PRO: Advantages of Liposomal Bupivacaine for Postoperative Analgesia

May 1, 2019, 10:15 AM by Rodney Gabriel, MD, MAS, Brian M Ilfeld, MD, MS

The duration of postoperative pain is frequently greater than the duration of a single administration of local anesthetic. Local anesthetic may be encased in liposomes which, as they break down, release medication over a period of multiple days and increase the duration of action.[1] In 2011, the first formulation of liposomal bupivacaine (LB) (Exparel; Pacira Pharmaceuticals, Inc., USA) was approved by the U.S. Food and Drug Administration (FDA). It is now approved for use in surgical site infiltration, transversus abdominis plane blocks, and interscalene nerve blocks for shoulder surgery. Although evidence of LB’s superiority over normal saline may be found—validating prolonged analgesic effects[2-5]—we will limit our discussion here to the more clinically relevant comparison of LB and unencapsulated local anesthetics (“standard” bupivacaine HCl). Similarly, with a plethora of randomized, controlled trials (RCTs) now published, we will focus on these investigations over retrospective cohort studies.

For surgical infiltration of liposomal bupivacaine, RCTs provide sparse high-quality evidence suggesting a switch from unencapsulated local anesthetic is warranted. What little positive evidence exists is, at best, equivocal.

Surgical Infiltration

Four RCTs involving three different types of surgical procedures produced evidence demonstrating benefits of LB over bupivacaine HCl. LB infiltration improved analgesia over bupivacaine HCl following breast augmentation in one study. However, the authors concluded that “although there is a statistically significant decrease in postoperative pain with the use of LB, this may not translate to an appreciable clinical benefit that justifies the additional cost” because the improvement in pain scores was less than 1 on a 10-point pain scale.[6] Conversely, two additional investigations were unable to show statistically significant differences with a similar primary end point, raising further doubt on the findings of the initial positive study.[7],[8]

Other studies on surgical infiltration have been of patients undergoing hemorrhoidectomy, inguinal hernia repair, or laparoscopic urologic surgery. In patients undergoing hemorrhoidectomy, one RCT reported decreased pain with LB infiltration,[9] whereas another had negative findings.[7] Additional RCTs were uniformly negative for their primary end point for inguinal hernia repair[7],[10],[11] and laparoscopic urologic surgery.[12]

Thirteen published RCTs involve the use of LB infiltration of the knee joint following arthroplasty.[13] Two trials reported positive results in favor of LB over bupivacaine HCl; however, one of those studies was not prospectively registered nor was a primary end point defined and therefore has questionable data integrity.[14] The other “positive” RCT was the Postsurgical Infiltration with LB for Long Lasting Analgesia in total knee aRthroplasty (PILLAR) study.[15] However, as Shafer[16] described, the study results are negative if the original statistical methods published prior to enrollment were followed. Instead and without explanation, the investigators performed a post hoc one-sided statistical analysis (instead of the prespecified two-sided analysis), ignored a Bonferroni penalty for multiple primary end points, and “propagated the type I error to the analysis of opioid consumption . . . rendering invalid the finding of a statistically significant reduction in opioid consumption.”[15],[16] Thus, the positive evidence of benefit pales relative to the negative findings of the remaining 11 RCTs.

When compared with a single-injection femoral nerve block of unencapsulated bupivacaine, surgically infiltrated LB results in a higher percentage of patients able to perform a straight leg raise the day of surgery and decreased opioid consumption the day following surgery.[17] However, the value of this is questionable given that LB also provides inferior analgesia and thus results in greatly increased opioid use the day of surgery.[17] Similar inferior analgesia of infiltrated LB has been documented in RCTs involving knee and shoulder surgery for both single-injection[18-20] and continuous peripheral nerve blocks.[21],[22]

The one exception is an RCT in which all subjects having shoulder arthroplasty received a single-injection interscalene block with unencapsulated bupivacaine followed by either surgical infiltration with LB or an interscalene perineural catheter and 100-hour bupivacaine HCl (0.125%) infusion.[23] The primary end points of pain scores and opioid use within the first 24 hours were both negative, as were comparisons for subsequent time points up to 48 hours. This was a superiority study and, therefore, a lack of statistically significant differences in analgesia and opioid use must not be interpreted as equivalence; rather, the study is simply inconclusive. However, two of three patient-reported outcome measures—the American Shoulder and Elbow Surgeons as well as Penn shoulder scores—were improved for subjects who received LB infiltration at the final surgical follow-up visit. Unfortunately, the risk of a type 1 error is high because more than 50 comparisons were reported without any statistical correction. Nonetheless, if future studies demonstrated at least noninferior analgesia and opioid requirements with LB compared with a perineural unencapsulated local anesthetic infusion, it could decrease administration time, catheter-related complications, and possibly costs.[24],[25]

In summary, for surgical infiltration of liposomal bupivacaine, RCTs provide sparse high-quality evidence suggesting a switch from unencapsulated local anesthetic is warranted. What little positive evidence exists is, at best, equivocal.

Peripheral Nerve Blocks

In contrast, some promising results involve LB when administered as part of a single-injection peripheral nerve block.[26-28] Adding LB to standard bupivacaine for interscalene brachial plexus blocks lowered patients’ worst pain scores with major shoulder surgery.[28] In that study, all subjects received 5 mL of bupivacaine HCl (0.25%) and were randomly assigned to receive 10 mL of either additional unencapsulated bupivacaine or LB. The primary outcome of interest was worst pain in the first postoperative week. Overall, the liposomal group had modest improvements in the primary outcome (by about 1.5 points on the numerical rating scale) as well as improvement in overall benefit of analgesia scores. No differences were found in additional secondary outcomes, including daily worst pain scores, although the study was not powered to detect such differences. Unfortunately, average and median pain scores were not included in the results and a lack of differences between the treatments in time to first opioid request, total opioid consumption, and sleep duration makes interpreting the results more challenging.

Two prospective RCTs investigating the benefits of LB for subcostal transversus abdominis plane blocks reported decreased pain scores and opioid requirement for up to 72 hours after robot-assisted hysterectomy and laparoscopic hand-assisted donor nephrectomy.[26],[27] Unfortunately, both were registered only after enrollment was completed and one did not specify a primary outcome measure without any correction for multiple end-point comparisons.[27] How bupivacaine HCl would provide inferior analgesia immediately after surgery is unclear, considering it theoretically provides a denser block compared to the prolonged release of bupivacaine in its liposomal form. In fact, the manufacturer and FDA revised the label to specifically permit the mixing of LB and bupivacaine HCL to increase potency.

LB may be of use in other anatomic locations that have yet to be FDA approved. For example, when used in a femoral nerve block, LB demonstrated analgesic effects for as long as 72 hours.[4] A future trial should compare the use of LB to that of bupivacaine HCl. Another investigation examined the use of LB for single-injection epidural blocks in healthy volunteers.[29] The findings were promising, in which LB at the current maximum-approved dose of 266 mg resulted in longer duration of sensory blockade and shorter duration of motor block as compared to unencapsulated bupivacaine.

In summary, the available evidence for liposomal bupivacaine in peripheral and epidural nerve blocks appears promising; therefore, future large-scale, high-quality RCTs (and additional FDA approval) are greatly needed to definitively determine the relative risks and benefits of using LB as part of a single-injection nerve block.


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