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A prospective randomized trial comparing liposomal bupivacaine vs standard bupivacaine wound infiltration in open gynecologic surgery on an enhanced recovery pathway

      Background

      Value in healthcare is reflected by patient-centered outcomes of care per health dollar expended. Although liposomal bupivacaine is more expensive, it has been shown to provide prolonged analgesia (up to 72 hours).

      Objective

      This study aimed to evaluate whether the addition of liposomal bupivacaine to standard bupivacaine could decrease opioid intake and improve pain control after laparotomy for gynecologic surgery compared with standard bupivacaine alone in an enhanced recovery after surgery pathway.

      Study Design

      A prospective randomized controlled single-blinded trial of wound infiltration with liposomal bupivacaine plus 0.25% bupivacaine (study arm) vs 0.25% bupivacaine (control arm) was performed at a National Cancer Institute–designated tertiary referral cancer center. Participants were patients aged ≥18 years undergoing exploratory laparotomy for a gynecologic indication. All patients were treated on an enhanced recovery pathway including local wound infiltration before closure. In this study, 266 mg of liposomal bupivacaine (free base; equal to 300 mg bupivacaine HCL)+150 mg of bupivacaine mixed in the same syringe was used in the study arm, and 150 mg of bupivacaine was used in the control arm. The primary outcome was the proportion of patients who were opioid-free within 48 hours after surgery. Secondary outcomes included number of opioid-free days from postoperative day 0 to postoperative day 3, days to first opioid administration, morphine equivalent daily dose, and patient-reported outcomes collected with the MD Anderson Symptom Inventory. The MD Anderson Symptom Inventory was administered as a preoperative baseline, daily while hospitalized, and at least weekly for 8 weeks after discharge. All outcomes were prespecified before data collection.

      Results

      In this study, 102 patients were evaluated. Among them, 16.7% of patients in the study arm received no opioids up to 48 hours compared with 14.8% in the control arm (P=.99). There were no significant differences in the amount of intraoperative opioids administered or days to first opioid use. There was no significant difference between the 2 arms in median cumulative morphine equivalent daily dose (21.3 [study arm] vs 33.8 [control arm]; P=.36) or between the groups in morphine equivalent daily dose per individual day. There were no significant differences in patient-reported pain or interference with walking between the 2 arms or other patient-reported outcomes.

      Conclusion

      Within an enhanced recovery after surgery pathway, adding liposomal bupivacaine to 0.25% bupivacaine wound infiltration did not decrease the proportion of patients who were opioid-free within 48 hours after surgery, did not decrease opioid intake, or did not improve patient’s self-reported pain and functional recovery compared with standard bupivacaine.

      Key words

      With the recent focus on the opioid epidemic, there is growing recognition of the potential harm of persistent opioid use after surgery.
      • Brummett C.M.
      • Waljee J.F.
      • Goesling J.
      • et al.
      New persistent opioid use after minor and major surgical procedures in US adults.
      ,
      • Volkow N.D.
      • Jones E.B.
      • Einstein E.B.
      • Wargo E.M.
      Prevention and treatment of opioid misuse and addiction: a review.
      Multimodal, opioid-sparing analgesia is a key tenant of enhanced recovery after surgery (ERAS) programs.
      • Ljungqvist O.
      • Scott M.
      • Fearon K.C.
      Enhanced recovery after surgery: a review.
      • Nelson G.
      • Altman A.D.
      • Nick A.
      • et al.
      Guidelines for postoperative care in gynecologic/oncology surgery: Enhanced Recovery After Surgery (ERAS®) Society recommendations—part II.
      • Nelson G.
      • Altman A.D.
      • Nick A.
      • et al.
      Guidelines for pre- and intra-operative care in gynecologic/oncology surgery: Enhanced Recovery After Surgery (ERAS®) Society recommendations—part I.
      Multimodal analgesia incorporates different opioids, nonopioid analgesics, and nonanalgesic drugs to act on the central and peripheral nervous systems and the local surgical site.
      • Kehlet H.
      • Dahl J.B.
      The value of “multimodal” or “balanced analgesia” in postoperative pain treatment.
      Utilizing this approach, ERAS programs in gynecologic surgery have demonstrated significant reductions in intraoperative and postoperative opioid use.
      • Kalogera E.
      • Bakkum-Gamez J.N.
      • Jankowski C.J.
      • et al.
      Enhanced recovery in gynecologic surgery.
      • Modesitt S.C.
      • Sarosiek B.M.
      • Trowbridge E.R.
      • et al.
      Enhanced recovery implementation in major gynecologic surgeries: effect of care standardization.
      • Meyer L.A.
      • Lasala J.
      • Iniesta M.D.
      • et al.
      Effect of an enhanced recovery after surgery program on opioid use and patient-reported outcomes.
      After the implementation of a departmental ERAS program, we noted a 39% reduction in intraoperative opioid use and a 72% reduction in postoperative in-hospital opioid use between postoperative days 0 and 3 for women undergoing open gynecologic procedures. We showed that 16% of women utilized no opioids after surgery for the first 4 days while hospitalized.
      • Meyer L.A.
      • Lasala J.
      • Iniesta M.D.
      • et al.
      Effect of an enhanced recovery after surgery program on opioid use and patient-reported outcomes.
      Our ERAS protocol included injection of a local anesthetic into the fascial and skin layers of the incision immediately before wound closure.
      • Miralpeix E.
      • Nick A.M.
      • Meyer L.A.
      • et al.
      A call for new standard of care in perioperative gynecologic oncology practice: impact of enhanced recovery after surgery (ERAS) programs.
      Retrospective data suggested that liposomal bupivacaine could further improve outcomes of women undergoing open gynecologic oncology surgery on an ERAS pathway.
      • Kalogera E.
      • Bakkum-Gamez J.N.
      • Weaver A.L.
      • et al.
      Abdominal incision injection of liposomal bupivacaine and opioid use after laparotomy for gynecologic malignancies.
      Liposomal bupivacaine is approved by the Food and Drug Administration for postsurgical anesthesia in any surgical site. By design, it releases local anesthetic in a controlled fashion over 48 to 72 hours.
      • Davidson E.M.
      • Barenholz Y.
      • Cohen R.
      • Haroutiunian S.
      • Kagan L.
      • Ginosar Y.
      High-dose bupivacaine remotely loaded into multivesicular liposomes demonstrates slow drug release without systemic toxic plasma concentrations after subcutaneous administration in humans.
      We hypothesized that the implementation of liposomal bupivacaine with its prolonged analgesic effects on an enhanced recovery pathway has the potential to further improve pain management and decrease opioid administration. Given the fact that there is approximately a 100-fold cost difference between liposomal bupivacaine and standard 0.25% bupivacaine, our goal was to investigate whether, in fact, there is an added benefit to liposomal bupivacaine in our patients undergoing gynecologic surgery on an enhanced recovery pathway.
      • Nadeau M.H.
      • Saraswat A.
      • Vasko A.
      • Elliott J.O.
      • Vasko S.D.
      Bupivacaine versus liposomal bupivacaine for postoperative pain control after augmentation mammaplasty: a prospective, randomized, double-blind trial.

      Why was this study conducted?

      This study purported to answer the question of whether the addition of long-acting liposomal bupivacaine to 0.25% bupivacaine local wound infiltration on an enhanced recovery after surgery care pathway would allow patients to decrease or avoid opioid intake postoperatively.

      Key findings

      In this randomized single-blinded clinical trial including 102 women, the proportion of patients receiving no opioids in the first 48 hours after surgery was not significantly different. Within the first 48 hours after surgery, 16.7% of patients in the study arm received no postoperative opioids compared with 14.8% in the control arm.

      What does this add to what is known?

      The adoption of long-acting liposomal bupivacaine on enhanced recovery pathways may not improve patient-centered outcomes.
      The objective of this study was to compare the analgesic efficacy and the functional recovery of patients who underwent open gynecologic surgery (laparotomy) on an enhanced recovery pathway receiving local wound infiltration with liposomal bupivacaine plus 0.25% bupivacaine to those receiving 0.25% bupivacaine (our standard before the implementation of this study). We hypothesized that we would see an absolute increase of 20% in the proportion of patients who were opioid-free up to postoperative day 2 after surgery in the study arm that included the liposomal bupivacaine. The underlying rationale for the investigational arm was that the liposomal bupivacaine would release more slowly over 48 to 72 hours and that the 0.25% bupivacaine would provide a more rapid onset to improve immediate coverage.

      Materials and Methods

      This was a prospective randomized single-blinded study of wound infiltration of liposomal bupivacaine mixed with 0.25% bupivacaine (study arm) vs 0.25% bupivacaine (control arm) in patients undergoing open gynecologic surgery on an ERAS pathway. Our pathway follows published guidelines for gynecologic surgery.
      • Nelson G.
      • Altman A.D.
      • Nick A.
      • et al.
      Guidelines for postoperative care in gynecologic/oncology surgery: Enhanced Recovery After Surgery (ERAS®) Society recommendations—part II.
      ,
      • Nelson G.
      • Altman A.D.
      • Nick A.
      • et al.
      Guidelines for pre- and intra-operative care in gynecologic/oncology surgery: Enhanced Recovery After Surgery (ERAS®) Society recommendations—part I.
      ,
      • Nelson G.
      • Bakkum-Gamez J.
      • Kalogera E.
      • et al.
      Guidelines for perioperative care in gynecologic/oncology: Enhanced Recovery After Surgery (ERAS) Society recommendations-2019 update.
      This protocol was approved by the institutional review board. The primary outcome measure was proportion of patients who did not receive any postoperative opioids within the first 48 hours after surgery. Secondary outcome measures included number of opioid-free days from postoperative day 0 to postoperative day 3, total morphine equivalent daily dose (MEDD) from postoperative day 0 to postoperative day 3, symptom burden and functional recovery measured with the MD Anderson Symptom Inventory for gynecologic cancer (MDASI-GYN) (the MDASI for ovarian cancer module
      • Sailors M.H.
      • Bodurka D.C.
      • Gning I.
      • et al.
      Validating the M. D. Anderson Symptom Inventory (MDASI) for use in patients with ovarian cancer.
      plus questions regarding diarrhea and indigestion), routine pain assessment from nursing staff, and time to first postoperative opioid administration (including the postanesthesia care unit [PACU]). The Clavien-Dindo surgical complication grading system was used to grade 30-day complications.
      • Dindo D.
      • Demartines N.
      • Clavien P.A.
      Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey.
      Study endpoints and analyses were prespecified.
      Participants had to be 18 years or older and undergo exploratory laparotomy for suspected or known cancer on our departmental ERAS pathway.
      • Meyer L.A.
      • Lasala J.
      • Iniesta M.D.
      • et al.
      Effect of an enhanced recovery after surgery program on opioid use and patient-reported outcomes.
      ,
      • Miralpeix E.
      • Nick A.M.
      • Meyer L.A.
      • et al.
      A call for new standard of care in perioperative gynecologic oncology practice: impact of enhanced recovery after surgery (ERAS) programs.
      Patients with an active opioid prescription at the time of the preoperative evaluation were excluded. Patients undergoing pelvic exenteration or abdominal wall hernia repairs were excluded as we could not ensure full participation in the ERAS pathway because of comanagement with surgeons outside the service line. Full inclusion and exclusion criteria are outlined in the Supplemental Figure. Patients were randomized using Research Electronic Data Capture in a 1:1 fashion stratified by primary surgeon. Research data coordinators enrolled participants. Participants and postoperative nursing staff were blinded to the treatment arm. The surgeons participating in the procedure were not blinded.
      All surgeons underwent training that included direct observation of their injection technique for both arms from the sponsor, Pacira BioSciences, Inc before study accrual. Injections were performed before closure both along the fascia and beneath the skin with the needle inserted in a perpendicular fashion to the long axis of the incision with the fan-like distribution parallel to the skin. In the control arm, patients received 150 mg of bupivacaine alone. In the control arm, an even volume of 60 mL (150 mg total dose) of 0.25% bupivacaine was injected in a standardized fashion with 20 mL fascial injection and 10 mL skin injection on each side of the wound. In the study arm, patients received 266 mg of liposomal bupivacaine (free base; equal to 300 mg bupivacaine HCl)+150 mg of bupivacaine mixed in the same syringe. The 20 mL (266 mg) of liposomal bupivacaine was diluted in a volume of 60 mL 0.25% bupivacaine (150 mg) in addition to normal saline. The addition of saline was prespecified per protocol and dependent on incision length (Supplemental Table).
      Perioperative patient-reported symptom burden was evaluated with the MDASI-GYN. For each symptom component, individuals were asked to rank symptom severity during the previous 24 hours on a scale of 0 to 10, with 0 being “not present” and 10 being “as bad as you can imagine.” Symptom interference was also assessed on a 0 to 10 scale, with 0 being “did not interfere” and 10 being “interfered completely.”
      • Sailors M.H.
      • Bodurka D.C.
      • Gning I.
      • et al.
      Validating the M. D. Anderson Symptom Inventory (MDASI) for use in patients with ovarian cancer.
      The total interference score was a composite endpoint of 6 interference questions that asked patients to report how much their symptoms interfered with general activity, mood, work (including work around the house), relations with other people, walking, and enjoyment of life. Patient-reported outcomes (PROs) were collected using the MDASI questionnaire at the following time points: preoperative baseline, daily while hospitalized starting on postoperative day 1, then on day 3 and day 7 after discharge, and then weekly to complete 8 weeks from the date of surgery. The MDASI-GYN was administered in person on paper, by phone, or electronically via email link. Linear mixed-effects modeling was used to examine the longitudinal change of symptom burden and symptom interference during hospitalization, as well as longitudinally after hospital discharge. Age, race, length of stay (LOS), and surgical time were included in the models. In addition to worst pain in the preceding 24 hours as reported using the MDASI, daily pain scores were ascertained by routine nursing care every 4 hours while awake, on a 0 to 10 scale.

      Statistical Methods

      A sample size of 100 patients per arm was estimated to yield at least 80% power to detect an absolute increase of 20% in the proportion of patients who were opioid-free up to 48 hours in the liposomal bupivacaine plus 0.25% bupivacaine arm (study arm) compared with the standard bupivacaine arm (control arm), regardless of the proportion of patients who were opioid-free in the control arm, with a 2-sided significance level of 0.05. A planned interim analysis for efficacy and futility was performed after half the patients were enrolled and had completed the 48-hour postsurgery follow-up period. The interim analysis for futility utilized an O’Brien-Fleming stopping boundary with a nominal significance level of 0.7221, whereas the interim analysis of efficacy would employ an O’Brien-Fleming stopping boundary with a nominal significance level of 0.0031.
      • O’Brien P.C.
      • Fleming T.R.
      A multiple testing procedure for clinical trials.
      Wilcoxon rank-sum and chi-square tests were used to compare continuous and categorical variables between the study groups, respectively. The primary aim to compare the treatment arms with respect to the proportion of patients who were opioid-free within the first 48 hours was calculated using the Cochran-Mantel-Haenszel test stratified by surgeon. In this study, the 95% confidence intervals (CIs) were calculated using the exact binomial approximation. Kaplan-Meier methods were used to assess time to first opioid. Time to first opioid was measured from the end of surgery date-time until first opioid given date-time. For secondary analyses, P<.05 was considered statistically significant. This report reflects data collected until September 12, 2017. Analyses were completed using the Statistical Analysis System (version 9.4, SAS Institute, Cary, NC).

      Results

      A total of 105 patients were accrued between August 31, 2016, and August 31, 2017, and 102 patients were eligible for analysis (Figure 1). One patient was excluded after randomization because of scheduled opioid use, and 2 patients were excluded because the surgical approach changed to minimally invasive surgery. Therefore, 54 patients in the control arm of 0.25% bupivacaine and 48 patients randomized to the study arm of liposomal bupivacaine plus 0.25% bupivacaine were included in the final analysis. Analysis was performed per assigned study arm. Clinical and demographic data are summarized in Table 1. The median age of the study participants was 60 years (range, 20–84). There were no significant differences in age, race, ethnicity, Charlson comorbidity score, history of chronic opioid use or chronic pain, or tumor type. The determination of small, medium, and large incisions did not differ among treatment groups (P=.15). In addition, there were no significant differences in the length of the incision between the 2 groups with a median length of 24.9 cm in the control group and 27.1 cm in the experimental arm (P=.11). Most patients in both arms had an American Society of Anesthesiologists score of 3 (83% in the control arm and 95.7% in the experimental arm). Most patients (70% in both arms) were undergoing surgery for a presumed primary malignancy. No patients had epidurals. The study was stopped for futility at the planned interim analysis. There was no difference in the primary endpoint with 16.7% of patients (95% CI, 7.4–30.2) in the experimental arm having received no opioids during the first 48 hours after surgery compared with 14.8% of patients (95% CI, 6.7–27.1) in the control arm (P=.99). In addition, there were no significant differences to the opioid-related secondary outcomes.
      Figure thumbnail gr1
      Figure 1CONSORT diagram
      Meyer et al. Liposomal bupivacaine vs standard bupivacaine wound infiltration on an enhanced recovery after surgery pathway. Am J Obstet Gynecol 2021.
      Table 1Demographics and clinical information
      CharacteristicOverall (N=102)Standard bupivacaine (n=54; 53.0%)Liposomal bupivacaine (n=48; 47.0%)P value
      Age, median (min–max)60.0 (20.0–84.0)62.5 (20.0–84.0)59.0 (22.0–81.0).28
      Ethnicity.63
       Not Hispanic or Latino78 (76.5)41 (75.9)37 (77.1)
       Hispanic or Latino15 (14.7)7 (13.0)8 (16.7)
       Unknown or not reported9 (8.8)6 (11.1)3 (6.3)
      Race.13
       Asian3 (2.9)1 (1.9)2 (4.2)
       Native Hawaiian or Other Pacific Islander1 (1.0)0 (0.0)1 (2.1)
       Black or African American6 (5.9)6 (11.1)0 (0.0)
       White77 (75.5)40 (74.1)37 (77.1)
       Unknown or not reported15 (14.7)7 (13.0)8 (16.7)
      The ASA physical status.05
       II11 (10.7)9 (16.7)2 (4.2)
       III87 (85.3)42 (77.8)45 (93.7)
       IV2 (2.0)2 (3.7)0 (0.0)
       Unknown or not reported2 (2.0)1 (1.8)1 (2.1)
      Charlson Comorbidity Index.10
       0–123 (22.5)15 (27.8)8 (16.7)
       2–468 (66.7)31 (57.4)37 (77.1)
       ≥511 (10.8)8 (14.8)3 (6.3)
      Current tumor.52
       Malignant, primary72 (70.6)38 (70.4)34 (70.8)
       Malignant, recurrent7 (6.9)2 (3.7)5 (10.4)
       Benign18 (17.6)11 (20.4)7 (14.6)
       Neoplasm of unknown malignant potential, primary5 (4.9)3 (5.6)2 (4.2)
      Previous open abdominal surgery54 (54.5)24 (45.3)30 (65.2).05
      Previous laparoscopic abdominal surgery47 (46.1)26 (48.1)21 (43.8).66
      History of chronic pain3 (2.9)2 (3.7)1 (2.1).63
      Chronic opioid use
       No102 (100.0)54 (100.0)48 (100.0)
      Estimated blood loss (mL), median (min–max)200.0 (5.0–1750.0)200.0 (5.0–1750.0)200 (25.0–1000.0).80
      Length of stay (d), median (min–max)3.0 (1.0–9.0)3.0 (1.0–8.0)2.0 (1.0–9.0).64
      Data are presented as number (percentage), unless otherwise specified.
      ASA, American Society of Anesthesiologists.
      Meyer et al. Liposomal bupivacaine vs standard bupivacaine wound infiltration on an enhanced recovery after surgery pathway. Am J Obstet Gynecol 2021.
      Postoperatively, there was no significant difference in the number of patients who were opioid-free each postoperative day or in the total number of days that patients were opioid-free between postoperative days 0 and 4. Figure 2 displays the time to first opioid from the end of surgery. Overall, most patients (82%) received opioids within 24 hours after surgery (control arm, 0.25% bupivacaine [45 patients (44%)]; experimental arm, liposomal bupivacaine plus 0.25% bupivacaine [39 patients (38%)]). Within the standard bupivacaine-only group (control group), 6 patients (11%) did not receive any postoperative opioids, 8 patients (15%) received postoperative opioids only in the PACU, and 40 patients (74%) received postoperative opioids both in the PACU and in the postoperative ward. In the liposomal bupivacaine group (study group), 8 patients (17%) did not receive any postoperative opioids, 3 patients (6%) received postoperative opioids only in the PACU, and 37 patients (77%) received postoperative opioids both in the PACU and in the postoperative ward.
      Figure thumbnail gr2
      Figure 2Time to first opioid from end of surgery
      The dashed lines exclude opioids received while patients were in the PACU (denoted by an ∗).
      PACU, postanesthesia care unit.
      Meyer et al. Liposomal bupivacaine vs standard bupivacaine wound infiltration on an enhanced recovery after surgery pathway. Am J Obstet Gynecol 2021.
      There was no significant difference in the MEDD used between the 2 arms of the study (Table 2). The median MEDD on postoperative day 0 was 10 in the control arm and 6.9 in the study arm (P=.71). There was no difference in the MEDD by postoperative day, and the cumulative MEDD between postoperative days 0 and 4 was 33.8 in the control arm and 21.3 in the study arm (P=.36).
      Table 2Morphine equivalent daily dose


      Time point
      Control: 0.25% bupivacaineExperimental: liposomal bupivacaine+0.25% bupivacaineP value
      Median (IQR)Mean (SD)Median (IQR)Mean (SD)
      POD 010.0 (5.0–15.0)13.4 (13.9)6.9 (5.0–20.0)11.3 (10.4).71
      POD 17.5 (0.0–22.5)16.4 (22.9)7.5 (0.0–30.0)15.7 (18.7).68
      POD 20.0 (0.0–22.5)13.3 (18.5)0.0 (0.0–15.0)10.0 (16.1).42
      POD 30.0 (0.0–0.0)5.6 (13.1)0.0 (0.0–0.0)3.9 (9.2).76
      Cumulative33.8 (10.0–82.5)48.7 (51.8)21.3 (11.3–67.5)40.9 (41.7).36
      IQR, interquartile range; POD, postoperative day; SD, standard deviation.
      Meyer et al. Liposomal bupivacaine vs standard bupivacaine wound infiltration on an enhanced recovery after surgery pathway. Am J Obstet Gynecol 2021.
      There was no significant difference between the 2 arms, with median daily pain scores of 2.5 (interquartile range [IQR], 1.5–4.0) in the control arm vs 2.7 (IQR, 1.6–4.2) in the experimental arm as ascertained by routine nursing care on postoperative day 0 (P=.60). There continued to be no significant differences between the 2 arms on postoperative days 1 to 4. On postoperative day 2, the median daily pain score was 2.2 (IQR, 0.6–3.5) in the control arm and 2.5 (IQR, 1.0–3.0) in the experimental arm (P=.53). By postoperative day 4, the median daily pain score was 0.8 (IQR, 0.2–3.0) in the control arm and 1.2 (IQR, 0.6–3.4) in the experimental arm (P=.34). Pain and other symptoms assessed by the MDASI reflected symptoms at their worst in the preceding 24 hours. Using mixed-effects models for longitudinal comparison, there was no difference in pain (P=.36) or interference with walking (P=.93) from baseline to postoperative day 3 (Figure 3). There were no differences in any of the longitudinal PROs between the 2 arms.
      Figure thumbnail gr3
      Figure 3Longitudinal patient-reported outcomes
      The solid line represents control group of local wound infiltration with 0.25% bupivacaine. The dotted line represents the experimental group of local wound infiltration of liposomal bupivacaine+0.25% bupivacaine. A, Longitudinal assessment of worst pain during hospitalization (postoperative days 0–3). B, Longitudinal assessment of interference with walking during hospitalization (postoperative days 0–3). C, Longitudinal assessment of worst pain after hospital discharge (up to 8 weeks postoperatively). D, Longitudinal assessment of interference with walking after hospital discharge (up to 8 weeks postoperatively).
      Meyer et al. Liposomal bupivacaine vs standard bupivacaine wound infiltration on an enhanced recovery after surgery pathway. Am J Obstet Gynecol 2021.
      The median LOS was 3 days (range, 1–8) in the control arm and 2 days (range, 1–9) in the experimental arm (P=.64). A cross-sectional comparison of the worst abdominal pain 24 hours before discharge demonstrated that patients in the control arm had less pain with a mean pain score of 3.65 than in the experimental arm with a mean pain score of 4.96 (P=.02). In a longitudinal comparison of symptoms up to 8 weeks after hospital discharge, pain was significantly better in the control arm than in the experimental arm (P=.03) (Figure 3).
      No adverse events were attributed to the study treatment. Overall, there were no grade 3 to 5 adverse events in either arm. There was no difference in the distribution of any grade of 30-day surgical complications between the 2 arms (P=.71). In the experimental arm, 1 patient had a grade 1 adverse event, and 1 patient had a grade 2 event; both events were deemed unlikely to be related to the treatment. There was 1 grade 3 gastrointestinal complication and 1 grade 3 renal or genitourinary complication in each study arm. In addition, there was 1 grade 3 wound complication in the experimental arm.

      Comment

      Principal findings

      Within an enhanced recovery pathway, the addition of long-acting liposomal bupivacaine to 0.25% bupivacaine administered via local wound infiltration did not improve the percentage of patients who were opioid-free up to the first 48 hours after surgery. Importantly, we were also unable to detect a difference in key secondary endpoints such as time to first opioid administration, percentage of patients who were opioid-free by day, or total opioid-free days up to postoperative day 3. In addition, from longitudinal analysis of PROs, we were unable to identify improvements in any of the measured PROs, including pain or interference with walking, PRO items that we hypothesized might be improved with liposomal bupivacaine. Although patients in the combination experimental arm of liposomal bupivacaine plus 0.25% bupivacaine had higher pain scores on the day of discharge, the median LOS in the experimental arm was 1 day less than in the control group.

      Results

      There have been multiple retrospective studies and prospective randomized trials evaluating the use of liposomal bupivacaine for local wound infiltration. However, because of the fact that the studies differ in design, study population, and outcome, it was difficult to draw meaningful conclusions. A recent Cochrane review of liposomal bupivacaine infiltration at the surgical site found significant heterogeneity of studies that precluded metaanalysis. The authors concluded that the limited evidence did not demonstrate a superiority of liposomal bupivacaine compared with bupivacaine HCl.
      • Hamilton T.W.
      • Athanassoglou V.
      • Mellon S.
      • et al.
      Liposomal bupivacaine infiltration at the surgical site for the management of postoperative pain.
      In a randomized trial of liposomal bupivacaine vs placebo in women undergoing cesarean delivery via Pfannenstiel incisions, there was no difference in pain score at 48 hours or median opioid use at 48 hours.
      • Prabhu M.
      • Clapp M.A.
      • McQuaid-Hanson E.
      • et al.
      Liposomal bupivacaine block at the time of cesarean delivery to decrease postoperative pain: a randomized controlled trial.
      A single-blind randomized study of preoperative injection of liposomal bupivacaine vs 0.25% bupivacaine in patients undergoing laparoscopic hysterectomy reported a lower average pain score at postoperative day 3 with no difference in total opioid use in the liposomal bupivacaine arm.
      • Barron K.I.
      • Lamvu G.M.
      • Schmidt R.C.
      • Fisk M.
      • Blanton E.
      • Patanwala I.
      Wound infiltration with extended-release versus short-acting bupivacaine before laparoscopic hysterectomy: a randomized controlled trial.
      A retrospective cohort study by Kalogera et al,
      • Kalogera E.
      • Bakkum-Gamez J.N.
      • Weaver A.L.
      • et al.
      Abdominal incision injection of liposomal bupivacaine and opioid use after laparotomy for gynecologic malignancies.
      performed in a similar patient population undergoing laparotomy for gynecologic malignancies on an ERAS pathway, demonstrated lower morphine equivalents up to 24 hours, 48 hours, and the entire LOS for patients who received liposomal bupivacaine than those who received standard bupivacaine HCl. Although the study was performed in a very similar patient population to our study, it is important to note that the study by Kalogera et al
      • Kalogera E.
      • Bakkum-Gamez J.N.
      • Weaver A.L.
      • et al.
      Abdominal incision injection of liposomal bupivacaine and opioid use after laparotomy for gynecologic malignancies.
      was not randomized but compared with a historic control arm. By virtue of the study design, other improvements and developments over time could potentially have introduced potential sources of bias and may account for the difference between our findings and theirs.

      Strengths and limitations

      This study differs in that this is the first randomized single-blind designed trial of liposomal bupivacaine within a well-established ERAS program in patients undergoing gynecologic surgery. The strength here is that pain management and opioid-sparing techniques were already standardized and established via our enhanced recovery pathway.
      • Meyer L.A.
      • Lasala J.
      • Iniesta M.D.
      • et al.
      Effect of an enhanced recovery after surgery program on opioid use and patient-reported outcomes.
      ,
      • Iniesta M.D.
      • Lasala J.
      • Mena G.
      • et al.
      Impact of compliance with an enhanced recovery after surgery pathway on patient outcomes in open gynecologic surgery.
      In addition, we included a standardized protocol for dilution of the liposomal bupivacaine depending on incision length and individualized training, standardization, and observation of injection technique for every individual involved with local wound infiltration in this study. Surgical teams and techniques were not different between the groups, and as a result of the prospective randomized design, patients were compared in a concurrent manner rather than in a sequential manner, as generally done in retrospective studies. Furthermore, although this study focused on women undergoing surgery in a large gynecologic oncology practice, the variety of procedures performed and incision sizes make the findings of this study more broadly applicable to any open abdominal surgical procedure on an ERAS pathway. It is not clear whether the findings would have been similar in the absence of a structured ERAS pathway. We recognize that our study is subject to a number of limitations. Among these are the fact that our results cannot be extrapolated to a broader population, such as those who are chronic opioid users, those taking other concomitant medications, or those undergoing nongynecologic surgery. In addition, we do recognize that pain assessment is subjective; however, this is an inherent limitation to any study evaluating pain management.

      Research implications

      Our study only evaluated the use of combined liposomal bupivacaine with standard bupivacaine to standard dosing of bupivacaine in the setting of wound infiltration; thus, our findings may not apply in the setting of other analgesic strategies such as transversus abdominis blocks. In addition, our study was not designed to evaluate a cost analysis of liposomal bupivacaine vs standard bupivacaine. Lastly, our study does not provide data to support or refute the use of liposomal bupivacaine outside the setting of a well-established ERAS program.

      Conclusions

      New approaches in medicine and surgery are often adopted despite little evidence of efficacy or superiority over existing options.
      • Wilson C.B.
      Adoption of new surgical technology.
      The findings from this study did not support the addition of liposomal bupivacaine to standard wound infiltration with 0.25% bupivacaine HCl. Although the lack of positive findings for the liposomal bupivacaine arm in terms of secondary outcomes is exploratory, the weight of evidence did not support the widespread addition of liposomal bupivacaine within our enhanced recovery pathway.

      Appendix

      Figure thumbnail fx1a
      Supplemental FigureInclusion and exclusion criteria
      Meyer et al. Liposomal bupivacaine vs standard bupivacaine wound infiltration on an enhanced recovery after surgery pathway. Am J Obstet Gynecol 2021.
      Figure thumbnail fx1b
      Supplemental FigureInclusion and exclusion criteria
      Meyer et al. Liposomal bupivacaine vs standard bupivacaine wound infiltration on an enhanced recovery after surgery pathway. Am J Obstet Gynecol 2021.
      Supplemental TableProtocol for injection in experimental arm: the ratio of saline, 0.25% bupivacaine plus liposomal bupivacaine by incision length
      Summary of a 3.5-in needleLarge incisionMedium incisionSmall incision
      Incision length, cm≥3125–30≤24
      Total volume, mL275220165
      Subdermal, mL554035
      Above fascia, mL220180130
      Liposomal bupivacaine volume, mL202020
      Standard 0.25% bupivacaine volume, mL606060
      Additional saline,
      If the volume of normal saline changes within the allowed parameters, the total volume will be equally modified and reflected in a greater or lesser volume injected either subdermal or above fascia.
      mL
      195±10140±1085±10
      Meyer et al. Liposomal bupivacaine vs standard bupivacaine wound infiltration on an enhanced recovery after surgery pathway. Am J Obstet Gynecol 2021.
      a If the volume of normal saline changes within the allowed parameters, the total volume will be equally modified and reflected in a greater or lesser volume injected either subdermal or above fascia.

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