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The Efficacy of Liposomal Bupivacaine Over Traditional Local Anesthetics in

Periarticular Infiltration and Regional Anesthesia During Total Knee
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Accepted Manuscript

The Efficacy of Liposomal Bupivacaine over Traditional Local Anesthetics in

Periarticular Infiltration and Regional Anesthesia During Total Knee Arthroplasty: A
Systematic Review and Meta-analysis

Michael Yayac, MD, William T. Li, BS, Alvin C. Ong, MD, P. Maxwell Courtney, MD,
Arjun Saxena, MD
PII: S0883-5403(19)30414-0
DOI: https://doi.org/10.1016/j.arth.2019.04.046
Reference: YARTH 57245

To appear in: The Journal of Arthroplasty

Received Date: 14 February 2019

Revised Date: 30 March 2019
Accepted Date: 23 April 2019

Please cite this article as: Yayac M, Li WT, Ong AC, Courtney PM, Saxena A, The Efficacy of Liposomal
Bupivacaine over Traditional Local Anesthetics in Periarticular Infiltration and Regional Anesthesia
During Total Knee Arthroplasty: A Systematic Review and Meta-analysis, The Journal of Arthroplasty
(2019), doi: https://doi.org/10.1016/j.arth.2019.04.046.

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 ACCEPTED MANUSCRIPT

The Efficacy of Liposomal Bupivacaine over Traditional Local Anesthetics in Periarticular

Infiltration and Regional Anesthesia During Total Knee Arthroplasty: A Systematic

Review and Meta-analysis

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Michael Yayac, MDa; William T. Li, BSa; Alvin C. Ong, MDa; P. Maxwell Courtney, MDa;

Arjun Saxena, MDa

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a
Rothman Institute at Thomas Jefferson University, 925 Chestnut St., Philadelphia, PA 19107

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Corresponding Author:
Michael Yayac, MD
Rothman Institute at Thomas Jefferson University

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125 S. 9th St., Suite 1000
Philadephia, PA 19107
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Email address: michaelyayac@gmail.com
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Alijanipour 2017

Amundson 2017
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Bramlett 2012
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Collis 2016
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Danoff 2018

DeClaire 2017
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Jain 2016

Mont 2018
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Schroer 2015
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Schwarzkopf 2016

Smith 2017

Snyder 2016

Suarez 2018

Surdam 2015

Talmo 2018

Zlotnicki 2018

*Blank value denotes unclear risk of bias

 ACCEPTED MANUSCRIPT
1 The Efficacy of Liposomal Bupivacaine over Traditional Local Anesthetics in Periarticular

2 Infiltration and Regional Anesthesia During Total Knee Arthroplasty: A Systematic

3 Review and Meta-analysis

4 ABSTRACT

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5 Background: Since its FDA approval in 2011 as a local anesthetic for postsurgical analgesia,

6 liposomal bupivacaine (LB) has been incorporated into the periarticular injection (PAI) of many

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7 knee surgeons. The slow-release of this medication from vesicles should significantly extend the

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8 duration of its analgesic effect, but current evidence has not clearly demonstrated this benefit.

9 Methods: We systematically searched electronic databases including PubMed, Medline,

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10 Cochrane Library, EMBASE, ScienceDirect, and Scopus, as well as the Journal of Arthroplasty
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11 web page for relevant articles. All calculations were made using Review Manager 5.3.
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12 Results: We identified forty-two studies that compared LB to an alternate analgesic modality.

13 Seventeen of these studies were controlled trials that were included in meta-analysis. Significant
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14 differences were seen in pain scores with LB over a peripheral nerve block (MD=0.45,p=0.02)
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15 and LB over a traditional PAI (SMD = -0.08, p=0.004).

16 Conclusion: While LB may offer a statistically significant benefit over a traditional PAI, the
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17 increase in pain control may not be clinically significant and it does not appear to offer a benefit
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18 in reducing opioid consumption. However, there is no standardization amongst current studies,

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19 as they vary greatly in design, infiltration technique, and outcome measurement, which precludes

20 any reliable summarization of their results. Future independent studies using a standardized

21 protocol are needed to provide clear unbiased evidence.

22 Funding Sources: This research did not receive any specific grant from funding agencies in the

23 public, commercial, or not-for-profit sectors.

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24 Keywords: liposomal bupivacaine, periarticular injection, total knee arthroplasty, local

25 anesthetic, multimodal analgesia

26

27 INTRODUCTION

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28 Total Knee Arthroplasty (TKA) is an effective treatment for knee osteoarthritis, providing pain

29 relief and improved functionality in the large majority of patients [1]. As the procedure has

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30 become more common, much focus over the last 15 years has been centered on improvement of

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31 the patient experience. Postoperative analgesia has been an area of extensive research. An

32 epidemic of opioid usage in the United States has placed a particular focus on minimizing the

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33 need for narcotic medication in the perioperative period. Prescribing of opioids has more than
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34 tripled since the early 1990’s, in part due to the literature early in that decade highlighting

35 inadequate pain control amongst patients and the FDA approval of extended-release oxycodone
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36 in 1995, which was, at the time, believed to not have addictive potential [2].Orthopaedic
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37 surgeons are the third leading prescribers of opioids[3] and opioid-naïve patients are at a 1.4-2%
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38 risk of prolonged opioid use following TKA[4,5]. Therefore, any effort to reduce opioid use in

39 orthopaedic procedures may have a large impact on the opioid epidemic. New strategies have
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40 been developed to improve pain control while decreasing narcotic usage in the immediate

41 postoperative period. Multimodal analgesia, periarticular injections (PAI), and peripheral nerve
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42 blocks (PNB) have been demonstrated to be effective adjuncts for analgesia[6].

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43 In recent years much study has been focused on the efficacy of liposomal bupivacaine (LB)

44 (Exparel, Pacira Pharmaceuticals, Parsippany NJ). This medication consists of a multivesicular

45 liposome that houses bupivacaine which is released in the surrounding tissue over a period of

46 approximately 72-96 hours[7]. This new method of drug delivery has the potential for significant

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47 improvements in postoperative analgesia. The manufacturer claims that LB provides greater pain

48 control over a longer duration with less reliance on opioid medications compared to a standard

49 bupivacaine injection [8]. The cost of LB is typically at least ten-fold greater than a traditional

50 PAI. Much of the current research on LB focuses on whether or not there is a clinically

51 significant difference in pain control, opioid consumption, or length of stay that would justify its

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52 use despite increased direct cost.

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53 Failure to control postoperative pain has also been associated with delay in discharge, increased

54 healthcare costs, and a higher risk of chronic pain [9]. Multiple studies have proven multimodal

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55 analgesia to be effective in both controlling postoperative pain and minimizing opioid use in

TKA patients [10–12]. Typical multimodal regimens target multiple pathways to minimize use

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56

of opioids, especially through intravenous administration. NSAIDs function by inhibiting the

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57

58 production of COX-1 and COX-2 which prevents production of proinflammatory mediators such
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59 as prostaglandins. Corticosteroids bind directly to receptors to inhibit production of

60 proinflammatory molecules. Opioids act mostly on mu receptors in the central nervous system
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61 but also act on receptors in the knee joint [13]. Local anesthetics such as bupivacaine and
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62 ropivacaine block voltage-gated sodium channels in nociceptors which decreases transmission of

63 pain signals to the brain [14].

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64 Intra-operative analgesia can be achieved through a variety of modalities. Anesthesia can be

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65 either general or neuraxial, with the latter shown to have reduced risk of nausea, vomiting, and
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66 delirium postoperatively over general anesthesia [15]. Neuraxial anesthesia does however carry

67 the risk of hypotension and urinary retention, as well as small but serious risk of spinal/epidural

68 hematoma, spinal abscess, cauda equina syndrome, and meningitis [16]. PNBs have been shown

69 to have a number of benefits over other methods of analgesia, such as shorter length of stay,

70 reduced opioid use, and therefore a reduction in adverse effects of opioid use, and reduced risk of

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71 hypotension or urinary retention over epidural anesthesia [17,18]. Unfortunately, the failure rate

72 of this analgesic method varies and can be as high as 67% [19]. PNBs have a low risk (0.1%) of

73 serious complication including cardiac arrest, seizure, peripheral nerve injury, or death [20].

74 More commonly, patients can experience significant quadriceps weakness, especially if the

75 injection is performed in the femoral canal to target the femoral, lateral femoral cutaneous, and

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76 obturator nerves. A measurable weakness can be seen in up to one-third of patients following

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77 FNB which increases the risk of postoperative falls, potentially leading to injury and the need for

78 re-operation [21–23].

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79 Interest in the use of a periarticular injection intra-operatively as an analgesic adjunct has

developed since Busch et al. showed that its use resulted in lower VAS scores and morphine

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80

consumption in 2006 [24]. Common medications used include corticosteroids, clonidine,

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82 ketorolac, morphine, epinephrine, and amide anesthetics. Typically either bupivacaine or

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83 ropivacaine are used as the local anesthetic due to their long duration of effect [6]. Several

84 studies have shown PAI to be at least as effective as PNBs in controlling postoperative pain
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85 without the risk of quadriceps weakness and subsequent falls [24–26]. The knee joint has
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86 innervation from the femoral, common peroneal, saphenous, tibial, and obturator nerves as well

87 as nonspecific muscular branches which enter the joint [27–29]. High concentrations of
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88 nociceptors are present in the medial and lateral retinacula, patella tendon, pes anserinus, anterior

89 synovium, fat pad and meniscofemoral ligaments while fewer nociceptors were observed in the
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90 ACL and lateral retinaculum [30,31]. By targeting various specific sites in the knee with
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91 periarticular injections there is significant potential to decrease postoperative pain after TKA,

92 making injection technique of great importance [32].

93 METHODS and MATERIALS

94 Search Strategy

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95 Clinical trials, cohort studies, and meta-analyses were identified by searching electronic

96 databases including PubMed, Medline, Cochrane Library, EMBASE, ScienceDirect, and Scopus,

97 as well as the Journal of Arthroplasty web page. The MESH terms “Arthroplasty, Replacement,

98 Knee”, “Bupivacaine”, and “Liposome” were used to search Medline using the Boolean operator

99 AND. “Liposomal bupivacaine” and “Total knee arthroplasty” were used as keywords for

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100 searching through other databases. Search results were uploaded into Covidence systematic

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101 review software (Veritas Health Innovation, Melbourne, Australia. Available at

102 www.covidence.org) for review and data extraction.

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103 Inclusion/Exclusion Criteria

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104 Studies were considered eligible for qualitative analysis if they met the following criteria: 1)
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105 Patients underwent primary total knee arthroplasty; 2) Intervention group received a periarticular

106 injection with LB; 3) Control group received either a peripheral nerve block, periarticular
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107 injection with a traditional local anesthetic, or intra-articular local anesthetic; 4) Reported

108 outcomes included one or more of the following: postoperative pain scores, opioid consumption,
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109 length of stay, range of motion, functional measures including ambulation or straight leg raise,
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110 and adverse events such as nausea or vomiting. Two independent authors initially screened

abstracts of potentially eligible studies and then performed a full text review of remaining
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112 eligible studies for final inclusion. Of the remaining studies, the clinical randomized controlled
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113 trials (RCTs) or controlled clinical trials (CCTs) were included in the quantitative analysis.
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114 Consensus was reached between reviewers through discussion.

115 Data Extraction and Quality Assessment

116 A standard data extraction form was utilized within Covidence for the data extraction and quality

117 assessment process. Two reviewers independently assessed the quality of studies using a

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118 modified JADAD score. In addition to the 7-point scale, studies were assessed for conflict of

119 interest bias by reviewing conflict of interest statements for all authors of included studies.

120 Extracted data from studies included authors, study design, sample size, formulation and

121 technique of anesthetics, postoperative pain scores, opioid consumption, length of stay,

122 complications, ambulation, straight leg raise, ROM, opioid-related adverse events, cost, and

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123 patient-reported outcome measures. All opioid consumption data was converted to oral morphine

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124 milligram equivalents (MME). Corresponding authors were contacted for missing data. If data

125 regarding variability of outcomes was not available from the study or author, then standard

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126 deviation was calculated from the P-value, as is recommended by the Cochrane Handbook for

127 Systematic Reviews of Interventions [33].

Data Analysis
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128

129 Extracted data was imported into Review Manager Software for Mac (version 5.3, Copenhagen:
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130 The Nordic Cochrane Center, The Cochrane Collaboration, 2014) for analysis. When I2 was >

131 50% and P<0.1, indicating significant heterogeneity, a random-effect model was used.
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132 Otherwise, a fixed-effect model was used. Effect size of continuous outcomes was calculated
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133 using either mean differences or standard mean differences and 95% confidence intervals.

Dichotomous outcomes were expressed as risk difference and 95% confidence intervals. For pain
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135 scores and opioid consumption, effect size was calculated overall and excluding POD0 values
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136 since LB is known to not take effect for several hours.

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137 RESULTS

138 Search Results

139 After removal of duplications, a total of 133 studies were initially screened. 42 studies were

140 included in qualitative synthesis, of which 17 studies were included in the quantitative synthesis.

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141 The complete PRISMA flow diagram is presented in Figure 1. Results of the quality assessment

142 utilizing the modified JADAD score are summarized in Figure 2.

143 LB versus Peripheral Nerve Blocks

144 Numerous studies have attempted to evaluate the effectiveness of LB over standard local

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145 anesthetics in PAI and other analgesic adjuncts, but a definitive answer has yet to be reached.

146 The results of these studies vary greatly and they are difficult to compare to one another as the

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147 study design, injection technique, cocktail mixture, and endpoints measured differ between

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148 studies. Many studies have compared LB with a PNB, including Surdam et al. who published the

149 findings of their prospective, randomized but unblinded study of 80 consecutive patients that

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150 received either a PAI with LB or a femoral nerve block (FNB) with ropivacaine, epinephrine,
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151 and tetracaine. No significant difference was observed between the two study groups in terms of

152 overall pain, narcotic consumption, or nausea/vomiting [34]. In criticism of this study, the
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153 postoperative pain management regimen included scheduled doses of extended-release

154 oxycodone and hydrocodone in addition to celecoxib and as needed oxycodone. Given that the
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155 average pain scores were never above 4 and often below 3, there may have been a significant
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156 portion of patients unnecessarily receiving opioids for pain control. For this reason, if difference

in opioid consumption is to be evaluated, an opioid-minimizing postoperative pain management

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157

158 protocol should be utilized. The only significant difference in pain control noted between the two
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159 groups was on postoperative day (POD) 0. Immediately following surgery, pain scores were
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160 significantly higher for the group of patients receiving the LB PAI [34]. This may be explained

161 by the fact that the PAI cocktail did not include bupivacaine HCL, as is recommended by Pacira.

162 Pharmacokinetic studies have shown that serum levels of bupivacaine do not reach a maximum

163 level until 12-36 hours following local injection with LB [35,36]. Addition of bupivacaine HCL

164 provides a more immediate onset of analgesia until the LB reaches an efficacious level.

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165 There has been one other randomized controlled trial (RCT) primarily comparing a PNB to an

166 LB PAI. 373 patients undergoing total knee arthroplasty were randomized to receive either FNB

167 with a posterior capsular injection of bupivacaine or a placebo FNB with a PAI of LB and

168 bupivacaine. Results of this study showed significantly lower VAS scores in the FNB cohort for

169 the first 24 hours postoperatively, but no difference afterwards. Those who received a FNB had

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170 greater early range of motion whereas the LB group were more likely to perform a straight leg

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171 raise at 12 hours postoperatively. No difference was seen in opioid consumption. Overall, the

172 differences between the two groups were not substantial and only seen early on in recovery [37].

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173 The delayed onset of LB can explain early differences in pain control, which likely limited range

174 of motion in these patients, whereas transient weakness secondary to FNB may explain the fewer

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percentage of these patients performing a straight leg raise in the early postoperative period.
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176 (Table 1)
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177 Our meta-analysis of these two studies along with Amundson et al.[38], which included an FNB

178 study arm, revealed an overall higher mean pain score with LB over PNB (MD=0.45,p=0.02).
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179 However, when POD0 pain scores were removed from the analysis, the difference in mean pain
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180 scores was no longer significant (Figure 3). There was no significant difference in overall opioid

181 consumption either overall (p=0.22) or from 12 hours postoperatively on (p=0.08) (Figure 4).
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182 Aside from straight leg raise on POD0 (OR=4.89, p=0.000), there were not statistical differences

183 between the groups in any other outcome analyzed, including length of stay (p=0.38) or
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184 ambulation (p=0.35).

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185 Thirteen other studies have compared PAI with LB to a PNB, all retrospective studies, with

186 varying PAI cocktails, injection techniques, PNB techniques, endpoints, and outcomes [39–51].

187 Two meta-analyses have been performed summarizing the data of these studies [52,53]. In terms

188 of pain control, four of these studies found overall better pain control with LB over PNB, with

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189 the other eight showing no overall difference in pain control. Both meta-analyses showed no

190 statistical difference in pain control between LB and FNB. Opioid use was significantly less in

191 patients receiving LB in eleven of these studies and both meta-analyses. LOS was also

192 significantly shorter for LB in seven of the retrospective studies and both meta-analyses.

193 Function was significantly improved for LB in seven of the eight studies that assessed this

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194 outcome, but was found not significantly different in the one meta-analysis that assessed

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195 postoperative lower extremity function. Results of differences in complication rates were mixed

196 with two showing no difference and two showing fewer inpatient falls with LB [39,43,45,48].

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197 Both meta-analyses failed to show any difference in complications [52,53]. Of the four studies

198 that compared cost, all found a lower hospital cost in those receiving LB [43–45,48].

LB versus Intra-articular Local Anesthetic

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199

200 Two randomized controlled trial have compared LB to local anesthetic administered intra-
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201 articularly. Smith et al. found significantly higher pain scores with walking and physical therapy,

202 but no overall difference in pain control, in patients receiving a LB PAI compared to those
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203 receiving a ropivacaine elastomeric pump.[54] Jain et al. was a three-armed study in which one
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204 arm received an intra-articular injection of bupivacaine HCl while the other two groups received

a PAI with either LB or bupivacaine HCl.[55] Comparison of LB to intra-articular anesthesia in

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205

206 meta-analysis revealed no statistical difference in pain score (p=0.27), opioid consumption
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207 (p=0.35), or length of stay (p=0.10).

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208 LB versus Traditional Periarticular Injection

209 One of the first studies to compare LB to a traditional PAI found significantly higher overall

210 postoperative pain during hospital stay in patients who received bupivacaine, epinephrine, and

211 LB to those who received ropivacaine, morphine, and epinephrine. This was a retrospective,

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212 nonrandomized study and pain scores were compared as means over the entire hospital stay

213 which was considerably more variable in the traditional PAI group [56]. For this study, the

214 experimental group received an injection of 30 mL of 0.5% bupivacaine followed by 20mL of

215 LB with 30mL normal saline for a total volume of 80mL at the conclusion of the procedure [56].

216 This technique did not adhere to the recommended infiltration technique developed with support

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217 from the manufacturer and the International Congress for Joint Reconstruction, an organization

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218 of orthopaedic surgeons devoted to providing global access to educational resources [57].

219 Numerous other studies have also attempted to compare a PAI with LB to a PAI with a standard

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220 local anesthetic. The methodology, injection cocktails, and control groups are not consistent

between studies. The results of these studies are difficult to summarize as many are starkly

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contrasting in their findings. A randomized, controlled trial of 70 patients receiving either LB or

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223 a cocktail with ropivacaine found significantly lower pain scores and fewer opioid use in the LB
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224 group [58]. A retrospective study of 50 patients who received either LB PAI or a ropivacaine

225 cocktail along with epidural anesthesia also found significantly less pain and rescue opioid use
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226 after POD 1[59], as did two meta-analyses of comparing LB PAI to a standard PAI [60,61].
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227 Another RCT of 157 patients performed at the Mayo Clinic found higher POD 0 and 1 pain

228 scores and more opioid use in the LB PAI group compared to patients who had received a PNB
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229 [61]. Twelve other studies, including 8 RCTs, 2 retrospective observation, and 2 meta-analyses,

230 all found no significant difference in pain control or opioid use between patients who had
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231 received LB or a standard local anesthetic as part of their PAI cocktail [55,62–72]. Danoff et al.
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232 recently published the findings of the randomized, controlled trial of patients undergoing

233 bilateral total knee or unicompartmental arthroplasty. These patients received a LB PAI cocktail

234 in one knee and a ropivacaine PAI cocktail in the other knee. They found no significant

235 difference in VAS scores or functional recovery between the cocktails. Differences in opioid

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236 consumption could not be assessed as it was not measured [73]. A similar recent study of 156

237 patients receiving either an LB PAI or standard PAI with either oral or intravenous

238 acetaminophen also found no significant difference in pain control, but did find higher opioid

239 consumption in the LB group [74]. However, three meta-analyses have shown significantly

240 better pain control at 24 and 72 hours with one also showing less opioid consumption on POD1

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241 [50,60,75]. These studies are summarized in Tables 4-6.

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242 Meta-analysis of the RCTs showed a statistically significant lower pain score (SMD = -0.08,

243 p=0.004) overall with the use of LB, which remained unchanged with POD0 values excluded

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244 (Figure 5). Differences in opioid consumption were not statistically significant however (MD = -

5.21, p=0.14), even when POD0 values were removed from analysis (MD = -5.88, p=0.31)

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(Figure 6).
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246

247 In terms of LOS or functional status, analysis revealed no significant difference for either, with
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248 mean difference of 0.02 days (95% CI -0.08 to 0.12, p=0.69) favoring traditional PAI for LOS

249 and a mean difference of 0.98 degrees (95% CI, -3.16 to 1.21, p=0.38) for ROM. Only two
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250 studies showed a potential benefit, Heim et al.[59] found improved function and shorter LOS,
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251 but these results may be confounded by the fact that the control group in this study received

epidural anesthesia for 24 postoperatively. Multiple studies have shown the benefit of PAI over
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252

253 epidural anesthesia in regards to pain control, functional status and LOS[76–78]. This study may
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254 simply be offering more evidence in favor of a PAI over epidural anesthesia than showing any
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255 true benefit of LB over other PAI cocktails. Other studies assessing these two outcomes have

256 found no significant difference[38,54,62–64,66,70]. The meta-analysis by Singh et al. also

257 showed a shorter LOS by 0.17, which may not be clinically significant, and was likely subject to

258 publication bias [61].

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259 Some of the strongest evidence in support of LB comes from the PILLAR study, an industry

260 sponsored RCT of 140 patients undergoing TKA who received a PAI with either bupivacaine

261 alone or bupivacaine with LB. Results of this study showed improved postsurgical pain, reduced

262 opioid consumption and longer time to first rescue opioid dose in those patients who received

263 LB, with 10% of patients not requiring rescue opioids as opposed to 0% in the bupivacaine alone

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264 group. Having noted the limitations of prior studies, the investigators ensured all surgeons were

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265 trained and adhered to a standard infiltration protocol and an opioid-minimizing multimodal

266 postoperative pain management regimen was used. The design of this study did not allow the

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267 investigators to analyze any difference in length of stay or the difference in healthcare cost that

268 may result from a shorter hospital stay [8].

DISCUSSION
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270 LB has gained much interest in the surgical community since its introduction as a way to offer
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271 patients all of the benefits of a local anesthetic for a significantly longer duration than standard

272 local anesthetics. Evidence suggests that LB is effective in offering extended analgesia
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273 following breast surgery [79–81], colorectal surgery [82–84], urologic and gynecologic
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274 procedures [85,86], yet the evidence for its use in orthopaedic procedures, especially total knee

arthroplasty, is conflicting. Numerous studies have attempted to assess its effectiveness in both
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275

276 controlling pain and reducing opioid consumption and the results vary from worse than other
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277 analgesic modalities to significantly better in both aspects. While many show no benefit over a
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278 standard local anesthetic in a periarticular injection, there are a few which show clinically

279 relevant improved pain control and decreased opioid consumption, thus warranting further

280 investigation.

281 Whereas the cost of LB is significantly greater than standard local anesthetics, if it can provide at

282 least equivalent pain control over an extended duration resulting in significantly less opioid

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283 consumption, then long-term benefits of its use may outweigh increased direct costs. Of the

284 thirty-eight studies reviewed in this article, six evaluated cost differences, of which only four

285 assessed total hospital costs [43,44,48,55,70]. The results of these studies favor an overall cost

286 benefit to the use of LB, but the four studies to show decreased cost were in comparison to

287 PNBs, which could be explained by a shorter length of stay, as was found in 10 of the 14 studies

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288 to compare length of stay in LB versus PNBs [34,37,40–49,52,53]. In comparing LB to

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289 traditional PAI, only one study evaluated cost and found a significantly higher cost of pain

290 control [55]. As well, only one of twelve studies found a significantly shorter length of stay

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291 [38,54,59,62,63,65–68,70,87,88]. This may all be viewed as more evidence that PAI results in

292 shorter length of stay and decreased costs over PNBs, likely secondary to increased early

293 mobility.
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294 In reviewing these studies to discern why there is such variability in results, one might first
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295 notice that the control groups differ considerably between studies. Control groups of these

296 studies have received epidural anesthesia, peripheral nerve blocks, no local anesthetic, and
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297 periarticular injections with local anesthetic. Since Busch et al.[24] first showed that periarticular
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298 injections can offer good pain control and reduce opioid consumption, there have been many

299 subsequent studies providing adequate evidence to suggest that periarticular injections are
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300 effective in controlling pain and reducing opioid use without the risks of other analgesic

301 modalities[25,89,90]. Therefore, it would be logical that the purpose of further studies should be
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302 to assess whether the use of LB extends these benefits beyond the initial postoperative period
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303 and results in even less opioid use than standard local anesthetics. Future studies should include

304 a control group that receives a periarticular injection with a standard local anesthetic and no

305 other analgesic adjuncts that might confound results. To further limit the potential for

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306 confounding factors, the PAI cocktail should be identical in the control and experimental group

307 except for that the experimental PAI contains LB.

308 Another way in which these studies differ that might explain the conflicting results is the

309 formulation and technique of the PAI used in the experimental groups. Many of the earlier

studies on this topic utilized relatively small volumes and administered the injection in a manner

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310

311 similar to standard local anesthetic. Proponents of LB have argued that the infiltration technique

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312 is critical to the success of the medication. Its viscosity and slow release from vesicles prevents it

313 from widely dispersing throughout the tissue and therefore, it is only effective on a relatively

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314 small volume of tissue around the injection site. The infiltration technique is crucial in ensuring

all of the nociceptors in the knee are effectively anesthetized. This is accomplished by expanding

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315

the LB to a large volume with saline and injecting small volumes over multiple closely spaced
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316

317 sites in tissues that are dense in nociceptors. Bupivacaine HCL is added to the cocktail to provide
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318 more immediate analgesia until the LB reaches a therapeutic level, roughly 24 hours after

319 administration [91,92]. The manufacturer recommends the infiltration technique developed for
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320 the PILLAR study which calls for 20mL of LB, 20mL of bupivacaine HCL, and 80mL of normal
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321 saline be injected in 1-1.5mL volumes over 80-120 equally spaced sites based on the case report

322 of Dr. Stanley Dysart of Pinnacle Orthopaedics and one of the investigators of the PILLAR
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323 study[93] as well as the consensus recommendation published by a group of seven hip and knee

324 surgeons[91]. While the manufacturer and the PILLAR study investigators claim this technique
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325 is vital to obtain adequate analgesic coverage, a retrospective cohort study of 285 patients who
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326 received either a traditional PAI, PAI with LB and standard infiltration technique, or a PAI with

327 LB and the recommended infiltration technique found no benefit with LB over a conventional

328 PAI despite using the manufacturer –recommended infiltration technique [68].

329 CONCLUSION

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330 Given that total knee arthroplasty has become one of the most common inpatient procedures

331 [94], and the current focus in the surgical community to address the opioid epidemic in part by

332 limiting postoperative opioids, there is a continued need to explore opioid-free analgesic

333 modalities. The use of local anesthetic agents in a periarticular injection at the time of operation

334 has been shown to aid in achieving this goal, but its effectiveness is limited by duration of action.

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335 LB has the potential to further extend the analgesic effects of periarticular injections. Much of

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336 the current evidence regarding the use of LB in TKA suggests that it offers no benefit over

337 traditional bupivacaine. Evidence in its favor comes in the form of retrospective cohort studies

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338 and the industry-sponsored PILLAR study. Meta-analysis of these studies determined that LB

339 offers no benefit over other analgesic modalities. Even though, there was a statistical difference

340
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in pain control between LB and traditional PAI, this difference does not meet the minimal
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341 clinically important difference, defined as an increase of 22.6 or greater on a 100-point scale.

342 [95] This review also highlights the potentially key differences in study design that may explain
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343 the high degree of variability. Hip and knee surgeons would greatly benefit from an
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344 independently-funded, well-designed randomized clinical trial that utilizes validated outcome
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345 measures in order to reach a conclusion on the effectiveness of LB in total knee arthroplasty.

346 References
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578 Liposomal Bupivacaine (Exparel) for Postoperative Analgesia. Plast Reconstr Surg 2016;138:748e-
579 56e. doi:10.1097/PRS.0000000000002547.
580 [81] Gatherwright J, Knackstedt RW, Ghaznavi AM, Bernard S, Schwarz G, Moreira A, et al.

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581 Prospective, Randomized, Controlled Comparison of Bupivacaine versus Liposomal Bupivacaine
582 for Pain Management after Unilateral Delayed Deep Inferior Epigastric Perforator Free Flap
583 Reconstruction. Plast Reconstr Surg 2018;141:1327–30. doi:10.1097/PRS.0000000000004360.
584 [82] Gorfine SR, Onel E, Patou G, Krivokapic ZV. Bupivacaine extended-release liposome injection for

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585 prolonged postsurgical analgesia in patients undergoing hemorrhoidectomy: a multicenter,
586 randomized, double-blind, placebo-controlled trial. Dis Colon Rectum 2011;54:1552–9.
587 doi:10.1097/DCR.0b013e318232d4c1.

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588 [83] Stokes AL, Adhikary SD, Quintili A, Puleo FJ, Choi CS, Hollenbeak CS, et al. Liposomal
589 Bupivacaine Use in Transversus Abdominis Plane Blocks Reduces Pain and Postoperative
590 Intravenous Opioid Requirement After Colorectal Surgery. Dis Colon Rectum 2017;60:170–7.
591 doi:10.1097/DCR.0000000000000747.

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592 [84] Raman S, Lin M, Krishnan N. Systematic review and meta-analysis of the efficacy of liposomal
593 bupivacaine in colorectal resections. J Drug Assess 2018;7:43–50.
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594 doi:10.1080/21556660.2018.1487445.
595 [85] Cotta BH, Welliver C, Brahmamdam A, Bednarchik CL, Dynda D, Köhler TS. Long-acting
596 liposomal bupivacaine decreases inpatient narcotic requirements in men undergoing penile
597 prosthesis implantation. Turk J Urol 2016;42:230–4. doi:10.5152/tud.2016.44442.
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598 [86] Mazloomdoost D, Pauls RN, Hennen EN, Yeung JY, Smith BC, Kleeman SD, et al. Liposomal
599 bupivacaine decreases pain following retropubic sling placement: a randomized placebo-controlled
600 trial. Am J Obstet Gynecol 2017;217:598.e1-598.e11. doi:10.1016/j.ajog.2017.07.001.
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601 [87] Yu Z-X, Yang Z-Z, Yao L-L. Effectiveness of liposome bupivacaine for postoperative pain control
602 in total knee arthroplasty: A PRISMA-compliant meta-analysis of randomized controlled trials.
603 Medicine (Baltimore) 2018;97:e0171. doi:10.1097/MD.0000000000010171.
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604 [88] Alijanipour P, Adeli B, Hansen EN, Chen AF, Parvizi J. Intraoperative Purulence Is Not Reliable
605 for Diagnosing Periprosthetic Joint Infection. J Arthroplasty 2015;30:1403–6.
606 doi:10.1016/j.arth.2015.03.005.
607 [89] Grosso MJ, Murtaugh T, Lakra A, Brown AR, Maniker RB, Cooper HJ, et al. Adductor Canal
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608 Block Compared with Periarticular Bupivacaine Injection for Total Knee Arthroplasty: A
609 Prospective Randomized Trial. J Bone Joint Surg Am 2018;100:1141–6.
610 doi:10.2106/JBJS.17.01177.
611 [90] Chung AS, Spangehl MJ. Peripheral Nerve Blocks vs Periarticular Injections in Total Knee
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612 Arthroplasty. J Arthroplasty 2018. doi:10.1016/j.arth.2018.08.006.

613 [91] Joshi GP, Cushner FD, Barrington JW, Lombardi AV, Long WJ, Springer BD, et al. Techniques for
AC

614 periarticular infiltration with liposomal bupivacaine for the management of pain after hip and knee
615 arthroplasty: a consensus recommendation. J Surg Orthop Adv 2015;24:27–35.
616 [92] Khlopas A, Elmallah RK, Chughtai M, Yakubek GA, Faour M, Klika AK, et al. The Learning
617 Curve Associated with the Administration of Intra-Articular Liposomal Bupivacaine for Total Knee
618 Arthroplasty: A Pilot Study. Surg Technol Int 2017;30:314–20.
619 [93] Pacira Pharmaceuticals, Inc. Administration Case Report With EXPAREL 2018.
620 [94] Williams SN, Wolford, Monica L., Bercovitz, Anita. Hospitalization for Total Knee Replacement
621 Among Inpatients Aged 45 and Over: United States, 2000–2010. NCHS Data Brief 2015:8.

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622 [95] Danoff JR, Goel R, Sutton R, Maltenfort MG, Austin MS. How Much Pain Is Significant? Defining
623 the Minimal Clinically Important Difference for the Visual Analog Scale for Pain After Total Joint
624 Arthroplasty. J Arthroplasty 2018;33:S71-S75.e2. doi:10.1016/j.arth.2018.02.029.
625

626

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Figure Legend
Figure 1: PRISMA Study Flow Diagram
Figure 2: Risk of Bias Summary
Figure 3: LB vs. PNB Pain Score Forest Plot

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Figure 4: LB vs. PNB Opioid Consumption Forest Plot
Figure 5: LB vs. Traditional PAI Pain Score Forest Plot

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Figure 6: LB vs. Tradition PAI Pain Score Forest Plot

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AN
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Table 1. Liposomal Bupivacaine versus Peripheral Nerve Block – Level 1 Studies

Study Study Intervention Control Pain Opioid Use Function Comments

Design

PT
Surdam Unblinded LB (N=40) Single Shot FNB (N=40) POD0: 3.84 vs 2.91, P<.05 More use on POD0 More patients able to ambulate on POD0: Increased early postoperative
et al. RCT LB 20 mL, 0.5% ropivacaine 40 (MME, mg): 100% vs 67% pain could be due to lack of
(2015) NS 40 mL mL, epinephrine, 1% POD0: 2 5.5 vs 13.9, Greater ambulation on POD1(ft): bupivacaine HCL in injection
tetracaine 30 mg P<.05 152.1 vs 108.2, P<.05

RI
No significant difference Less use on POD1: Difference in pain scores may
POD1-3 or overall pain POD1: 3.9 vs 9.1, P<.05 not be clinically relevant

SC
No significant difference Small sample size
on POD2-3
Scheduled doses of opioids in
postoperative analgesic

U
regimen

AN
Talmo et Double- LB PAI + placebo FNB + Bupivacaine HCL PAI Higher pain scores for No difference in opioid More likely to perform SLR at 12 hours: 73% Did not use recommended
al. blinded RCT FNB (N=114) (N=120) first 24 hours (VAS): use vs 50% (P=.0003) infiltration protocol
(2018)

M
Placebo FNB: 20mL FNB: 20 mL 0.25% 12h: 3.93 vs 3.17 Difference in pain scores may
NS bupivacaine (P=.0027) not be clinically relevant

20 mL LB, 40 mL NS PAI: 30 mL 0.25% 24h: 4.68 vs 4.08

D
bupivacaine (P=.0027)
30 mL 0.25%

TE
bupivacaine

Total Volume: 90 mL
C EP
AC
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Table 2. Liposomal Bupivacaine versus Peripheral Nerve Block – Level 3 & 4 Studies

Study Study Design/ Intervention Control Pain Opioid Use Function Comments

PT
Barrington et al. Retrospective LB (N=1124) Bupivacaine cocktail with or w/o Less pain & more patients No difference in nausea Not assessed Included TKA & THA

RI
(2015) observational ketorolac & morphine + FNB reporting no pain: patients
study (N=1124) Opioid consumption not
Overall (VAS): 2.21 vs assessed Difference in pain scores

SC
2.52, P<.0001 may not be clinically
relevant
% Reporting no pain:
47.2% vs 42.1%, P<.0001 Potential COI

U
AN
Cien et al. (2015) Retrospective LB cocktail (N=59) Single Shot FNB + PCA Lower peak PO pain score Trending toward less opioid Not assessed Small sample size
observational (VAS): 4.4 vs 7.5, P<.001 use overall (mg):
study LB cocktail: LB 20 mL, .25% (N=66) PCA usage in control group

M
Bupivacaine 20 mL, 121 vs 199, P=.075
Epinephrine, NS 40 mL Single shot FNB: .5% Bupivacaine, Single surgeon
1.5% Mepivacaine + PO Infiltration

D
Total volume: 80 mL of .25% Bupivacaine 20 mL with Single institution
Epinephrine + PCA

TE
Emerson et al. Retrospective LB (N=36) Continuous FNB(N=36) No significant difference in Less opioid use Not assessed Small sample size
(2016) observational overall VAS scores (hydrocodone equivalents,
study LB 20 mL, NS FNB: bupivacaine 0.5% + mg): Potential COI
EP
bupivacaine cocktail injection (60 Higher postop pain in
Total volume: 60-100 mL + mL) females and younger 90 vs 162, P<.001, adj
bupivacaine cocktail injection patients P=.0188
(60 mL) Fewer rescue opioid doses:
C

7.5 vs 15, P<.001, adj

P=.0018
AC

Jinnah et al. (2016) Retrospective LB infiltration (N=162) Single shot FNB (N=70) Not assessed Not assessed Not assessed Included TKA & THA
observational patients
study 20 mL LB, 40 mL NS, 0.5% No details
bupivacaine HCl with 1:200,000
epinephrine (30 cc), & 30 mg (1
cc) of ketorolac
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Phillips et al. (2016) Retrospective LB cocktail + Adductor canal Bupivacaine cocktail + FNB (N=86) No significant difference in Less total opioid More patients ACB in experimental group
observational block (ACB; N=86) VAS scores consumption (MME, mg): achieved Sit -to - while FNB in control group
study FNB + cocktail Stand:
ACB + LB 20 mL + cocktail 64.6 vs 83.7, P=.0016
Total volume: 80 mL Total volume: 80 mL POD1: 99% vs

PT
81%, P=.0001
Cocktail: 0.25% Bupivacaine 50 mg,
Epinephrine 0.3 mg, morphine sulfate POD2: 90% vs
10 mg, ketorolac 30 mg 77%, P=.0212

RI
No difference in %
achieved Range of

SC
Motion Flexion
Goal:

45.3% vs 22.6%,

U
P=.07

AN
Sporer and Rogers Retrospective LB Cocktail (N=272) Single Shot FNB + Bupivacaine PAI Less pain at 12 hrs postop Fewer patients used opioids Earlier time to Few patients in both groups
(2016) observational (N=325) (NRS): for breakthrough pain: ambulation (hrs): ambulating on POD 0
study LB 20 mL, 30 mL Bupivacaine, 29.5 vs 32.2,

M
10 mL NS FNB & PAI Bupivacaine 30 mL 12hr: 3.2 vs 3.6, P<.003 16.9% vs 36.3%, P<.001 P<.017 Difference in early pain
scores may not be clinically
No difference in time to first *adjusted for relevant
dose (hrs): demographic

D
Total volume: 60 mL factors: LB Potentially confounded by
16.4 vs 9.8, P=.101 patients ambulated FNB in control group

TE
2.3 hrs earlier
Potential COI
EP
Kirkness et al. Retrospective LB (N=134) Cocktails + Continuous FNB (N=134) No significant difference in Less opioid use on POD2 More patients Few patients in both groups
(2016) observational pain scores (MME): POD2: 37 vs 60, ambulated on ambulating on POD 0
study LB 20 mL, 0.5% Bupivacaine 30 Continuous FNB with 0.2% P=.006 POD0:
mL + epinephrine ropivacaine + Cocktails (vary): Extended LOS for both
C

POD0: 22% vs groups

Total volume: 50 mL Ropivacaine 120 mg, epi, ketorolac 3%, P<.05
AC

60 mg, morphine 4 mg, OR Potential COI

bupivacaine 150 mg, epi, ketorolac Greater
15-30 mg, OR, ropivacaine 20 mg, ambulation
ketorolac 30 mg epinephrine distance (m):

POD0: 6 vs 3.1,
P<.001

POD1: 63.7 vs
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25.5, P<.001

POD2: 69.1 vs
72.7, P=.856

PT
Kirkness et al. Retrospective LB (N=134) FNB (N=134) Not assessed Not assessed More patients Few patients in both groups
(2017) observational walked on POD0: ambulating on POD 0
study No details Single shot FNB 22% vs 3%, P<.01
Potential COI

RI
No details Patients walked
further (m):
POD1: 31.9 vs

SC
12.6, P<.001

U
AN
Sakamoto et al. Retrospective LB (N=98) FNB (N=101) Higher pain scores 48-96 Less opioid use 0-24hrs: Not assessed LB group also received FNB
(2017) observational hrs postop (NRS):
study LB 20mL, 20mL NS 12.50 vs 22.50, P=0.001 No bupivacaine HCL and

M
48hr:5.5 vs 5.0, P=0.01 low total volume in PAI
Received FNB No PAI 72hr:5.0 vs 4.0, P=0.002 Greater opioid use 48-72hrs:
96hr:5.0 vs 3.0, P=0.003
20.00 vs 15.00, P=0.003

D
Torres et al. (2017) Retrospective LB (N=23) Continuous FNB (N=23) Not assessed Less opioid use (MME): Greater walking Small sample size

TE
observational distance (ft/day):
study 20 mL LB, 40 mL NS Ropivacaine 0.2% (2 mg/mL) at Total: 145.47 vs 214.30, Patients underwent staged
basal rate of 8 mL/h for 48 hours P=.02 135.9 vs 84.2, bilateral TKA
30 mL 0.25% bupivacaine + P<.01
EP
epinephrine in a separate needle Potential COI
Greater extension
Total volume: 90 mL plus flexion at 3
C

weeks: 116.3 vs
107.2, P=.02
AC

Yu et al. (2017) Retrospective LB (N=527) Single Shot FNB (N=583) Less pain at 8, 64, 72hrs –: Less overall opioid use Better Adhered to recommended
observational (MME, mg)†: postoperative injection technique at time
study LB 20 mL, NS 40 mL FNB: 0.25% bupivacaine Pain (VAS): function- of study
84 vs 96, P=.004
Total volume: 60 mL (+46 mL 8hr: 3.2 vs 4, P=.012 % achieving gait Difference in pain scores not
cocktail) 64hr: 4 vs 4, P=.049 milestone:77% vs deemed clinically significant
72hr: 4 vs 4, P=.018 60%, OR=2.26, by authors
P<.001
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Stair climb:94% Potential COI

vs 73%, OR=6.05,
P<.001

Kim et al. (2018) Retrospective LB (N=685) vs LB + PCA FNB + PCA (N=583) Higher pain scores in first Lower opioid use (MME): Higher prevalence Cohort not using PCA had

PT
observational (N=540) 8h (VAS): 4.0 vs 1.0 vs. of achieving stair- higher discharge to home
study FNB + PCA: 1.2, P<.001 66 vs 82 vs 96, P<.001 climbing & and shorter LOS
LB: 20 mL in 40-100 mL NS walking for 100
20 mL 0.25% bupivacaine in FNB feet: Possible design flaw –no

RI
LB + PCA: true control
All patients received 40 mL 0.25% POD1: 47% vs
20 mL in 40-100 mL NS Marcaine, 5 cc (5 mg) Duramorph, 30% vs 16%, Potential COI

SC
P<.001
& 1 cc (30 mg) Toradol
Remainder of stay
(%): 90% vs 93%

U
vs NR, P<.001 (vs
FNB)

AN
Yu et al. (2018) Retrospective Cohort 2: LB PAI + PCA Cohort 1: Single shot FNB + PCA Higher pain scores Less total opioid use More likely to Used PCA in control and
observational immediately after surgery: (MME): achieve functional one experimental group

M
study Cohort 3: LB PAI 20 mL 0.25% bupivacaine milestones by
Cohort 3 vs 2 vs 1: 4.0 vs Cohort 3 vs 2 vs 1: 66 vs 82 POD1: Possible design flaw –no
20 mL LB, 40 mL NS 1.2 vs 1.2 (P<.001) vs 96 true control

D
Cohort 3 vs 2 vs 1:
Total Volume: 60 mL More opioid use on POD1 47% vs 30% vs Potential COI
(MME): 16% (P<.001)

TE Cohort 3 vs 2: 23 vs 12
(P<.001)
More likely to be
discharged home:
EP
Cohort 3 vs 2 vs 1:
84% vs 78% vs
72% (P=.010)
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Table 3. Liposomal Bupivacaine versus Peripheral Nerve Block – Meta-analyses

Study Study Design/ Level of Intervention Control Pain Opioid Use Functio Comments
Evidence n

PT
Ma et al. (2016) Meta-analysis LB infiltration (N=620) FNB (N=669) No difference in Less opioid use on POD 1 & 2 Not Only one Level 1 study
pain (SMD): assessed
1 RCT, 5 retrospective Small sample sizes
observational POD1: .625, P=.028

RI
Total volumes not reported. Total volumes not reported. Varied endpoints measured
POD2: .410, P=.037
Different concomitant pain

SC
management in each study

Different types of anesthesia

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Low level of evidence studies

AN
Liu et al. (2017) Meta-analysis LB infiltration (N=1114) FNB (N=1293) No difference in Less total opioid use (MD, No Only two Level 1 studies
pain MME) differenc
2 RCTs, 6 retrospective e in Different types of anesthesia

M
observational MD=-29.32, P=.042 ROM
Interventions not described Interventions not described Small sample sizes

Varied endpoints measured

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Different concomitant pain

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management in each study

Low level of evidence studies

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Table 4. Liposomal Bupivacaine versus Traditional Local Anesthetic – Level 1 Studies

Study Study Design Intervention Control Pain Opioid Use Function Comments

Bramlett et al. Phase 2 DepoFoam Bupivacaine HCL DepoFoam bupivacaine 532-mg: Not assessed Not assessed Dose-ranging study for

PT
(2012) Double- bupivacaine (N=96) (N=32) Phase II development
blinded RCT Mean NRS-R scores lower vs bupivacaine
DepoFoam Bupivacaine HCl 150 HCl on POD1&5 (P < 0.05) Small sample size
bupivacaine 133 mg, mg

RI
266 mg, 399 mg, or Mean AUC NRS-R scores significantly Industry-funded
532-mg dose Total volume: 60 mL lower POD 2–5
Potential COI

SC
Total volume: 60 mL

Schroer et al. Subject- LB (N=58) Bupivacaine (N=53) No difference in pain (VAS) No difference in opioid use No difference in Small sample size
(2015) blinded RCT range of motion

U
LB 20 mL, 0.25% 0.25% Bupivacaine (MME) at discharge or 3-
bupivacaine 30 mL wk follow-up

AN
Total volume: 60 mL
Total volume: 50 mL

M
Snyder et al. (2016) Double- LB (N=35) Ropivacaine cocktail Less pain, PACU, POD1-2 (NRS): Less opioid use, PACU, POD1-2 Not assessed Small sample size
blinded RCT (N=35) (MME):
LB 266 mg (20 mL), PACU: 2.11 vs 3.49, P=.033 Difference in NRS scores

D
NS Ropivacaine 400 mg, POD0: 2.89 vs 3.60, P=.114 PACU: 2.99 vs 6.85, P=.002 may not be clinically
epinephrine .6 mg, POD1: 2.57 vs 3.31, P=.023 POD0: 6.89 vs 8.73, P=.267 significant
Total volume: 100

TE
ketorolac 30 mg, POD2: 2.40 vs 3.51, P=.002 POD1: 10.91 vs 15.57, P=.079
mL morphine 5 mg, NS POD3: 4.0 vs 4.0 POD2: 6.89 vs 13.11, P=.005 Varied anesthetic
Greater satisfaction with pain control (5pt POD3: 11.25 vs 16.25 techniques 25% general,
scale, POD10): Less nausea: 75% spinal
EP
Total volume: 100 mL Hospital: 4.91 vs 4.11, P=.0001 25.71% vs 54.29%, P=.011
Overall: 4.57 vs 3.97, P=.001
Collis et al. (2016) Double- LB (N=54) Ropivacaine cocktail No difference in pain (VAS) No difference in opioid consumption No difference in Small sample size
blinded RCT (N=51)
C

LB 266mg (20 mL), Walking Limited confounding

NS Ropivacaine 246.25 mg, distance, range of given only variable was
AC

epinephrine .5 mg, motion, ability to LB in experimental group

Total volume: 60 mL ketorolac 30 mg, rise from seated – both groups received
clonidine .08 mg, NS position, or use FNB
All received single- of ambulatory
shot ropivacaine Total volume: 100 mL devices
FNB + SNB
All received single-shot
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ropivacaine FNB + SNB

Jain et al. (2016) Subject- PAI LB (N=63) PAI cocktail (N=62) vs No difference in maximum pain (NRS) No difference in average daily Not assessed Potential benefits of LB
blinded RCT IAA cocktail (N=82) opioid consumption (MME, mg) may not be seen due to
20 mL LB, 20 mL short LOS and follow-up

PT
NS Bupivacaine cocktail:
75 mg Bupi, epi, Compared intra-articular
Total volume: 60 mL morphine 10 mg (peri- to peri-articular injection
vs intra-articular) and found no difference

RI
Total volume: 60 mL

SC
Schwarzkopf et al. Subject- LB (N=20) Ropivacaine cocktail No difference in pain No difference in daily opioid Not assessed Included chronic opioid
(2016) blinded RCT (N=18) consumption users only
20 mL LB, 40 mL
NS 246.25 mg Ropivacaine, No difference in time to first opioid Single surgeon

U
8 mg clonidine, 30 mg dose
Total volume: 60 mL ketorolac, epinephrine,

AN
NS
(0.25% Bupivacaine
20 mL injected with Total volume: 100 mL

M
a different syringe)

D
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Barrington et al. Double- Spinal without Spinal with intrathecal Less pain on POD1 compared to ropivacaine No difference in total narcotics No difference in Small sample size
(2017) blinded RCT morphine plus LB morphine plus local cocktail w/o intrathecal morphine at 6 & 12 consumed function:
cocktail (N=40) ropivacaine cocktail hrs PO (VAS): Potential COI
(N=41) - POD1 Range
Intrathecal 6hrs: 1.8 vs 3.3, P=.005 of Motion
- Knee Society

PT
bupivacaine+ Intrathecal bupivacaine 12hrs: 1.5 vs 3.3, P<.001
Score (KSS,
with morphine + PAI More pain compared to spinal with morphine
functional)
PAI LB 266 mg (20 Ropivacaine 250 mg, at 6 hrs PO (NRS): 1.8 vs 0.9, P=.035 - Total KSS
mL), Bupivacaine ketorolac 30 mg,

RI
Score
125 mg, ketorolac 30 epinephrine, NS Total No differences between groups on POD1-3 - Day of surgery
mg, epinephrine, NS PAI volume: 60 mL (NRS) ambulation
- Postoperative

SC
Spinal without day 1 straight
leg raise
morphine plus local
Total PAI volume: 60 ropivacaine cocktail
mL (N=38)

U
Intrathecal bupivacaine

AN
without morphine + PAI
of Ropivacaine 250 mg,
ketorolac 30 mg,

M
epinephrine, NS

Total PAI volume: 60

D
mL

Smith et al. (2017) Double- LB (N=104) On-Q with bupivacaine Higher pain scores while walking: 4.6 vs 3.5, No difference in total opioid Not assessed Catheter leakage reported

TE
blinded RCT (N=96) P=.019 & with physical therapy: 4.5 vs 3.2, consumption in 20% of patients
20 mL LB, 40 mL P=.01
NS On-Q with bupivacaine Small sample size
EP
Total volume: 60 mL Total volume: unclear

Dummy On-Q pump

C

was used
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Amundson et al. Unblinded LB Cocktail (N=52) Ropivacaine cocktail More pain on POD0 & POD 1 vs nerve block More opioids vs nerve block on No difference in Small sample size
(2017) RCT (Ropi, N=55) (NRS): POD0 & POD1 (MME): SF36 (physical
composite scale), Protocol modified after
Ropivacaine 200- Max pain (LB vs NB): POD0:5 vs 1, P<.001 (LB vs NB) PACU: 0 vs 0, P=.475 or unipedal commencing study due to
LB cocktail: 20 mL 400mg, epinephrine POD1: 6 vs 5.5, P=.043 stance 3 months IRB request

PT
LB, 30mg Ketorolac, 100-300mcg, Ketorolac POD0: 15 vs 0, P<.001 POD1: 45 vs post op
125mg Bupivacaine, 30mg (dose was weight 26, P=.007 Enrollment exceeded
125mcg Epinephrine dependent) power analysis
No difference compared to ropivacaine No difference in opioids vs

RI
Total volume: 120 mL cocktail ropivacaine cocktail Potential COI

Total volume: 120 continuous FNB + SNB

SC
mL (N=50)

FNB: 100mg

U
bupivacaine bolus
preop; .2% bupi,

AN
10mL/hr PACU – 5am
POD1

M
.1% at 10mL/hr until
6am POD2
SNB: bupi 75mg,
clonidine 100mcg,

D
1:400,000 epinephrine
Alijanipour et al. Double- LB (N=87) Bupivacaine (N=75) No difference in average, worst, or least daily No difference in opioid use No difference in Met power analysis

TE
(2017) blinded RCT pain function (KSS
20 mL LB, 40 mL 0.25% Bupivacaine with score) 26% dropout rate
NS, 0.5 mL 20 mL epinephrine, 40
EP
epinephrine mL NS No difference in
QoL (SF12)
Total volume: 60.5 Total volume: 60 mL
mL
C

DeClaire et al. Double- LB (N=47) Ropivacaine (N=49) No difference in pain on POD1 or POD2 No difference in total opioid use No difference in Small sample size
AC

(2017) blinded RCT (VAS) time to ambulate

LB cocktail: 20 mL Ropivacaine cocktail: 100’
LB, ketorolac,
bupivacaine, Ropivacaine, Powered appropriately
morphine, epinephrine, ketorolac,
epinephrine morphine Potential COI

Total volume: 100

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mL Total volume: 100 mL

Mont et al. (2018) Double- LB (N=69) Bupivacaine (N=70) Less pain 12-48 hrs (AUC of VAS): Less opioid consumption (MME) Not assessed Industry-sponsored
blinded RCT
LB 266 mg (20 mL), bupivacaine 100mg (20 180.8 vs 209.3, P=.0381 0-48 hrs: 18.7 vs 84.9, (P=.0048) Potential COI

PT
bupivacaine 100mg mL), NS 0-72 hrs: 20.9 vs 93.6 (P=.0108)
(20 mL), NS More opioid free: Standardized infiltration
Total volume: 120 mL 0-72 hrs: 10% vs 0 (P<.01) protocol
Total volume: 120 Longer time to rescue (50% of

RI
mL rescued patients): Phase IV study
4.1 vs 2.9 hrs, P=.023
Met power analysis

SC
Only 10% decrease in
patients requiring rescue

U
medication
Zlotnicki et al. RCT LB (N=38) Bupivacaine HCL PAI Significantly less pain during first 24 hours Significantly less opioid Improvement in Small sample size

AN
(2018) (N=38) with LB vs. bupivacaine (5.4 vs. 6.9) & LB consumption with LB vs. control in flexion with PAI
LB 20 mL, vs. control (5.4 vs. 7.3) first 24 hours over control Retrospective control
Bupivacaine 20 mL, NS
NS 70 mL 70 mL No difference after 24 hours No other statistical difference noted LB: 82.7° No power analysis

M
Historical control with Bupivacaine:
no PAI (N=40) 80.0°

D
Control: 66.4°

TE
Danoff et al. (2018) RCT LB (N=29) Ropivacaine (N=29) No difference in pain (VAS) Not assessed No difference in Patients underwent
subjective simultaneous bilateral
LB 20 mL, 0.25% Ropivacaine 50 mL, functional TKA
EP
bupivacaine 30 mL, epinephrine 0.5 mL recovery
NS 50 mL (0.5mg), ketorolac 1 mL
(30mg), clonidine 0.8
mL (0.08mg)
C

Suarez et al. (2018) Single-blinded LB (N=52) Bupivacaine HCL No difference in pain score at 24 or 48 hours Significantly greater opioid use with No difference in Utilized infiltration
AC

RCT (N=104) post-operatively LB over standard PAI ROM at 2 or 6 protocol similar to

LB 20mL, week follow up PILLAR study
Bupivacaine HCL -with IV acetaminophen w/ PO acetaminophen
30mL, NS 50mL (N=52) 51.51 vs 30.03 (P=0.025) Potential COI
w/ IV acetaminophen
Total Volume 100mL -with PO 51.51 vs 31.05 (P=0.032)
acetaminophen (N=52)
BupivacaineHCL 30mL,
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lidocaine w/ epi 15mL,

morphine 1 mL
ketorolac 2mL
NS 50mL

PT
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Table 5. Liposomal Bupivacaine versus Traditional Local Anesthetic – Level 3 & 4 Studies

Study Study Design/ Intervention Control Pain Opioid Use Function Comments
Level of
Evidence

PT
Bagsby et al. (2014) Retrospective LB PAI (N=65) Ropivacaine PAI (N=85) Higher pain scores POD1 to No difference in opioid use Not assessed Despite bupivacaine HCL
observational discharge: with LB, experimental still
study 1st syringe: 30 mL bupivacaine w/ 400mg ropivacaine had increased early postop

RI
epi 5mg morphine 4.9 vs 4.4 (P=0.04) pain
Level 4 2nd syringe: 20 mL LB, 30 mL NS 0.4mg epinephrine
Total volume: 80 mL Total Volume: 100 mL

U SC
Barrington et al. Retrospective LB PAI (N=316) Traditional PAI (N=349) Significantly lower VAS Not assessed Not assessed Potential COI
(2016) observational scores POD 1-5

AN
study Total volume 50-90 mL Bupivacaine, ketorolac, Difference in pain scores
morphine POD1: 2.47 vs 2.95 (<.001) may not be clinically
POD2: 2.83 vs 2.29 (<.001)
significant
POD3: 2.40 vs 2.64 (<.001)

M
Total volume 50-90 mL
POD4: 2.34 vs 2.87 (<.001)
Level 4 POD5: 1.58 vs 1.85 (0.014)

D
Heim et al. (2015) Retrospective LB Cocktail (N=25) 24hr epidural plus Ropivacaine Less pain after POD1 (NRS- Fewer rescue opioids after POD1 Greater Control group received 24

TE
observational cocktail (N=25) cumulative): to discharge (mg): POD1: 13.4 vs extension: hour epidural
study 20 mL LB, 150 mg Bupivacaine, 19.0 mg, P=.274 After POD1 to
epinephrine, 30 mg ketorolac 24h epidural + 400 mg POD1: 14.4 vs 10.2, P=.322 discharge: 18.7 vs 42.4, P=.001 3.2° vs 6.2° on LOS affected by limited
EP
Level 4 Ropivacaine, epinephrine, 30 mg POD 1, P=.002 ambulation in control
After POD1: 2 vs 32.7,
Total volume: 60 mL ketorolac group secondary to
P<.001
Greater range of epidural
Total volume: 60 mL motion:84.3° vs
C

75.0° on POD1,
P=.04
AC

Longer walking
distance
(ft):133.8 vs 75.0
on POD1,
P<.001
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Meneghini et al. Retrospective LB recommended technique LB traditional technique (N=60) Not assessed No difference in opioid use Not assessed Used recommended
(2017) observational (N=41) infiltration technique in
study experimental group

Level 3 LB 20 mL, saline 30 mL

PT
Total volume: 50 mL

Ropivacaine cocktail (N=184)

RI
ropivacaine 400 mg,
epinephrine, morphine 5 mg

SC
Total volume: 100 mL

U
AN
M
D
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C EP
AC
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Table 6. Liposomal Bupivacaine versus Traditional Local Anesthetic – Meta-analyses

Study Study Design Intervention Control Pain Opioid Use Function Comments

Wu et al. (2016) Meta-analysis LB infiltration (N=276) FNB or traditional PAI (N=298) Less pain at 24 & 72 hours (VAS): Not assessed Not Included studies

PT
assessed with different
24hr: MD=-0.50, P=0.034 controls

5 RCTs 72hr: MD=-0.26, P=0.003

RI
Singh et al. (2016) Meta-analysis LB infiltration (N=15822) FNB, traditional PAI, IAA, or no Significantly better pain control No statistical difference in No Used different
PAI (N=81426) compared to traditional PAI but opioid use statistical analgesic

SC
FNB on POD 0 difference techniques
in ROM (infiltration, FNB,
7 RCTs Superior pain control on POD 1 and multimodal
and 2 compared to both FNB and

U
pain management –
8 retrospective traditional PAI grouped separately
studies

AN
and together)

1 case-control Pain scores not

similarly reported

M
throughout studies

Various design and

D
endpoints between
studies

TE
Wang et al. (2017) Meta-analysis LB infiltration (N=481) PAI (N=733) Less pain at 24 & 48 hours (VAS): Fewer opioids at POD1 Not
(MME): assessed
3 RCTs 24 hr: SMD=-0.241, P=.000
EP
48 hr: SMD=-0.124, P=.0068 POD1: SMD=-0.275, P=.000
2 non-RCTs 266 mg (20 mL), 0 mL, 30 mL or 40 mL 20 mL to 60 mL 0.25% or 0.5%
NS bupivacaine,
C

Kuang et al. (2017) A Systematic LB infiltration (N=15,428) Periarticular injection (N=81,104) No difference in pain scores (VAS) No difference in opioid No Varying criteria
Review & consumption (MME) difference analyzed between
AC

Meta-Analysis LB infiltration: in range of studies

motion or
4 RCTs 133 or 266 mg ambulation Varying doses of
distance LB in experimental
7 non-RCTs groups

Sun et al. (2018) Meta-analysis LB infiltration (N=924) Traditional PAI (N=1293) Not assessed No difference in opioid No
difference
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9 RCTs consumption in range of

motion
7 non-RCTs

Yu et al. (2018) Meta-analysis LB infiltration (N=413) Control (N=413) Significantly lower pain scores at No difference in opioid use Increased

PT
72 hours (VAS) ROM over
7 RCTs traditional
VAS MD at hours: -4.22 (P=.011) bupivacaine
(P<.05)

RI
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