Secondary Logo

Journal Logo

Review Articles: Systematic Review Article

Comparison of Liposomal Bupivacaine and Conventional Local Anesthetic Agents in Regional Anesthesia: A Systematic Review

Jin, Zhaosheng MBBS*; Ding, Olivia MD; Islam, Ali BE; Li, Ru PhD*; Lin, Jun MD, PhD*

Author Information
doi: 10.1213/ANE.0000000000005406

Abstract

KEY POINTS

  • Question: Does liposomal bupivacaine prolong the analgesic duration of regional anesthesia compared to conventional local anesthetic agents?
  • Findings: Analyzed studies show conflicting results regarding liposomal bupivacaine’s analgesia-prolonging effects.
  • Meaning: Further studies are required to draw definitive conclusions about liposomal bupivacaine’s analgesia-prolonging effects.

Pain is one of the most common adverse events after surgery. It can be highly distressing for patients and has a significant impact on patient satisfaction.1 Pain can prolong postanesthesia care unit (PACU) and hospital stay as well as slow postoperative recovery.2 In addition, both pain and postoperative opioid use are associated with increased risk of complications, such as atelectasis and ileus. One way of managing postoperative pain while minimizing opioid consumption is using regional anesthesia. Regional anesthesia techniques (eg, brachial plexus block and transversus abdominis plane [TAP] block) have been shown in numerous studies to reduce postoperative pain and opioid requirements.

One of the main limitations, however, is that single-injection regional anesthesia techniques have limited duration of analgesia, with limited evidence for analgesic effects beyond 24 hours postoperatively. One alternatve is using catheter-based techniques, which continuously infuse local anesthetic to the target area. However, catheter-based regional anesthesia techniques are more technically challenging and resource intensive.

Liposomal bupivacaine is a lipid emulsion formulation, where bupivacaine is contained in biodegradable liposomes.3 Liposomes confer the advantage of slowly losing integrity in vivo, which results in a sustained release of bupivacaine into surrounding tissue.4 This mechanism prolongs analgesic duration, which varies depending on individual technique and anatomy, but has been reported to be as long as 72 hours.5 As such, liposomal bupivacaine wound infiltration has demonstrated its clinical efficacy in prolonging the duration of analgesia and reducing opioid requirement.6 In regional anesthesia, local anesthetic was deposited around the major nerve trunk and may achieve more effective anesthesia or analgesia. It therefore stands to reason that liposomal bupivacaine may also prolong the duration of analgesia with regional anesthesia. A 2016 Cochrane review identified 7 studies—most of which were incomplete study reports—and concluded that inadequate evidence to evaluate the efficacy of liposomal bupivacaine in regional anesthesia.7 Since the publication of the above review, there have been several new studies on this topic. We therefore perform this systematic review to summarize the recent evidence on the use of liposomal bupivacaine compared to conventional local anesthetics for regional anesthesia.

METHODS

Study Objectives

Our aim is to compare postoperative pain control in patients who received regional anesthesia with liposomal bupivacaine compared to those who received blocks with conventional local anesthetics. The primary outcome of interest is the opioid requirement within 24–72 hours postoperatively (postoperative days [PODs] 1–2); secondary outcomes include pain score and opioid requirements on POD 0 (0–24 hours), pain scores on POD 1 (24–48 hours) and POD 2 (48–72 hours), and the risk of complications and unplanned hospital readmission.

Search Strategy

This study adhered to the Preferred Reporting Items for Systematic reviews and Meta-analysis (PRISMA) statement.8 The study protocol is registered on PROSPERO under registration number CRD42020163853. We used search terms “liposom*,” “bupivacaine,” “Exparel,” and their Boolean combinations in PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE (Ovid), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Google Scholar, Web of Science citation index, and US clinical trials register. We also hand-searched the abstracts from major conferences in the last 3 years. The full search protocol is included in the Supplemental Digital Content, https://links.lww.com/AA/D391. We did not impose any language restrictions at the time of the literature search. All searches were conducted independently by 2 authors (Z.J. and A.I.) and discrepancies were discussed after the search process.

Study Selection

We included randomized control trials (RCTs) of adult patients (≥18 years of age) undergoing surgery under general or neuraxial anesthesia. The intervention of interest is nerve block (including but not limited to brachial plexus blocks, forearm blocks, and sciatic nerve blocks) or fascial plane blocks (including but not limited to TAP block, quadratus lumborum [QL] block, and pectoral nerve [PECs] block) with liposomal bupivacaine. The control procedures were performed using the same regional anesthesia technique with plain local anesthetic or the same regional anesthesia technique plus perineural catheter.

Exclusion criteria include non-RCT studies and patients <18 years of age. We did not impose a language restriction. Conference abstracts >3 years old were excluded.

Data Extraction

Data extraction was done according to the standardized pro forma using Microsoft Excel. The data were then checked by a second author. Extracted data included bibliographical information (ie. author, year, PubMed ID, or article URL), study design (ie, description of regional anesthesia techniques, dose of local anesthetics, type of surgery, patient characteristics, and number of participants), and outcomes (ie, pain, opioid requirement, time to rescue analgesia, and complications).

We used the RoB 2: a revised Cochrane risk-of-bias tool for randomized trials, which is a 5-item questionnaire designed for assessing clinical trials. Each item represents a risk category and can be determined to be low, intermediate (some concerns), and high risk.9 Potential bias was evaluated at study and outcome level with all assessments done independently by 2 authors (Z.J. and A.I.) and any disagreements discussed and resolved with a third author (J.L.). Due to the number of studies with potential conflicts of interest, an extra criterion was added to reflect this.

We used GRADEpro Guideline Development Tool (GRADEpro GDT, McMaster University, 2015) to assess the quality of the findings.

RESULTS

Table. - Characteristics of Included Studies
Participants Block technique Interventions Control Outcomes
Baja et al10 30 patients undergoing colorectal surgeries TAP block (bilateral) 133 mg liposomal bupivacaine each side TAP block with catheter Opioid requirement
Belsh et al11 192 patients undergoing knee replacement Adductor canal block 10-mL 1.3% liposomal bupivacaine 20-mL 0.5% ropivacaine Opioid requirement, pain score, length of hospital stay, anrange of movement
De Meirsman et al12 40 patients undergoing shoulder surgery Brachial plexus block 10-mL 1.33% liposomal bupivacaine plus 5-mL 0.25% bupivacaine 15-mL 0.25% bupivacaine Pain score at rest and on movement
Gatherwright et al13 16 patients undergoing breast reconstruction with DIEP flap TAP block (bilateral) 266-mg liposomal bupivacaine and 20-mL 0.25% bupivacaine 2 mg/kg of 0.25% bupivacaine Opioid requirement, pain score, length of stay, antiemetic requirement, time to ambulation
Ha et al14 44 patients undergoing breast reconstruction with DIEP flap TAP block (surgical) 266-mg in 30-mL liposomal bupivacaine 30-mL 0.25% bupivacaine Opioid requirement, pain score, length of stay
Hutchins et al15 58 patients undergoing hysterectomy TAP block (bilateral) 10-mL 1.3% liposomal bupivacaine with 20-mL saline per side 30-mL 0.25% bupivacaine Opioid requirement, pain score, PONV, and length of stay
Hutchins et al 201615 59 patients undergoing nephrectomy TAP block (bilateral) 10-mL 1.3% liposomal bupivacaine with 20-mL saline per side 30-mL 0.25% bupivacaine Opioid requirement, time to rescue analgesia, pain score, PONV, and length of stay
Nair et al17 25 patients undergoing knee replacement Adductor canal block 1.3% liposomal bupivacaine + 0.25% bupivacaine 0.25% bupivacaine Opioid requirement and PONV
Nedeljkovic et al18 186 patients undergoing cesarean delivery TAP block (bilateral) 266 mg of liposomal bupivacaine + 50-g bupivacaine in 30 mL 50-mg bupivacaine in 30 mL Opioid requirement
Purcell et al19 70 patients undergoing hip arthroscopy Fascia iliaca block 20-mL (266 mg) liposomal bupivacaine+ 20-mL 0.25 bupivacaine 40-mL 0.25% bupivacaine Opioid requirement, pain score, length of stay
Shariat20 39 patients undergoing shoulder arthroscopy Interscalene block 20-mL (88 mg) liposomal bupivacaine 20 mL of 0.25% bupivacaine Opioid requirement, pain score, and sleep quality
Van Boxstael et al21 26 patients undergoing hallux surgery Posterior tibial and deep peroneal nerve blocks 10 mL of 1.3% liposomal bupivacaine and 5 mL of 0.5% bupivacaine 15 mL of 0.5% bupivacaine 1-week opioid requirement
Vandepitte 201721 30 patients undergoing shoulder surgeries Interscalene block 10-mL 1.3% liposomal bupivacaine + 5-mL 0.25% bupivacaine 15-mL 0.25% bupivacaine Opioid requirement, pain score, complications, and sleep quality
Abbreviations: DIEP, deep inferior epigastric perforators (flap); PONV, postoperative nausea and vomiting; TAP, transversus abdominis plane.

F1
Figure 1.:
Search flow chart. AAGBI indicates Association of Anaesthetists of Great Britain and Ireland; ASA, American Society of Anesthesiologists; ASRA, American Society of Regional Anesthesia and Pain Medicine; CENTRAL, Cochrane Central Register of Controlled Trials; CINAHL, Cumulative Index to Nursing and Allied Health Literature; ESRA, European Society of Regional Anaesthesia & Pain Therapy; IARS, International Anesthesia Research Society.
F2
Figure 2.:
Risk of bias summary.

The last search was conducted on October 8, 2020. We screened a total of 1810 publications and identified a total of 13 relevant studies10–22 (Figure 1). Twelve studies compared liposomal bupivacaine to plain local anesthetic, and 1 study compared liposomal bupivacaine to catheter-based blocks; the studies are summarized in the Table. The risk of bias grading for each study is summarized in Figure 2 and reported in Supplemental Digital Content, https://links.lww.com/AA/D391. There were 6 studies on TAP block, 3 studies on brachial plexus block, and 2 studies on adductor canal block. There was 1 study each on fascia iliaca block and ankle block.

TAP Block

There were 5 studies comparing TAP block with liposomal bupivacaine to TAP block with plain bupivacaine. The studies were of moderate quality, limited by lack of trial registration, and were unclear allocation concealment. In all 5 studies, liposomal bupivacaine was compared to 0.25% plain bupivacaine. Due to the heterogeneity in surgery type (ie, hysterectomy, breast reconstruction, and nephrectomy) as well as heterogeneity in the reporting of outcomes, quantitative analysis was not attempted.

Nedeljkovic et al18 administered TAP block in patients undergoing cesarean delivery. The authors reported that the liposomal bupivacaine cohort had significantly lower opioid requirements 24–72 hours postoperatively (POD 1–2). Interestingly, despite the lower opioid requirements in the liposomal bupivacaine cohort, the patients had higher risk of postoperative nausea and vomiting (PONV).18

Ha et al14 administered TAP block in patients with inferior epigastric perforator artery flap extraction using the blind surgical approach in breast reconstruction surgery. The authors reported no differences in 72-hour opioid requirements or length of hospital stay. There was no difference in the POD 1 pain score; POD 2 pain score was lower in the liposomal bupivacaine cohort, but this was not statistically significant. There are several possible explanations for the negative findings in this study. First, patients received T2 and T4 paravertebral block in addition to TAP block to cover the incision site on the chest which may confound the findings; in addition, the high intraoperative (110 and 100 mg) and early postoperative (55 and 46 mg per day) opioid requirements suggest a high incidence of ineffective block. The risk of bias of the study is high.14

Gatherwright et al13 administered TAP block in patients undergoing breast flap extraction. Total opioid requirement in 72 hours was found to be significantly lower in the liposomal bupivacaine cohort. Pain score on POD 1 was also lower in the liposomal bupivacaine cohort, though this finding was not statistically significant. The time to ambulation was significantly lower in the liposomal bupivacaine cohort (21 vs 36 hours). Notably, this is a very small study which only contained 8 patients per cohort. The risk of bias of the study is moderate to high.13

Hutchins et al15 administered TAP block in patients undergoing laparoscopic hysterectomy. The authors reported that the liposomal bupivacaine cohort had slightly lower opioid requirements on POD 1 (mean difference: 4.6 mg) and lower pain scores on POD 1 and 2 (both by 2 points). The liposomal bupivacaine cohort also had significantly lower incidences of PONV (25% vs 57%) and shorter lengths of stay (mean difference of 6 hours). The risk of bias of the study is moderate due to the author’s affiliation to the liposomal bupivacaine manufacturer.15

The same group subsequently published another study on administering TAP block in patients undergoing laparoscopic nephrectomy. The authors reported that the liposomal bupivacaine cohort had slightly lower opioid requirements on POD 2 (mean difference: 3 mg) and lower pain scores on PODs 1 and 2 (by 1 and 2 points, respectively). The liposomal bupivacaine cohort also had significantly lower incidences of PONV (23% vs 52%) and shorter lengths of stay (mean difference of 11 hours). The risk of bias of the study is moderate.16

In addition, Baja et al10 conducted a study investigating the efficacy of liposomal bupivacaine TAP block plus intrafascial catheter. The authors reported no significant differences in postoperative opioid requirements but noted that the liposomal bupivacaine cohort had significantly higher intraoperative opioid requirements. The risk of bias of the study is moderate to high.10

Overall, most studies on the use of liposomal bupivacaine in TAP block had significant quality concerns. Both studies by Hutchins et al15,16 were well designed and reported that liposomal bupivacaine had significantly longer analgesia duration, but the conflict of interest of the primary investigator is concerning. The study by Gatherwright et al13 is limited by an extremely small sample size as well as an unclear description of study methodology. It is unclear whether the surgical TAP approach used by Ha et al14 is comparable to ultrasound-guided TAP block, and the high-block failure rate is concerning. In summary, there is currently insufficient reliable evidence to assess the efficacy of liposomal bupivacaine in TAP block.

Brachial Plexus Block

There were 3 studies on brachial plexus block for shoulder surgery. This included a total of 66 patients who received liposomal bupivacaine and 63 patients who received bupivacaine. Two of the studies compared plain bupivacaine to a bupivacaine/liposomal bupivacaine mixture,12,22 while the other study compared liposomal bupivacaine to plain bupivacaine.20

In the study by Shariat,20 while the liposomal bupivacaine cohort had slightly lower opioid requirements and pain scores on PODs 1 and 2, neither were statistically significant. The time to rescue analgesia was also slightly shorter but not significant. There were no differences in PONV. The risk of bias is high.20

De Meirsman et al12 found that the liposomal bupivacaine cohort had significantly lower pain scores on PODs 0, 1, and 2 (1.5, 1.5, and 2 points difference, respectively). The risk of bias is high.

In an industry-funded study by Vandepitte et al,22 the authors reported that there were no significant differences in postoperative opioid requirements; however, the liposomal bupivacaine cohort reported significantly lower pain scores on PODs 0, 1, and 2 (mean difference of 1.6, 2, and 2 points, respectively). The risk of bias of the study is high.22

Due to direct conflict of interest, the study by Vandepitte et al22 was not taken into consideration in the qualitative analysis. While the studies by De Meirsman et al12 and Shariat20 suggest that liposomal bupivacaine may be associated with longer duration of analgesia, the quality of evidence is low due to heterogeneity in reporting and small study sizes.

Adductor Canal Block

There were 2 studies on adductor canal block for patients undergoing knee replacement. There were 109 patients in the liposomal bupivacaine cohort and 108 patients in the plain bupivacaine cohort.

Belsh et al11 administered adductor canal block in 192 patients undergoing knee replacement. The authors reported that the liposomal bupivacaine cohort had significantly lower opioid requirements on POD 2, as well as significantly lower pain scores on PODs 1 and 2. There was no significant difference in terms of length of stay. The overall risk of bias is high.11 In addition, it is noted that the principal investigator is on the advisory board for the liposomal bupivacaine manufacturer.

Nair et al17 administered adductor canal block for patients undergoing knee replacement. Authors reported no significant differences in opioid requirements from 0–48 hours, postoperatively. The overall risk of bias is moderate.17

The study by Belsh et al11 included a reasonable number of patients and reported promising findings; however, the conflict of interest needs to be considered. More studies are needed before any conclusions can be drawn.

Other Regional Anesthesia Techniques

Purcell et al19 administered fascia iliaca block to patients undergoing hip replacement. The authors reported no differences in 72-hour opioid requirements or lengths of hospital stay, nor any differences in pain scores on PODs 1 and 2. The overall risk of bias is low.19

Van Boxstael et al21 administered posterior tibial plus deep peroneal nerve block to patients undergoing hallux surgery. Authors reported that opioid requirements were significantly lower in the liposomal bupivacaine cohort. The overall risk of bias is moderate to high.21

DISCUSSION

The previous Cochrane review includes multiple “control” interventions (no block/block with plain local anesthetics); our article focuses on the comparison between liposomal bupivacaine and conventional local anesthetics as this to us is a more clinically relevant comparison. We identified a total of 12 studies that compared the use of conventional local anesthetics and liposomal bupivacaine in regional anesthesia. Due to heterogeneity of the patient population, procedures, and outcome reporting, quantitative analysis of the studies was not attempted. Various doses of liposomal bupivacaine (88–266 mg) were used in the included studies. This is comparable to the dose used in surgical field infiltration.23,24 The liposomal bupivacaine was either administered alone11,20; diluted with saline14–16; or mixed with plain bupivacaine.10,12,19,21,22 All 3 approaches have been used successfully for surgical field infiltration.

We identified 6 studies that used liposomal bupivacaine in TAP blocks, 4 of which reported longer duration of analgesia. However, concerns over potential conflict of interest, small sample size, and risk of bias score limited the reliability of the evidence. Three studies examined liposomal bupivacaine in brachial plexus block, which reported conflicting findings regarding the efficacy of liposomal bupivacaine. Five studies examined liposomal bupivacaine for various other blocks; all but one reported negative finding.

Taken together, there is currently little evidence that in regional anesthesia, liposomal bupivacaine significantly prolongs the duration of analgesia compared to conventional local anesthetics. In comparison to the previous Cochrane review, which identified 3 studies that compared conventional regional anesthesia with liposomal bupivacaine block, our study includes a total of 12 studies. The negative findings reported in the majority of studies are suggestive that further studies may not change the conclusion. The validity of the current conclusion should ideally be assessed using trial sequential analysis, which estimates the likelihood of the current conclusion being altered by further evidence. However, trial sequential analysis is not possible due to the heterogeneous outcome reporting across the studies. In our experience, regional anesthesia interventions that do not demonstrate significant benefits across multiple studies are unlikely to reach clinically significant margin of benefits in meta-analyses.

It has been shown that liposomal bupivacaine provides better analgesia compared to conventional local anesthetics in surgical site infiltration.6,24–26 There are several possible reasons why liposomal bupivacaine extends the duration of local infiltration but not regional blocks. For a block to be effective, an adequate concentration of free bupivacaine is needed to penetrate the nerve sheath. Nerve fibers targeted by regional blocks are much larger than the small nerve fibers surrounding the wound. An adequate concentration gradient of the free bupivacaine is needed to facilitate effective diffusion across the connective tissue around the nerve fibers including the epineurium and perineurium. As liposomal bupivacaine releases a limited amount of free bupivacaine after its initial phase, the concentration gradient may not remain large enough for adequate neuronal blockade. While the tissue concentration of free bupivacaine is not known, the plasma bupivacaine concentration is easily measurable and may serve as a surrogate for measuring tissue concentration. Hu et al27 reported that the peak plasma concentration after 100 mg plain bupivacaine administration is estimated to be 300 ng/mL, which is comparable to the peak plasma concentration after 399 mg of liposomal bupivacaine. In other words, considerably higher doses of liposomal bupivacaine are likely necessary to achieve a comparable tissue concentration as plain bupivacaine. Fortunately, liposomal bupivacaine has been found to have no significant cardiac toxicity at high doses 30 mg/kg.28–30 We encourage that pharmacokinetic factors be studied in humans and be taken into consideration for future clinical trials.

Other clinical factors may affect analgesic efficacy as well, such as anatomical site, tissue vascularity, the variability of surgical procedures, and the coadministration of systemic analgesics. In fact, several studies of local infiltration in breast surgery,31 urological laparoscopic surgery,32 and total knee replacement,33 reported that liposomal bupivacaine was not superior to conventional bupivacaine in analgesic efficacy.

It is worth noting that block adjuncts (eg, dexamethasone and dexmedetomidine) have been shown to prolong the duration of regional anesthesia in several clinical trials and meta-analyses.34,35 There is no reported study to our knowledge to compare the efficacy of liposomal bupivacaine to the use of other block adjuncts. However, as the liposomal bupivacaine did not show superior efficacy to conventional local anesthetics in regional anesthesia, it could predict that regional anesthesia with liposomal bupivacaine at the current settings has no better efficacy than the use of block adjuncts.

The current systematic review has several limitations. Most notable is the limited number of studies comparing different regional anesthesia techniques and for different surgical procedures. This limits the strength of evidence and makes quantitative analysis impractical. In addition, several studies were not reported in full while others had potential conflicts of interest. These factors weaken the reliability of the data.

CONCLUSIONS

We conducted a systematic review on the efficacy of liposomal bupivacaine in regional anesthesia. While there are some studies suggesting that liposomal bupivacaine provides longer analgesia in TAP block and brachial plexus block, the evidence does not currently support its use over conventional local anesthetics. There is also limited evidence supporting liposomal bupivacaine’s efficacy in other regional anesthesia techniques. We suggest that the pharmacokinetic factors be considered to potentially improve the efficacy of liposomal bupivacaine in regional blocks in future trials.

DISCLOSURES

Name: Zhaosheng Jin, MBBS.

Contribution: This author helped with statistical analysis, literature search, and writing of the manuscript.

Name: Olivia Ding, MD.

Contribution: This author helped with literature search, data extraction, and review of the manuscript.

Name: Ali Islam, BE.

Contribution: This author helped with literature search, data extraction, and review of the manuscript.

Name: Ru Li, PhD.

Contribution: This author helped with literature search and review of the manuscript.

Name: Jun Lin, MD, PhD.

Contribution: This author helped with the writing, review, and editing of the manuscript.

This manuscript was handled by: Jianren Mao, MD, PhD.

    REFERENCES

    1. Myles PS, Williams DL, Hendrata M, Anderson H, Weeks AM. Patient satisfaction after anaesthesia and surgery: results of a prospective survey of 10,811 patients. Br J Anaesth. 2000;84:6–10.
    2. Tan M, Law LS, Gan TJ. Optimizing pain management to facilitate enhanced recovery after surgery pathways. Can J Anaesth. 2015;62:203–218.
    3. Chahar P, Cummings K. Liposomal bupivacaine: a review of a new bupivacaine formulation. J Pain Res. 2012;5257–264.
    4. Mantripragada S. A lipid based depot (DepoFoam technology) for sustained release drug delivery. Prog Lipid Res. 2002;41:392–406.
    5. 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.
    6. Wang X, Xiao L, Wang Z, Zhao G, Ma J. Comparison of peri-articular liposomal bupivacaine and standard bupivacaine for postsurgical analgesia in total knee arthroplasty: a systematic review and meta-analysis. Int J Surg (London, England). 2017;39:238–248.
    7. Hamilton TW, Athanassoglou V, Trivella M, et al. Liposomal bupivacaine peripheral nerve block for the management of postoperative pain. Cochrane Database Syst Rev. 2016CD011476.
    8. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097.
    9. Hayden JA, van der Windt DA, Cartwright JL, Côté P, Bombardier C. Assessing bias in studies of prognostic factors. Ann Intern Med. 2013;158:280–286.
    10. Baja D, Baqai Z, Macres S, Farkas L, Applegate R, Zhou J. Transversus abdominus plane block catheters vs liposomal bupivacaine for pain control after colorectal surgery: a prospective randomized control trial. 2018.2018 World Congress on Regional Anesthesia & Pain Medicine. New York;
    11. Belsh Y, Pyler R, Keegan N, et al. A prospective, randomized, double-blind, controlled trial comparing liposomal bupivacaine with ropivacaine in adductor canal block for total knee arthroplasty patients. 2018.2018 World Congress on Regional Anesthesia & Pain Medicine. New York;
    12. De Meirsman S, Smeets A, Byloos B, Buck R, Hassanin J, Leunen I. Addition of liposome bupivacaine in interscalene brachial plexus block lowers postoperative pain up to 1 week after rotator cuff surgery. 2017.Euroanesthesia. Geneva;
    13. Gatherwright J, Knackstedt RW, Ghaznavi AM, et al. Prospective, randomized, controlled comparison of bupivacaine versus liposomal bupivacaine for pain management after unilateral delayed deep inferior epigastric perforator free flap reconstruction. Plast Reconstr Surg. 2018;141:1327–1330.
    14. Ha AY, Keane G, Parikh R, et al. The analgesic effects of liposomal bupivacaine versus bupivacaine hydrochloride administered as a transversus abdominis plane block after abdominally based autologous microvascular breast reconstruction: a prospective, single-blind, randomized, controlled trial. Plast Reconstr Surg. 2019;144:35–44.
    15. 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.
    16. 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.
    17. Nair S. 0.25% Bupivacaine versus a mixture of 0.25% bupivacaine and 1.3 % liposomal bupivacaine in patients undergoing TKA - study results - ClinicalTrials.gov. Accessed June 14, 2020. https://clinicaltrials.gov/ct2/show/results/NCT03303794.
    18. Nedeljkovic SS, Kett A, Vallejo MC, et al. Transversus abdominis plane block with liposomal bupivacaine for pain after cesarean delivery in a multicenter, randomized, double-blind, controlled trial. Anesth Analg. 2020;131:1830–1839.
    19. Purcell RL, Brooks DI, Steelman TJ, et al. Fascia iliaca blockade with the addition of liposomal bupivacaine versus plain bupivacaine for perioperative pain management during hip arthroscopy: a double-blinded prospective randomized control trial. Arthroscopy. 2019;35:2608–2616.
    20. Shariat A. Efficacy of interscalene brachial plexus block with liposomal bupivacaine for arthroscopic shoulder surgery. Accessed June 14, 2020. https://clinicaltrials.gov/ct2/show/NCT01977352.
    21. Van Boxstael S, Wierinckx J, Vandepitte C, Leunen I, Jalil H, Kuroda M. Liposome bupivacaine in ankle blocks decreases opioid consumption compared to bupivacaine alone or general anesthesia after corrective osteotomy for hallux valgus. Euroanesthesia. 2018; Copenhagen.
    22. 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.
    23. Kuang MJ, Du Y, Ma JX, He W, Fu L, Ma XL. The efficacy of liposomal bupivacaine using periarticular injection in total knee arthroplasty: a systematic review and meta-analysis. J Arthroplasty. 2017;32:1395–1402.
    24. Yan Z, Chen Z, Ma C. Liposomal bupivacaine versus interscalene nerve block for pain control after shoulder arthroplasty: a meta-analysis. Medicine (Baltimore). 2017;96:e7226.
    25. Ma T, Wang Y, Jiang Y, et al. Liposomal bupivacaine versus traditional bupivacaine for pain control after total hip arthroplasty: a meta-analysis. Medicine. 2017;96:e7190.
    26. Liu Y, Zeng JF, Zeng Y, Wu YG, Bao XC, Shen B. Comprehensive comparison of liposomal bupivacaine with femoral nerve block for pain control following total knee arthroplasty: an updated systematic review and meta-analysis. Orthop Surg. 2019;11:943–953.
    27. Hu D, Onel E, Singla N, Kramer WG, Hadzic A. Pharmacokinetic profile of liposome bupivacaine injection following a single administration at the surgical site. Clin Drug Investig. 2013;33:109–115.
    28. Balocco AL, Van Zundert PGE, Gan SS, Gan TJ, Hadzic A. Extended release bupivacaine formulations for postoperative analgesia: an update. Curr Opin Anaesthesiol. 2018;31:636–642.
    29. Richard BM, Newton P, Ott LR, et al. The safety of EXPAREL® (abupivacaine liposome injectable suspension) administered by peripheral nerve block in rabbits and dogs. J Drug Deliv. 2012;2012:962101.
    30. Richard BM, Rickert DE, Newton PE, et al. Safety evaluation of EXPAREL (DepoFoam Bupivacaine) administered by repeated subcutaneous injection in rabbits and dogs: species comparison. J Drug Deliv. 2011;2011:467429.
    31. Tan P, Martin MS, Shank N, et al. A comparison of 4 analgesic regimens for acute postoperative pain control in breast augmentation patients. Ann Plast Surg. 2017;78:S299–S304.
    32. 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.
    33. Schroer WC, Diesfeld PG, LeMarr AR, Morton DJ, Reedy ME. Does extended-release liposomal bupivacaine better control pain than bupivacaine after total knee arthroplasty (TKA)? a prospective, randomized clinical trial. J Arthroplasty. 2015;30:64–67.
    34. Vorobeichik L, Brull R, Abdallah FW. Evidence basis for using perineural dexmedetomidine to enhance the quality of brachial plexus nerve blocks: a systematic review and meta-analysis of randomized controlled trials. Br J Anaesth. 2017;118:167–181.
    35. Kirkham KR, Jacot-Guillarmod A, Albrecht E. Optimal dose of perineural dexamethasone to prolong analgesia after brachial plexus blockade: a systematic review and meta-analysis. Anesth Analg. 2018;126:270–279.

    Supplemental Digital Content

    Copyright © 2021 International Anesthesia Research Society