, the investigation is not intended to support a significant 
change in the advertising for the drug. 
 
This study is an investigator-initiated study; the investigators have no relationship – financial 
or otherwise – with the manufacturer. 
• The investigation does not involve a route of administration, dose, patient population, or other 
factor that significantly increases the risk (or decreases the acceptability of the risk) 
associated with the use of the drug product (21 CFR 312.2(b)(1)(iii)). 
 
This drug will be administered in a manner consistent with its current instructions for use.        
• The investigation is conducted in compliance with the requirements for review by an IRB (21 
CFR part 56) and with the requirements for informed consent (21 CFR part 50).  
 
The Allina Health IRB is reviewing this study and its informed consent aspects. 
• The investigation is conducted in compliance with the requirements of § 312.7 (i.e., the 
investigation is not intended to promote or commercialize the drug product).  
 
This investigation is not intended to promote or commercialize the drug. 
Therefore, the test drug does not require an IND. 
 
Subject Selection 
Inclusion Criteria 
To be a participant, a patient must have both of the following: 
1. 
Have a primary diagnosis of single-level lumbar stenosis, disc herniation, and/or 
spondylolisthesis excluding degenerative disc disease 
2. 
Receive open, one-level posterior spinal fusion 
 

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Exclusion Criteria 
Excluded patients meet one or more of the following: 
1. Are opioid-tolerant. Opioid tolerant patients are receiving, for one week or longer, at least 60 
mg oral morphine/day, 25 mcg transdermal fentanyl/hour, 30 mg oral oxycodone/day, 8 mg 
oral hydromorphone/day, 25 mg oral oxymorphone/day, or an equianalgesic dose of another 
opioid.25 
2. Experienced intraoperative complications (i.e., a dural tear or durotomy). Intra- and post-
operative data will be excluded from the analysis for these patients. 
3. Have severe liver disease. Bupivacaine is primarily metabolized in the liver via conjugation 
with glucuronic acid. Patients with liver disease, especially severe disease may be more 
susceptible to toxicity. 
4. Have severe renal disease. Bupivacaine and the metabolite are primarily excreted by the 
kidneys. Excretion can be significantly changed by urinary perfusion, the presence of renal 
disease, factors affecting urinary pH, and renal blood flow 
5. Are less than 18 years old. 
6. Is pregnant. 
7. Cannot read and speak English. 
 
Study Procedures 
Subject Consenting 
The PI or co-PI will identify a potential subject in clinic based upon his diagnosis and 
recommended surgical treatment. Either will explain the study to the patient and ask if he/she 
would be interested in participating. If the patient is interested in participating, the investigator or 
his clinic nurse will contact TCSC research staff to come to the clinic to consent the patient. 
TCSC will discuss the study with the patient in a private clinic examination room and consent 
the subject. The potential subject must not be pregnant as demonstrated by a pregnancy test (this 
is SOC) and must not have severe liver or renal disease as demonstrated by a complete metabolic 
plan  
 
Pain Assessments 
After written patient consent is obtained, subjects will be instructed on the use of the 100-mm 
Visual Analog Scale (VAS) for pain26 and the Overall Benefit of Analgesia Score (OBAS).27  

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Visual Analog Pain Scale (VAS) (Attachment 1) 
Respondents indicate their pain by marking a position long a line between 0 (no pain) and 
10 (intolerable pain) (Attachment, Page 1). Scores will be obtained when the patient is 
transferred to the hospital spine care unit from the Post-anesthesia Care Unit (PACU) 
(“Index”), once per day thereafter (every 24 hours), and at hospital discharge 
(“Discharge”). Subjects will be instructed to give responses in relation to their incision 
and drain sites only. 
 
Overall Benefit of Analgesia Score (OBAS) (Attachment 2) 
Respondents complete seven questions, each with a score of 0 to 4 (Attachment, Page 2); 
the OBAS ranges between 0 (complete relief of pain) and 28 (no benefit). Scores will be 
obtained once per day (every 24 hours) after the patient is transferred from the PACU and 
at discharge from the hospital (“Discharge”).  (Note: Time intervals are approximate to 
respect the comfort of the patient. It is not, for instance, intended to awaken the subject in 
the middle of the night.) Subjects will be instructed at the time of each assessment to give 
responses in relation to their incision and drain sites only. 
 
Assessment Schedule 
Assessment 
Transfer from PACU 
(“Index”) 
Once per day 
(Every 24 hours) 
Hospital Discharge 
(“Discharge”) 
VAS 
Yes 
Yes 
Yes 
OBAS 
No 
Yes 
Yes 
 
Randomization 
Randomization will be performed prior to surgery using sealed envelopes. Sixty (60) envelopes 
will be sequentially numbered and 60 chits with either the letter “A” (SOC+Exparel group, 
n=30) or the letter “B” (SOC, n=30) will be prepared. Chits will be drawn at random and 
sequentially placed in the envelopes, which will be sealed. For each consented subject, when 
surgery is scheduled, an envelope will be opened and the surgery worksheet annotated, as 
appropriate. 
 
Blinding 
This will be a semi-blinded trial. Investigators cannot be for the following reasons:  

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1. Exparel is a milky-white substance that will be recognizable; to use a placebo of similar 
appearance (such as neutral buffered sterile saline with colorant) would introduce an 
experimental substance. 
2. Group A subjects will receive 140ml of Exparel plus saline plus free bupivacaine. The 
administration of the same volume of a placebo may itself cause pain. 
Subjects will be blinded and will not be informed if they received the study drug or not. 
 
Intraoperative Administration of Exparel 
Intraoperatively at closing, for Group A patients, 140ml Exparel plus Bupivacaine plus saline 
will be injected under the skin and into the paraspinal muscles of the surgical wound and at the 
drain site.  (Note: 140ml = 20ml Exparel 1.3% (266mg) + 50ml 0.25% Bupivacaine (150mg) + 
70ml preservative-free 0.9% neutral saline. This volume will be equally divided between four 
20cc syringes with 20-21 gauge spinal needles for deep injections and three 20cc syringes with 
20-21g 1½” long needles for subdermal and drain site injections.) Cardiovascular status, 
neurological status, and vital signs will be routinely monitored during and after injections. Group 
B patients will receive SOC.  
 
Postoperative pain control 
Post-operative pain will be managed per patient needs versus a set protocol. Dilaudid or 
Morphine Sulfate is sometimes administered post-operatively for pain via Patient-Controlled 
Analgesia (PCA). The PCA system is typically programmed to administer incremental doses of 
0.2 mg Dilaudid or 1 mg Morphine Sulfate at intervals of not less than 10 minutes and not more 
than 6 mg Dilaudid or 30mg Morphine Sulfate in a 4 hour period. Typically, the PCA will be 
discontinued after 24 hours (unless prevented by patient need). Subjects should not receive 
additional bupivacaine for pain during their hospitalization. 
 
Risk/Safety Information 
In ten prior clinical studies cited by the drug manufacturer (Pacira Pharmaceuticals, Inc.), the 
most common adverse reactions with incidence greater than or equal to 10% were nausea, 
constipation, and vomiting. Adverse reactions with incidence greater than or equal to 2% to less 
than 10% were fever, dizziness, swelling of the legs, feet, ankles, arms, or hands, lowered ability 
of the blood to carry oxygen, low blood pressure, severe itching of the skin, abnormally rapid 

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heart rate, headache, insomnia, anemia, postoperative muscle spasms, anemia resulting directly 
from loss of blood, back pain, drowsiness or sleepiness, and procedural pain. Other less common 
side effects have been reported (each occurring in less than 2% of patients): chills, superficial 
reddening of the skin, abnormally slow heart rate,  anxiety, urinary retention, pain, watery fluid 
collection in the cavities or tissues of the body, tremor, postural dizziness, abnormal skin 
sensation (such as tingling), fainting, incision site reddening, procedural high blood pressure, 
procedural low blood pressure, procedural nausea, muscular weakness, neck pain, generalized 
itching, itching rash, sweating, cold sweat, hives, palpitations, abnormal heartbeat, abnormally 
fast heartbeat, hypertension, pallor, anxiety, confusional state, depression, agitation, restlessness, 
abnormally low level of oxygen in the blood, uncontrolled/involuntary muscular contraction of 
the vocal chords, suspension of breathing, respiratory depression, respiratory failure, body 
temperature increased, blood pressure increased, blood pressure decreased, oxygen saturation 
decreased, urinary incontinence, vision blurred, ringing in the ears, drug hypersensitivity, and 
hypersensitivity. 
 
The drug manufacturer has previously trained research and ANW spine OR, and spine floor staff, 
21-22 August 2017. New in-training will be provided to ANW floor staff and to United spine 
floor and OR staff by the Principal Investigator and TCSC Research Staff. Training will occur at 
a staff meeting, before or after shift change prior to the start of subject enrollment. Training will 
include a short didactic presentation (10 minutes) followed by time for questions. In addition to 
an overview of the study, the drug manufacturer’s “Patient Fact Sheet” and “Nurse Information 
Sheet” (see Attachments) will be provided as educational material. We will provide examples of 
the patient assessments (VAS and OBAS) as well. Pharmacy, Anesthesia, and PACU are already 
familiar with the study drug at ANW and United hospitals. 
 
Monitoring/Reporting of AE/SAE 
The Principal Investigator (PI) will monitor for Unanticipated Problems Involving Risk to 
Subjects or Others (UPIRTSO) including Adverse Events (AE) and Serious Adverse Events. 
(Definitions of these are detailed in the Allina Health Human Research Protection Program and  
Institutional Review Board (HRPP/IRB) Standard Operating Procedures.) Per the SOP, the PI 
will report a death, a Serious Adverse Event, or an Unanticipated Problem to the IRB within 7 
days. The Allina Health IRB “Event Report” will be used. 

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Safety Monitoring Plan 
Safety will be monitored by experts who are knowledgeable about the disease and treatment 
under study, who will be able to interpret the data to ensure patient safety, and who have no 
direct involvement with the study. Experts include Joseph H. Perra, MD, Twin Cities Spine 
Center staff surgeon (fellowship trained and board certified), Matthew R Monsein, MD (board-
certified in chronic pain management), and Stan Skinner, MD (board-certified in neurology). 
Each will sign a Conflict of Interest Statement which includes any relationship that could be 
perceived as a conflict of interest including commercial or non-commercial interests pertinent to 
study objectives. The PI will provide a report of safety (Serious Adverse Events and 
Unanticipated Problems, UPIRTSO) to them twice a year. The report will also include updates 
on study progress, procedures for maintaining the confidentiality of data, the quality of data 
collection, and UPIRTSO. They will conduct an ad hoc safety review within 30 days of receipt. 
They will make a recommendation to continue, terminate or modify the study based on observed 
benefit or harm. If individuals given the investigational intervention (Exparel) are found to be at 
higher risk for UPIRTSO including AEs and SAEs than those not receiving the drug, the Board 
may consider recommending early termination on safety grounds. The Board may also consider 
recommending early termination if external reports raise serious, unexpected safety concerns. 
 
Study Oversight 
Study data will be made available for monitoring, auditing, IRB review and regulatory inspection 
by providing direct access to study related source data. The study may be prematurely closed for 
administrative reasons by the Principal Investigator (for examples, lack of enrollment, lack of 
adequate research staffing, lack of adequate funding). The study may be prematurely by the 
safety monitors based on study progress or UPIRTSO. 
 
Data Management 
Data Collection – Primary Outcome   
The primary outcome is the area under the curve (AUC) of the VAS pain intensity scores from 
when the patient is transferred to the hospital spine care unit from the PACU (“Index”) until 
hospital discharge (“Discharge”). This will be calculated using the trapezoidal rule. The AUC 
will be adjusted for differences in length of hospital stay. Discharge criteria include ability to 

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self-ambulate or self-care, no signs of wound problems, absence of infectious signs or increased 
infectious parameters, and pain controlled by oral analgesics. 
 
Data Collection – Secondary Outcomes 
1. 
Proportion of subjects who are pain free (VAS pain intensity score of ≤1.5 and no prior 
rescue medication), Index until Discharge in 24 hour intervals 
2. 
OBAS, Index until Discharge, in 24 hour intervals 
3. 
Total postsurgical opioid consumption (morphine equivalents), Index until Discharge 
4. 
Percentage of opioid-free subjects, Index until Discharge 
5. 
Time to first opioid rescue, Index until Discharge 
6. 
Opioid-related adverse events, Index until Discharge: respiratory depression, 
hypoventilation, hypoxia, dry mouth, nausea, vomiting, constipation, altered mental 
status, pruritus, urinary retention, and postoperative ileus 
7. 
Costs (e.g., hospital room, drugs, laboratory, physical therapy, and respiratory therapy), 
until discharge. 
8. 
Length of stay from Index until Discharge 
 
Data Collection – Tertiary Outcomes 
Collected patient information will include sex, age, height, weight, ASA physical status, 
smoking status, worker’s compensation claim status, and co-morbidities (diabetes, chronic 
kidney disease, coronary artery disease, and chronic obstructive pulmonary disease). 
Perioperative data to be documented includes duration of anesthesia, intraoperative 
complications, duration of surgery (from skin incision to end of closure), and time in PACU. 
 
Data Analyses 
Research staff members will be abstracting data. They will be trained by the Lead Study 
Coordinator to collect data in the same manner. Results will be analyzed by descriptive and 
inferential statistics. We will look for difference between cohorts using t-tests; if the data are 
robust, then a regression analysis will be considered. Assumptions for statistical tests will be 
tested and alternate tests used if necessary. Missing data will be assessed and reported; it will not 
be imputed.  
 

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IRB Review/Ethics/Informed Consent 
The protocol, informed consent document and relevant supporting information will submitted to 
the IRB for review and must be approved before the study is initiated. This study will be 
conducted in accordance with the ethical principles that have their origin in the Declaration of 
Helsinki and that are consistent with Good Clinical Practice and applicable regulatory 
requirements. The study will be conducted in accordance with the regulations of the United 
States Food and Drug Administration (FDA) as described in 21 CFR 50 and 56 [add 312 for IND 
studies or 812 for device studies], applicable laws and the IRB requirements. A protocol change 
intended to eliminate an apparent immediate hazard to subjects may be implemented 
immediately provided the IRB is notified within 10 working days.  
 
It will be the responsibility of the investigator to provide each subject with full and adequate 
verbal and written information using the IRB-approved informed consent document, including 
the objective and procedures of the study and the possible risks involved before inclusion in the 
study. Informed consent will be obtained prior to performing any study-related procedures, 
including screening and changes in medications including any washout of medications. A copy 
of the signed informed consent will be given to the study subject.  
 
Confidentiality 
Data will be stored on TCSC computers, which are linked by Allina Health servers. No data will 
be physically removed from TCSC. The United States Food and Drug Administration may 
inspect all records related to the study. The IRB and/or other regulatory authorities (for example, 
the United States Food and Drug Administration) will have access to study-related medical 
records. Study-related records identifying the subject will be kept confidential and, to the extent 
permitted by applicable laws and/or regulations will not be made publicly available. If any 
results of the study are published, the subject’s identity will remain confidential.  
 
Intended Use of the Data 
The study investigators may publish the results of the study in medical journals and society 
meetings. The study investigators may use the results to modify the Standard of Care. 
 
 

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Study Funding 
This study is funded through the Twin Cities Spine John H. Moe Research Fund. No funds from 
the drug manufacturer are being used to pay for this study. None of the study investigators or 
staff are receiving support of any kind from the manufacturer. Study procedures will occur at 
Twin Cities Spine Center and Allina Health facilities. Subjects incur no costs. 
 
References 
1. Vaishya R, Wani AM, Vijay V. Local Infiltration Analgesia reduces pain and hospital stay 
after primary TKA: randomized controlled double blind trial. Acta Orthop Belg. 2015 
Dec;81(4):720-9. 
2. Apfelbaum JL, Chen C, Mehta SS, Gan TJ. Postoperative pain experience: results from a 
national survey suggest postoperative pain continues to be undermanaged. Anesth Analg. 
2003 Aug;97(2):534-40. 
3. Dias AS, Rinaldi T, Barbosa LG. The impact of patients controlled analgesia undergoing 
orthopedic surgery. Braz J Anesthesiol. 2016 May-Jun;66(3):265-71. Epub 2015 Apr 17. 
4. McBeath DM, Shah J, Sebastian L, Sledzinski K. The effect of patient controlled analgesia 
and continuous epidural infusion on length of hospital stay after total knee or total hip 
replacement. CRNA. 1995 Feb;6(1):31-6. 
5. Gordon DB. American Pain Society Acute Postoperative Pain Guidelines. JCR Webinar, 
Sept 2015. Available at http://www.jcrinc.com/acute-postoperative-pain-guidelines. 
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6. Chahar P, Cummings KC. Liposomal bupivacaine: a review of a new bupivacaine 
formulation. J Pain Res. 2012; 5: 257–264. Published online 2012. 
7. Barrington JW, Olugbode O, Lovald S, Ong K, Watson H, Emerson RH Jr. Liposomal 
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Bupivacaine Suspension Can Reduce Length of Stay and Improve Discharge Status of 
Patients Undergoing Total Hip Arthroplasty. Surg Technol Int. 2015 Nov;27:235 
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Program in Total Hip Replacement. J Surg Orthop Adv. 2015 Winter;24(4):235-41. 
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2016 May 1;39(3):e449-55. Epub 2016 Mar 29. 
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Reference ID: 3860081. 14 December 2015. Available at http://media.corporate-
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Page 18 of 21 
 
Version A, 19 October 2018 
 
Attachment – Patient Assessments (Page 1) 
 
Visual Analog Pain Scale 
 
 
Instructions:  
 
a. Attach patient sticker or complete information below 
b. Ask the subject to complete the two statements below. Score is determined by measuring in 
millimeters from the left hand end of the line to the point that the patient marks 
c. Record when the assessment was made and by whom 
 
Patient Name (Last, First MI) ___________________, ___________________  _____ 
Date of Birth (DD/MM/YYYY) ___ ___ / ___ ___ / ___ ___ ___ ___ 
MRN ___ ___ ___ ___ ___ ___ 
 
 
1. How severe is your pain at the place where you were operated on (your incision site)? 
 
 
 
 
 
Score: _____ 
 
 
2. How severe is your pain at the place where your surgeon placed a drain? 
 
 
 
 
Score: _____ 
 
 
 
 
 
 
 
 
Assessment: 
 
 
 Post-
 
 
 
 
 
 
 
 
Time (HH:MM DD/MM/YYYY) ___ ___ : ___ ___ AM/PM ___ ___ / ___ ___ / ___ ___ ___ ___ 
 
 
(Circle) 
 
Assessor Name (Last, First MI) ___________________, ___________________   _____ 
Attach Patient 
Sticker Here 
No 
Pain 
Intolerable 
Pain 
No 
Pain 
Intolerable 
Pain 

Page 19 of 21 
 
Version A, 19 October 2018 
 
Attachment – Patient Assessments (Page 2) 
 
Overall Benefit of Analgesia Score (OBAS) 
 
 
Instructions: 
 
a. Attach patient sticker or complete information below 
b. Ask the subject to complete the seven statements below. Record responses in the rating 
column. The score is the sum of items 1 – 6 and “4-score in item 7.” 
c. Record when the assessment was made and by whom 
 
Patient Name (Last, First MI) ___________________, ___________________  _____ 
Date of Birth (DD/MM/YYYY) ___ ___ / ___ ___ / ___ ___ ___ ___ 
MRN ___ ___ ___ ___ ___ ___ 
 
With respect to the place where the place where you were operated on (your incision site) and 
the place where your surgeon placed a drain: 
1. 
Please rate your current pain at rest on a scale between 
 
0=minimal pain and 4=maximum imaginable pain 
 
______ 
2. 
Please grade any distress and bother from vomiting in the past 
24 hours (0=not at all to 4=very much)  
______ 
3. 
Please grade any distress and bother from itching in the past 
24 hours (0=not at all to 4=very much)  
______ 
4. 
Please grade any distress and bother from sweating in the past 
24 hours (0=not at all to 4=very much)  
______ 
5. 
Please grade any distress and bother from freezing in the past 
24 hours (0=not at all to 4=very much)  
______ 
6. 
Please grade any distress and bother from dizziness in the past 
24 hours (0=not at all to 4=very much)  
______ 
7. 
How satisfied are you with your pain treatment during the 
past 24 hours (0=not at all to 4= very much)  
4 - ______ = ______ 
Overall Benefit of Analgesia Score 
______ 
 
 
 
Assessment: 
 
 
 Post-
 
 
 
 
 
 
 
 
Time (HH:MM DD/MM/YYYY) ___ ___ : ___ ___ AM/PM ___ ___ / ___ ___ / ___ ___ ___ ___ 
 
 
(Circle) 
 
Assessor Name (Last, First MI) ___________________, ___________________   _____ 
Attach Patient 
Sticker Here 

Page 20 of 21 
 
Version A, 19 October 2018 
 
Attachment: Educational Materials (Page 1) 

Page 21 of 21 
 
Version A, 19 October 2018 
 
Attachment: Educational Materials (Page 2)