The authors provide a comprehensive summary of all randomized, controlled trials (n = 76) involving the clinical administration of liposomal bupivacaine (Exparel; Pacira Pharmaceuticals, USA) to control postoperative pain that are currently published. When infiltrated surgically and compared with unencapsulated bupivacaine or ropivacaine, only 11% of trials (4 of 36) reported a clinically relevant and statistically significant improvement in the primary outcome favoring liposomal bupivacaine. Ninety-two percent of trials (11 of 12) suggested a peripheral nerve block with unencapsulated bupivacaine provides superior analgesia to infiltrated liposomal bupivacaine. Results were mixed for the 16 trials comparing liposomal and unencapsulated bupivacaine, both within peripheral nerve blocks. Overall, of the trials deemed at high risk for bias, 84% (16 of 19) reported statistically significant differences for their primary outcome measure(s) compared with only 14% (4 of 28) of those with a low risk of bias. The preponderance of evidence fails to support the routine use of liposomal bupivacaine over standard local anesthetics.
The pain of many surgical procedures extends beyond the duration of analgesia provided with a single administration of standard local anesthetic. Bupivacaine hydrochloride is currently the longest-acting local anesthetic approved by the U.S. Food and Drug Administration (Silver Spring, Maryland), with a duration of up to 18 h when administered in some peripheral nerve blocks. While multiple adjuvants such as dexamethasone and dexmedetomidine have been proposed, there is currently no Food and Drug Administration–approved medication that reliably extends the duration of action of local anesthetic beyond 24 h.1 However, by encasing standard local anesthetic within various carriers, a sustained release may be achieved that extends the analgesic duration, perhaps to multiple days. Many such formulations have been described,2 but only a single sustained released local anesthetic is currently approved for clinical use by the Food and Drug Administration: liposomal bupivacaine. Currently, a number of publications are available that review the use of liposomal bupivacaine, but all involve a specific topic area (e.g., shoulder surgery), and therefore include only a small subset (n = 7 to 27 studies) of available randomized, controlled trials.3–7 The current article aims to provide a comprehensive summary of all the published randomized, controlled trials (n = 76) involving the clinical use of liposomal bupivacaine when administered to control acute postsurgical pain.
Liposomal Local Anesthetic
Liposomes consist of a hydrophilic head and two hydrophobic tails and come in multiple permutations. Unilamellar vesicles are created with a single outer bilayer—effectively a hollow sphere—that may hold medication within its cavity.8 Far larger multilamellar liposomes are basically a sphere containing additional nested concentric spheres, much like a Russian matryoshka or babushka doll.9 In contrast, nonconcentric multivesicular liposomes are essentially an uncoordinated mass creating a myriad of cavities that may be filled with medication.10 Their large size creates a “medication depot,” which gradually discharges the contents with natural liposome membrane breakdown. This creates a sustained release, which enables prolonged pharmacologic effects. First proposed as a medication carrier in 1965, multivesicular liposomes have been used to encapsulate pharmaceuticals as diverse as ibuprofen, neostigmine, chemotherapeutics, and opioids.11 In 2004, liposome morphine (DepoDur; Pacira Pharmaceuticals, USA) became the first liposome-encased medication to be approved for postoperative analgesia by the U.S. Food and Drug Administration.12–14
Extending the duration of local anesthetic (lidocaine) using liposomes was first proposed in 1979,15 followed a year later by the first in vivo use in guinea pigs (dibucaine),16 and the first use in humans in 1988 (topical tetracaine).17 The first report of treating postoperative pain with liposomal local anesthetic occurred in 1994: subjects undergoing major abdominal, thoracic, or orthopedic surgery were given a single epidural injection of either liposomal bupivacaine 0.5% or “standard” bupivacaine hydrochloride 0.5% (subject- and observer-masked, although not randomized).18 Subjects receiving unencapsulated bupivacaine experienced a mean ± SD duration of analgesia of 3.2 ± 0.4 h versus 6.3 ± 1.1 h for those receiving liposomal bupivacaine (P < 0.05). Such encouraging results helped propel future preclinical and human subject research.19
In 2011 the U.S. Food and Drug Administration approved a liposome encapsulated bupivacaine (Exparel; Pacira Pharmaceuticals) with an explicit indication: single-dose infiltration into the surgical site to produce postsurgical analgesia in adults.20 The label was subsequently expanded to explicitly approve use in transversus abdominis plane blocks, as well as interscalene blocks specifically for shoulder surgery.21 The medication is provided in 20-ml ampules that contain the maximum-approved dose: 266 mg (13.3 mg/ml or 1.33%).22 Of note, the milligram dose is expressed as the free base, so 266 mg of liposomal bupivacaine is roughly equivalent to 300 mg of unencapsulated bupivacaine hydrochloride.23 Each ampule should be administered within 4 h of opening, diluted with normal saline or lactated Ringer’s solution (up to 1:14), and administered with a 25-gauge or larger bore needle.24 Local anesthetics other than bupivacaine hydrochloride may result in a premature release of bupivacaine from the liposome vesicles if administered together locally.24 Therefore, liposomal bupivacaine should be administered after a minimum delay of 20 min after injection of a different local anesthetic.25 In contrast, bupivacaine hydrochloride may be administered simultaneously—even admixed within the same syringe—up to a maximum dose of 50% of the liposomal bupivacaine.26
Liposomal bupivacaine exhibits a biphasic plasma peak when infiltrated directly into tissues.27 The initial peak occurring within 1 to 2 h is due to the extra-liposomal bupivacaine hydrochloride included in every ampule (less than 3% of all bupivacaine in vial), which also provides an onset similar to unencapsulated bupivacaine.28 This is followed by a second peak due to the slow release of bupivacaine hydrochloride from the liposomes at nearly twice the plasma concentration 24 to 48 h after administration compared to unencapsulated bupivacaine (even longer with a mixture of encapsulated and unencapsulated bupivacaine).26,27 Bupivacaine can still be detected within the plasma 3 to 14 days after administration, depending on the route, dose, and additional factors.27,29,30 However, local pharmacologic effect does not necessarily mirror plasma concentration, and analgesic duration cannot be inferred from the time of bupivacaine detectability within the blood. For example, tissue infiltration with 150 mg of bupivacaine hydrochloride results in detectable plasma concentrations for over 72 h,31 yet no clinical trial has demonstrated an analgesic effect of even 24 h duration: blood concentration is correlated with systemic toxicity, not local effect.24 After liposome release, the bupivacaine absorption, distribution, metabolism, and excretion are similar to the bupivacaine hydrochloride formulation.24
Due to the gradual—versus immediate—release of bupivacaine, determining the safety profile of liposomal bupivacaine requires medication-specific investigations.32 Preclinical studies demonstrate a similar or larger margin of safety with liposomal bupivacaine than unencapsulated bupivacaine.32–39 For example, in rabbits, roughly twice as much liposomal bupivacaine must be intravenously infused to induce seizures, ventricular tachycardia, and asystole compared with bupivacaine hydrochloride.40 In humans, 823 subjects exposed to liposomal bupivacaine within 10 randomized, controlled trials involving surgical site infiltration experienced no more adverse events than subjects receiving bupivacaine hydrochloride,41 a finding reproduced when liposomal bupivacaine was administered as part of a peripheral nerve block in 335 patients among six studies.42 Liposomal bupivacaine appears to have no negative influence on wound healing when infiltrated into the surgical site,43 and it is compatible with common implanted materials such as titanium, silicone, and polypropylene.44,45
While local anesthetic systemic toxicity can occur with liposomal bupivacaine,46 it appears to have a favorable cardiac safety profile compared to bupivacaine hydrochloride.47–51 In humans, there have been three suspected intravenous injections of liposomal bupivacaine, involving 150 to 450 mg of injectate intended for surgical site tissue infiltration after knee arthroplasty.47 Other subjects within this study had mean bupivacaine plasma concentrations of 255 ng/ml (for 150 mg group) and 520 ng/ml (450 mg group). In contrast, the three subjects with suspected intravascular injections had concentrations of approximately 8,000 to 34,000 ng/ml. Yet none had symptoms or signs of local anesthetic toxicity, including no electrocardiogram/QTcF changes from baseline.47 Toxicity has resulted from far lower doses of unencapsulated long-acting local anesthetics.52–54
Early in the development of new medications and devices, case reports and retrospective studies are of great service to generate hypotheses that may then be tested with randomized, controlled trials. This was the case for liposomal bupivacaine during much of the last decade, with 28 of 30 (93%) of reviewed retrospective studies reporting positive findings.55–84 However, in the last few years, there has been a substantial increase in the number of randomized, controlled trials, with 76 published at the time of this writing (tables 1–10). Given the new plethora of data from investigations with a design considered the accepted standard when evaluating medical interventions, this review will focus on published randomized, controlled trials.
Unfortunately, 30 (40%) of these trials were either unregistered or registered after enrollment, and 26 (35%) failed to define a primary outcome measure or had a significant problem with the definition (e.g., discrepancy between registry and published article). Interpretation of results can be problematic for investigations lacking prospective registration and/or a predetermined primary outcome measure. The latter is critical in evaluating randomized, controlled trials with multiple endpoints (outcomes) since the risk of erroneously finding a difference when none truly exists (type I error) is greatly multiplied with each comparison without statistical control (e.g., a Bonferroni correction).85 To illustrate, one trial designated three daily variables during a 7 to 14 day period as coprimary outcomes without a statistical plan managing multiple endpoints, and reported P values greater than 0.05 for all but a single comparison (pain on postoperative day 2).86 With 35 comparisons, the risk of erroneously finding at least one positive outcome is 83%; yet, within the abstract the single statistically significant finding was emphasized, greatly skewing interpretation of the results. Designating a priori and subsequently focusing on a single comparison—the primary outcome—reduces the risk of a type I error to (typically) 5% (minimizing the type II risk as well).
Infiltration with Liposomal Bupivacaine versus Placebo
There are 12 placebo-controlled randomized trials investigating the use of liposomal bupivacaine infiltrated into the surgical site to control postoperative pain after procedures of the trunk, extremities, and dentition (tables 1 and 2).86–97 Seven of the 12 (58%) failed to find a statistically significant difference for the primary outcome measure between active and placebo treatments,86–92 and all but one had an overall low risk of bias based on the Cochrane risk-of-bias tool for randomized trials.98,99 In contrast, 5 of the 12 (42%) reported a statistically significant difference between active and placebo treatments for either the primary outcome measure or most of the outcomes (for studies which did not predefine a specific primary outcome); and, all five of these randomized, controlled trials had a high risk of bias based on the Cochrane tool.93–97 We will discuss the study methodology and interpretation of results for key investigations and then draw conclusions regarding clinical effectiveness.
The Food and Drug Administration used data from three pivotal phase III studies to evaluate—and ultimately approve—the use of liposomal bupivacaine for surgical site infiltration.94,95 Two of these randomized, controlled trials were published in the peer-reviewed literature and reported that liposomal bupivacaine infiltration compared with placebo resulted in reduced pain scores for up to 36 and 72 h after bunion removal and hemorrhoidectomy, respectively (table 1).94,95 Total opioid use, time until first opioid use, and patient satisfaction were all improved with liposomal bupivacaine. However, two notable factors greatly influence interpretation of these results. The first is that the pain and opioid consumption outcomes were calculated using the area under the receiver operating characteristics curve (AUC), which essentially compares the integral of all values over a period of time between the two treatments. If differences are large for a short period of time but nonexistent subsequently, the AUC can still be statistically significant over the total study period, giving the impression of extended duration when none exists. Indeed, the Food and Drug Administration clinical review stated that for the hemorrhoidectomy study, “although the primary endpoint was the AUC for pain intensity during the first 72 h postoperatively, the two treatments (bupivacaine liposomal and placebo) differed significantly and clinically only during the first 24 h” (fig. 1A).100 Similarly, for this same study, cumulative opioid use was reported as lower at 0 to 72 h, yet there is only an improvement within the first 12 postoperative hours, and there are virtually no differences between the groups over the subsequent 60 h (group differences of 0.2 to 1.2 mg during each 12-h period, with the treatment group requiring more opioid in three of the five 12-h periods).95 The same issue may be found with the pivotal bunion removal randomized, controlled trial, with no differences in effect on pain measures after 24 h (fig. 1B).94,100 So, while it is reassuring that liposomal bupivacaine was an improvement over placebo for up to 24 h, it is not compelling evidence for clinical use.
A second important and frequently overlooked factor when interpreting the results of these two placebo-controlled trials is that pain score AUCs were not determined exclusively using actual pain scores, but rather with the “windowed worst-observation-carried-forward + last-observation-carried-forward (“wWOCF+LOCF”) imputation method” in which “NRS [Numeric Rating Scale] scores were recorded within a time window for patients who took postsurgical rescue pain medication (6 h, based on the half-life of rescue medication…) and replaced by the ‘worst’ observation (i.e., the highest pain score before taking their first rescue medication).” Furthermore, missing scores were replaced by one of three methods including last-observation-carried-forward. While imputation techniques such as last-observation-carried-forward were accepted by the Food and Drug Administration at the time of the original liposomal bupivacaine submission, it subsequently determined that “single imputation methods like last observation carried forward…should not be used as the primary approach to the treatment of missing data” because it can result in an “exaggerated positive effect, biased in favor of treatment.”101
Moreover, the windowed worst-observation-carried-forward imputation—while unquestionably a valid statistical technique—remains an artificial construct of the randomized, controlled trial and decreases generalizability of the results to patients outside of the investigation. For example, in a hypothetical study using this imputation technique, if a study subject has a pain score of 6 on the 0 to 10 scale and takes an opioid resulting in perfect analgesia for 6 h, the study reports this subject in moderate pain for the entire 6 h. However, this result would not accurately reflect the experience of patients outside of the randomized, controlled trial who would—again, hypothetically solely for illustration—experience moderate pain for the duration of analgesia onset, but then experience no pain for the remainder of the 6 h. This difficulty in interpreting imputed results may be partially alleviated if both the imputed and nonimputed scores are provided, or if the number of missing data points is provided. However, these two pivotal studies reported only the imputed values and no actual pain scores at any time point.94,95
Three additional randomized, controlled trials provide evidence of liposomal bupivacaine superiority over normal saline when infiltrated into the surgical site after a variety of orthopedic and soft tissue procedures, including ankle open reduction internal fixation,93 retropubic sling placement,96 and laparotomy,97 although all had a high risk of bias with two failing to specify a primary outcome,93,97 and the third demonstrating a discrepancy in primary outcome between the registry and published article.96 Pain scores and opioid consumption were inconsistently improved at various time points within the first 72 postoperative hours, and the authors of one study questioned the cost–benefit ratio given the minimal benefit reflected in their results.96 In contrast, seven other placebo-controlled randomized trials failed to detect a statistically significant difference between liposomal bupivacaine infiltration and normal saline for pain scores—usually the primary outcome—opioid consumption, and hospital length of stay.86–92 Many of these studies involved surgical procedures similar to investigations reporting statistical significance, such as shoulder arthroplasty,29,90 gynecologic surgery,88,92,96 and cesarean delivery.91,97
To summarize the evidence for the use of surgical site infiltration with liposomal bupivacaine over normal saline, of the 12 published randomized, controlled trials, seven (58%) failed to find a statistically significant difference for the primary outcome measure; all but one with an overall low risk of bias.86–92 In contrast, five of the 12 (42%) reported a statistically significance difference between active and placebo treatments for either the primary outcome measure or, for studies that did not predefine a specific primary outcome, most of the outcomes.93–97 All five of these trials had an overall high risk of bias.93–97 Results from the two pivotal placebo-controlled randomized trials suggest that liposomal bupivacaine infiltration results in decreased NRS after hemorrhoidectomy and hallux valgus osteotomy,94,95 but the reporting of pain score data as AUC makes the actual duration of analgesia impossible to determine. Only with access to the primary data set could the Food and Drug Administration conclude that any analgesia improvements from liposomal bupivacaine were limited to only 24 h for hemorrhoidectomy and 12 h for hallux valgus osteotomy.100 Furthermore, the imputation method used in both pivotal randomized, controlled trials exaggerates positive effects and decreases applicability to nonstudy patients.
Infiltration with Liposomal Bupivacaine versus an Active Control for Procedures other than Knee Arthroplasty
Long-acting local anesthetics, such as unencapsulated bupivacaine, have been clinically available for decades. For healthcare providers, the choice, therefore, is not between liposomal bupivacaine and a placebo, but rather replacing an older medication with the new. Only studies including an active control can provide data on which to base a decision. Fortunately, at the time of this writing, there are 36 randomized, controlled trials involving surgical site infiltration comparing liposomal bupivacaine and unencapsulated bupivacaine or ropivacaine (tables 3-6).23,31,102–131 Since nearly half of these include a single surgical procedure—knee arthroplasty—we will present these studies separately (tables 5 and 6).23,31,117–131
Of the 19 randomized, active-controlled trials involving surgical procedures other than knee arthroplasty, 15 (79%) failed to find a statistically significant difference for their primary outcome measure (tables 3 and 4).23,102–112 These included both open and laparoscopic orthopedic and soft tissue procedures of the trunk, extremities, and dentition. While a few detected improvements favoring liposomal bupivacaine in some secondary endpoints,102,103,105,109 the majority failed to detect statistically significant differences between treatments for all variables at all time points.23,104,106–108,110–112 Overall risk of bias was deemed low in eight,23,105–108,110 some concerns in three,104,111,112 and high in three studies.102,103,109 Multiple investigations were unregistered and/or did not specify a primary outcome measure time point, although the impact of these deficiencies appears minimal with the near total lack of statistical significance between treatments. Furthermore, some of the negative studies were phase II and III dose–response trials that were not specifically designed to investigate clinical effectiveness.23 However, they were included in a manufacturer-supported review article that highlighted positive findings in various secondary and tertiary endpoints23 ; thus, it appears reasonable to include the negative findings here as well.
In contrast, 4 of the 19 randomized, controlled trials (21%) reported a statistically significant difference for their primary outcome measure(s) between liposomal bupivacaine and unencapsulated local anesthetic.113–116 Three of these were rated as having a high risk of bias,113,114,116 while one was rated as “some concerns.”115 The investigation with the strongest findings involved oral/dental implant surgery, with liposomal bupivacaine resulting in lower cumulative pain scores at all time points during the first postoperative week.114 Satisfaction with analgesia was higher within the first 24 h after surgery, although there were no differences in opioid consumption.114 Unfortunately, only 12.5 ml (63 mg) of bupivacaine hydrochloride was utilized for the comparison/control group—less than half of the 30 ml frequently used for simple molar extraction—while the maximum approved liposomal bupivacaine dose was utilized for the experimental group.132 The registry provided no details as to how the primary outcome measure would be analyzed (“postsurgical pain severity [time frame: 7 days]”), and the published article did not mention a primary outcome measure (but stated that “no sample size calculation was performed”). Therefore, this trial was deemed to be at high risk of bias.98,99
Another randomized, controlled trial reporting a statistically significant difference for its primary outcome measure involved hemorrhoidectomy, which demonstrated liposomal bupivacaine benefits in pain scores, opioid consumption, and opioid-related side effects.113 Pain scores were provided only in the cumulative 0 to 72 h AUC format, without daily totals, precluding assessment of the time window of true difference.113 It is also noteworthy that comparing the maximum approved dose of liposomal bupivacaine (266 mg) to 75 mg of bupivacaine hydrochloride in this study resulted in a statistically significant difference; however, a very similar randomized, controlled trial that used a 100 mg bupivacaine hydrochloride dose did not detect a statistically significant difference between treatments.23 Importantly, 100 mg still remains far below the maximum Food and Drug Administration–approved dose of bupivacaine hydrochloride—2.5 mg/kg up to 175 mg (3 mg/kg up to 225 mg with the addition of epinephrine)—while the maximum approved liposomal bupivacaine dose of 266 mg was utilized.100 Due to a discrepancy between the registry description of the primary outcome measure and the published manuscript, this study was rated at high risk of bias.98,99
The remaining two investigations with statistically significant differences for their primary endpoints involved soft tissue surgical procedures.115,116 The first examined infiltrating liposomal bupivacaine after midurethral sling placement and identified lower pain scores exclusively on the first postoperative day of seven.115 The investigators concluded that liposomal bupivacaine “did not result in a clinically significant [emphasis added] difference in POD [postoperative day] 1 pain scores,” and given the lack of analgesic improvement and opioid at other time points, “the cost of this anesthetic…may not justify its use…”115 Similarly, while the authors of the second article found a statistically significant reduction in pain scores within the 72 h after mammoplasty, these improvements were less than 1.0 point on the 0 to 10 Numeric Rating Scale, leading the authors to conclude “that the additional cost of liposomal bupivacaine is unjustified for this particular use.”116
Both of the two positive trials used a dose of bupivacaine hydrochloride for the control arm at less than half of the Food and Drug Administration–approved and frequently used maximum for these surgical procedures.23,113,114,132 Both liposomal and unencapsulated bupivacaine have a dose–response relationship with increasing doses resulting in increased effects/duration and, conversely, decreasing dose resulting in decreased effects/duration.23 Therefore, when evaluating active-controlled trials, lower dosing of the comparator local anesthetic reduces confidence in the clinical applicability of the results.
To summarize the evidence for the use of infiltration with liposomal bupivacaine over unencapsulated bupivacaine, of the 19 randomized, active-controlled trials (excluding knee arthroplasty), only two (11%) reported both a statistically and clinically significant difference for their primary outcome measure.113,114 Both of these trials compared the maximum approved dose of liposomal bupivacaine (266 mg) to submaximal doses of the unencapsulated bupivacaine comparator.113,114 This discrepancy greatly decreases confidence that the difference would remain had a maximum dose of both treatments been compared.113 Furthermore, both trials were rated at high risk of bias for multiple reasons, the most critical being discrepancies between the registry entries and published articles involving the primary outcome measures. Therefore, there is currently no published evidence with a low risk of bias for surgical procedures other than knee arthroplasty demonstrating that infiltration with the maximum approved liposomal bupivacaine dose is superior to unencapsulated bupivacaine to a statistically and clinically significant degree.
Infiltration with Liposomal Bupivacaine versus an Active Control for Knee Arthroplasty
Knee arthroplasty is among the most common and painful surgical procedures, with more than 700,000 performed annually within the United States alone. Infiltrating the surgical site with local anesthetic is frequently performed by surgeons to provide postoperative analgesia, although the duration of effect is far less than the duration of surgically related pain.
Of the 17 randomized, active-controlled trials involving knee arthroplasty, 15 (88%) failed to find a statistically significant difference for their primary outcome measure (tables 5 and 6).23,31,117–129 Risk of bias for these 15 trials was deemed low in eight studies23,31,119,122–124,126,127 and “some concerns” in seven trials.117,118,120,121,125,128,129 Within these studies, differences between treatments for nearly every secondary endpoint involving pain level, opioid use, physical therapy, or discharge day also failed to reach statistical significance. Nearly no statistically significant differences between infiltration with liposomal bupivacaine and unencapsulated bupivacaine after total knee arthroplasty were identified. Of the few exceptions, the unencapsulated local anesthetic control was found superior to liposomal bupivacaine118,126–128 more times than vice versa.119 Multiple investigations were unregistered and/or did not specify a primary outcome measure time point, although the impact of these deficiencies appears minimal with the near-total lack of statistical significance between treatments. A unique and illuminating investigation randomized each side of subjects having bilateral knee arthroplasty (n = 29) to either a combination of liposomal bupivacaine (266 mg) and bupivacaine hydrochloride (75 mg) or ropivacaine hydrochloride (250 mg) plus epinephrine, ketorolac, and clonidine.121 This split-body study design is especially powerful since it inherently controls for intersubject differences in pain evaluation and supplemental opioid consumption between treatment groups (each subject receives both treatments, and therefore each treatment is associated with identical opioid doses). No statistically significant or clinically relevant (defined by the authors as greater than 18 mm on the 0 to 100 mm visual analogue scale [VAS]) differences between treatments were detected, mirroring the vast majority of published trials (tables 5 and 6).
In contrast, two of the 17 randomized, controlled trials (12%) reported a statistically significant difference for their primary outcome measure(s) between liposomal bupivacaine and unencapsulated local anesthetic.130,131 The first randomized subjects (n = 70) to either a maximum dose of liposomal bupivacaine (266 mg) or a multicomponent injection of ropivacaine (400 mg), ketorolac, morphine, and epinephrine.131 Considering the Food and Drug Administration–recommended maximum dose of ropivacaine (with epinephrine) is 4 mg/kg up to 225 mg, an optimized control group was certainly provided with 400 mg used in this study. Statistically significant differences were identified not only for the primary outcome of pain level on postoperative day 1 but also in pain scores within the recovery room and postoperative day 2. Differences were also detected in opioid consumption in the recovery room and postoperative days 1 and 2, and the risk of bias was evaluated as low using the Cochrane risk-of-bias tool.98,99
The second randomized, controlled trial, the PILLAR trial, randomized subjects (n = 140) to infiltration with either a combination of liposomal (266 mg) and unencapsulated (100 mg) bupivacaine, or solely bupivacaine hydrochloride (100 mg).130 The results of this investigation were overwhelmingly positive not only for the two coprimary outcomes of pain scores (AUC, 12 to 48 h) and opioid consumption (cumulative, 0 to 48 h),133 but also for secondary and tertiary endpoints at 24, 48, and 72 h.130,133,134 For example, mean total opioid consumption in the first 48 h postsurgery was 16 versus 80 mg for the experimental versus control groups, respectively (P = 0.0029).133 More subjects receiving liposomal bupivacaine remained opioid-free, exhibited a greater amount of time until request for first opioid rescue, were more satisfied with postoperative analgesia, and met discharge criteria earlier than in the control group.130,133,134
The authors attribute their dramatically different results compared to most other randomized, active-controlled trials to their use of a large volume of injectate (120 ml);135 the “use of a small-bore (22-gauge), 1.5-inch needle to reduce the leakage of anesthetic solution from the injection site and for achievement of maximal tissue exposure”135–137 ; and their “use of a meticulous and standardized infiltration protocol.”130,138 This protocol entailed the use of six 20-ml syringes of study fluid with 94 to 103 separate needle passes/injections.130,135 However, six of the trials that did not detect statistically significant differences in their primary outcome measure(s) employed similarly high injection volumes of 90 to 120 ml,118,121,122,127–129 and a seventh described administering “approximately 50 injections,” although the total volume was not specified.119 In addition, authors of many of the trials without statistically significant findings describe an involved infiltration protocol very similar to the PILLAR technique, including one group of authors who pointedly noted that “the collaborating surgeon received extensive printed and in-person education on appropriate installation technique as recommended by the manufacturer before study initiation, and a drug manufacturer representative was present in the operating room to provide support on proper drug administration as needed for the first study patients.”123
An additional possible difference among studies accounting for the vastly dissimilar analgesic findings might be that the PILLAR trial was unique in applying the windowed worst-observation-carried-forward method, specifying that “pain intensity scores during periods of rescue medication administration were replaced by the highest observed score before rescue medication use” [emphasis added].130 The results without the “window” adjustments were not provided—unlike other manufacturer-supported randomized, controlled trials29,139 —so it remains unknown whether the relatively small difference in pain scores between treatments (approximately 180 vs. 207 AUC during 36 h; P = 0.038) would have remained statistically significant without replacing the lower with higher scores. The authors had published their protocol—including details of the statistical plan—before beginning enrollment,135 but the windowed technique was not mentioned in that publication or the clinicaltrials.gov registry (NCT02713490). More importantly, the ultimate statistical analysis deviated from the prespecified statistical plan in three critical aspects, and if the original plan had been adhered to, the primary outcome measures would not have reached statistical significance, even with the “window” imputation.140 These two factors resulted in a high risk of bias using the Cochrane tool.98,99 Last, while for the experimental group the maximum Food and Drug Administration–approved liposomal bupivacaine (266 mg) combined with an additional 100 mg of bupivacaine hydrochloride was employed, the control group received only 57% of the possible maximum unencapsulated bupivacaine dose, and without epinephrine, which is commonly included to increase both the maximum dose (to 225 mg) and duration of effect.
To summarize the evidence for the use of infiltration with liposomal bupivacaine over unencapsulated bupivacaine during knee arthroplasty, of the 17 available randomized, active-controlled trials, only two (12%) reported a statistically significant difference for their primary outcome measure(s),130,131 with the remainder observing few if any statistically significant differences in secondary and tertiary endpoints (tables 5 and 6).23,31,117–129 For one of the two trials with statistically significant findings,130 deviation from the published prespecified statistical plan resulted in a positive outcome when adherence to the original design would have rendered neither of the two coprimary endpoints statistically significant.140 In addition, this study used a submaximal dose of unencapsulated bupivacaine for the comparison group, while subjects of the treatment group received the maximum approved dose of liposomal bupivacaine plus additional bupivacaine hydrochloride.130 This discrepancy greatly decreases confidence that the statistically significant differences would remain had a maximum dose of both treatments been compared.130 Consequently, there is currently little published evidence with a low risk of bias demonstrating that administration of the maximum approved liposomal bupivacaine dose is superior to unencapsulated bupivacaine hydrochloride when surgically infiltrated for knee arthroplasty.
Infiltration with Liposomal Bupivacaine versus a Peripheral Nerve Block with Unencapsulated Long-acting Local Anesthetic
Single-injection Peripheral Nerve Block
A single-injection peripheral nerve block using the longest acting local anesthetic approved in the United States, bupivacaine hydrochloride, provides a sensory and motor block with a typical duration of 8 to 12 h, although a longer period may occur depending on the anatomic location, inclusion of additives, and other factors. Regardless, nearly all bupivacaine hydrochloride–based regional anesthetics resolve in less than 24 h. Since peripheral nerve blocks require additional equipment (e.g., ultrasound), expertise, and time to administer, surgical infiltration of a sustained released local anesthetic may be a useful alternative if found to deliver at least equivalent analgesia.
Eleven randomized, controlled trials compare a single-injection peripheral nerve block of unencapsulated long-acting local anesthetic with surgical infiltration of liposomal bupivacaine (tables 7 and 8).90,105,118,141–148 Of the eight that involve shoulder and knee procedures,90,118,141–146 all were deemed to have some concerns regarding bias due mainly to a lack of treatment group masking. All either had an inadequately defined primary outcome measure or used a primary outcome that included a longer duration than anticipated for the unencapsulated local anesthetic peripheral nerve block (greater than 12 h).90,118,141–146 However, the secondary outcomes allow a comparison of liposomal bupivacaine infiltration and peripheral nerve blocks. All eight reported statistically significant and clinically relevant improvements in pain scores in favor of the peripheral nerve block during the anticipated duration of the block (8 to 12 h). Of these, half also found that the peripheral nerve block group concurrently required a lower dose of supplemental opioids,90,118,143,145 while the remainder reported little difference during this period of time.141,142,144,146 Collectively, these eight studies provide evidence that a single-injection peripheral nerve block with unencapsulated ropivacaine or bupivacaine provides superior analgesia compared with liposomal bupivacaine infiltration for the duration of the peripheral nerve block.
However, one of the proposed benefits of using liposomal bupivacaine infiltration is the possibility of prolonging analgesia beyond the typical 8 to 12 h peripheral nerve block duration. Of the eight randomized, controlled trials just described,90,118,141–146 three included an additional continuous peripheral nerve block in which unencapsulated local anesthetic was infused through a percutaneous perineural catheter to extend analgesia beyond the duration of the initial single-injection peripheral nerve block.118,145,146 Therefore, the remaining five randomized, controlled trials describe a single-injection peripheral nerve block without a subsequent confounding perineural infusion: one reported that subjects receiving infiltrated liposomal bupivacaine did have less pain at 24 h (although not beyond),90 with the remaining four trials finding no statistically significant differences between treatments.141–144 Similarly, of these five trials,90,141–144 two detected lower opioid requirements for liposomal bupivacaine subjects after block resolution: one on postoperative day 1,143 and the other during postoperative hours 13 through 16 (although this was reversed in favor of the peripheral nerve block group during hours 49 to 56, suggesting a high probability of type I errors for these two findings due to multiple comparisons with a limited sample size).142 Thus, these five randomized, controlled trials failed to provide evidence that liposomal bupivacaine provided any analgesic or opioid-sparing benefits beyond postoperative day 1.
Continuous Peripheral Nerve Block
Four randomized, controlled trials included a continuous peripheral nerve block for knee and shoulder surgery, allowing a comparison of liposomal bupivacaine infiltration and perineural local anesthetic infusion (tables 7 and 8).118,145,146,149 The two involving knee arthroplasty reported lower pain scores for subjects with continuous femoral nerve blocks during the period of perineural local anesthetic infusion based on both primary and secondary outcome measures.118,146 One of these also found concurrent lower opioid use for continuous peripheral nerve block subjects,118 while the other detected a longer time to first use of rescue opioids for subjects who had received liposomal bupivacaine.146
Two additional randomized, controlled trials involved shoulder arthroplasty; neither found differences in pain scores after resolution of the single-injection peripheral nerve block.145,149 However, both detected greater opioid sparing in favor of the continuous peripheral nerve block during this same duration. Unfortunately, neither was registered or had a well-defined primary outcome measure. In addition, one provided no information on the perineural infusion dosing in the manuscript, rendering the findings for postoperative days 1 and 2 difficult to interpret.145 Furthermore, unlike the other continuous peripheral nerve block investigations, the second trial provided a single-injection interscalene block to both treatment groups.149
The reason for the finding of continuous peripheral nerve block analgesic superiority over infiltrated liposomal bupivacaine for femoral but not interscalene catheters is not readily apparent.118,146,149 It may simply be due to the very low number of studies with underpowered sample sizes, or that in one shoulder study, both treatment groups received a single-injection peripheral nerve block. Regardless, this latter study is a good example of the potential benefit of local infiltration analgesia over continuous peripheral nerve blocks: two subjects experienced residual hand numbness that resolved with catheter removal, and five had an inadvertent, premature catheter dislodgement.149 Moreover, unlike perineural infusion, tissue/joint infiltration carries little risk of inducing muscle weakness,146 patient burden is decreased without an infusion pump and local anesthetic reservoir to carry, and provider workload is reduced without an infusion to manage.1 Given these potential benefits of liposomal bupivacaine combined with the equivocal available comparison data, additional research is greatly needed to assist stakeholders in optimizing patients’ perioperative experience.
Three studies involved hip arthroplasty or abdominal hysterectomy (tables 7 and 8).105,148 One hip arthroplasty study compared infiltration with liposomal bupivacaine with a fascia iliaca block without a subsequent infusion,148 while the other compared liposomal bupivacaine to single-injection and continuous psoas compartment (posterior lumbar plexus) blocks.105 Liposomal bupivacaine infiltration was not inferior to a fascia iliaca block in the first study, but interpretation of this result is complicated by results of multiple randomized, placebo-controlled trials demonstrating that fascia iliaca blocks provide little to no analgesic benefit after hip arthroplasty.150,151 In contrast, psoas compartment blocks/infusions do offer pain control for hip arthroplasty,152,153 and liposomal bupivacaine infiltration was not inferior to this block, which had a high incidence of motor weakness and complications, indicating benefits from liposomal bupivacaine in this comparison.105
Last, one randomized, controlled trial compared liposomal bupivacaine infiltration with a bilateral transversus abdominis block with bupivacaine hydrochloride for total abdominal hysterectomy.147 The results were statistically significant in favor of the liposomal bupivacaine infiltration for both the primary outcome of pain upon coughing 6 h after surgery and nearly every secondary pain (at rest and on coughing) and opioid endpoint from 2 to 48 postoperative hours. Unfortunately, a discrepancy between the primary outcome provided in the registry and published manuscript results in a high risk of bias for this trial.
To summarize the evidence for the use of infiltration with liposomal bupivacaine compared with a peripheral nerve block with unencapsulated local anesthetic for knee and shoulder procedures, all of eight randomized, controlled trials found evidence that a single-injection peripheral nerve block provides superior analgesia and concurrent opioid sparing for the duration of the block based on secondary outcomes.90,118,141–146 After block resolution, only one trial found any analgesic benefit of liposomal bupivacaine infiltration—and then only at 24 h90 ; two detected opioid sparing on postoperative day 0 or 1.142,143 Four randomized, controlled trials are available comparing liposomal bupivacaine infiltration with a continuous peripheral nerve block, and all reported lower pain scores and/or less opioid use for subjects with continuous peripheral nerve blocks based on primary and secondary outcomes.118,145,146,149 Therefore, there is evidence demonstrating the superiority of single-injection and/or continuous peripheral nerve blocks to liposomal bupivacaine infiltration for knee and shoulder surgery. However, the improved analgesia and opioid sparing must be balanced against the time and expertise required for administration, increased patient and provider burden, and other block-related limitations. Only a single randomized, controlled trial provides reliable data involving hip surgery, and while it does not demonstrate any superiority of liposomal bupivacaine over single-injection and continuous peripheral nerve blocks, the lack of block-related limitations will favor the liposomal bupivacaine infiltration method for many providers.105 Finally, the one randomized, controlled trial investigating abdominal hysterectomy provides evidence that liposomal bupivacaine infiltration is superior to a bilateral transversus abdominis block with unencapsulated bupivacaine,147 but this trial was deemed at high risk for bias due to a discrepancy between the primary outcome provided in the registry and published manuscript.98,99
Liposomal Bupivacaine Administered as an Epidural or Peripheral Nerve Block
Liposomal bupivacaine is approved by the Food and Drug Administration for use in two specific peripheral nerve blocks: transversus abdominis plane and interscalene (exclusively for postoperative analgesia after shoulder surgery). However, data are available for additional anatomic locations such as the epidural space, with studies performed under investigational new drug applications. We include these published randomized, controlled trials along with those investigating currently approved applications (tables 9 and 10).29,139,154–167 The 16 disparate trials of this section are not easily categorized or compared due to their heterogenous surgical procedures, experimental treatments (e.g., peripheral nerve block vs. epidural), and comparison groups (e.g., placebo vs. liposomal bupivacaine).
Peripheral Nerve Block with Liposomal Bupivacaine versus Placebo
There are four randomized, controlled trials comparing a peripheral nerve block using liposomal bupivacaine and a placebo control.29,139,154,160 The first involved elective coronary artery bypass grafting through a median sternotomy and sequential intercostal nerve blocks performed through the surgical incision, as well as infiltration surrounding the mediastinal drains.154 Although the authors designated pain scores and opioid use as primary outcomes, no time point was specified, warranting “some concerns” regarding possible bias using the Cochrane tool. At none of 10 individual time points between 0 and 72 postoperative hours was liposomal bupivacaine found to be superior to placebo. However, when overall pain scores were compared using a linear mixed-effects model, the treatment group demonstrated lower scores (P = 0.040). Except for the 2-h time point, the treatment group did not demonstrate a significant reduction in pain medication requirements either at individual time points or overall. Similarly, there were no differences in secondary outcomes such as time to extubation, hospital or intensive care unit length of stay, time to first bowel movement, or time to return to work or daily activity. Considering the comparison group was normal saline and not active unencapsulated bupivacaine, the authors concluded, “there is currently not enough evidence to justify the clinical use of this drug for this purpose.”154
In contrast, two other placebo-controlled trials with low risk of bias offer stronger evidence in favor of liposomal bupivacaine when administered as an ultrasound-guided femoral, or interscalene nerve block before major knee or shoulder surgery, respectively.29,139 Subjects experienced lower pain when all scores during the first 48 to 72 postoperative hours were evaluated together using AUC. Importantly, the windowed worst-observation-carried-forward technique was employed; however, the difference between treatments remained with a post hoc analysis without score imputation, although the effect size was reduced by approximately 25 to 39%. With data imputation, daily pain score AUC for the 0 to 24, 24 to 48, and 48 to 72-h periods were approximately 13 to 39% (femoral) and 26 to 51% (interscalene) lower in the treatment groups, providing evidence that there is pharmacologic activity beyond 48 h. For interscalene blocks, the actual resting pain scores (not AUC) were dramatically improved for the active treatment—approximately 30 to 60% lower—for all three time periods, as was the opioid consumption (reduced by 66 to 86%). In contrast, benefits for femoral blocks were far more modest, with resting pain scores and opioid consumption improved to a clinical and statistically significant degree only through 24 h. One important caveat is that neither investigation allowed unencapsulated local anesthetic infiltration or perioperative nonsteroidal anti-inflammatory drug administration, both of which can be important components of multimodal analgesia frequently provided for major joint surgery. Regardless, these studies suggest that single-injection femoral and interscalene nerve blocks with liposomal bupivacaine have pharmacologic activity greater than 48 h when compared to placebo—far longer than would be expected for unencapsulated bupivacaine.
Somewhat less informative for liposomal bupivacaine effectiveness is the fourth placebo-controlled study involving laparoscopic hysterectomy comparing bilateral transversus abdominis plane with a combination of liposomal bupivacaine and bupivacaine hydrochloride to a placebo (but with port site infiltration of unencapsulated bupivacaine).160 While the difference between treatments was statistically significant for the primary outcome of 72-h cumulative opioid consumption, the 1.5 mg per day difference suggests clinical irrelevance. However, the secondary analgesic outcomes are both statistically and clinically significant for most of this same time period. Unfortunately, since two independent variables were varied—both the type of local anesthetic and the location of administration (transversus abdominis plane vs. ports)—it remains unknown if the observed outcome differences are related to the use of liposomal bupivacaine.
Transversus Abdominis Plane Block with Liposomal Bupivacaine versus an Active Control
Of the 12 randomized, controlled trials comparing a peripheral or epidural nerve block using liposomal bupivacaine and an active control, seven involve the transversus abdominis plane block (tables 9 and 10).155–159,161,162 When the control group consisted of a transversus abdominis plane with unencapsulated bupivacaine, the results were mixed: one study involving abdominally based autologous breast reconstruction detected no statistically significant differences between the two treatments,157 while three randomized, controlled trials involving hysterectomy and donor nephrectomy reported analgesic and opioid-sparing benefits of liposomal bupivacaine over unencapsulated bupivacaine.158,159,161 Unfortunately, these last three trials were at high risk of bias: two due to registration occurring after enrollment completion and a change in primary outcome after the initial registration,158,159 and the third resulting from protocol revisions during the enrollment period with 28% of randomized subjects excluded from the primary analysis.161 Notably, of the 50 excluded subjects, total opioid consumption through 72 h was five times higher with liposomal bupivacaine added to unencapsulated bupivacaine (52.1 mg) than with bupivacaine hydrochloride alone (10.5 mg). This third study also used the lowest concentration of bupivacaine hydrochloride (less than 0.09%) and among the lowest—if not the lowest—bupivacaine hydrochloride dose for the control group relative to all other published single-injection transversus abdominis plane randomized, controlled trials.168,169
Two of the remaining three trials involving a liposomal bupivacaine transversus abdominis plane block included an epidural infusion as the control group.156,162 The first trial involving colorectal surgery, listed different primary outcome measures in the registry and manuscript, lacked a power analysis for sample size, and provided a statistical plan lacking detail.156 These factors render interpreting the study results problematic. Pain scores were collected at 11 time points during 4 days, and the registry lists three primary outcome measures as these scores on each of the first 3 postoperative days; however, only a single undefined pain score comparison is reported for the published article with the difference between treatments failing to reach statistical significance. The investigators concluded that the two treatments provide “equal” analgesia even though superiority and not equivalence statistical tests were applied (“absence of proof is not proof of absence”).170 In contrast, supplemental opioid requirements for the liposomal bupivacaine transversus abdominis plane group were twice that of the epidural subjects on postoperative days 0, 1, and 0 through 3 (P < 0.001), suggesting improved analgesia with the neuraxial technique.
The second randomized, controlled trial, also involving colorectal surgery, found that subjects with a liposomal bupivacaine transversus abdominis plane had a shorter hospital stay of 0.5 days (primary outcome) compared with those who received the epidural infusion for colorectal procedures.162 However, interpretation is difficult as the only three secondary outcomes presented—time to flatus, nausea, and urinary retention—were all negative, and no pain scores or opioid consumption were recorded. Therefore, the reason for the shorter hospitalization remains unclear. These two trials fail to bring much clarity to the issue. An unpublished, multicenter (n = 493), prospectively registered randomized, controlled trial (NCT02996227) found that after abdominal surgery, subjects with a liposomal bupivacaine transversus abdominis plane experienced noninferior analgesia compared with the epidural group, but required more opioids to achieve this level of pain control (principal investigator, Alparslan Turan, M.D.; presentation, American Society of Anesthesiologists 2019 by Barak Cohen, M.D.). Full publication of these results will add meaningfully to this literature.
The final randomized, controlled trial comparing liposomal bupivacaine transversus abdominis plane to intrathecal hydromorphone for colorectal procedures demonstrated lower pain scores and opioid requirements for control subjects with intrathecal hydromorphone during the first 48 postoperative hours.155 However, when discrete time periods were compared, differences were detected solely during the anticipated duration of the intrathecal opioid of approximately 12 to 16 h.171 Secondary outcomes such as the duration of hospital stay and postoperative ileus were negative with the exception of cost, which was consistently higher in the liposomal bupivacaine transversus abdominis plane group.
Non–Transversus Abdominis Plane Peripheral Nerve Blocks with Liposomal Bupivacaine versus an Active Control
Five remaining randomized, controlled trials involve different surgical procedures, interventions, control groups, and primary outcomes (tables 9 and 10).163–167 Three of these do not provide actionable information regarding liposomal bupivacaine when used in a peripheral nerve block, all for different reasons.163–165 The first compared liposomal bupivacaine as part of an adductor canal nerve block and liposomal bupivacaine infiltrated directly into the joint for knee arthroplasty, revealing essentially no differences in analgesia or opioid consumption.163 Since both treatment groups included liposomal bupivacaine, the results do not provide information on liposomal bupivacaine versus unencapsulated local anesthetic. A second trial found no analgesic or opioid requirement differences between liposomal bupivacaine and unencapsulated bupivacaine when used in a fascia iliaca block for hip arthroplasty.164 Unfortunately, as noted previously, placebo-controlled clinical trials demonstrate that this peripheral nerve block provides poor, if any, analgesia for hip arthroplasty,150,151 and consequently, the results of this study are not particularly enlightening.172 A third investigation randomized subjects having upper extremity orthopedic surgery to either three forearm nerve blocks (median, ulnar, radial) followed by a supraclavicular block with mepivacaine, or a single supraclavicular block with unencapsulated bupivacaine.165 Interpreting the results is difficult since the investigators varied two independent variables (block location and local anesthetic type), so it remains unknown to what to attribute the few differences detected between treatments.
A fourth investigation involved subjects having major shoulder surgery who all received an interscalene block with bupivacaine hydrochloride and were then randomly administered either liposomal bupivacaine or additional bupivacaine hydrochloride.166 Interpreting the results is difficult due to an unclear primary outcome measure. Within the text of the published article, the primary outcome is specified as the worst pain queried on postoperative day 2 (for the previous 24 h) with a matching sample size estimate—and the difference between treatments was not statistically significant for this endpoint. In contrast, the article abstract states the primary outcome as the worst pain during the entire first postoperative week.173,174 Unfortunately, the prospective registration does not help resolve this issue due to a registry–publication discrepancy.175,176 Average/median pain scores and opioid consumption were not presented, and the two groups did not differ to a statistically significant degree in daily worst pain scores, overall benefit of analgesic scores, and cumulative supplemental analgesic consumption. However, chi-square tests of worst pain scores and overall benefit of analgesic scores across all time points (postoperative days 1 to 7) based on generalized estimating equations were statistically significant. Unfortunately, no hierarchical or alpha-spending testing strategy was prespecified to control type I error across outcomes, time points, and the generalized estimating equations chi-square tests. A Bonferroni correction was used to adjust P values for the five time points within an outcome, but the chi-square test was not corrected. The P values for generalized estimating equations t tests applied at each time point were not reported. Combined, all of these issues decrease confidence in the conclusion that adding liposomal bupivacaine to unencapsulated bupivacaine single-injection interscalene nerve blocks resulted in clinical benefits. Of additional concern, a retrospective study of 352 patients who received liposomal bupivacaine as part of an interscalene nerve block for ambulatory shoulder surgery found that 12% returned to the emergency department due to dyspnea.177
In preclinical studies, liposomal bupivacaine exhibited no toxicity when administered in the epidural space of both rats and dogs.178 The only published clinical trial involved 26 volunteers given a single 20-ml injection into the lumbar epidural space consisting of liposomal bupivacaine (89, 155, or 266 mg) or bupivacaine hydrochloride (50 mg).167 Due to the relatively small number of subjects in each treatment group of this phase I study, no statistics were applied to the collected data. Nevertheless, the results of this pilot study strongly suggest a dramatic increase in analgesia duration: median time until recovery of pinprick sensation was 11 h for unencapsulated bupivacaine, compared with 35 h for liposomal bupivacaine (all doses combined). In contrast, 100% of those receiving bupivacaine hydrochloride had some degree of motor block compared with only 57% for the liposomal bupivacaine group. This left 67% of those in the unencapsulated bupivacaine group unable to ambulate after 4 h versus only 39% for those who had received liposomal bupivacaine. There were no serious adverse events. It is emphasized that Exparel is not currently approved for use in the epidural space, and although promising, must be considered experimental at this time.
A succinct summary of the evidence for the use of liposomal bupivacaine within an epidural or peripheral nerve block is challenging due to the heterogeneity of the 16 published randomized, controlled trials (tables 9 and 10).29,139,154–167 The four placebo-controlled trials provide evidence of pharmacologic effects for more than 48 h, although clinical benefit was often limited to 24 h.139,154 Based on seven randomized, controlled trials—four with a high risk of bias and the remaining three with “some concerns” regarding bias—the evidence is mixed regarding the benefits of liposomal bupivacaine over unencapsulated bupivacaine in transversus abdominis plane blocks, possibly due to various surgical applications or administration protocols.155–159,161,162 While the limited data suggest that epidural and intrathecal opioids provide superior analgesia and/or are opioid-sparing compared with liposomal bupivacaine transversus abdominis planes, they may also prolong hospitalization, induce hypotension, and increase overall costs.155,156,162 Although four randomized, active-controlled trials involve using liposomal bupivacaine as part of a peripheral nerve other than a transversus abdominis plane block, three provide minimal useful data for various reasons,163–165 and interpreting the fourth is problematic.166 Thus, there are currently insufficient data to conclusively support or refute the use of liposomal bupivacaine administered as a peripheral nerve block. Last, a single injection of liposomal bupivacaine into the epidural space more than tripled the duration of sensory effects to skin testing while greatly decreasing any motor block in a small cohort of healthy volunteers.167
Randomized versus Retrospective Data Discrepancies
Sustained released local anesthetic offers the possibility of prolonging postoperative analgesia beyond the normal duration of unencapsulated bupivacaine. Since liposomal bupivacaine may be detected within the serum more than twice as long as bupivacaine hydrochloride,31 the findings suggesting liposomal bupivacaine benefits reported in early cohort and case-control studies appeared reasonable—even obvious.55–78 However, the strength of evidence for clinical effectiveness provided by randomized, controlled trials far surpasses that of nonexperimental study designs, and there are now more than 76 published experimental investigations. As detailed in this review, the preponderance of high-quality evidence fails to support the retrospective data: when liposomal bupivacaine and unencapsulated local anesthetic were infiltrated directly into a surgical site, only four of 36 randomized, controlled trials (11%) were positive for their primary outcome to a clinically relevant degree. Indeed, recent meta-analyses that included exclusively randomized studies universally concur3–7 —in contrast to meta-analyses that included retrospective investigations and universally reported liposomal bupivacaine superiority.179–185 The overwhelming majority of randomized, controlled trials failed to demonstrate liposomal bupivacaine superiority even though the dose of liposomal bupivacaine was almost always maximized, while that of the comparator was rarely optimized. Even when compared to a placebo, infiltration with liposomal bupivacaine improved effects in only a minority of randomized, controlled trials (42%).
We can only speculate on possible reasons for these unexpected findings where most randomized, controlled trials did not support the positive effects of liposomal bupivacaine suggested in retrospective studies. It may be that while bupivacaine hydrochloride is slowly released from the liposomes and detectable in serum over a prolonged duration, the concentration of local anesthetic at the target nerves is often subtherapeutic. Evidence for this may be found in the lower potency of liposomal bupivacaine: unlike bupivacaine hydrochloride, encapsulated bupivacaine will not provide a surgical block,186 and for this reason, the manufacturer recommends “the ability to admix long-acting liposomal bupivacaine with immediate-release bupivacaine [which] can help ensure rapid onset of pain relief that spans both the acute and later postsurgical periods.”135 Just as clinical effects are limited to less than 18 h after administration of unencapsulated bupivacaine—even though this medication may be detected in the serum for two to three times this duration—so too might the clinical effects of liposomal bupivacaine be limited to far less time than serum concentration might suggest.139
Risk of Bias
Of the 76 clinical trials included in this review, the Cochrane risk-of-bias tool identified 19 (25%) with a high overall risk of bias.98,99 It is notable that of the 19 deemed at high risk for bias, 84% (16) reported statistically significant differences for their primary outcome measure(s) compared with only 14% (4) of the 28 trials with a low risk of bias (fig. 2). Multiple factors accounted for trials with a high risk of bias. The most common was a lack of a prospectively designated or inadequately defined primary outcome measure, which increases the risk of selective reporting. This was one of the primary reasons for requiring prospective registration,187 which 29 (38%) lacked within this review. Few of the 76 randomized, controlled trials had a prospectively determined plan for statistical analysis, which can greatly increase the risk of bias due to so-called “data torturing.”188 Even with a prospective analytic plan, deviations can dramatically affect the results, as evidenced by one trial involving infiltration for knee arthroplasty reporting superiority of liposomal bupivacaine, when no statistically significant difference would exist had the original published statistical plan been followed.130,140 Similarly, selectively removing randomized subjects can alter study results, avoidance of which is the purpose of intention-to-treat analysis (“once randomized, always randomized”). For example, one randomized, controlled trial reported superiority of liposomal bupivacaine added to unencapsulated bupivacaine over bupivacaine hydrochloride alone within postcesarean delivery transversus abdominis plane blocks.161 However, the protocol had multiple revisions during enrollment and excluded 28% of randomized subjects from the final analysis.161 Of the 50 excluded participants, total opioid consumption through 72 h was five times higher with liposomal bupivacaine added to unencapsulated bupivacaine (52.1 mg) than with bupivacaine hydrochloride alone (10.5 mg).161
Explicitly excluded from the Cochrane bias tool is industry funding. It has been demonstrated that “drug and device studies sponsored by manufacturing companies have more favorable efficacy results and conclusions than studies sponsored by other sources.”189 One previously published analysis determined that liposomal bupivacaine was found superior to a control in 67% of studies reporting funding from the manufacturer, while only 7% of studies without such funding detected superiority of liposomal bupivacaine.6 Within the current review, 35% of studies reported funding from the manufacturer of liposomal bupivacaine (25 of the 71 with conflict of interest statements and excluding one phase I study167 ), and this increased to 49% (35 of 71) for studies with any conflicts including funding or authors who were concurrently paid consultants and/or employees. Liposomal bupivacaine was found superior to a control in 46% (16 of 35) with a conflict present, versus only 11% (4 of 36) without (fig. 2). This correlation was strongest among 13 randomized, controlled trials involving exclusively peripheral nerve blocks (excluding a phase I study and two randomized, controlled trials lacking conflict information): liposomal bupivacaine was reported superior to a control in 78% (7 of 9) for studies with a conflict present, versus 0% without (0 of 4; fig. 2).
An additional potential source of bias may be found in the choice of comparator/control. For the randomized, active-controlled trials of this review (excluding phase III dose–response studies), the maximum approved dose of liposomal bupivacaine (266 mg) was nearly always used, while the unencapsulated local anesthetic comparator was rarely maximized. This is all the more conspicuous since one of the earliest manufacturer-supported randomized, active-controlled trials used 200 mg of unencapsulated bupivacaine for a comparator—without detecting superiority of liposomal bupivacaine (266 mg).23 The dose was then lowered for a subsequent study to 150 mg of unencapsulated bupivacaine for the control group—again without detecting superiority of liposomal bupivacaine (266 mg).31 Ultimately, the most-recent “PILLAR” trial used only 100 mg of unencapsulated bupivacaine for the control group (“finding” a statistical superiority for liposomal bupivacaine, 266 mg,130,133 yet the difference failing to reach statistical significance if the prospectively-described statistical plan was used).135,140 Indeed, of the three phase IV manufacturer-supported, multicenter, randomized, active-controlled trials,114,130,161 the unencapsulated bupivacaine control group included a fraction of the approved maximum100 or commonly utilized dose for these procedures.132,168,169
Whether introduced by surgical infiltration or as part of a peripheral nerve block, the preponderance of current evidence fails to support the routine use of liposomal bupivacaine over standard local anesthetics when treating postoperative pain (fig. 3). However, medicine is constantly evolving with ongoing research, and the use of liposomal bupivacaine for postoperative analgesia will certainly be no different. Identified knowledge gaps for future research include the concurrent use of liposomal and unencapsulated bupivacaine in both surgical site infiltration and peripheral nerve blocks135 ; optimizing administration techniques130,138,190,191 ; maximizing comparator local anesthetic dose; comparisons with regional analgesics that are not local anesthetic based192,193 ; prospective registration with a clearly defined primary outcome measure and statistical plan194 ; large cohorts to investigate rare adverse events195–197 ; and additional sustained release local anesthetic formulations.2,198–203 As noted previously by others,6 minimizing conflicts of interest should be emphasized. The purported advantages of sustained released over standard local anesthetics in treating acute pain include improved analgesia, decreased opioid requirements, shortened hospitalization, and decreased costs.22 However, before widespread adoption, it is incumbent on those proposing a switch to liposomal bupivacaine to provide high-quality data from multicenter, randomized, active-controlled trials with a low risk of bias conclusively demonstrating benefits that justify the 100-fold increase in cost over unencapsulated bupivacaine.123,124,204
The authors would like to thank Michael C. Donohue, Ph.D. (Associate Professor of Neurology, University of Southern California, Los Angeles, California), for his expertise and thoughtful contributions to this article.
Support was provided solely from institutional and departmental sources.
The University of California has received funding and product for Drs. Ilfeld and Gabriel’s research from cryoneurolysis device manufacturers Myoscience (Fremont, California) and Epimed International (Farmers Branch, Texas); perineural catheter manufacturer Ferrosan Medical (Szczecin, Poland); and a manufacturer of a peripheral nerve stimulation device, SPR Therapeutics (Cleveland, Ohio). Dr. Ilfeld performed consulting work for Pacira Pharmaceuticals from 2011 to 2014. Neither author has performed consulting work for any private company in the last 6 yr. No company was involved with the conceptualization or preparation of this review. Neither the manuscript nor its contents were made available to any company before publication.