PRO: Advantages of Liposomal Bupivacaine for Postoperative Analgesia

May 2019 Issue

  1. Rodney Gabriel, MD, MAS Clinical Research Chief, Division of Regional Anesthesia and Acute Pain; Clinical Director of Anesthesia, Koman Family Outpatient Pavilion; Assistant Clinical Professor, Department of Anesthesiology, Department of Biomedical Informatics, University of California, San Diego Co-author
  2. Brian M Ilfeld, MD, MS Clinical Investigation; Professor of Anesthesiology in Residence; Department of Anesthesiology, University of California, San Diego Co-author


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.

References

  1. Boogaerts JG, Lafont ND, Declercq AG, et al. Epidural administration of liposome-associated bupivacaine for the management of postsurgical pain: a first study. J Clin Anesth 1994;6:315–320.
  2. Golf M, Daniels SE, Onel E. A phase 3, randomized, placebo-controlled trial of DepoFoam® bupivacaine (extended-release bupivacaine local analgesic) in bunionectomy. Adv Ther 2011;28:776–788.
  3. Gorfine SR, Onel E, Patou G, Krivokapic ZV. Bupivacaine extended-release liposome injection for prolonged postsurgical analgesia in patients undergoing hemorrhoidectomy: a multicenter, randomized, double-blind, placebo-controlled trial. Dis Colon Rectum 2011;54:1552–1529.
  4. Hadzic A, Minkowitz HS, Melson TI, et al. Liposome bupivacaine femoral nerve block for postsurgical analgesia after total knee arthroplasty. Anesthesiology 2016;124:1372–1383.
  5. Ilfeld BM, Malhotra N, Furnish TJ, Donohue MC, Madison SJ. Liposomal bupivacaine as a single-injection peripheral nerve block: a dose-response study. Anesth Analg 2013;117:1248–1256.
  6. Nadeau MH, Saraswat A, Vasko A, Elliott JO, Vasko SD. Bupivacaine versus liposomal bupivacaine for postoperative pain control after augmentation mammaplasty: a prospective, randomized, double-blind trial. Aesthet Surg J 2016;36:NP47–NP52.
  7. Bergese SD, Ramamoorthy S, Patou G, Bramlett K, Gorfine SR, Candiotti KA. Efficacy profile of liposome bupivacaine, a novel formulation of bupivacaine for postsurgical analgesia. J Pain Res 2012;5:107–116.
  8. Smoot JD, Bergese SD, Onel E, Williams HT, Hedden W. The efficacy and safety of DepoFoam bupivacaine in patients undergoing bilateral, cosmetic, submuscular augmentation mammaplasty: a randomized, double-blind, activecontrol study. Aesthet Surg J 2012;32:69–76.
  9. Haas E, Onel E, Miller H, Ragupathi M, White PF. A double-blind, randomized, active-controlled study for post-hemorrhoidectomy pain management with liposome bupivacaine, a novel local analgesic formulation. Am Surg 2012;78:574–581.
  10. Langford RM, Chappell GM, Karrasch JA. A single administration of depobupivacaine intraoperatively results in prolonged detectable plasma bupivacaine and analgesia in patients undergoing inguinal hernia repair. Presented at: the Annual Postgraduate Assembly in Anesthesiology of the New York State Society of Anesthesiologists; December 2008; New York, NY. Abstract p-9088.
  11. White PF, Schooley GL, Ardeleanu M. Analgesia following a single administration of depobupivacaine intraoperatively in patients undergoing inguinal herniorrhaphy: preliminary dose-ranging studies (abstract s-242). Anesth Analg 2009;108(suppl 3S):S242.
  12. Knight RB, Walker PW, Keegan KA, et al. A randomized controlled trial for pain control in laparoscopic urologic surgery: 0.25% bupivacaine versus long-acting liposomal bupivacaine. J Endourol 2015;29:1019–1024.
  13. Ilfeld BM, Gabriel RA, Eisenach JC. Liposomal bupivacaine infiltration for knee arthroplasty: significant analgesic benefits or just a bunch of fat? Anesthesiology 2018;129:623–626.
  14. Snyder MA, Scheuerman CM, Gregg JL, Ruhnke CJ, Eten K. Improving total knee arthroplasty perioperative pain management using a periarticular injection with bupivacaine liposomal suspension. Arthroplast Today 2016;2:37–42.
  15. Mont MA, Beaver WB, Dysart SH, Barrington JW, Del Gaizo DJ. Local infiltration analgesia with liposomal bupivacaine improves pain scores and reduces opioid use after total knee arthroplasty: results of a randomized controlled trial. J Arthroplasty 2018;33:90–96.
  16. Shafer SL. Letter to the editor on “local infiltration analgesia with liposomal bupivacaine improves pain scores and reduces opioid use after total knee arthroplasty: results of a randomized controlled trial.” J Arthroplasty 2018;33:2694. Available at: https://doi.org/10.1016/j.arth.2018.03.032.
  17. Surdam JW, Licini DJ, Baynes NT, Arce BR. The use of Exparel (liposomal bupivacaine) to manage postoperative pain in unilateral total knee arthroplasty patients. J Arthroplasty 2015;30:325–329.
  18. Okoroha KR, Keller RA, Marshall NE, et al. Liposomal bupivacaine versus femoral nerve block for pain control after anterior cruciate ligament reconstruction: a prospective randomized trial. Arthroscopy 2016;32:1838–1845.
  19. Okoroha KR, Lynch JR, Keller RA, et al. Liposomal bupivacaine versus interscalene nerve block for pain control after shoulder arthroplasty: a prospective randomized trial. J Shoulder Elbow Surg 2016;25:1742–1748.
  20. Namdari S, Nicholson T, Abboud J, Lazarus M, Steinberg D, Williams G. Randomized controlled trial of interscalene block compared with injectable liposomal bupivacaine in shoulder arthroplasty. J Bone Joint Surg Am 2017;99:550–556.
  21. Abildgaard JT, Lonergan KT, Tolan SJ, et al. Liposomal bupivacaine versus indwelling interscalene nerve block for postoperative pain control in shoulder arthroplasty: a prospective randomized controlled trial. J Shoulder Elbow Surg 2017;26:1175–1181.
  22. Amundson AW, Johnson RL, Abdel MP, et al. A three-arm randomized clinical trial comparing continuous femoral plus single-injection sciatic peripheral nerve blocks versus periarticular injection with ropivacaine or liposomal bupivacaine for patients undergoing total knee arthroplasty. Anesthesiology 2017;126:1139–1150.
  23. Sabesan VJ, Shahriar R, Petersen-Fitts GR, et al. A prospective randomized controlled trial to identify the optimal postoperative pain management in shoulder arthroplasty: liposomal bupivacaine versus continuous interscalene catheter. J Shoulder Elbow Surg 2017;26:1810–1817.
  24. Corman S, Shah N, Dagenais S. Medication, equipment, and supply costs for common interventions providing extended post-surgical analgesia following total knee arthroplasty in US hospitals. J Med Econ 2018;21:11–18.
  25. Ilfeld BM. Continuous peripheral nerve blocks: an update of the published evidence and comparison with novel, alternative analgesic modalities. Anesth Analg 2017;124:308–335.
  26. Hutchins J, Delaney D, Vogel RI, et al. Ultrasound guided subcostal transversus abdominis plane (tap) infiltration with liposomal bupivacaine for patients undergoing robotic assisted hysterectomy: a prospective randomized controlled study. Gynecol Oncol 2015;138:609–613.
  27. Hutchins JL, Kesha R, Blanco F, Dunn T, Hochhalter R. Ultrasound-guided subcostal transversus abdominis plane blocks with liposomal bupivacaine vs. non-liposomal bupivacaine for postoperative pain control after laparoscopic
    hand-assisted donor nephrectomy: a prospective randomised observer-blinded study. Anaesthesia 2016;71:930–937.
  28. Vandepitte C, Kuroda M, Witvrouw R, et al. Addition of liposome bupivacaine to bupivacaine hcl versus bupivacaine hcl alone for interscalene brachial plexus block in patients having major shoulder surgery. Reg Anesth Pain Med 2017;42:334–341.
  29. Viscusi ER, Candiotti KA, Onel E, Morren M, Ludbrook GL. The pharmacokinetics and pharmacodynamics of liposome bupivacaine administered via a single epidural injection to healthy volunteers. Reg Anesth Pain Med 2012;37:616–622.

Tags: liposomal bupivacaine

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