Clinical trial NCT04685876
Conditions: Abdominal Surgery
Sponsor: Edward Mascha
Start date: 2021-06-04; Completion date: 2024-02-20
Enrollment: 285 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study will prospectively compare the analgesic efficacy of TAP blocks with liposomal bupivacaine, plain bupivacaine, and placebo in patients who are scheduled for major abdominal surgery. The primary aim is to assess the duration of the local analgesia (determined by pinprick and cold) in all four quadrants. Comparing opioid consumption and pain scores is a secondary aim. All aims will be assessed over 72 hours or the duration of hospitalization if shorter.

Detailed description:
The investigators propose a randomized double-blind trial comparing TAP blocks with liposomal bupivacaine, plain bupivacaine, and placebo in patients having elective abdominal surgery.

After eligibility is confirmed, patients will receive complete information about the study both verbally and in writing. Informed consent will be obtained from the patients prior to randomization and study-specific procedures.

Randomization will be based on computer-generated codes and use random-sized blocks. Allocations will be concealed until the morning of surgery where they will be provided by a web-based system. Randomization will be stratified by study site and chronic opioid use, defined by opioid use for more than 30 consecutive days within three preoperative months, at a daily dose of 15 mg or more of morphine or equivalent. Randomization will also be stratified according to anticipated type of surgery (open vs. laparoscopic-assisted). Clinicians doing the blocks will not be involved in data collection and all the evaluators will be blinded to group allocations.

All blocks will be performed preoperatively or after induction of anesthesia by attending anesthesiologists or regional anesthesia fellows who are experienced in TAP blocks. Premedication will be administered at the discretion of the attending anesthesiologist and standard monitors will be used. Patients will be given 1 g oral acetaminophen an hour before surgery, and an additional 500 mg every 6 hours for 72 hours after surgery starting with oral intake.

Patients will be randomly assigned to: 1) 4-quadrant TAP block with liposomal bupivacaine; 2) 4-quadrant TAP block with plain bupivacaine; or, 3) placebo (normal saline). An in-plane ultrasound will be guide TAP blocks. Two subcostal injections will be applied by placing the probe midline and then moving lateral along the subcostal margin identifying area between the rectus abdominis sheath and the transversus abdominis muscle. The lateral two TAP block injections will be applied in the midaxillary line between the thoracic cage and iliac crest between external oblique and transversus abdominis muscles. Once the target area is positioned, the following injections will be given, based on randomization:

Liposomal bupivacaine. 40 ml of plain bupivacaine 0.25% will be mixed with 20 ml liposomal bupivacaine and 20 ml of saline. 20 ml of the mix will be injected at each location of the 4-quadrant TAP block.

Plain bupivacaine group. 50 ml of plain bupivacaine 0.5% will be combined with 30 ml of normal saline making a total of 80 ml. 20 ml will be injected at each location of the 4-quadrant TAP block.

Placebo group; patients will receive total of 80 ml of normal saline, injected 20 ml in each of the four-quadrant sites.

General anesthesia will be induced using propofol or etomidate, fentanyl, and rocuronium to facilitate intubation. Anesthesia will be maintained with sevoflurane or isoflurane, along with opioids and muscle relaxants as clinically indicated. However, intraoperative analgesic use will be limited to fentanyl, a short-acting opioid.

Postoperatively, patients will be given intravenous patient-controlled analgesia and nurses will be free to give additional opioid as clinically indicated. Hydromorphone will be the default drug, but fentanyl will be substituted if necessary. Clinicians blinded to trial drug will adjust analgesic management as necessary in an effort to keep verbal response pain scores (details below) \<4 points on a 0-10 scale, with 10 being worst pain. When patients no longer need PCA, they will be switched to as-needed hydromorphone or fentanyl.

A single dose of dexamethasone (4-8 mg) will be permitted for PONV prophylaxis, and inhaled steroids will be permitted as necessary to treat reactive airway disease. The use of non-steroidal anti-inflammatory drugs and gabapentinoids will be allowed as part of the ERAS approach (enhanced recovery after surgery) according to hospital's clinical practice. Other opioid-sparing medications such as ketamine and lidocaine patches will not be permitted through the initial 72 postoperative hours.

Patients will be allowed to receive prophylactic anti-emetic (first choice ondansetron) intraoperatively based on the risk assessment for nausea and vomiting. Postoperative anti-emetics for symptomatic treatment will also be allowed; again ondansetron will be the first choice.

Arms: arm 1: 40 ml of plain bupivacaine 0.25% will be mixed with 20 ml liposomal bupivacaine and 20 ml of saline. 20 ml of the mix will be injected at each location of the 4-quadrant TAP block. arm 2: 50 ml of plain bupivacaine 0.5% will be combined with 30 ml of normal saline making a total of 80 ml. 20 ml will be injected at each location of the 4-quadrant TAP block. arm 3: patients will receive total of 80 ml of normal saline, injected 20 ml in each of the four-quadrant sites.
Interventions: intervention 1: Liposomal bupivacaine intervention 2: Plain bupivacaine intervention 3: Normal saline
Intervention descriptions: intervention 1: 4-quadrant TAP block with liposomal bupivacaine intervention 2: 4-quadrant TAP block with plain bupivacaine intervention 3: placebo (normal saline).

Protocol documents:
Prot_SAP_000.pdf: 
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Comparison of Liposomal Bupivacaine, Plain 
Bupivacaine, and Placebo for Transversus 
Abdominis Plane Blocks: 
A Randomized, Blinded Trial 
NCT04685876 
 
 
 
Alparslan Turan, MD,  
And Colleagues 
 
 
 
Department of OUTCOMES RESEARCH 
Cleveland Clinic 
 
 
 
 
 


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Amendments 
Amendment 1: 10/1/2021 
Summary of Changes:  
1. The primary outcome was changed to opioid consumption in the first 24 hours and 24-48 
hours after surgery. 
2. The secondary outcomes are now abdominal wall sensation with ice and pinprick, pain 
scores 72 hours after surgery, and opioid consumption 48-72 hours after surgery. 
3. Sample Size Considerations was updated to reflect the changes in the study outcomes.  
 
 


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Table of Contents 
Specific Aims ......................................................................................................................... 4 
1. Background ....................................................................................................................... 6 
A. Postoperative Pain .....................................................................................................................6 
B. Postoperative pain management and Regional Analgesia ............................................................6 
C. Transversus Abdominis Block ......................................................................................................7 
D. Liposomal bupivacaine (Exparel; bupivacaine liposome injectable suspension, Pacira 
Pharmaceuticals, Inc., Parsippany, NJ USA) .....................................................................................9 
E. Rationale of the Study .............................................................................................................. 12 
2. Study Objectives .............................................................................................................. 13 
3. Method and Study Design ................................................................................................ 16 
A. Study Overview ........................................................................................................................ 16 
B. Setting and Population ............................................................................................................. 16 
Inclusion criteria ................................................................................................................................................. 16 
Exclusion criteria: ................................................................................................................................................ 16 
C. Withdrawal Criteria .................................................................................................................. 17 
D. Protocol ................................................................................................................................... 17 
E. Measurements ......................................................................................................................... 19 
F. Data Analysis ............................................................................................................................ 22 
G. Sample Size Considerations ...................................................................................................... 25 
H. Economic Analysis ............................................................................ Error! Bookmark not defined. 
3. References ....................................................................................................................... 27 
 
 
 


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Specific Aims 
Pain management after major abdominal surgery remains challenging. The best-
accepted traditional analgesic approach is continuous epidural analgesia. However, 
epidural analgesia is rapidly being replaced by transversus abdominis plane (TAP) 
blocks. TAP infiltration is an alternative to epidural blocks for providing postoperative 
analgesia to the anterior abdominal wall. TAP infiltrations are relatively easy to perform, 
generally safe, and can be performed in patients who are anti-coagulated. TAP infiltration 
can be performed as a single injection, or a catheter can be inserted for continuous local 
anesthetic infusion.  
Single shot plain bupivacaine is often used for TAP blocks, but plain bupivacaine 
provides <24 hours of analgesia Catheters provide analgesia for longer, but they are 
difficult to position properly and difficult to maintain in the proper anatomical location. An 
alternative to TAP catheters is infiltration of liposomal bupivacaine which, in other sites, 
lasts up to three days. But whether liposomal bupivacaine is preferable to plain 
bupivacaine for TAP blocks remains controversial, with available studies being sparse 
and inconclusive. 
We therefore proposed to compare single-shot TAP infiltration with liposomal 
bupivacaine, plain bupivacaine, and placebo on length of anesthetic effect  determined by 
the opioid consumption. We will evaluate the following specific aims, all of which will be 
assessed over 72 hours, or the duration of hospitalization if shorter:  
 
 Primary Aim 1: To assess the relative effects of TAP blocks with liposomal bupivacaine, 
plain bupivacaine and placebo on cumulative opioid consumption in first 24 hours with 
TAP blocks.  
Primary Aim 2: To assess the relative effects of TAP blocks with liposomal bupivacaine, 
plain bupivacaine and placebo on cumulative opioid consumption in 24 to 48 hours with 
TAP blocks. 


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Secondary Aim 1: To assess the relative effects of TAP blocks with liposomal 
bupivacaine, plain bupivacaine and placebo on the duration of abdominal wall analgesia 
(determined by pinprick and cold).  
Secondary Aim 2: To assess the relative effects of TAP blocks with liposomal 
bupivacaine, plain bupivacaine and placebo on pain after surgery in first 72 hours.  
Secondary Aim 3: To assess the relative effects of TAP blocks with liposomal 
bupivacaine, plain bupivacaine and placebo on cumulative opioid consumption 48 to 72 
hours. 
Tertiary Aim 1: To compare the effects of TAP blocks with liposomal bupivacaine, plain 
bupivacaine, and placebo on a composite of postoperative opioid-related side effects.  
Tertiary Aim 2: To compare the effects of TAP blocks with liposomal bupivacaine, plain 
bupivacaine and placebo on patients’ satisfaction with their pain treatments after 72 
hours/discharge surgery. 
Tertiary Aim 3: To assess total and specific costs of hospital care in patients receiving 
TAP with liposomal bupivacaine vs. those with plain bupivacaine following abdominal 
surgery. [2 groups only] 
Tertiary Aim 4: To compare the effects of TAP blocks with liposomal bupivacaine, plain 
bupivacaine and placebo on patients’ pain with movement for 72 hours/discharge surgery. 
Tertiary Aim 5. To compare the effects of TAP blocks with liposomal bupivacaine, plain 
bupivacaine and placebo on patients’ mobility for 72 hours/discharge surgery. 
 
 
 
 


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1. Background 
A. Postoperative Pain 
Pain is a psychological sensory experience that is provoked by surgical tissue 
injury. Postoperative pain results from a of combination of nociceptive and inflammatory 
components.1 The nociceptive component results from activation of peripheral sensory 
neurons damaged by surgical incision and fades gradually as tissues heal. The 
inflammatory component enhances pain sensitivity via release of mediators from 
surgically injured tissue. Central neuronal sensitization also seems to contribute to 
postoperative pain and hyperalgesia.1,2 Both mechanisms contribute to resting pain is in 
and around surgical incisions. Movement of wounds or touching them, breathing, 
coughing, and gastrointestinal motility can all provoke pain. 
Postoperative pain causes a number physiological and psychological 
consequence, which potentially worsen outcomes. For example, inadequate 
perioperative analgesia is associated with myocardial ischemia, impaired wound healing, 
delayed 
gastrointestinal motility, 
atelectasis, 
and 
postoperative 
pneumonia.3-5 
Furthermore, poorly controlled acute pain is strongly associated with development of 
persistent incisional pain, which can be devastating for patients.6,7 
B. Postoperative pain management and Regional Analgesia 
Pain management after major abdominal surgery is difficult and complicated. Thirty 
percent of patients report severe postoperative pain and 47% report moderate pain.8 
Furthermore, 10-40% report persistent pain after abdominal and pelvic surgery.9 
Multimodal analgesia combines various classes of drugs in an effort to provide good 
analgesia with few side effects.1,10,11 But the most common approaches are a combination 
of an opioid and non-opioid, with or without regional anesthesia-analgesia.11 Opioids 
cause various complications including ileus, sedation, and hyperalgesia. Opioids also 
impair cellular and humoral immune function in humans, thereby potentially enhancing 
infection risk.13-16 But the most lethal complication of opioid use is respiratory depression 
which has been identified as a safety target by the Joint Commission on Hospital 
Accreditation.12 Reducing perioperative opioid use is thus a clinical priority. 


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Regional Anesthesia or analgesia reduces the need for high-dose opioids. 
Regional analgesia techniques can be categorized as neuraxial (spinal and epidural 
blocks) that involve injection of local anesthetics around the spinal cord, or as peripheral 
nerve blocks that involve local anesthetic administration near peripheral nerves. The 
basis of regional analgesia is local anesthetics which locally block voltage-gated sodium 
channels, thus interrupting nerve conductions and causing regions to be insensitive to 
pain.17 Peripheral nerve blocks, especially, have become popular in recent decades 
largely because improvements in ultrasound technology make blocks faster and safer — 
and more importantly, because peripheral nerve blocks speed recovery and improve 
patient satisfaction.18  
Surgery provokes a stress response which releases catecholamines, cortisol, and 
inflammatory cytokines systemically.19 The stress response is associated with increased 
catabolism, immunosuppression, poor postoperative outcomes, and prolonged 
recovery.20,21 Regional anesthesia blocks afferent neural transmission from reaching the 
central nervous system and activating the stress response, thereby blocking descending 
efferent activation of the sympathetic nervous system.22-24 In clinical practice, regional 
anesthesia has proven to be superior to systemic opioids alone after thoracic, abdominal, 
gynecological, and orthopedic surgeries.25-28 Studies have consistently shown that 
regional anesthesia reduces postoperative pulmonary, gastrointestinal, and cardiac 
morbidities. Furthermore, there is evidence that RA decreases postoperative morbidity 
and mortality, and shortens postoperative hospitalization.29-32  
Epidural analgesia is the reference method for controlling post-operative pain after 
abdominal surgery. However epidural analgesia provokes hypotension, delays 
mobilization and discharge. Furthermore, catheter related problems are common, as is 
failure of epidural analgesia. Rarely, epidural analgesia results in inadvertent dural 
puncture, epidural hematoma, abscess, cord compression, and permanent paraplegia 
due to hematoma. An important limitation of epidural analgesia is that it should not be 
used in anticoagulated patients. These limitations have prompted clinicians to use 
alternative blocks, including the transvers abdominal block.    
C. Transversus Abdominis Block 


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Transversus Abdominis Block was described by Rafi in 2001 and provides post-
operative analgesia for anterior abdominal wall.33 The target area of the local anesthetics 
is between the transvers abdominis and internal oblique muscle to block the spinal nerves 
(T6-L1). There are various types of TAP blocks, including intercostal/subcostal, 
lateral/classical, anterior, and posterior approaches.34 
Figure 1: 4-quadrant TAP block 
 
 
Ultrasound-guided TAP blocks are easier and safer than epidural blocks, and 
complications are rare. TAP blocks are generally performed with a single injection, 
because catheters are tricky to insert properly and are frequently dislodged, especially 
when they are near the surgical site.44 TAP blocks have been used for various types of 


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surgeries including open appendectomies, hysterectomies, caesarean deliveries, 
abdominoplasties, 
prostatectomies, 
renal 
transplantation, 
and 
laparoscopic 
procedures.35-41 In open gynecologic surgeries, cesarean deliveries, and open 
gastrectomies, bilateral TAP blocks provides better analgesia than placebo groups.33  
All anterior branches of spinal nerves communicates, each segmental nerve 
supplies different areas and therefore analgesic effect and sensorial distribution of local 
anesthetics vary.42 Four-quadrant TAP blocks (Bilateral Dual) were described by Borglum 
et al. and provides wider coverage for upper- and lower-abdominal wall incisions because 
there is no communication between upper and lateral TAP spaces. (Figure 1).43 Dual 
blocks combine subcostal and lateral/posterior TAP blocks, thus providing complete 
coverage. Four quadrant TAP blocks should be performed to have good coverage 
especially for any incision that goes above umbilicus.  
TAP blocks only provide somatic pain relief; they therefore provide analgesia for 
surgical incisions, but not for visceral pain. Numerous studies show that TAP block with 
plain bupivacaine provided substantially better analgesia and reduced opioid 
consumption compared to unblocked or placebo patients for up to 24 hours.44 TAP blocks 
with 
conventional 
local 
anesthetics 
including 
bupivacaine, 
ropivacaine 
and 
levobupivacaine in TAP block provide safe and effective analgesia, but only for the initial 
24 postoperative hours. Long-acting local anesthetics are an alternative that might 
provide analgesia through the initial and most painful postoperative days.    
D. Liposomal bupivacaine (Exparel; bupivacaine liposome injectable 
suspension, Pacira Pharmaceuticals, Inc., Parsippany, NJ USA)  
Exparel is the prolonged-release formulation of the bupivacaine used for a single-
shot infiltration of surgical sites or for nerve blocks. Exparel was approved by the US Food 
and Drug Administration (FDA) in 2011 for infiltration blocks, and in 2018 it received 
approval for the interscalene brachial plexus block.45 
Liposomal bupivacaine depofoam technology is based on multiple microscopic 
spherical particles with many aqueous chambers separated by lipid membranes. When 
refrigerated, the particles are stable; but after injection of liposomal bupivacaine into soft 


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tissue, bupivacaine is released from the multivesicular liposomes. The components of 
depofoam particles are non-toxic and clinical trials have demonstrated no adverse events. 
Furthermore, this technology previously has been safely used in various settings and 
provides sustained release of bupivacaine in other target areas. Liposomal bupivacaine 
administration 
produces 
dose-dependent 
increases 
in 
plasma 
bupivacaine 
concentrations, and that the half-life of liposomal bupivacaine was almost twice that of 
plain bupivacaine. However, maximum plasma concentrations are no higher with plain 
than liposomal bupivacaine.  
a. Infiltration and liposomal bupivacaine   
Postsurgical pain is intense in first few days and liposomal bupivacaine may be 
good option for controlling post-surgical pain. Many studies have evaluated infiltration of 
liposomal bupivacaine. Golf et al,46 for example, compared liposomal bupivacaine and 
placebo in bunionectomies. Cumulative pain scores were lower, and the time to first 
opioid use was significantly prolonged by liposomal bupivacaine. Hass et al.47 compared 
bupivacaine and various doses of liposomal bupivacaine in hemorrhoidectomies and 
found progressive reductions in opioid consumption as the dose of liposomal bupivacaine 
increased. Postoperative opioid consumption was significantly lower in patients given 
266 mg of Exparel than in those given plain bupivacaine over 12 to 72 hours 
postoperatively. Local infiltration of liposomal bupivacaine also reduced postoperative 
pain compare with plain bupivacaine. A recent meta-analysis of 10 randomized wound 
infiltration studies concluded that cumulative pain scores were improved with liposomal 
bupivacaine through 24-72 hours. First use of opioid rescue medication was also delayed, 
and patient were more satisfied and experienced fewer opioid-related side effects.48 
A systematic review that evaluated liposomal bupivacaine infiltration for total hip 
arthroplasty showed that local liposomal bupivacaine infiltration reduced pain score, 
nausea and vomiting, and opioid consumption. However, this analysis was weakened by 
inclusion of studies with small sample sizes and others that were observational.49 The 
PILLAR cohort study compared liposomal and plain bupivacaine infiltration for total knee 
arthroplasty and showed that 10% of patients in liposomal bupivacaine group were opioid 
free. Total opioid consumption and pain intensity score also less when compared to 


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bupivacaine group. These PILLAR study results suggest that local infiltration of liposomal 
bupivacaine is analgesic and reduces or even eliminates the need for opioids after total 
knee arthroplasty.50 A number of studies report that liposomal bupivacaine has good 
efficacy and safety profiles in patients having knee, hip, and shoulder replacements.51-61 
Liposomal bupivacaine has also been effective in plastic surgical procedures including 
mammoplasty and abdominoplasty, and provides longer pain relief. However, dose 
heterogeneity and small sample sizes make these results difficult to interpret.  
b. Nerve block and liposomal bupivacaine  
Single-shot peripheral nerve blocks with liposomal bupivacaine have distinct 
advantages compared to a continuous catheter. Specifically, patients given liposomal 
bupivacaine will not require infusion pumps and cannot develop catheter-related infection, 
hematoma, or dislodgement. Because liposomal bupivacaine was only recently approved 
for peripheral nerve blocks, and only at one site, there is currently little information about 
the approach. However, Hadzic et al. compared liposomal bupivacaine to placebo for 
femoral nerve blocks and found lower pain score and decreased opioid consumption were 
reduced.62 A retrospective analysis of peripheral nerve blocks with liposomal bupivacaine 
suggests that safety and the side effect profile are similar with bupivacaine and placebo.63 
Intercostal nerve blocks with liposomal bupivacaine were evaluated after thoracic 
surgeries and compared with plain bupivacaine. Liposomal bupivacaine reduced hospital 
duration — but curiously without a reduction in postoperative pain score or opioid use.64,65 
Further studies are clearly needed to evaluate the efficacy of liposomal bupivacaine in 
nerve blocks.66 
c. TAP block and liposomal bupivacaine 
So far only a few trials directly compare liposomal and plain bupivacaine for TAP 
blocks, and there is no consensus among them. According to a Cochrane systemic 
review, evidence is lacking for the efficacy of liposomal bupivacaine in TAP blocks, and 
concludes that there is no advantage to use of liposomal bupivacaine for this indication.67 
It is important to recognize, though, that this conclusion is based on lack of evidence for 
benefit rather than robust evidence against. In another study, Guarre et al.68 compared 


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plain and liposomal bupivacaine in TAP blocks for laparoscopic colorectal surgery. 
Patients treated with liposomal bupivacaine required less opioid, had earlier return of 
bowel function, and left the hospital sooner. Hutchins et al.69 showed that TAP blocks with 
liposomal bupivacaine provided long-lasting analgesia compared to plain bupivacaine for 
laparoscopic-assisted donor nephrectomy, and reduced nausea and vomiting and the 
duration of hospitalization.69 In contrast, Ha et al.70 compared liposomal bupivacaine and 
plain bupivacaine in TAP blocks for breast reconstruction and reported no benefit.70 
E. Rationale of the Study  
The recent enhancement of conventional bupivacaine with encapsulated 
bupivacaine much prolongs the duration-of-action and resulting pain control with a single 
application. TAP blocks appear to be easier to perform (especially with ultrasound 
guidance), safer, relatively inexpensive, and can be used safely in patients who are anti-
coagulated. However, the literature is scarce on comparison of plain bupivacaine versus 
liposomal bupivacaine in TAP blocks. Some clinicians therefore question the efficacy and 
benefit of liposomal bupivacaine for TAP blocks, especially considering the cost of 
liposomal bupivacaine. We therefore aim to compare the analgesic efficacy of TAP blocks 
with liposomal bupivacaine, plain bupivacaine, and placebo in patients who are scheduled 
for major abdominal surgery. 
 
 


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2. Study Objectives 
We will prospectively compare the analgesic efficacy of TAP blocks with liposomal 
bupivacaine, plain bupivacaine, and placebo in patients who are scheduled for major 
abdominal surgery. The proposed research will have the following aims:  
  
Primary Aims 
  Primary Aim 1: 
          To assess the relative effects of TAP blocks with liposomal bupivacaine, plain 
bupivacaine and placebo on opioid consumption in first 24 hours post surgery.  
Hypothesis. Opioid consumption over the initial 24 hours after major abdominal surgery 
is less when four-quadrant TAP blocks are performed with liposomal bupivacaine and 
plain bupivacaine compared to placebo. Opioid consumption will be evaluated as 
morphine sulfate equivalents; a difference of at least 10 mg in first 24 hours will be 
considered to be a clinically meaningful difference.   
Primary Aim 2: 
To assess the relative effects of TAP blocks with liposomal bupivacaine, plain 
bupivacaine and placebo on opioid consumption between 24 and 48 hours post surgery.  
Hypothesis. Opioid consumption between 24 and 48 hours after major abdominal surgery 
is less when four-quadrant TAP blocks are performed with liposomal bupivacaine than 
with plain bupivacaine or placebo. Opioid consumption will be evaluated as morphine 
sulfate equivalents; a difference of at least 10 mg will be considered to be a clinically 
meaningful difference.   
Criteria for success will be 1) superiority of bupivacaine and exparel groups over placebo 
and noninferiority between plain bupivacaine and exparel groups in the first 24 hours of 
opioid consumption and superiority of exparel group over placebo and bupivacaine in the 
24-48 
hours 
opioid 
consumption.   
 
Criterion for success of each intervention in each period.  
0-24 hours: for each of bupivacaine and exparel, success will be concluded if found to be 
superior over placebo (i.e., less opioid consumption).  As well, exparel or bupivacaine will 
be concluded better than the other if found superior on opioid consumption. 


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24-48 hours:  exparel will be concluded successful if found better than both placebo and 
bupivacaine in the 24-48 hours opioid consumption.   
 
Secondary Aims   
Secondary Aim 1:  
            To assess the duration of the local analgesia (determined by pinprick and cold) in 
all four quadrants with liposomal bupivacaine, plain bupivacaine, and placebo after major 
abdominal surgery. 
Hypothesis. Abdominal wall analgesia from four-quadrant TAP blocks with single‐shot 
liposomal bupivacaine lasts longer after major abdominal surgery than the same blocks 
with plain bupivacaine or placebo. Our major outcome will be time from end of the block 
until abdominal wall sensation with both ice and pinprick recovers in at least six of eight 
designated locations. Two sequential evaluations will be needed to be negative and first 
negative time point will be accepted as the return of sensation. 
Secondary Aim 2:  
           To compare the effect of liposomal bupivacaine, plain bupivacaine, and placebo 
on pain after surgery in first 72 hours or the duration of hospitalization if shorter. 
Hypothesis. Pain scores over the initial 72 hours or duration of hospitalization after major 
abdominal surgery are lower when four-quadrant TAP blocks are performed with 
liposomal bupivacaine than with plain bupivacaine or placebo. Pain will be assessed on 
a 0-10-point scale (10 points being worst) at 4-hour intervals while patients are awake. A 
difference of at least 1.2 points will be considered clinically meaningful.  
 Secondary Aim 3: 
To evaluate TAP blocks with liposomal bupivacaine, plain bupivacaine, and 
placebo on opioid consumption in 24 to 48 hours.  
Hypothesis. Opioid consumption from the 48 to 72 hours or duration of hospitalization 
after major abdominal surgery is less when four-quadrant TAP blocks are performed with 
liposomal bupivacaine than with plain bupivacaine or placebo. Opioid consumption will 
be evaluated as morphine sulfate equivalents; a difference of at least 10 mg will be 
considered to be a clinically meaningful difference.   
Tertiary  


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Tertiary Aim 1. To compare the effect of liposomal bupivacaine, conventional 
bupivacaine, and placebo on a composite of opioid-related postoperative side effects. 
Hypothesis. Opioid-related side effects over the initial 72 hours or duration of 
hospitalization after major abdominal surgery are less common when four-quadrant TAP 
blocks are performed with liposomal bupivacaine than with plain bupivacaine or placebo. 
Opioid-related side effects will be evaluated as composite of events, and a difference of 
20% in incidence will be accepted as clinically important difference. 
Tertiary Aim 2. To compare the effect of liposomal bupivacaine, conventional 
bupivacaine, and placebo on satisfaction with their pain treatment after first 72 hours or 
the duration of hospitalization if shorter. 
Hypothesis.  Patients are more satisfied with pain management over the initial 72 hours 
or duration of hospitalization after major abdominal surgery when four-quadrant TAP 
blocks are performed with liposomal bupivacaine than with plain bupivacaine or placebo.  
Tertiary Aim 3. To assess total and specific costs of hospital care in patients receiving 
TAP with liposomal bupivacaine vs. those with plain bupivacaine following abdominal 
surgery. 
Tertiary Aim 4. To compare the effects of TAP blocks with liposomal bupivacaine, plain 
bupivacaine and placebo on patients’ pain with movement for 72 hours/discharge surgery. 
Hypothesis. Pain scores with movement over the initial 72 hours or duration of 
hospitalization after major abdominal surgery are lower when four-quadrant TAP blocks 
are performed with liposomal bupivacaine than with plain bupivacaine or placebo. Pain 
will be assessed on a 0-10-point scale (10 points being worst) at 12-hour intervals while 
patients are elevating their leg. A difference of at least 1.2 points will be considered 
clinically meaningful.   
Tertiary Aim 5. To compare the effects of TAP blocks with liposomal bupivacaine, plain 
bupivacaine and placebo on patients’ mobility for 72 hours/discharge surgery. 
Hypothesis. Total amount of mobilization over the initial 72 hours or duration of 
hospitalization after major abdominal surgery are higher when four-quadrant TAP blocks 
are performed with liposomal bupivacaine than with plain bupivacaine or placebo. 
 
 


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3. Method and Study Design 
A. Study Overview 
We propose a randomized double-blind trial comparing TAP blocks with liposomal 
bupivacaine, plain bupivacaine, and placebo in patients having elective abdominal 
surgery. The study will be performed at various Cleveland Clinic hospitals with IRB 
approval and written consent from patients. Study will be registered at ClinicalTrials.gov 
website before the first patient is enrolled. 
B. Setting and Population 
Inclusion criteria:  
(1) Written informed consent;  
(2) 18-85 years old;  
(3) ASA Physical Status 1-3;  
(4) Scheduled for elective open or laparoscopic-assisted abdominal surgery;  
(5) Anticipated hospitalization of at least three nights;  
(6) Expected requirement for parenteral opioids for at least 72 hours for 
postoperative pain;  
(7) Able to use IV PCA systems.  
 
Exclusion criteria:  
(1) Hepatic disease, e.g. twice the normal levels of liver enzymes;  
(2) Kidney disease, e.g. twice the normal level of serum creatinine;  
(3) Bupivacaine sensitivity or known allergy;  
(4) Women who are pregnant or breastfeeding;  
(5) Anticoagulants considered to be a contraindication for TAP blocks;  
(6) Surgeries with high port sites; 
(7) Weight <70 kg. 


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C. Withdrawal Criteria  
Patients will be free to withdraw from study at any time. Patients will also be 
removed from study at any time for adverse events, or deemed necessary for patient 
safety. 
D. Protocol 
After eligibility is confirmed, patients will receive complete information about the 
study both verbally and in writing. Informed consent will be obtained from the patients 
prior to randomization and study-specific procedures.   
Randomization will be based on computer-generated codes and use random-sized 
blocks. Allocations will be concealed until the morning of surgery where they will be 
provided by a web-based system. Randomization will be stratified by study site and 
chronic opioid use, defined by opioid use for more than 30 consecutive days within three 
preoperative months, at a daily dose of 15 mg or more of morphine or equivalent. 
Randomization will also be stratified according to anticipated type of surgery (open vs. 
laparoscopic-assisted). Clinicians doing the blocks will not be involved in data collection 
and all the evaluators will be blinded to group allocations. 
All blocks will be performed preoperatively or after induction of anesthesia by 
attending anesthesiologists or regional anesthesia fellows who are experienced in TAP 
blocks. Premedication will be administered at the discretion of the attending 
anesthesiologist and standard monitors will be used. Patients will be given 1 g oral 
acetaminophen an hour before surgery, and an additional 500 mg every 6 hours for 72 
hours after surgery starting with oral intake. 
Patients will be randomly assigned to: 1) 4-quadrant TAP block with liposomal 
bupivacaine; 2) 4-quadrant TAP block with plain bupivacaine; or, 3) placebo (normal 
saline). An in-plane ultrasound will be guide TAP blocks. Two subcostal injections will be 
applied by placing the probe midline and then moving lateral along the subcostal margin 
identifying area between the rectus abdominis sheath and the transversus abdominis 
muscle. The lateral two TAP block injections will be applied in the midaxillary line between 


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the thoracic cage and iliac crest between external oblique and transversus abdominis 
muscles. Once the target area is positioned, the following injections will be given, based 
on randomization: 
Liposomal bupivacaine. 40 ml of plain bupivacaine 0.25% will be mixed with 
20 ml liposomal bupivacaine and 20 ml of saline.  20 ml of the mix will be injected at each 
location of the 4-quadrant TAP block.  
Plain bupivacaine group. 50 ml of plain bupivacaine 0.5% will be combined with 
30 ml of normal saline making a total of 80 ml. 20 ml will be injected at each location of 
the 4-quadrant TAP block.  
Placebo group; patients will receive total of 80 ml of normal saline, injected 20 ml 
in each of the four-quadrant sites.  
General anesthesia will be induced using propofol or etomidate, fentanyl, and 
rocuronium to facilitate intubation. Anesthesia will be maintained with sevoflurane or 
isoflurane, along with opioids and muscle relaxants as clinically indicated. However, 
intraoperative analgesic use will be limited to fentanyl, a short-acting opioid.  
Postoperatively, patients will be given intravenous patient-controlled analgesia and 
nurses will be free to give additional opioid as clinically indicated. Hydromorphone will be 
the default drug, but fentanyl will be substituted if necessary. Clinicians blinded to trial 
drug will adjust analgesic management as necessary in an effort to keep verbal response 
pain scores (details below) <4 points on a 0-10 scale, with 10 being worst pain. When 
patients no longer need PCA, they will be switched to as-needed hydromorphone or 
fentanyl.  
A single dose of dexamethasone (4-8 mg) will be given to all patients for PONV 
prophylaxis, and inhaled steroids will be permitted as necessary to treat reactive airway 
disease. The use of non-steroidal anti-inflammatory drugs and gabapentinoids will be 
allowed as part of the ERAS approach (enhanced recovery after surgery) according to 
hospital’s clinical practice. Other opioid-sparing medications such as ketamine and 
lidocaine patches will not be permitted through the initial 72 postoperative hours. Vital 


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signs and patient activity will be continuously monitored and recorded with a wireless 
monitor (ViSi mobile, Sotera Wireless, San Diego, CA). Monitoring will be started about 
30 minutes after arrival in the postanesthesia care unit and continued for 72 hours while 
patients remained hospitalized. Clinicians will be blinded to continuous monitoring data; 
clinical decisions therefore will be guided by routine intermittent vital signs which were 
typically obtained at 4-hour intervals. 
Patients will be allowed to receive prophylactic anti-emetic (first choice 
ondansetron) intraoperatively based on the risk assessment for nausea and vomiting. 
Postoperative anti-emetics for symptomatic treatment will also be allowed; again 
ondansetron will be the first choice. 
E. Measurements 
Demographic data to be obtained includes height (cm), weight (kg), age (yr), sex, 
(ASA) physical status, self-declared ethnicity, and the specific type of procedure will be 
recorded. Patients will be questioned about tobacco and alcohol use, and about illegal 
drug use. They will also be asked about their medical history including pulmonary 
disease, kidney disease, diabetes mellitus, neurological disease, chronic pain conditions, 
previous surgery or stent placement, and medications. Available preoperative laboratory 
tests and medication list will be recorded. Preoperative pain scores and opioid use will be 
recorded. Patients excluded for any reason including technical considerations or 
contraindications will be recorded.   
All the procedures for the ultrasound guided TAP blocks will be recorded to the 
ultrasound and two blinded independent adjudicators will evaluate the success of the 
blocks. Blocks will be accepted as successful if 3 out of 4 locations were done correctly 
according to adjudicators.  
 
Primary Outcome 1 


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Opioid requirements will be measured as the total amount of opioids (converted to 
morphine sulfate equivalents) used during the first 24 postoperative hours after surgery. 
Use of PCA and discontinuation will be recorded.  
Primary Outcome 2 
Opioid consumption will be measured as morphine equivalents between 24-48 
hours.   
To evaluate TAP blocks with liposomal bupivacaine, plain bupivacaine, and 
placebo on opioid consumption in 24 to 48 hours. Use of PCA and discontinuation will be 
recorded. 
Secondary Outcome 1 
           The duration of the local anesthetic effect (determined by pinprick and cold) will be 
evaluated in all four quadrants. The evaluation will be made in eight locations, three in 
each side and two in midline. The first will be below the subcostal margin at midclavicular 
line, the second will be on the midclavicular line between the thoracic cage and iliac crest 
level of umbilicus, the third will be below umbilicus on the same line. The same sites will 
be evaluated on the contralateral side. There will be two more locations on midline. The 
first will be midway between umbilicus and xiphoid, and the second will be midway 
between umbilicus and midpoint of a line drawn between iliac crests.  
Cold tests will be performed by using ice contained in a clean nitrile glove, first 
applied to the patient’s forearm where they will be asked to describe how it feels to confirm 
ice cold. Then the same ice-filled glove will be applied to the same 8 points on the 
abdomen described above, asking the patient to confirm “yes” when they feel cold 
equivalent or greater to that on their forearm. Pinprick will be evaluated by calibrated force 
of 256 mN and a flat contact area of 0.2 mm in diameter using a stimulator (PinPrick 
Stimulator Set, MRC Systems, Heidelberg, Germany).  
The initial measurement will be in the preanesthesia care unit, prior to block 
administration. The first postsurgical evaluation will be performed within 5-30 minutes of 
the patient arriving in the post-anesthetic care unit (PACU) or the intensive care unit (ICU), 
whichever is applicable. Two further assessments will be performed in PACU/ICU/regular 


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nursing floor at one hour intervals. Subsequently, assessments will be performed at 2 
hourly intervals (x3) then at 12 hours postop (defined as patient leaving the OR), 18 hours 
postop, 24 hours postop, 30, 36 hours postop, 48 hours postop, 60 hours postop, 72 
hours postop (when patients are not sleeping). Testing will continue until abdominal wall 
sensation returns or 72 hours have elapsed since surgery. We will consider sensation 
recovered when patients feel both ice and pinprick in at least 6 of the 8 designated test 
locations. If the TAP block did not initially cover all eight locations, sensation will be 
considered recovered when patients sense ice and pinprick at ≥75% of the covered points 
(i.e., 5/7, 5/6, 4/5, 3/4, 3/3, etc.). Two sequential evaluations will be needed to be negative 
and first negative time will be accepted as the return of sensation. 
Secondary outcome 2 
Pain Scores after surgery will be measured using a Verbal Response Scale (VRS). 
VRS is a scale from 0 to 10 where 0 signifies no pain and 10 signifies worst pain ever 
experienced. The VRS will be recorded at the same intervals as cold and pinprick 
sensation assessment described in secondary outcome 2 above and thereafter at 4-hour 
intervals while patients are awake for 72 hours.  
Secondary outcome 3 
Opioid consumption will be measured as morphine equivalent in first between 48-
72 hours.   
To evaluate TAP blocks with liposomal bupivacaine, plain bupivacaine, and 
placebo on opioid consumption in 48 to 72 hours. Use of PCA and discontinuation will be 
recorded. 
Tertiary Outcome 1  
A composite of opioid-related side effect after surgery will be recorded for 72 hours. 
Components of the composite include nausea, vomiting, ileus, constipation, pruritus, 
itching, urinary retention, use of antiemetics or naloxone or antihistamines.  
 


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Tertiary Outcome 2 
Patients will be asked to rate their satisfaction with pain management at using a 0-
10 point scale at 72 hours or upon discharge if earlier.  
Tertiary Outcome 3 
Total cost of hospital care and specific care costs will be estimated from data in 
the electronic medical records database. Data obtained from electronic medical records 
will include: operation time, surgery type, intraoperative opioid consumption, 
postoperative opioid consumption in PACU and in ward, breakthrough pain medication 
requirements, pain scores in PACU and ward, requirement of oxygen in PACU and ward, 
pruritus, requirement of antihistaminic medications, requirement of naloxone, itching, 
ambulation time, flatus, ileus, bowel movements (first time documented), constipation, 
length of stay and any side effects or complications.  
Tertiary Outcome 4  
Pain Scores with movement after surgery will be measured using a Verbal 
Response Scale (VRS). The VRS will be recorded every 12 hours by asking patient to lift 
their legs up to 72 hours postop or until discharge, whichever is sooner. The patient will 
also be asked to report their VRS at rest prior to leg raise for reference.  
Tertiary Outcome 5. 
           Patient’s mobility will be obtained from VISI monitoring device for 72 
hours/discharge surgery 
 
F. Data Analysis 
Randomized groups will be compared for baseline balance using standard descriptive 
statistics and the standardized difference (difference in means or proportions divided by 
the pooled standard deviation). 
 


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Primary Outcomes.  Opioid consumption.  The following tests for superiority on opioid 
consumption will be conducted (see type I error control below):  1) 0-24 hours post-
surgery: compare each of exparel and plain bupivacaine to placebo; and 2) 24-48 hours 
post-surgery: compare exparel to each of plain bupivacaine and placebo.   Groups will be 
compared using linear regression on log-transformed morphine equivalents, with results 
reported as ratio of geometric means between each pair of interventions.   
Type I error control across Primary outcomes 1 and 2. We will use a parallel 
gatekeeping procedure to control the type I error at 5% across the 2 primary outcomes.  
The 2 comparisons for the 0-24 hour period will constitute Set #1, and the 2 comparisons 
for the 24-48 hour period will constitute Set #2. Within each set we will use the Holm-
Bonferroni (HB) multiple comparison procedure among the two comparisons.  If either 
test in the first Set is significant (HB: significance criterion of 0.025 for smaller P-value 
and 0.05 for the larger), analysis will continue to Set #2. Otherwise, Set #2 will not be 
analyzed.   If analysis proceeds to Set #2, the overall alpha for Set #2 will be 0.05 x 
proportion of significant tests in Set #1 (i.e., Set #2 alpha = either 0.05 x 1 or 0.05 x ,5 = 
0.025).  
Secondary Outcomes.    
Time to return of sensation.   We will compare the 3 randomized groups on the time to 
detection of return of sensation (see above; i.e., when patients feels both ice and pinprick 
in at least 6 of the 8 designated test locations, or ≥75% of the covered points if the TAP 
block did not initially cover all eight locations) using a time-to event Kaplan-Meier analysis 
and log-rank test, and comparing patients on the estimated median time to return of 
sensation.  If all patients do have return of sensation (as expected), the analysis will be 
equivalent to a Wilcoxon rank sum test, and so this test and the corresponding Hodges-
Lehman estimator of median difference (CI) will be reported as a sensitivity analysis. The 
significance criterion for each of the 3 comparisons will be 0.05/3 = 0.0167 to control the 
type I error at 0.05 for the primary outcome. 
Pain score. We will compare the 3 randomized groups on mean pain score over the first 
72 hours using a linear mixed effects model in which we adjust for within-subject 


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correlation assuming an autoregressive correlation structure (or unstructured or other, 
whichever fits best; but making sure to also account for the differences in timing between 
the measurements) with fixed effects of treatment and categorical time.  While we will 
assess the treatment-by-time interaction, main results will be reported collapsing over 
time regardless of a significant interaction. 
Opioid consumption 48-72 hours.  This will be analyzed using linear regression as with 
the primary outcomes. 
Type I error will be controlled at 0.05 for secondary outcomes by using a significance 
criterion of 0.05/3=0.017 for each outcome. 
Tertiary Outcomes. 
Groups will be compared on the collapsed composite of opioid-related side effects in the 
first 
72 
hours 
after 
surgery 
using 
chi-square tests.  Groups will be compared on satisfaction with pain management at using 
a 0-10 point scale at 72 hours, or upon discharge if earlier, using the Kruskal-Wallis test 
overall and Wilcoxon rank sum test between interventions.     
Economic Analysis.   Finally, if a treatment effect between the 2 local anesthetic TAP 
blocks is detected, we will conduct a cost-effectiveness analysis estimating the 
incremental cost-effectiveness ratio (ICER) as the mean difference in costs divided by the 
mean difference in the primary outcome of time to return of sensation [or an analogous 
ratio 
using 
summaries 
which 
best 
fit 
the 
distribution 
of 
the 
data].    
Total cost of hospital care and specific care costs will be estimated from data in the 
electronic medical records database. Data obtained from electronic medical records will 
include: operation time, surgery type, intraoperative opioid consumption, postoperative 
opioid consumption in PACU and in ward, breakthrough pain medication requirements, 
pain scores in PACU and ward, requirement of oxygen in PACU and ward, pruritus, 
requirement of antihistaminic medications, requirement of naloxone, itching, ambulation 
time, flatus, ileus, bowel movements (first time documented), constipation, length of stay 
and any side effects or complications.  


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Interim Analyses.  We will use a group sequential design to conduct interim analyses at 
each 25% of the planned enrollment to assess efficacy and futility of the intervention using 
a gamma spending function. Specifically, we will maintain the overall alpha level 
(monitoring efficacy) at 0.05 using gamma parameter of -4 [similar to O’Brien Fleming], 
and power at 90% (monitoring beta, type II error) using gamma parameter of 0 [more 
aggressive, similar to Pocock].  Under the alternative hypothesis (assuming a true 50% 
relative reduction in the primary outcome) the cumulative probability of crossing an 
efficacy (and futility in parentheses) boundary at the 1st through 4th analyses will be 0.09 
(0.025), 0.39 (0.05), 0.75 (0.075) and 0.90 (0.10) as shown in Figure 1. 
 
 
Figure 1.  Group sequential stopping boundaries as a function of sample size.  
Pink region represents futility.  Lower blue represents efficacy of NAC, upper blue  
represents harm.  Y-axis represents the treatment effect (Z= difference in means 
divided by standard error).  
 
G. Sample Size Considerations 
 


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We plan the study to have 90% power at the overall 0.05 significance level to be 
able to detect a relative improvement of 40% or more in mean opioid consumption(i.e., 
ratio of geometric means of 0.60) between any of the 3 interventions, assessing 
separately for 0-24 hours (primary outcome #1) and 24-48 hours (primary outcome #2) 
postoperatively.   Assuming a coefficient of variation (CV = SD/,mean) for opioid 
consumption of 0.85 [since the outcome is expected to be log-normal], the required 
sample size to will be 67 per group or 201 total.  After adjusting for the interim analyses 
the maximum sample size will be 79 per group or a total of 237.  Alternatively, for example, 
a total (maximum) sample size of 722 would be required to detect a more modest 25% 
reduction in the mean.  
 
Internal pilot assessment of variability. At the second interim analysis, we will 
conduct an internal pilot study to assess the observed variability in the primary outcome 
and the related coefficient of variation (CV). If the CV is larger than planned in the 
protocol, we will resize the study accordingly, keeping everything else the same. For 
example, if the observed CV is 1.0 (instead of 0.85), the new maximum sample size would 
be a total of 298 patients to detect the same 40% relative reduction in the outcomes. The 
internal pilot assessment will not affect the type I error of the study nor alter the effect size 
of interest.  
 
Adaptive design option.  At the 3rd interim analysis we may consider an adaptive design 
in which the study is repowered for a smaller but still clinically important treatment effect.  
Specifically, if the conditional power at the 3rd look is between 30% and 75%, the DSMB 
(or Executive Committee) we will consider resizing the study to have 90% power to detect 
a relative reduction as small as 20% (i.e., a ratio of geometric means of 0.80). 71  
 
 
 


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