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Liposomal Bupivacaine During Robotic Colpopexy and Posterior Repair: A Randomized Controlled Trial

Yeung, Jennifer DO; Crisp, Catrina C. MD, MSc; Mazloomdoost, Donna MD; Kleeman, Steven D. MD; Pauls, Rachel N. MD

doi: 10.1097/AOG.0000000000002375
Contents: Original Research
Journal Club

OBJECTIVE: To evaluate the effect of liposomal bupivacaine on postoperative pain among patients undergoing robotic sacrocolpopexy with posterior repair.

METHODS: This was a randomized, patient-blinded, placebo-controlled trial of women undergoing robotic sacrocolpopexy with posterior repair. Liposomal bupivacaine or normal saline placebo was injected into laparoscopic and vaginal incisions at completion of surgery. Perioperative care was standardized. Visual analog scales were collected at 4, 18, and 24 hours postoperatively in hospital. Starting on postoperative day 1, participants completed twice-daily pain scales and a pain medication diary up until the evening of postoperative day 3. The primary outcome was a 20-mm change in the visual analog scale 18 hours postoperatively. Secondary measures included additional pain scores, satisfaction, and narcotic use. Sample size calculation revealed that 32 patients per arm were required to detect the 20-mm difference with 90% power and an α of 0.05. To allocate for dropout, a goal of 70 was set.

RESULTS: Between March 2015 and April 2016, 100 women were screened and 70 women were enrolled: 35 women were randomized to liposomal bupivacaine and 35 to placebo, of whom 64 (91%) were included in the final analysis: 33 liposomal bupivacaine and 31 placebo. No difference in demographics, surgical data, or satisfaction between groups was noted. Median VAS at 18 hours after surgery was not statistically different in those who received liposomal bupivacaine compared with normal saline (15 mm compared with 20 mm; P=.52). Other pain scales and total morphine equivalents were also similar (P=.90).

CONCLUSION: In this study of robotic sacrocolpopexy with posterior repair, there were no differences in pain scores or narcotic use between liposomal bupivacaine and placebo injected into laparoscopic and vaginal incisions. Given its lack of clinical benefit, routine use of liposomal bupivacaine is not supported for this surgical intervention.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02449915.

Incisional injection of liposomal bupivacaine during robotic sacrocolpopexy and posterior repair does not reduce postoperative pain compared with placebo.

Division of Urogynecology and Pelvic Reconstructive Surgery, Department of Obstetrics and Gynecology, TriHealth Good Samaritan Hospital, Cincinnati, Ohio.

Corresponding author: Jennifer Yeung, DO, 3219 Clifton Avenue, MOB Suite #100, Cincinnati, OH 45220; email: jennifer_yeung@trihealth.com.

Supported by a grant from the TriHealth Good Samaritan Hospital Medical Education Research Fund.

Financial Disclosure The authors did not report any potential conflicts of interest.

Presented at the 43rd Annual Scientific Meeting of the Society of Gynecologic Surgeons, March 26–29, 2017, San Antonio, Texas.

The authors thank Vivian Ghodsi for data collection and Eunsun Yook for data analysis.

Each author has indicated that he or she has met the journal's requirements for authorship.

Despite advances in minimally invasive surgery, postoperative pain remains a common disorder in 5–15% of patients.1–3 Previous studies have shown that when postoperative pain is poorly managed, analgesics are used more liberally with more than 10% of patients continuing to use opioids 1 year later.4,5 Various treatments have been attempted to better address postoperative pain; however, no single standard of care exists.6–10

Liposomal bupivacaine was approved for local surgical site injection for postoperative pain after hemorrhoidectomy and bunionectomy by the U.S. Food and Drug Administration in 2011.11 It has also been successfully utilized in patients undergoing total knee arthroplasty and breast augmentation.11,12 Each liposomal bupivacaine particle is composed of a honeycomb-like structure of internal aqueous chambers containing encapsulated bupivacaine. Bupivacaine is released by a complex mechanism involving reorganization of the barrier lipid membranes and diffusion of bupivacaine over 72 hours.12 Studies have demonstrated decreased postoperative pain compared with placebo with decreased opioid requirements, potentially decreasing the risk of long-term postoperative opioid use.13–15

Infiltration of local anesthetic into laparoscopic port sites and perineal incisions is common practice and has been shown to improve postoperative pain.16–20 However, few reports have evaluated the application of liposomal bupivacaine after minimally invasive pelvic reconstructive surgery.

The aim of the study was to assess whether local liposomal bupivacaine injection would decrease postoperative pain compared with placebo in patients undergoing robotic sacrocolpopexy with posterior repair.

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MATERIALS AND METHODS

This was a randomized, placebo-controlled trial approved by the institutional review board and conducted at two TriHealth Hospitals with the Division of Female Pelvic Medicine and Reconstructive Surgery in Cincinnati, Ohio. Six patients were enrolled before the study was made public on ClinicalTrials.gov (NCT02449915) as a result of personnel and website issues.

Women were eligible for enrollment if they were older than 18 years, English-speaking, and consented for robotic sacrocolpopexy with posterior repair with or without hysterectomy or midurethral sling. Exclusion criteria included any additional procedures; pregnancy or lactation; allergy or contraindication to liposomal bupivacaine, opioids, acetaminophen, or nonsteroidal antiinflammatory drugs; daily nonsteroidal antiinflammatory drug or opioid consumption; chronic pain disorders; or a history of alcohol or drug abuse. Individuals with severe cardiovascular, hepatic, or renal disease were also ineligible. Patients were excluded after enrollment if they did not undergo robotic sacrocolpopexy for intraoperative indications.

Study personnel approached patients at the preoperative counseling office visit or on the day of surgery. All participants provided written informed consent. Permuted block randomization was used in SPSS; each block consisted of five participants. Sequentially numbered, opaque, sealed envelopes were created using random participant numbers and assignments to the intervention and control groups were according to the randomization table. The patients and nursing staff were blinded. Surgeons became unblinded at the time of injection as a result of the opaqueness and viscosity of liposomal bupivacaine.

The 20-mL (266 mg) vial of liposomal bupivacaine was expanded with 10 mL injectable saline to yield a total injection volume of 30 mL based on previous hemorrhoidectomy and bunionectomy studies.13,14 Also similar to previous studies, individuals in the placebo arm received 30 mL injectable preservative-free sterile normal saline (0.9%) to help control for any anesthesia that may be induced from tissue distention.14,21,22 Because we were interested in both immediate and extended postoperative pain levels, normal saline was deemed an appropriate placebo.

The three physicians performing the procedure were fellowship-trained and board-certified in female pelvic reconstructive surgery. All hysterectomies were performed vaginally at the initiation of surgery. As standard of care, all patients received 10 mL of 0.25% bupivacaine divided among the abdominal incisions before incision and port placement. The 8-mm robotic trocars and 10-mm camera port were then placed in an “M”-shaped fashion. After the sacrocolpopexy was performed using polypropylene mesh, the vaginal posterior repair was initiated by injecting 10 mL of 1% lidocaine with epinephrine posteriorly, which is the standard at our institution. Polyglactin suture was used for plication and incision closure. At procedure completion, the sealed opaque envelope was opened revealing the study group allocation. The study drug was then administered a minimum of 20 minutes after the injection of lidocaine with epinephrine.14,23 Ten milliliters were injected into the perineum and the posterior vagina by infiltrating both sides of the incision using several injection sites. The remaining 20 mL was equally injected into each of the five abdominal port sites along the fascia and beneath the skin. Those in the placebo arm received 30 mL injectable saline in a similar fashion.

Postoperatively, a standardized order set was used: intravenous hydromorphone was given as needed with scheduled intravenous ketorolac and intravenous acetaminophen. One patient did not have scheduled ketorolac ordered as a result of elevated preoperative creatinine. Patients were transitioned to oral oxycodone–acetaminophen and ibuprofen the first morning after surgery. Morphine equivalents were calculated for each opioid dosage, and time of the dose was recorded. Before discharge, patients underwent a voiding trial. Participants were discharged home with a prescription for oxycodone–acetaminophen and ibuprofen.

The primary outcome was evaluated using horizontal visual analog scales (VAS).24,25 The VAS is a validated 100-mm scale with a range of 0–10. “No pain” on the far left was represented as 0 mm and “most pain” on the far right equated to 100 mm.25,26 Patients drew a vertical line on the VAS corresponding to their pain level.

The VAS was collected for 3 days postoperatively to study the extended-release mechanism of the medication.27 Initial scores were recorded by blinded nursing staff 4, 18, and 24 hours after surgery. Patients were then sent home with a booklet for recording VAS scores and pain medication. Patients self-recorded VAS pain scores every morning and at bedtime. At bedtime, participants also rated their “most intense pain today,” “average pain today” with and without activity, and level of pain in the “vagina or rectum” and “belly or abdomen.” The patient indicated the most painful incision on an abdominal diagram. Patient satisfaction was evaluated daily using nonvalidated 5-point Likert scales with the options of “very unsatisfied,” “unsatisfied,” “neutral,” “satisfied,” and “very satisfied.”26 Finally, the patient documented any bowel movements or passing of gas.

Patients completed a pain medication diary from the time of their discharge through the evening of postoperative day 3. Patients received a phone call on postoperative day 1 to remind them to complete the booklet. After 2 weeks, patients completed an adverse events form. The patient and research nurse conducting these postoperative assessments remained blinded to the assigned treatment throughout the study.

Liposomal bupivacaine follows a bimodal release profile with an initial peak soon after administration followed by a later peak 10–36 hours later.28 Our primary outcome was a 20-mm change in the VAS pain score 18 hours after surgery to capture effects of the second peak while the pain score could still be collected by the blinded nursing staff. Secondary outcomes were exploratory and included all other VAS pain scores, satisfaction, narcotic use, location of “the most painful” site, voiding trial results, and time to first bowel movement.

Literature in the surgical arena has suggested that decrease in pain scores of 24 mm or 35% is clinically significant.29,30 For this study, we deemed a difference of 20 mm on the VAS would be clinically significant and suggestive of benefit from this intervention. Sample size calculation revealed 32 patients per arm was deemed necessary to detect a difference of 20 mm on the VAS scores with 90% power and an α of 0.05. To account for a 10% dropout, a total of 70 patients was set for enrollment.

The data reported were entered manually by our research specialist and validated by both the statistician and first author. Statistical analysis was performed using SPSS Statistics 19. Descriptive statistics were utilized for all continuous and categorical data. Means and SD were used for normally distributed data and median and interquartile range or range for data not meeting this assumption. Continuous data with only one collection time were analyzed using independent-samples t tests to test for significant differences between groups. Continuous data with more than one collection time were analyzed using repeated-measures analysis of variance. χ2 or Fisher exact test was used to identify differences between groups.

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RESULTS

Between March 2015 and April 2016, 100 eligible women were recruited; 70 were enrolled and 70 were randomized. Six were excluded: two converted to vaginal repairs, two withdrew after randomization, one patient had an elevated creatinine, and one reported a history of cocaine abuse. Sixty-four patients were analyzed (33 liposomal bupivacaine and 31 placebo) (Fig. 1) No differences with respect to age, body mass index, gravidity, parity, race, or smoking status were noted (Table 1). No surgical differences were noted between the two arms. The two groups also received similar anesthesia medications (Table 2). No complications were directly attributed to the injection of liposomal bupivacaine or normal saline. All patients received the treatments that they were designated by their group allocation.

Fig. 1

Fig. 1

Table 1

Table 1

Table 2

Table 2

Diaries were returned by 62 patients (96.9%); however, our primary outcome (18-hour VAS) was collected for all analyzed patients because it was done by the blinded nursing staff in the hospital. No difference in pain was noted when comparing the median VAS score at 18 hours for those who received liposomal bupivacaine (15 [interquartile range 34]) to placebo (20.5 [interquartile range 39]) (P=.52) (Table 3). Median VAS scores were also not different at any of the measured time points throughout the 3 days postoperatively (Table 3).

Table 3

Table 3

We inquired about pain details each evening. The median VAS describing “average pain” over the entire day was similar for the liposomal bupivacaine group compared with the placebo arm on all 3 postoperative days. The VAS describing “pain in your vagina or rectum” was no different between the two groups on any of the days nor was the VAS describing “pain on your belly or abdomen.” The majority of patients (60.8%) described the umbilical port site (the largest incision site) to be the most painful (Table 3).

The median consumption of opiates for the first 3 days postoperatively measured in morphine equivalents was 27.2 mg (interquartile range 31.5) for those who received liposomal bupivacaine. For those who received the placebo, the median opiate use during the first 3 days was 17.5 mg (interquartile range 29.2). The consumption of opiates was not different (P=.90) between cohorts.

With regard to other outcomes, no difference was observed between the two treatment arms. Both groups reported high satisfaction with pain control (Table 3). No difference was noted in time to first bowel movement. A similar number of people went home with Foley catheters after the voiding trial was unsuccessful (Table 2). The most commonly reported postoperative side effects were nausea (23.4%), insomnia (21.9%), itching (18.8%), and irritation at the injection sites (14%) with no differences based on treatment allocation.

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DISCUSSION

This study demonstrated no difference in postoperative pain scales between liposomal bupivacaine and placebo when infiltrated around abdominal and vaginal incisions during robotic sacrocolpopexy with posterior repair. Additionally, no differences in narcotic consumption or satisfaction were noted. We speculate that the low level of baseline postoperative pain after robotic sacrocolpopexy with posterior repair explains why liposomal bupivacaine provided no pain relief difference in our validated questionnaires. Additionally, some recent reports have suggested larger volumes of liposomal bupivacaine may be necessary to cover surgical areas adequately.31 It is possible that a greater volume expansion of liposomal bupivacaine may have resulted in a larger difference than we were able to demonstrate.

The use of liposomal bupivacaine for postoperative pain has shown promising results in prior research. Benefit after hemorrhoidectomies, bunionectomies, total knee arthroplasties, and breast augmentations has been documented.13,14,32,33 Nevertheless, a recent Cochrane review stated the quality of evidence regarding liposomal bupivacaine was moderate to very low.34 Additionally, another Cochrane review concluded a lack of data to support or refute the use of liposomal bupivacaine for postoperative pain.35 We did not detect any differences in our report. Pain, in general, is low after pelvic reconstructive and laparoscopic surgery.36–38 A more significant benefit has been noted with larger abdominal incisions when postoperative pain is more problematic.39

Study strengths include a randomized and blinded design. Standardized techniques among the three surgeons improved the consistency of the findings. Standard preoperative, postoperative, and discharge order sets minimized variability in perioperative care. Because the procedure included both laparoscopic (sacrocolpopexy) and vaginal (posterior repair) elements, our study results may be generalizable to both laparoscopic and vaginal gynecologic surgeries. Patients with chronic pain or preoperative opioid analgesic use were excluded, thus theoretically decreasing the variability in opioid consumption within each group. However, this exclusion also decreased the generalizability of the results to this specific patient population. We did not study the demographics of the excluded cohort to determine how many had chronic pain or daily opioid use. Reminder phone calls as well as a convenient booklet improved data collection and minimized missing data. Furthermore, our primary aims were examined using a validated measure, the VAS.

We do acknowledge some limitations. These include an inability to blind the surgeon at the time of injection as a result of the cost-prohibitive nature of developing a placebo with similar viscosity. Thus, the surgeon may have inadvertently biased the patient's perception of pain and satisfaction. However, the group allocation was not revealed until completion of surgery, allowing the surgeon to be blinded while performing the surgery. Additionally, the surgeon was not involved in conducting postoperative assessments; only blinded study personnel were permitted to do so. Our study patient population was limited by an absence of diversity by race (Table 1) as a result of the nature of our patient population, which decreases the generalizability of our results. Patients typically also have a short hospital stay, rendering us largely dependent on self-reported pain scores and outpatient opiate consumption with questionable accuracy. Furthermore, patients willing to be enrolled in a study regarding pain management may be different from those who decline, which could affect our outcomes.

Although clinical significance is the foremost aim of any adjustment to patient care, it is important to evaluate the costs accompanying an innovation. The average wholesale price of liposomal bupivacaine is $285 per 20-mL vial.40 After reviewing the literature on acute pain, we designed our study to demonstrate a pain difference that would be clinically important and justify the high cost of liposomal bupivacaine.30 Although we did not perform a formal cost analysis given the lack of a significant effect on pain scores, narcotic use, and reported satisfaction, these costs do not appear warranted for liposomal bupivacaine and this application.

In this study of robotic sacrocolpopexy with posterior repair, use of liposomal bupivacaine did not significantly alter clinical outcomes. Therefore, we do not support its routine administration for this procedure. Further studies to address whether liposomal bupivacaine offers advantages for other surgical approaches or in regional anesthetic applications should be considered before widely adopting this local anesthetic.

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