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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. In addition to newer block-specific regional analgesia indications, the wording of liposomal bupivacaine’s first approved indication of infiltration to produce local 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
Four randomized controlled trials (RCTs) have investigated the effect of liposomal bupivacaine after cesarean delivery.2-5 The first study included women (n=103) who were undgoing cesarean section and received infiltration at the surgical site before incision closure with either liposomal bupivacaine 266 mg or placebo.2 All patients also received a multimodal analgesic regimen that included epidural or spinal morphine, ketorolac, ibuprofen, and acetaminophen. The primary outcome (pain scores with movement at 48 hours after delivery) was similar in both the liposomal bupivacaine and placebo groups (p=0.72). Pain scores with movement at other times and at rest throughout the study were also similar between groups. Opioid consumption during the first 48 hours was the same in both groups (median, 37.5 mg; p=0.44). These insignificant results are difficult to interpret because the study was underpowered.

The second trial evaluated the efficacy of transversus abdominis plane (TAP) block with liposomal bupivacaine 266 mg plus bupivacaine 50 mg compared to bupivacaine 50 mg alone in patients undergoing elective ceaserean delivery at 37 to 42 weeks gestation (n=186).3 All patients received intrathecal morphine 150 mcg and spinal anesthesia with bupivacaine plus fentanyl, and postoperative multimodal analgesia with acetaminophen and ibuprofen. The primary endpoint of 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=0.012). Secondary endpoints of total opioid consumption after 1 week (least squares mean, 23.3 mg vs. 45.8 mg; p=0.018), cumulative pain scores through 72 hours (p=0.002), and the proportion of patients who received no opioids (53.5% vs. 24.7%; p=0.001) were also significantly less with liposomal bupivacaine. Patients who received liposomal bupivacaine had significantly less opioid use at 48 hours (p=0.01) and 7 days (p=0.018) but not at 24 hours (p=0.054) or 14 days (p=0.054). A similar proportion of patients in each group experienced treatment-emergent adverse events with few serious events. Another trial comparing similar drug regimens found no difference in opioid consumption between groups, likely due to a small sample size.5

Lastly, the CHOICE study (n=169) was a 3-arm comparison of liposomal bupivacaine 266 mg TAP block + intrathecal morphine 50 mcg, intrathecal morphine 150 mcg alone, and liposomal bupivacaine 266 mg TAP block alone, all as elements of a multimodal pain regimen that also included ketorolac, acetaminophen, and ibuprofen.4 Liposomal bupivacaine infiltration was administered after incision closure, and all patients also received spinal anesthesia with bupivacaine (and fentanyl as appropriate). Total opioid consumption through 72 hours after delivery (the primary outcome) was significantly reduced in both liposomal bupivacaine groups compared to the intrathecal morphine group (both p<0.001). The proportion of patients who were opioid-free was similar between groups. Tolerability and adverse events were also similar between groups.

Retrospective studies also support the efficacy of liposomal bupivacaine for post-cesarean analgesia. 6-9 The largest retrospective study (n=402) reported less opioid use and lower pain scores with both liposomal bupivacaine infiltration and TAP block with liposomal bupivacaine compared to standard spinal anesthesia.6 Liposomal bupivacaine TAP blocks plus intrathecal morphine compared to TAP blocks with liposomal bupivacaine alone in another study (n=358) resulted in significantly less opoid use in the first 24 hours after surgery and overall.7 Another retrospective study of 201 patients undergoing cesarean delivery found that postsurgical pain scores, total opioid consumption, time to ambulation, time to solid food, and hospital length of stay were significantly lower in patients who received TAP block with liposomal bupivacaine 266 mg compared to patients who received intrathecal morphine and parenteral opioids.8 A retrospective study of 288 patients who received bilateral TAP blocks with liposomal bupivacaine and neuraxial morphine had significantly lower opioid use and length of stay compared to a variety of control regimens.9

Breastfeeding effects
Safety outcomes for breastfed neonates born to mothers who received liposomal bupivacaine for post-cesarean anaglesia have not been reported.2-9

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.10 Maternal plasma bupivacaine concentations 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 recommend a specific local anesthetic.11-13 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 as a TAP block, but not for local infiltration) have decreased opioid use relative to comparator regimens. The effect of liposomal bupivacaine on pain scores is inconsistent among studies. Further data is needed regarding neonatal safety and the effect on breast milk production with multimodal post-cesarean analgesic regimens that include liposomal bupivacaine.

References

  1. Exparel. Package insert. Pacira Pharmaceuticals, Inc.; 2023.
  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. 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(6):1830-1839. doi:10.1213/ANE.0000000000005075
  4. Habib AS, Nedeljkovic SS, Horn JL, et al. Randomized trial of transversus abdominis plane block with liposomal bupivacaine after cesarean delivery with or without intrathecal morphine. J Clin Anesth. 2021;75:110527. doi:10.1016/j.jclinane.2021.110527
  5. Antony KM, McDonald RC, Gaston L, Hetzel S, Li Z. Surgical transversus abdominis plane block with liposomal bupivacaine at cesarean: a pilot randomized trial. Am J Obstet Gynecol MFM. 2024;6(2):101273. doi:10.1016/j.ajogmf.2023.101273
  6. Peebles AF, Mouch A, Maxwell RA, Ruby T, Kindig MJ. Long-acting bupivacaine for pain control after cesarean birth. Nurs Womens Health. 2023;27(4):262-269. doi:10.1016/j.nwh.2023.03.003
  7. 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
  8. 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
  9. Feierman DE, Kim J, Bronstein A, et al. The use of bilateral transversus abdominis plane blocks with liposomal bupivacaine on postoperative cesarean delivery patients during COVID-19 pandemic is associated with reduced narcotics use and reduced length of stay. Womens Health (Lond). 2021;17:17455065211058046. doi:10.1177/17455065211058046
  10. 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
  11. Bollag L, Lim G, Sultan P, et al. Society for Obstetric Anesthesia and Perinatology: consensus statement and recommendations for enhanced recovery after cesarean. Anesth Analg. 2021;132(5):1362-1377. doi:10.1213/ANE.0000000000005257
  12. 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
  13. ACOG Practice Bulletin No. 209: obstetric analgesia and anesthesia. Obstet Gynecol. 2019;133(3):e208-e225. doi:10.1097/AOG.0000000000003132 (reaffirmed 2024)

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

June 2024

The information presented is current as of June 12, 2024. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.