What efficacy supports the use of liposomal bupivacaine for post-Cesarean pain control?

Introduction

Since its introduction to the US market in 2011, liposomal bupivacaine (Exparel) has been used in a wide variety of surgical procedures. The wording of its approved indication of single-dose infiltration to produce local analgesia and interscalene brachial plexus nerve block to produce postsurgical regional analgesia has allowed flexibility and creativity in clinical practice, resulting in ever-increasing indications and therapeutic uses.1 The potential for opioid-sparing effects and improved analgesia due to its long half-life/duration of action compared to other local anesthetics have prompted investigation into the efficacy and safety of liposomal bupivacaine as part of a multimodal regimen for postoperative analgesia following cesarean delivery.

Clinical literature

Published studies

One randomized controlled trial (RCT) that investigated the effect of liposomal bupivacaine after cesarean delivery has been published.2 Women (n=103) who were undergoing cesarean section received infiltration at the surgical site before incision closure with either liposomal bupivacaine 266 mg or placebo. All patients also received a multimodal analgesic regimen that included epidural or spinal morphine, ketorolac, ibuprofen, and acetaminophen. The primary outcome (11-point pain scores with movement at 48 hours after delivery) was similar in both the liposomal bupivacaine (median 4) and placebo (median 3.5) groups (p=0.72). Pain scores with movement at other times and at rest throughout the study were similar between groups. Opioid consumption during the first 48 hours was the same in both groups (median 37.5 mg; p=0.44).  The insignificant results for this trial are difficult to interpret because the study was underpowered for the primary outcome.

A few larger retrospective studies support the efficacy of liposomal bupivacaine for post-cesarean analgesia.3,4 The use of transversus abdominus plane (TAP) blocks with liposomal bupivacaine plus intrathecal morphine compared to TAP blocks with liposomal bupivacaine alone in one study (n=358) resulted in significantly less opioid use in the first 24 hours after surgery (5 mg vs 15 mg, respectively; p<0.0001) and overall (35 mg vs 47.5 mg, respectively; p=0.039).3 Another retrospective study of 201 patients undergoing cesarean delivery found that postsurgical pain scores (p<0.001), total opioid consumption (p<0.001), time to ambulation (p<0.01), time to solid food (p<0.01), and hospital length of stay (p<0.001) were lower in patients who received TAP block with liposomal bupivacaine 266 mg compared to patients who did not receive a TAP block.4

Unpublished data

The manufacturer of liposomal bupivacaine has conducted 2 Phase 4, multicenter, RCTs in patients undergoing elective ccesarean delivery at 37 to 42 weeks gestation.5,6 The full results of these studies remain unpublished, but preliminary results are available. The CHOICE study (n=169) was a 3-arm comparison of liposomal bupivacaine 133 mg TAP infiltration plus intrathecal morphine 50 mcg, intrathecal morphine 150 mcg alone, and liposomal bupivacaine 133 mg TAP infiltration alone, all as elements of a multimodal pain regimen that also included ketorolac, acetaminophen, and ibuprofen.5,7 According to unpublished information from the manufacturer, liposomal bupivacaine infiltration was administered after closure of the skin incision, and all patients also received spinal anesthesia with bupivacaine (and fentanyl as appropriate). According to preliminary results reported by the manufacturer, total opioid consumption through 72 hours after delivery (the primary outcome) was significantly different between groups (p≤0.001).5,7 Other outcomes included time to first use of opioid rescue medication, percentage of opioid-free subjects, pain scores, and measures of opioid tolerability. Patients in the liposomal bupivacaine group had better tolerability than the morphine group, with a lower incidence and severity of itching for 72 hours after surgery (p≤0.05).

The other unpublished study evaluated the efficacy of TAP field block with liposomal bupivacaine 266 mg plus bupivacaine 50 mg vs bupivacaine 50 mg alone in patients undergoing elective cesarean delivery at 37 to 42 weeks gestation (n=186).6,8 All patients also received intrathecal morphine 150 mcg and spinal anesthesia with bupivacaine plus fentanyl, plus postoperative multimodal analgesia with ketorolac, acetaminophen, and ibuprofen. The primary endpoint (total opioid consumption within 72 hours after surgery) was significantly less in the liposomal bupivacaine group (least squares mean, 15.5 mg vs. 32 mg; p=0.0117). Secondary endpoints of total opioid consumption after 1 week (least squares mean, 23.3 mg vs. 45.8 mg; p=0.0175), cumulative pain scores through 72 hours (p=0.002), and the proportion of patients who received no opioids (54% vs 25%; p=0.0012) were also significantly improved with liposomal bupivacaine. According to an unpublished study summary provided by the manufacturer, patients who received liposomal bupivacaine met noninferiority criteria for pain scores through 72 hours and had significantly less opioid use at 48 hours (p=0.0096) and 7 days (p=0.0175) but not at 24 hours (p=0.0543) or 14 days (p=0.0542). A similar proportion of patients in each group experienced treatment-emergent adverse events (64% vs 56%, respectively) with few serious events.

Breastfeeding effects

Safety outcomes for breastfed neonates born to mothers who received liposomal bupivacaine for post-cesarean analgesia have not been reported.2-8

A prospective pharmacokinetic study quantified bupivacaine concentrations in both maternal plasma and in breast milk among 30 women who received a TAP block with bupivacaine 52 mg plus liposomal bupivacaine 266 mg for elective cesarean delivery.9 Maternal plasma bupivacaine concentrations peaked after 6 hours and then again at 48 hours, followed by a steady decrease. In milk, bupivacaine concentrations peaked at 6 hours (37% of the corresponding maternal peak concentration) and decreased to almost undetectable levels at 96 hours. During the first 96 hours, estimated milk/plasma ratios ranged from 0.15 to 0.45 and the relative neonatal dosage was <1% at all time points. No neonatal adverse events during the 14-day follow-up period were attributed to the study medication.

Conclusion

Several practice guidelines address the use of local anesthetic wound infiltration and/or regional blocks for post-cesarean pain control, but none provide recommendations on the optimal local anesthetic for this treatment modality.10-12 In the absence of well-established practice standards, the choice of local anesthetic remains at the discretion of the clinician. In randomized trials, multimodal analgesic regimens that include liposomal bupivacaine (administered either as local infiltration or for TAP blockade) have decreased opioid use and improved pain scores relative to comparator regimens. Full results of the latest RCTs, including efficacy and safety of the opioid-free arm of the CHOICE trial, are anticipated; however, preliminary outcomes are promising. Further data is needed regarding neonatal safety outcomes and the effect on breast milk production with multimodal post-cesarean analgesic regimens that include liposomal bupivacaine.

References

  1. Package insert. Pacira Pharmaceuticals, Inc.; 2018.
  2. 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(1):70-78. doi:10.1097/AOG.0000000000002649
  3. Hutchins JL, Renfro L, Orza F, Honl C, Navare S, Berg AA. The addition of intrathecal morphine to a transversus abdominis plane block with liposome bupivacaine provides more effective analgesia than transversus abdominis plane block with liposome bupivacaine alone: a retrospective study. Local Reg Anesth. 2019;12:7-13. doi:10.2147/LRA.S190225
  4. Baker BW, Villadiego LG, Lake YN, et al. Transversus abdominis plane block with liposomal bupivacaine for pain control after cesarean delivery: a retrospective chart review. J Pain Res. 2018;11:3109-3116. doi:10.2147/JPR.S184279
  5. Efficacy and safety of Exparel versus standard of care (SoC) in subjects undergoing elective cesarean section (CHOICE). U.S. National Library of Medicine. Updated January 13, 2020. Accessed July 15, 2020. https://clinicaltrials.gov/ct2/show/NCT03853694?id=NCT03176459 OR NCT02353754 OR NCT03853694&draw=2&rank=1&load=cart
  6. Evaluate the safety and efficacy of Exparel when administered via infiltration into the TAP vs. bupivacaine alone in subjects undergoing elective C-sections (C-Section). S. National Library of Medicine. Updated April 22, 2019. Accessed July 15, 2020. https://clinicaltrials.gov/ct2/show/NCT03176459?id=NCT03176459 OR NCT02353754 OR NCT03853694&draw=2&rank=2&load=cart
  7. Exparel achieves primary and key secondary endpoints in Phase 4 CHOICE study in cesarean section patients. Pacira Pharmaceuticals. January 7, 2020. Accessed July 15, 2020. https://investor.pacira.com/news-releases/news-release-details/exparel-achieves-primary-and-key-secondary-endpoints-phase-4
  8. Phase 4 study demonstrates superiority of Exparel plus bupivacaine versus bupivacaine alone in cesearean section procedures. Pacira Pharmaceuticals. May 7, 2019. Accessed July 15, 2020. https://investor.pacira.com/news-releases/news-release-details/phase-4-study-demonstrates-superiority-exparel-plus-bupivacaine
  9. Mustafa HJ, Wong HL, Al-Kofahi M, Schaefer M, Karanam A, Todd MM. Bupivacaine pharmacokinetics and breast milk excretion of liposomal bupivacaine administered after cesarean birth. Obstet Gynecol. 2020;136(1):70-76. doi:10.1097/AOG.0000000000003886
  10. Enhanced recovery after cesarean (ERAC) full consensus statement. Society for Obstetric Anesthesia and Perinatology. May 23, 2019. Accessed July 15, 2020. https://soap.org/education/provider-education/member-erac-consensus-statement-5-23-19-2/
  11. Macones GA, Caughey AB, Wood SL, et al. Guidelines for postoperative care in cesarean delivery: Enhanced Recovery After Surgery (ERAS) Society recommendations (part 3). Am J Obstet Gynecol. 2019;221(3):247.e1-247.e9. doi:10.1016/j.ajog.2019.04.012
  12. ACOG Committee Opinion No. 742: postpartum pain management. Obstet Gynecol. 2018;132(1):e35-e43. doi:10.1097/AOG.0000000000002683

Prepared by:
Heather Ipema, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

August 2020

The information presented is current as of July 15, 2020. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

Return to top