The quest for an ultralong multi-day local anesthetic administered perioperatively that would reduce postoperative opioid needs, enhance the quality of postop analgesia and facilitate recovery has been the holy grail of acute pain management since first proposed by Dr. Chuck Berde and others several decades ago. Sure, continuous local anesthetic administration through inserted catheters usually but, not always, works. But catheters require placement skill, time and resources, and are associated with complications including accidental catheter dislodgement or migration that shorten their usefulness.1 Liposomal bupivacaine (Exparel™), which is a sustained release product, was approved by the US FDA in 2011 and promised to provide prolonged analgesia with a single dose. The holy grail! However whether liposomal bupivacaine lives up to its marketing and is any better than conventional soluble bupivacaine is not so clear, and actually is controversial.2,3 In today’s PAAD, Hussain, et al.4 performed a systematic review and meta-analysis of randomized trials that compared liposomal bupivacaine with plain local anesthetics for fascial plane blocks in adult patients undergoing a variety of abdominal surgeries. Dr. Nihar Patel of Texas Children’s Hospital provided a similar review of the adult and pediatric literature at the recent annual meeting of the Society for Pediatric Anesthesia in Austin.
I know that despite its increased costs and questionable benefit, liposomal bupivacaine liposomal bupivacaine use is increasing in adult and pediatric patients. “Why” And “Should it be?” are questions that demand answers. Myron Yaster MD and Elliot Krane MD.
Editorial
Habib AS, Gadsden J, Carvalho B. Liposomal Bupivacaine for Abdominal Fascial Plane Blocks: No Evidence or Lack of Relevant Evidence? Anesthesiology. 2024 May 1;140(5):871-873. doi: 10.1097/ALN.0000000000004933. PMID: 38592357.
Original article
Hussain N, Speer J, Abdallah FW. Analgesic Effectiveness of Liposomal Bupivacaine versus Plain Local Anesthetics for Abdominal Fascial Plane Blocks: A Systematic Review and Meta-analysis of Randomized Trials. Anesthesiology. 2024 May 1;140(5):906-919. doi: 10.1097/ALN.0000000000004932. PMID: 38592360.
Patel N: Society for Pediatric Anesthesia Annual Meeting Lecture: Liposomal bupivacaine in children: what do we know?
https://www2.pedsanesthesia.org/meetings/2024winter/guide/program/files/2024-CA-1712839993-1964.pdf
In today’s PAAD, Hussain et al.4 performed a systematic review and meta-analysis of randomized trials that compared liposomal bupivacaine with plain local anesthetics for fascial plane blocks (primarily transversus abdominal plane, TAP, blocks) in adult patients undergoing a variety of abdominal surgeries. They “designated differences in pain severity at rest between 24 and 72 h postoperatively as the primary outcome. Secondary outcomes included interval and cumulative pain severity, opioid consumption up to 72 h postoperatively, time to first analgesic request, hospital stay duration and incidence of opioid-related side effects.”4
Sixteen trials encompassing 1,287 patients (liposomal bupivacaine, 667; plain local anesthetics, 620) were included. The liposomal bupivacaine group received liposomal bupivacaine mixed with plain bupivacaine in 10 studies, liposomal bupivacaine alone in 5 studies, and both preparations in 1 three-armed study. No difference was observed between the two groups for area under the curve (AUC) pain scores, with a standardized mean difference (95% CI) of –0.21 cm.h (–0.43 to 0.01; P = 0.058; I 2 = 48%). Results were robust to subgroup analysis based on (1) potential conflict of interest and (2) mixing of plain local anesthetics with liposomal bupivacaine. Furthermore, the two groups were not different for any of the day 2 or day 3 secondary outcomes.”4
What did they conclude? “Our systematic review and meta-analysis suggests that the postoperative analgesic benefits of liposomal bupivacaine are not different compared to plain bupivacaine when used for abdominal fascial plane blocks. Specifically, we did not find any clinically important differences in pain severity and opioid consumption up to 72 h postoperatively, and no differences in the time to first analgesic request, time to hospital discharge, and incidence of opioid-related side effects. The current findings are consistent with the results of recent meta-analyses investigating the analgesic efficacy of other applications of liposomal bupivacaine for regional anesthesia, including periarticular infiltration for joint arthroplasty.”4
These results are essentially the same as other previously published studies1-7 and we wonder if the drug’s manufacturer, Pacira Pharmaceuticals, will sue the journal Anesthesiology, its editors, and the authors of today’s paper for libel in Federal court for publishing results that contradict their sponsored studies and marketing as they did without precedence and quite notoriously in 2022. That case was summarily dismissed with prejudice, a decision upheld on appeal in the US Third Circuit Court of Appeals in 2023, concluding that “a scientific conclusion based on nonfraudulent data in an academic publication is not a ‘fact’ that can be proven false through litigation.” Pacira failed to identify any aspect of the Articles, a Continuing Medical Education program, or a Podcast that “bring their conclusions outside the protected realm of scientific opinion.”8
We’ve previously published our thoughts on this company and its attempts to use the courts and libel laws to silence studies that show no improved outcomes when using liposomal bupivacaine compared to regular bupivacaine (Mary Ellen McCann is a a Hero, Feb 15, 2022 , https://ronlitman.substack.com/p/mary-ellen-mccann-is-a-hero). Hopefully, Pacira learned their lesson and this will not happen again with today’s article.
Interestingly, the editorial by Habib et al.1 did point out an interesting issue in this study. The blocks used in this study, primarily TAP blocks, require accurate and precise drug deposition in the fascial plane. They point out that the failure of liposomal bupivacaine may have been the result of poor block placement rather than the drug itself and in a meta analysis “garbage in equals garbage out”. But, the same may be said about the inaccurate injection of soluble bupivacaine, therefore any bias due to technique is likely to be equal in the two groups, and the results will stand.
Finally, Dr. Patel’s SPA lecture highlighted that almost all of the pediatric “studies” he could find in his literature review were really case reports (or as I like to say the plural of anecdote is not data) and that to date there have been NO randomized controlled trials of liposomal bupivacaine in pediatrics and its value remains speculative and unproven.
Are you using liposomal bupivacaine in your practice? Will today’s PAAD affect your decision making practice? Send your thoughts to Myron who will post in a Friday reader response.
References
1. Habib AS, Gadsden J, Carvalho B. Liposomal Bupivacaine for Abdominal Fascial Plane Blocks: No Evidence or Lack of Relevant Evidence? Anesthesiology 2024;140(5):871-873. (In eng). DOI: 10.1097/aln.0000000000004933.
2. Ilfeld BM, Eisenach JC, Gabriel RA. Clinical Effectiveness of Liposomal Bupivacaine Administered by Infiltration or Peripheral Nerve Block to Treat Postoperative Pain. Anesthesiology 2021;134(2):283-344. (In eng). DOI: 10.1097/aln.0000000000003630.
3. McCann ME. Liposomal Bupivacaine. Anesthesiology 2021;134(2):139-142. (In eng). DOI: 10.1097/aln.0000000000003658.
4. Hussain N, Speer J, Abdallah FW. Analgesic Effectiveness of Liposomal Bupivacaine versus Plain Local Anesthetics for Abdominal Fascial Plane Blocks: A Systematic Review and Meta-analysis of Randomized Trials. Anesthesiology 2024;140(5):906-919. (In eng). DOI: 10.1097/aln.0000000000004932.
5. Hussain N, Brull R, Sheehy BT, Kushelev M, Essandoh MK, Abdallah FW. The mornings after-periarticular liposomal bupivacaine infiltration does not improve analgesic outcomes beyond 24 hours following total knee arthroplasty: a systematic review and meta-analysis. Regional anesthesia and pain medicine 2021;46(1):61-72. (In eng). DOI: 10.1136/rapm-2020-101995.
6. Hussain N, Brull R, Sheehy B, et al. Perineural Liposomal Bupivacaine Is Not Superior to Nonliposomal Bupivacaine for Peripheral Nerve Block Analgesia. Anesthesiology 2021;134(2):147-164. (In eng). DOI: 10.1097/aln.0000000000003651.
7. Abdallah FW, Hussain N, Brull R. Analgesic efficacy of liposomal bupivacaine for surgical site infiltration: a single-outcome meta-analysis (the best we could do). Regional anesthesia and pain medicine 2021;46(4):291-292. (In eng). DOI: 10.1136/rapm-2020-102395.
8. https://law.justia.com/cases/federal/appellate-courts/ca3/22-1411/22-1411-2023-03-24.html