CON: Liposomal Bupivacaine: A Mission Incomplete
May 1, 2019
An anesthetist’s dream of having a long-acting, nonaddictive solution for the management of postoperative pain is a long-standing affair. Liposomal bupivacaine (LB), with its prolonged half-life and a longer duration of analgesia, was purported to meet that objective. Unfortunately, the available scientific data on LB has been inconclusive. Various publications have highlighted the dominance of LB over plain bupivacaine. However, the observed worthiness of LB calls for inclusion of more nonindustrial trials and consideration of additional viewpoints.
To be useful for clinical practice, any new drug should have low cost, ease of availability, multiple routes of administration, explicit clinical benefits over the current standards of care, reduced toxicity, high-quality evidence-based indications, predictable pharmacology, and regulatory approval for its clinical use. In those contexts, the current evidence for LB has so far been inconsistent. A Cochrane review described some of LB’s usefulness in comparison to placebo but not to bupivacaine or other analgesics.
The highlighted benefits of LB fail to extrapolate into clinical practice because of a deficiency in number of randomized controlled trials (RCTs) and advice on judicious interpretation of results.
Published scientific literature that includes phase II and III trials is inconclusive in building an opinion of approval or rejection of LB for management of postoperative pain. Pertinent issues requiring clarification include safety, analgesic efficacy, opioid-related issues, motor function, status of postoperative chronic pain, and cost effectiveness.,
The highlighted benefits of LB fail to extrapolate into clinical practice because of a deficiency in a number of randomized controlled trials (RCTs) and advice on judicious interpretation of results. Scarce data are available to approve LB for nerve blocks, and widespread clinical use is not justified in the context of its exorbitant cost. Supporting reviews on LB are also limited by publication bias and short-term follow-up. Reviews and meta-analyses on LB lament issues related to limited sample size, number of RCTs, study design, and optimal dosing.,
Nanolipid particles were acknowledged in 1965 as a drug vehicle to control the release and to improve the effects of local anesthetics. In 2011, the United States Food and Drug Administration (FDA) granted approval to use LB as a single-dose surgical site infiltration intended to provide postoperative analgesia., However, despite a long history, LB is still considered investigational and is in pursuit of an appropriate representation in the armamentarium of anesthetists. A change in study design, inclusion criteria, and consideration of more painful surgeries has been advised for future trials. Available studies with comparable,[14-16] negative,,[17-19] or beneficial outcomes,[20-22] on LB also suffer from suboptimal quantity and quality of evidence.
Regulatory Issues and Scope of Applicability
In the beginning, LB was granted approval for providing postoperative analgesia with surgical site infiltration in hemorrhoidectomy and bunionectomy. Later, approval was extended to include other surgeries as well. Hence, most of the data on LB relate to infiltration use. Transverse abdominal plane block was later added, but the data on those blocks have not been convincing. Wider indications are being explored for LB. Data on LB for perineural use and for postoperative pain management are scarce, and those available have been inconclusive to guide users, policy makers, or sponsors.
Results on perineural use of LB have been discouraging too. LB was associated with increased nociception because of femoral nerve irritation following a femoral nerve block in anterior crucial ligament reconstruction surgeries. Current data failed to demonstrate meaningful postoperative outcomes, including reduction in opioid consumption or resource use. A meta-analysis demonstrated equivalent pain control with LB infiltration or interscalene block (ISB) and recommended additional high-quality RCTs and longer follow-up to properly compare LB’s efficacy and safety.
Despite this, the FDA added ISB for shoulder surgeries to its approved list of LB indications, based on a single publication.
Pharmacoeconomics of LB
The cost effectiveness of using LB is questionable and remains a barrier that limits more widespread use. A 20-mL vial of LB is $285, whereas the same volume of bupivacaine costs only $1.15. This translates to LB being more than 100 times more expensive than conventional bupivacaine. The high cost of LB is prone to generate availability issues in developing countries; therefore, robust randomized trials are necessary to demonstrate LB’s actual cost effectiveness. In addition, no data are available on health economics for the use of analgesics after 72 hours.
Stability of LB solution in a mixture of other drugs is uncertain and the release for periarticular infiltration is unpredictable because of negligible data. In vitro pharmacologic studies are needed to assess potential systemic toxicities.
Because of a paucity of data, commenting on LB’s adverse effects is difficult. The frequency of adverse effects is either comparable or lower than that of bupivacaine. Side effects include fever, gastrointestinal disturbances, and irritation at the site of injection. Others have reported fecal incontinence, platelets inhibition, and femoral nerve palsy. LB has also been implicated in prolonging inflammation and producing myotoxic effects. LB should be used with caution in those at elevated risk for the development of compartment syndrome because of the scarcity of data regarding its onset of action, duration of sensorimotor blockade, and offsetting of effects.
Newer, Extended-Release LB
In a recent review, extended-release LB like HTX-011 and SABER bupivacaine have shown promising initial results in safety and efficacy; however, the studies tend to be sponsored by drug companies and caution must be exercised when interpreting the findings. For now, only LB has FDA-approved indications for clinical use. More studies are thus required to formulate an opinion on these agents. Extended-release LB SABER requires additional clinical studies to assess safety and efficacy.
LB is far from meeting expectations because of the paucity of robust studies. Additional areas of research could include robust comparisons of LB with continuous administration of conventional bupivacaine via perineural catheters or with single administration of conventional bupivacaine in combination with adjuvants. More studies on cost benefits are necessary, given LB’s cost. Newer evidence-based findings are essential to modify current judgement on LB.
- Olson MD, Moore EJ, Price DL. A randomized single-blinded trial of posttonsillectomy liposomal bupivacaine among adult patients. Otolaryngol Head Neck Surg 2018;159:835–842.
- Schroer WC, Diesfeld PG, LeMarr AR, Morton DJ, Reedy ME. Does extendedrelease liposomal bupivacaine better control pain than bupivacaine after total knee arthroplasty (TKA): a prospective, randomized clinical trial. J Arthroplasty 2015;30(suppl 9):64–67.
- Hamilton TW, Athanassoglou V, Mellon S, et al. Liposomal bupivacaine infiltration at the surgical site for the management of postoperative pain. Cochrane Database Syst Rev 2017;2:CD011419. Available at: https://doi.org/10.1002/14651858.CD011419.pub2.
- Alijanipour P, Tan TL, Matthews CN, et al. Peri-articular injection of liposomal bupivacaine offers no benefit over standard bupivacaine in total knee arthroplasty: a prospective, randomized, controlled trial. J Arthroplasty 2017;32:628–634.
- Uskova A, O’Connor JE. Liposomal bupivacaine for regional anesthesia. Curr Opin Anesthesiol 2015;28:593–597.
- Raman S, Lin M, Krishnan N. Systematic review and meta-analysis of the efficacy of liposomal bupivacaine in colorectal resections. J Drug Assess 2018;7:43–50.
- Hamilton TW, Athanassoglou V, Trivella M, et al. Liposomal bupivacaine peripheral nerve block for the management of postoperative pain. Cochrane Database Syst Rev 2016;8:CD011476. Available at: https://doi.org/10.1002/14651858.CD011476.pub2.
- Noviasky JN, Pierce DP, Whalen K, Guharoy R, Hildreth K. Bupivacaine liposomal versus bupivacaine: comparative review. Hosp Pharm 2014;49:539–543.
- Zhang X, Yang Q, Zhang Z. The efficiency and safety of local liposomal bupivacaine infiltration for pain control in total hip arthroplasty: a systematic review and meta-analysis. Medicine 2017;96:e8433. Available at: https://doi.org/10.1097/MD.0000000000008433.
- Wu ZQ, Min JK, Wang D, Yuan YJ, Li H. Liposomal Bupivacaine for pain control after total knee arthroplasty: a metaanalysis. J Orthop Surg Res 2016;11:84.
- Yan Z, Chen Z, Ma C. Liposomal bupivacaine versus interscalene nerve block for pain control after shoulder arthroplasty: a meta-analysis. Medicine 2017;96:e7226.
- Beiranvand S, Eatemadi Ali, Karimi A. New updates pertaining to drug delivery of local anesthetics in particular bupivacaine using lipid nanoparticles. Nanoscale Res Lett 2016;11:307. Available at: https://doi.org/10.1186/s11671-016-1520-8.
- Klug MJ, Rivey MP, Carter, JT. Comparison of intraoperative periarticular injections versus liposomal bupivacaine as part of a multimodal approach to pain management in total knee arthroplasty. Hosp Pharm 2016;5:305–311.
- Apseloff G, Onel E, Patou G. Time to onset of analgesia following local infiltration of liposome bupivacaine in healthy volunteers: a randomized, single-blind, sequential cohort, crossover study. Int J Clin Pharmacol Ther 2013;5:367–373.
- Kenes MT, Leonard MC, Bauer SR, Wyman MJ. Liposomal bupivacaine versus continuous infusion bupivacaine via an elastomeric pump for the treatment of postoperative pain. Am J Health Syst Pharm 2015;72(suppl 3):127–132.
- Meneghini RM, Bagsby D, Ireland PH, Ziemba-Davis M, Lovro LR. Liposomal bupivacaine injection technique in total knee arthroplasty. J Knee Surg 2017;30:88–96.
- Lee CY, Robinson DA, Johnson CA Jr, et al. A randomized controlled trial of liposomal bupivacaine parasternal intercostal block for sternotomy. Ann Thoracic Surg 2018;28:1167–1176.
- Prabhu M, Clapp MA, McQuaid-Hanson E, et al. Liposomal bupivacaine block at the time of cesarean delivery to decrease postoperative pain: a randomized controlled trial. Obstet Gynecol 2018;132:70–78.
- Perets I, Walsh JP, Mu BH, et al. Intraoperative infiltration of liposomal bupivacaine vs bupivacaine hydrochloride for pain management in primary total hip arthroplasty: a prospective randomized trial. J Arthroplasty 2018;33:441–446.
- Ma TT, Wang YH, Jiang YF et al. Liposomal bupivacaine versus traditional bupivacaine for pain control after total hip arthroplasty: a metaanalysis. Medicine 2017;96:e7190. Available at: https://doi.org/10.1097/MD.0000000000007190.
- Cloyd C, Moffetti BS, Bernhandt MB, Evelyn MM, Patel N, Hanson D. Efficacy of liposomal bupivacaine in pediatric patients undergoing spine surgery. Pediatr Anesth 2018;11. Available at: https://doi.org/10.1111/pan.13482.
- Yu ZX, Yang ZZ, Yao LL. Effectiveness of liposome bupivacaine for postoperative pain control in total knee arthroplasty: a PRISMA-compliant meta-analysis of randomised controlled trials. Medicine 2018;97:e0171. Available at: https://doi.org/10.1097/MD.0000000000010171.
- Yeung J, Crisp CC, Mazloomdoost D, Kleeman SD, Pauls RN. Liposomal bupivacaine during robotic colpopexy and posterior repair: a randomized control trial. Obstet Gynecol 2018;131:39–46.
- DiGiorgi M, Carangelo M, Scranton R. Transversus abdominis plane blocks with single-dose liposomal bupivacaine in conjunction with a nonnarcotic pain regimen help reduce length of stay following abdominally based microsurgical breast reconstruction. Plast Reconstr Surg 2018;142:94e. Available at: https://doi.org/10.1097/PRS.0000000000004480.
- Malik O, Kaye AD, Kaye A, Belani K, Urman RD. Emerging roles of liposomal bupivacaine in anesthesia practice. J Anaesthesiol Clin Pharmacol 2017;33:151–156.
- 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.
- Pichler L, Poeran J, Zubizarreta N, et al. Liposomal bupivacaine does not reduce inpatient opioid prescription or related complications after knee arthroplasty: a database analysis. Anesthesiology 2018;129:689–699.
- Cao X, Pan F. Comparison of liposomal bupivacaine infiltration versus interscalene nerve block for pain control in total shoulder arthroplasty: a metaanalysis of randomized control trails. Medicine 2017;96:e8079. Available at: https://doi.org/10.1097/MD.0000000000008079.
- Rabin T. In brief: FDA approves new use of Exparel for nerve block pain relief following shoulder surgeries. Available at: https://www.fda.gov/NewsEvents/Newsroom/FDAInBrief/ucm604021.htm. Updated April 6, 2018. Accessed November 7, 2018.
- Nadeau MH, Saraswat A, Vasko A, Elliott JO, Vasco SD. Bupivacaine versus liposomal bupivacaine for postoperative pain control after augmentation mammoplasty: a prospective, randomised, double-blind trial. Anesth Surg J 2016;36:47–52.
- Richebe P, Brulotte V. CORR Insights®: no difference in early analgesia between liposomal bupivacaine injection and intrathecal morphine after TKA. Clin Orthop Relat Res 2017;475:106–109.
- McAlvin JB, Padera RF, Shankarappa SA, et al. Multivesicular liposomal bupivacaine at the sciatic nerve. Biomaterials 2014;35:4557–4564.
- Shapera EA, Rai VK. A content incontinent: report of liposomal bupivacaine induced fecal incontinence. Case Rep Surg 2016;2016:7164983. Available at: https://doi.org/10.1155/2016/7164983.
- Pinto LM, Pereira R, de Paula E, et al. Influence of liposomal local anesthetics on platelet aggregation in vitro. J Liposome Res 2004;14:51–59.
- Soberón JR, Sisco-Wise LE, Dunbar RM. Compartment syndrome in a patient treated with perineural liposomal bupivacaine (Exparel). J Clin Anesth 2016;31:1–4.
- Balocco AL, Van Zundert PGE, Gan SS, Gan TJ, Hadzic A. Extended release bupivacaine formulations for postoperative analgesia: an update. Curr Opin Anaesthesiol 2018;3:636–642.
- Skolnik A, Gan TJ. New formulations of bupivacaine for the treatment of postoperative pain: liposomal bupivacaine and SABER-bupivacaine. Expert Opin Pharmacother 2014;15:1535–1542.