JOURNAL OF ENDOUROLOGY Volume 29, Number 9, September 2015 ª Mary Ann Liebert, Inc. Pp. 1019–1024 DOI: 10.1089/end.2014.0769
A Randomized Controlled Trial for Pain Control in Laparoscopic Urologic Surgery: 0.25% Bupivacaine Versus Long-Acting Liposomal Bupivacaine Richard B. Knight, MD,1 Paul W. Walker, MD,2 Kirk A. Keegan, MD, MPH,3 Stephen M. Overholser, MD,4 Timothy S. Baumgartner, MD,3 James S. Ebertowski II, MD,3 James K. Aden, PhD,3 and Michael A. White, DO 5
Abstract
Background and Purpose: Liposomal bupivacaine is a delayed-release preparation providing up to 72 hours of local analgesia. It costs much more than standard bupivacaine, however. A prospective, randomized, patientblinded, controlled trial was performed to assess the efficacy of liposomal bupivacaine versus 0.25% bupivacaine when injected into surgical incisions during laparoscopic and robot-assisted urologic surgery. Methods: A total of 206 adults were randomized to receive liposomal bupivacaine or 0.25% bupivacaine. All surgical incisions were injected with liposomal bupivacaine or 0.25% bupivacaine with systematic dosing. The primary outcome was total opioid consumption during the postoperative hospital stay. All opioid doses were converted to morphine equivalents. Secondary end points included pain scores using visual analog pain scales, duration of hospital stay, and the time to first opioid use. A subgroup analysis was performed for renal surgery patients. Results: There was no significant difference in median total opioid use during the hospital stay between those who received liposomal bupivacaine (15 [interquartile range (IQR) 6.7–27] mg) and 0.25% bupivacaine (17.3 [IQR 8.3–30.5] mg) (P = 0.39). Furthermore, pain scores, length of hospital stay, and time to first opioid use did not differ between groups. Subgroup analysis of laparoscopic renal surgery revealed no difference between liposomal bupivacaine and 0.25% bupivacaine. Conclusions: For laparoscopic and robot-assisted urologic surgery, there is no significant difference between liposomal bupivacaine and 0.25% bupivacaine for local analgesia at the incision sites. Introduction
L
iposomal bupivacaine is a sustained-release formulation of bupivacaine that is encapsulated within multivesicular liposomal particles. After injection at the surgical site, the lipid-encapsulated bupivacaine is released slowly over time, thus providing continued local pain control for up to 72 hours after surgery. The duration of 0.25% bupivacaine is typically 6 to 8 hours. The use of liposomes for encapsulating therapeutic agents has been described since the late 1970s.1 The prolonged duration of liposomal bupivacaine was initially demonstrated in mice in 1994.2 The current formulation of liposomal bupivacaine was approved by the Food and Drug Administration (FDA) in
November 2011 for local injection at the surgical site to provide postoperative pain control. The FDA approval was supported by two randomized controlled trials of liposomal bupivacaine—one involving hemorrhoidectomy and the other for bunionectomy.3,4 More recently, liposomal bupivacaine has also been found to improve pain control for patients undergoing total knee arthroplasty.5 Similar results to support the use of liposomal bupivacaine for local surgical site infiltration were reported in 2012 with a pooled analysis of nine clinical trials involving inguinal hernia repair, total knee arthroplasty, hemorrhoidectomy, breast augmentation, and bunionectomy.6 The use of liposomal bupivacaine has not been evaluated previously in the setting of laparoscopic surgery, however.
1
Department of Urology, 48th MDG, RAF Lakenheath, Brandon, Suffolk, United Kingdom. Louisiana Urology, LLC, Baton Rouge, Louisiana. 3 Department of Urology, San Antonio Military Medical Center, Fort Sam Houston, Texas. 4 University of Texas Health Science Center at San Antonio, San Antonio, Texas. 5 Urology San Antonio, San Antonio, Texas. 2
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Infiltration of a local anesthetic into laparoscopic port sites is a common practice and has been shown in some studies to improve postoperative pain.7–10 Given these findings, we designed a randomized, controlled trial to assess the central study question: Does liposomal bupivacaine provide superior analgesia compared with 0.25% bupivacaine after laparoscopic and robot-assisted urologic surgery? Methods
After obtaining Institutional Review Board approval and written informed consent, 206 adults were prospectively enrolled in the study between December 2012 and December 2013. Computer-generated block randomization schedules for each surgeon were created to assign patients to receive either 0.25% bupivacaine or liposomal bupivacaine. All patients underwent laparoscopic urologic surgery by one of two urologists, with or without robotic assistance. The study sites included five hospitals and two healthcare systems. The primary outcome was total opioid consumption measured in intravenous morphine equivalents during the postoperative hospital stay. All opioid dosages were converted to intravenous morphine equivalents (milligrams) using an Internet-based calculator (Table 1). Secondary outcomes included pain scores using the Wong-Baker visual analog pain scale (0–10), length of hospital stay in days, and time to first opioid use in minutes.11 The patients were blinded to randomization, but the surgeon was aware of which local anesthetic was delivered. This design was chosen given the difficulty in disguising the liposomal bupivacaine, which is opaque, compared with 0.25% bupivacaine, which is translucent. All of the laparoscopic port sites were injected systematically through the muscular layers of the abdominal wall including the preperitoneal space. This was accomplished using a 21- to 23gauge needle via direct laparoscopic visualization. The dose of liposomal bupivacaine was 266 mg in all patients. The 20 mL vial of liposomal bupivacaine (266 mg) was diluted with 40 mL of injectable physiologic saline to yield a total volume of 60 mL and then dispersed throughout all of the port sites. For 0.25% bupivacaine, a weight-based calculation was performed to determine the appropriate dose, not to exceed 2 mg/kg or a total of 150 mg, whichever threshold was met first. For all patients weighing >75 kg, the dose was 60 mL of 0.25% bupivacaine. The package insert for bupivacaine only lists 0.25% bupivacaine for local infiltration, and thus 0.5% bupivacaine was not used. Postoperatively, the exact dose of opioid analgesia was determined by a standardized order set to provide specific dosing according to a visual analog pain scale score. Hydrocodone-acetaminophen tablets served as first-line analgesia, followed by intravenous morphine for breakthrough
Table 1. Equianalgesic Dosages
Codeine Fentanyl Hydrocodone Hydromorphone Morphine Oxycodone
Route
Equianalgesic dosage
Oral Intravenous Oral Intravenous Intravenous Oral
200 mg 0.1 mg 30 mg 1.5 mg 10 mg 20 mg
pain. Modifications to postoperative pain control were dictated by patient-related factors such as allergies or adverse reactions to the standard opioids (hydrocodone and morphine). Intravenous morphine equivalents were calculated for every opioid dosage, including the time of the dose. Nonsteroidal anti-inflammatory drugs (NSAIDs) and patient controlled analgesia (PCA) were specifically prohibited in the order set. Acetaminophen was only given in combined formulation with an opioid such as oxycodone or hydrocodone. The amount of acetaminophen consumed was not included in the data. A color-printed visual-analog pain scale (range 0–10) was used to assess postoperative pain. The pain scale was printed on a single 8.5 · 11 inch paper and included the Wong-Baker FACESTM Pain Rating Scale.11–14 The patient’s pain scale score was assessed before every opioid dosage and with every set of vital signs. All pain scale scores and all opioid dosages were recorded in the electronic medical record. Exclusion criteria were age less than 18 years, history of hypersensitivity to bupivacaine, a hospital stay longer than 5 days, use of NSAIDs during the hospital stay, use of a PCA device, postoperative intubation, conversion to open surgery, or return to the operating room for surgical complications. The hospital duration of 5 days was chosen as an exclusion criterion, because these patients often remained in the hospital for reasons unrelated to surgery. Furthermore, liposomal bupivacaine was unlikely to affect the pain experienced by these patients beyond 5 days after surgery. Six patients were excluded from the 0.25% bupivacaine group: One for seizures; four for NSAID and/or PCA use; and one for incomplete data. Nine patients were excluded from the liposomal bupivacaine group: One for remaining intubated overnight; four for surgical complications; three for a hospital stay >5 days because of ileus; and one for NSAID use. After exclusions, data analysis was performed on 191 patients. The 0.25% bupivacaine group and the liposomal bupivacaine group included 94 and 97 patients, respectively. Statistical analysis was performed using SAS, version 9.2 (Statistical Analysis Software, Cary, NC). All power calculations were at the 80% level with an alpha of 0.05. Based on opioid consumption data previously reported for robot-assisted laparoscopic prostatectomy, a sample size of 74 would be necessary to detect a 10 mg difference in morphine equivalents totaled over the entire hospital stay.15 The detection level of 10 mg was chosen because morphine is often supplied in a 1 mL vial at 10 mg/mL. Using the pain scores reported for robot-assisted laparoscopic prostatectomy on postoperative day 1, a sample size of 112 would be necessary to detect a difference of 1 on the 10-point visual analog pain scale.15 Based on the surgeon’s previous experience with laparoscopic surgeries, the hospital stay was estimated at 2 – 1 days, thus yielding a sample size of 34 to detect a 1-day difference. Lastly, given the duration of 0.25% bupivacaine is 6 to 8 hours, the time to first opioid use after surgery was estimated at 360 – 100 minutes, therefore necessitating a sample size of 24 to detect a 120-minute difference. For continuous data, a Wilcoxon 2-sample test of significance or a two-tailed t test of significance was used, whichever was most appropriate based on the Shapiro-Wilk test. For categorical variables, a chi-squared test or Fisher exact test was performed to assess the treatment groups.
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Results
The liposomal bupivacaine and 0.25% bupivacaine groups were similar across all covariates (Table 2). No complications were directly attributed to the use of liposomal bupivacaine or 0.25% bupivacaine. Regarding the primary outcome, the median consumption of opiates measured in intravenous morphine equivalents during the hospital stay was 15 (interquartile range [IQR] 6.7–27) mg for those who received liposomal bupivacaine (Fig. 1). For those who received 0.25% bupivacaine, the median opiate use during the hospital stay was 17.3 (IQR 8.3–30.5) mg. The consumption of opiates was not statistically different (P = 0.39) between cohorts. For each group, there were three patients who needed no postoperative opiates. The consumption of opiates was also measured for each 8-hour period after the end of anesthesia, and no difference was seen between the two cohorts for any period (Fig. 2). With regard to our secondary outcomes, no difference was observed between the two treatment arms. The pain scores for each patient were averaged over the entire hospital stay, yielding a single mean pain score per patient that was compared between the two groups. The median pain score for the entire hospital stay was 3.75 (IQR 2.5–4.6) for the liposomal bupivacaine group versus 3.9 (IQR 3–4.75) for those who received 0.25% bupivacaine (P = 0.23) (Fig. 3). The pain scores were also compared between the two groups for each 8-hour interval, with no differences seen (Fig. 4). Regarding the time to first opioid use after surgery, the median time for the liposomal group was 261 (IQR 103–450) minutes compared with 305 (IQR 66–383) minutes for the 0.25% bupivacaine cohort
(P = 0.73). The median duration of hospital stay was the same for each cohort at 1 (IQR 1–2) day (P = 0.69). Given the lack of difference between the two groups, a subgroup analysis was performed for those patients who underwent laparoscopic renal surgery, with the hypothesis that these patients may experience more pain. For those patients undergoing renal surgery, the median consumption of opiates measured in intravenous morphine equivalents during the hospital stay was 15 (IQR 6.7–37) mg for liposomal bupivacaine (n = 68) and 21 (IQR 10.1–33.1) mg for 0.25% bupivacaine (n = 64). This was not significantly different (P = 0.30). Similarly, the median pain scores did not differ between the two groups (3.8 [IQR 2.6–4.9] and 4.3 [IQR 3.2– 5.1] for liposomal bupivacaine and 0.25% bupivacaine, respectively; P = 0.13). Discussion
Liposomal bupivacaine has been demonstrated in other studies to reduce postoperative pain and narcotic consumption.3–6 Contrary to other trials, however, the results of this prospective, patient-blinded, randomized trial demonstrate no significant clinical or measurable analgesic differences between liposomal bupivacaine and 0.25% bupivacaine when infiltrated around the incisions during laparoscopic urologic surgery. Several explanations may account for this lack of benefit between the two groups. Laparoscopic port site and extraction incisions are frequently smaller and undergo less retraction force than standard open surgical incisions and are
Table 2. Baseline Characteristics Liposomal bupivacaine Age Sex (n=) Male Female Race (n=) Hispanic White African American Asian/Pacific Islander Unknown BMI (kg/m2) ASA score EBL (mL) Operative time (minutes) Number of ports per patient 15 mm 12 mm 8 mm 5 mm Total port sites per patient Prostate weight (g) Renal/upper tract surgery (n=) Renal tumor size (cm) Robot-assisted prostatectomy (n=) Kidney morcellation (n=) Incision length >3 cm (n=)
0.25% bupivacaine
P value
62 (52–68)
63 (53–69)
0.510
63 (65%) 34 (35%)
57 (60%) 37 (40%)
0.238
55 32 6 1 3 28.2 3 75 159 0 2 2 1 5 42 68 4.8 25 31 7
(57%) (33%) (6%) (1%) (3%) (25.5–32.8) (2–3) (30–200) (95–204)
45 41 5 0 3 28.9 3 50 157
(48%) (44%) (5%) (0%) (3%) (25.6–34.8) (2–3) (30–175) (93–220)
0.532
0.363 0.198 0.383 0.927
(0–1) (1–3) (0–3) (0–3) (3–6) (34–49) (70%) (2.8–6.4) (26%) (32%) (7%)
0 2 2 1 5 39.5 64 4.4 24 25 6
(0–1) (1–3) (0–4) (0–3) (3–6) (31–47) (68%) (2.9–6) (26%) (27%) (6%)
0.430 0.382 0.691 0.915 0.388 0.362 0.765 0.991 1 0.449 0.774
Categorical variables are represented with their count and percentage. Continuous variables are represented with their median and interquartile range except for number of ports per patient, which are shown as median and range. BMI = body mass index; ASA = American Society of Anesthesiologists; EBL = estimated blood loss.
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FIG. 1. Total opioid consumption. The box plot demonstrates the median with interquartile range (IQR). The whiskers represent 1.5 times the IQR or the range, whichever is the least distance from the IQR. Outliers are data beyond these values and denoted by small circles.
routinely noted to cause less postoperative discomfort.16–18 Therefore, the decreased level of pain associated with laparoscopic incisions may explain why local anesthesia provides little or no additional pain relief. Moreover, the specific use of local anesthetics for laparoscopic surgical site infiltration has been evaluated in several previous studies with equivocal results, and further raises the question of the utility of local anesthesia for laparoscopic incisions.19–22 Furthermore, the large variability in postoperative pain perception within each group makes it difficult to observe a statistically significant difference between the two groups. In addition, patients with chronic pain and/or preoperative opioid analgesic use were not excluded, thus theoretically increasing the variability in opioid consumption within each group. The strengths of this study include the randomized, prospective, and patient-blinded design. This study is also the first to evaluate the use of liposomal bupivacaine in laparoscopic
surgery. Furthermore, the surgeries and postoperative care were performed by two high-volume surgeons with similar and standard operative techniques that improve the generalizability of the findings. In addition, standardized order sets were used at each hospital in attempt to minimize variability in opiate dosing. Lastly, the use of PCA devices and NSAIDs were not allowed to exclude the effect of adjunctive pain management regimens. Limitations of the study include a heterogeneous patient population that underwent a variety of laparoscopic urologic surgeries. Furthermore, the variability in opiate consumption within the study population as well as insufficient statistical power may preclude the ability to detect a small difference between the two groups. Moreover, the study comprised patients with a relatively short hospital stay (mean = 40 hours), and we were unable to accurately assess outpatient opiate consumption. With the 72-hour duration of liposomal bupivacaine, a difference between the groups may have been
FIG. 2. Opioid consumption in 8-hour intervals. The box plot demonstrates the median with interquartile range (IQR). The whiskers represent 1.5 times the IQR. Outliers are data beyond these values and denoted by small circles.
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FIG. 3. Pain score averaged over entire hospital stay. The box plot demonstrates the median with interquartile range (IQR). The whiskers represent 1.5 times the IQR or the range, whichever is the least distance from the IQR. Outliers are data beyond these values and denoted by small circles.
observed if opiate consumption had been monitored after discharge from the hospital. Another shortcoming is the tendency for patients with worse pain to have more pain scores recorded by the nursing staff. We attempted to counter this effect by assessing pain scores with every set of vital signs, to ensure consistency within and between study groups. Lastly, although the dosage determination for 0.25% bupivacaine was standardized based on patient weight to achieve the maximum dosage (2 mg/kg or 150 mg), the actual number of patients who received less than 60 mL of 0.25% bupivacaine was not recorded. While clinical efficacy is the principal aim of any healthcare intervention, it is also important to consider the costs associated with the use of any new technology. The average wholesale price of liposomal bupivacaine is $285 per 20 mL vial while 0.25% bupivacaine costs $1 to $3 per vial. Given the recent increased awareness and scrutiny of healthcare costs,
from a comparative effectiveness perspective, the use of liposomal bupivacaine for local infiltration during laparoscopic urologic surgery is not cost-effective. Further studies are under way to address whether liposomal bupivacaine offers advantages for procedures that typically produce more postoperative pain or in regional anesthetic applications. Conclusion
The benefit of liposomal bupivacaine has been demonstrated for inguinal hernia repair, total knee arthroplasty, hemorrhoidectomy, breast augmentation, and bunionectomy. These data suggest, however, that for laparoscopic urologic surgery, liposomal bupivacaine provides no clinical benefit compared with 0.25% bupivacaine. Given these findings, the increased cost associated with liposomal bupivacaine does not justify its routine use in laparoscopic urologic surgery. The potential
FIG. 4. Pain score in 8-hour intervals. The box plot demonstrates the median with interquartile range (IQR). The whiskers represent 1.5 times the IQR or the limits of the scale (0–10). Outliers are data beyond these values and denoted by small circles.
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benefit of liposomal bupivacaine during procedures typically associated with more pain should be evaluated with future clinical trials before widely adopting this local anesthetic. Acknowledgments
This work is attributed to the San Antonio Uniformed Services Health Education Consortium. An abstract has been published by the Society of Government Service Urologists at the Annual Kimbrough Meeting, January 16, 2014. This research was also presented at the European Association of Urology Annual Congress, March 22, 2015, and at the American Urological Association Annual Meeting, May 17, 2015. Institutional support was provided by Methodist Healthcare System and Baptist Health System. We would like to thank the nursing and ancillary staff at Methodist Healthcare System and Baptist Health System for their dedication to patient care and quality research. We would also like to thank the Wilford Hall Medical Art Department for assistance with graphic design. Author Disclosure Statement
No competing financial interests exist. References
1. Szoka F, Jr., Papahadjopoulos D. Procedure for preparation of liposomes with large internal aqueous space and high capture by reverse-phase evaporation. Proc Natl Acad Sci U S A 1978;75:4194–4198. 2. Grant GJ, Vermeulen K, Langerman L, et al. Prolonged analgesia with liposomal bupivacaine in a mouse model. Reg Anesth 1994;19:264–269. 3. Gorfine SR, Onel E, Patou G, et al. Bupivacaine extendedrelease liposome injection for prolonged postsurgical analgesia in patients undergoing hemorrhoidectomy: A multicenter, randomized, double-blind, placebo-controlled trial. Dis Colon Rectum 2011;54:1552–1559. 4. Golf M, Daniels SE, Onel E. A phase 3, randomized, placebo-controlled trial of DepoFoam bupivacaine (extended-release bupivacaine local analgesic) in bunionectomy. Adv Ther 2011;28:776–788. 5. Bramlett K, Onel E, Viscusi ER, Jones K. A randomized, double-blind, dose-ranging study comparing wound infiltration of DepoFoam bupivacaine, an extended-release liposomal bupivacaine, to bupivacaine HCl for postsurgical analgesia in total knee arthroplasty. Knee 2012;19:530– 536. 6. Dasta J, Ramamoorthy S, Patou G, Sinatra R. Bupivacaine liposome injectable suspension compared with bupivacaine HCl for the reduction of opioid burden in the postsurgical setting. Curr Med Res Opin 2012;28:1609–1615. 7. Beqiri AI, Domi RQ, Sula HH, et al. The combination of infiltrative bupivacaine with low-pressure laparoscopy reduces postcholecystectomy pain. A prospective randomized controlled study. Saudi Med J 2012;33:134–138. 8. Saleh A, Fox G, Felemban A, et al. Effects of local bupivacaine instillation on pain after laparoscopy. J Am Assoc Gynecol Laparosc 2001;8:203–206. 9. Ke RW, Portera SG, Lincoln SR. A randomized blinded trial of preemptive local anesthesia in laparoscopy. Prim Care Update Ob Gyns 1998;5:197–198.
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10. Khaira HS, Wolf JS, Jr. Intraoperative local anesthesia decreases postoperative parenteral opioid requirements for transperitoneal laparoscopic renal and adrenal surgery: A randomized, double-blind, placebo controlled investigation. J Urol 2004;172:1422–1426. 11. Wong DL, Baker CM. Pain in children: Comparison of assessment scales. Pediatr Nurs 1988;14:9–17. 12. Bijur PE, Silver W, Gallagher EJ. Reliability of the visual analog scale for measurement of acute pain. Acad Emerg Med 2001;8:1153–1157. 13. Whaley L, Wong, DL. Nursing care of infants and children. 3rd ed. St. Louis: CV Mosby Company; 1987. 14. DeLoach LJ, Higgins MS, Caplan AB, Stiff JL. The visual analog scale in the immediate postoperative period: Intrasubject variability and correlation with a numeric scale. Anesth Analg 1998;86:102–106. 15. Webster TM, Herrell SD, Chang SS, et al. Robotic assisted laparoscopic radical prostatectomy versus retropubic radical prostatectomy: A prospective assessment of postoperative pain. J Urol 2005;174:912–914. 16. Attwood SE, Hill AD, Murphy PG, et al. A prospective randomized trial of laparoscopic versus open appendectomy. Surgery 1992;112:497–501. 17. Smith JF, Boysen D, Tschirhart J, et al. Comparison of laparoscopic cholecystectomy versus elective open cholecystectomy. J Laparoendosc Surg 1992;2:311–317. 18. Stoker DL, Spiegelhalter DJ, Singh R, Wellwood JM. Laparoscopic versus open inguinal hernia repair: randomised prospective trial. Lancet 1994;343:1243–1245. 19. Ghezzi F, Cromi A, Bergamini V, et al. Preemptive port site local anesthesia in gynecologic laparoscopy: A randomized, controlled trial. J Minim Invasive Gynecol 2005; 12:210–215. 20. Papagiannopoulou P, Argiriadou H, Georgiou M, et al. Preincisional local infiltration of levobupivacaine vs ropivacaine for pain control after laparoscopic cholecystectomy. Surg Endosc 2003;17:1961–1964. 21. Loizides S, Gurusamy KS, Nagendran M, et al. Wound infiltration with local anaesthetic agents for laparoscopic cholecystectomy. Cochrane Database Syst Rev 2014;3: CD007049. 22. Moiniche S, Jorgensen H, Wetterslev J, Dahl JB. Local anesthetic infiltration for postoperative pain relief after laparoscopy: A qualitative and quantitative systematic review of intraperitoneal, port-site infiltration and mesosalpinx block. Anesth Analg 2000;90:899–912.
Address correspondence to: Richard B. Knight, MD 48th MDG, RAF Lakenheath PSC 41 Box 375 APO, AE 09464-0004 E-mail: [email protected]
Abbreviations Used FDA ¼ Food and Drug Administration IRB ¼ Institutional Review Board NSAID ¼ nonsteroidal anti-inflammatory drug PCA ¼ patient-controlled analgesia
A Randomized Controlled Trial for Pain Control in Laparoscopic Urologic Surgery: 0.25% Bupivacaine Versus Long-Acting Liposomal Bupivacaine Richard B. Knight, MD,1 Paul W. Walker, MD,2 Kirk A. Keegan, MD, MPH,3 Stephen M. Overholser, MD,4 Timothy S. Baumgartner, MD,3 James S. Ebertowski II, MD,3 James K. Aden, PhD,3 and Michael A. White, DO 5
Abstract
Background and Purpose: Liposomal bupivacaine is a delayed-release preparation providing up to 72 hours of local analgesia. It costs much more than standard bupivacaine, however. A prospective, randomized, patientblinded, controlled trial was performed to assess the efficacy of liposomal bupivacaine versus 0.25% bupivacaine when injected into surgical incisions during laparoscopic and robot-assisted urologic surgery. Methods: A total of 206 adults were randomized to receive liposomal bupivacaine or 0.25% bupivacaine. All surgical incisions were injected with liposomal bupivacaine or 0.25% bupivacaine with systematic dosing. The primary outcome was total opioid consumption during the postoperative hospital stay. All opioid doses were converted to morphine equivalents. Secondary end points included pain scores using visual analog pain scales, duration of hospital stay, and the time to first opioid use. A subgroup analysis was performed for renal surgery patients. Results: There was no significant difference in median total opioid use during the hospital stay between those who received liposomal bupivacaine (15 [interquartile range (IQR) 6.7–27] mg) and 0.25% bupivacaine (17.3 [IQR 8.3–30.5] mg) (P = 0.39). Furthermore, pain scores, length of hospital stay, and time to first opioid use did not differ between groups. Subgroup analysis of laparoscopic renal surgery revealed no difference between liposomal bupivacaine and 0.25% bupivacaine. Conclusions: For laparoscopic and robot-assisted urologic surgery, there is no significant difference between liposomal bupivacaine and 0.25% bupivacaine for local analgesia at the incision sites. Introduction
L
iposomal bupivacaine is a sustained-release formulation of bupivacaine that is encapsulated within multivesicular liposomal particles. After injection at the surgical site, the lipid-encapsulated bupivacaine is released slowly over time, thus providing continued local pain control for up to 72 hours after surgery. The duration of 0.25% bupivacaine is typically 6 to 8 hours. The use of liposomes for encapsulating therapeutic agents has been described since the late 1970s.1 The prolonged duration of liposomal bupivacaine was initially demonstrated in mice in 1994.2 The current formulation of liposomal bupivacaine was approved by the Food and Drug Administration (FDA) in
November 2011 for local injection at the surgical site to provide postoperative pain control. The FDA approval was supported by two randomized controlled trials of liposomal bupivacaine—one involving hemorrhoidectomy and the other for bunionectomy.3,4 More recently, liposomal bupivacaine has also been found to improve pain control for patients undergoing total knee arthroplasty.5 Similar results to support the use of liposomal bupivacaine for local surgical site infiltration were reported in 2012 with a pooled analysis of nine clinical trials involving inguinal hernia repair, total knee arthroplasty, hemorrhoidectomy, breast augmentation, and bunionectomy.6 The use of liposomal bupivacaine has not been evaluated previously in the setting of laparoscopic surgery, however.
1
Department of Urology, 48th MDG, RAF Lakenheath, Brandon, Suffolk, United Kingdom. Louisiana Urology, LLC, Baton Rouge, Louisiana. 3 Department of Urology, San Antonio Military Medical Center, Fort Sam Houston, Texas. 4 University of Texas Health Science Center at San Antonio, San Antonio, Texas. 5 Urology San Antonio, San Antonio, Texas. 2
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Infiltration of a local anesthetic into laparoscopic port sites is a common practice and has been shown in some studies to improve postoperative pain.7–10 Given these findings, we designed a randomized, controlled trial to assess the central study question: Does liposomal bupivacaine provide superior analgesia compared with 0.25% bupivacaine after laparoscopic and robot-assisted urologic surgery? Methods
After obtaining Institutional Review Board approval and written informed consent, 206 adults were prospectively enrolled in the study between December 2012 and December 2013. Computer-generated block randomization schedules for each surgeon were created to assign patients to receive either 0.25% bupivacaine or liposomal bupivacaine. All patients underwent laparoscopic urologic surgery by one of two urologists, with or without robotic assistance. The study sites included five hospitals and two healthcare systems. The primary outcome was total opioid consumption measured in intravenous morphine equivalents during the postoperative hospital stay. All opioid dosages were converted to intravenous morphine equivalents (milligrams) using an Internet-based calculator (Table 1). Secondary outcomes included pain scores using the Wong-Baker visual analog pain scale (0–10), length of hospital stay in days, and time to first opioid use in minutes.11 The patients were blinded to randomization, but the surgeon was aware of which local anesthetic was delivered. This design was chosen given the difficulty in disguising the liposomal bupivacaine, which is opaque, compared with 0.25% bupivacaine, which is translucent. All of the laparoscopic port sites were injected systematically through the muscular layers of the abdominal wall including the preperitoneal space. This was accomplished using a 21- to 23gauge needle via direct laparoscopic visualization. The dose of liposomal bupivacaine was 266 mg in all patients. The 20 mL vial of liposomal bupivacaine (266 mg) was diluted with 40 mL of injectable physiologic saline to yield a total volume of 60 mL and then dispersed throughout all of the port sites. For 0.25% bupivacaine, a weight-based calculation was performed to determine the appropriate dose, not to exceed 2 mg/kg or a total of 150 mg, whichever threshold was met first. For all patients weighing >75 kg, the dose was 60 mL of 0.25% bupivacaine. The package insert for bupivacaine only lists 0.25% bupivacaine for local infiltration, and thus 0.5% bupivacaine was not used. Postoperatively, the exact dose of opioid analgesia was determined by a standardized order set to provide specific dosing according to a visual analog pain scale score. Hydrocodone-acetaminophen tablets served as first-line analgesia, followed by intravenous morphine for breakthrough
Table 1. Equianalgesic Dosages
Codeine Fentanyl Hydrocodone Hydromorphone Morphine Oxycodone
Route
Equianalgesic dosage
Oral Intravenous Oral Intravenous Intravenous Oral
200 mg 0.1 mg 30 mg 1.5 mg 10 mg 20 mg
pain. Modifications to postoperative pain control were dictated by patient-related factors such as allergies or adverse reactions to the standard opioids (hydrocodone and morphine). Intravenous morphine equivalents were calculated for every opioid dosage, including the time of the dose. Nonsteroidal anti-inflammatory drugs (NSAIDs) and patient controlled analgesia (PCA) were specifically prohibited in the order set. Acetaminophen was only given in combined formulation with an opioid such as oxycodone or hydrocodone. The amount of acetaminophen consumed was not included in the data. A color-printed visual-analog pain scale (range 0–10) was used to assess postoperative pain. The pain scale was printed on a single 8.5 · 11 inch paper and included the Wong-Baker FACESTM Pain Rating Scale.11–14 The patient’s pain scale score was assessed before every opioid dosage and with every set of vital signs. All pain scale scores and all opioid dosages were recorded in the electronic medical record. Exclusion criteria were age less than 18 years, history of hypersensitivity to bupivacaine, a hospital stay longer than 5 days, use of NSAIDs during the hospital stay, use of a PCA device, postoperative intubation, conversion to open surgery, or return to the operating room for surgical complications. The hospital duration of 5 days was chosen as an exclusion criterion, because these patients often remained in the hospital for reasons unrelated to surgery. Furthermore, liposomal bupivacaine was unlikely to affect the pain experienced by these patients beyond 5 days after surgery. Six patients were excluded from the 0.25% bupivacaine group: One for seizures; four for NSAID and/or PCA use; and one for incomplete data. Nine patients were excluded from the liposomal bupivacaine group: One for remaining intubated overnight; four for surgical complications; three for a hospital stay >5 days because of ileus; and one for NSAID use. After exclusions, data analysis was performed on 191 patients. The 0.25% bupivacaine group and the liposomal bupivacaine group included 94 and 97 patients, respectively. Statistical analysis was performed using SAS, version 9.2 (Statistical Analysis Software, Cary, NC). All power calculations were at the 80% level with an alpha of 0.05. Based on opioid consumption data previously reported for robot-assisted laparoscopic prostatectomy, a sample size of 74 would be necessary to detect a 10 mg difference in morphine equivalents totaled over the entire hospital stay.15 The detection level of 10 mg was chosen because morphine is often supplied in a 1 mL vial at 10 mg/mL. Using the pain scores reported for robot-assisted laparoscopic prostatectomy on postoperative day 1, a sample size of 112 would be necessary to detect a difference of 1 on the 10-point visual analog pain scale.15 Based on the surgeon’s previous experience with laparoscopic surgeries, the hospital stay was estimated at 2 – 1 days, thus yielding a sample size of 34 to detect a 1-day difference. Lastly, given the duration of 0.25% bupivacaine is 6 to 8 hours, the time to first opioid use after surgery was estimated at 360 – 100 minutes, therefore necessitating a sample size of 24 to detect a 120-minute difference. For continuous data, a Wilcoxon 2-sample test of significance or a two-tailed t test of significance was used, whichever was most appropriate based on the Shapiro-Wilk test. For categorical variables, a chi-squared test or Fisher exact test was performed to assess the treatment groups.
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Results
The liposomal bupivacaine and 0.25% bupivacaine groups were similar across all covariates (Table 2). No complications were directly attributed to the use of liposomal bupivacaine or 0.25% bupivacaine. Regarding the primary outcome, the median consumption of opiates measured in intravenous morphine equivalents during the hospital stay was 15 (interquartile range [IQR] 6.7–27) mg for those who received liposomal bupivacaine (Fig. 1). For those who received 0.25% bupivacaine, the median opiate use during the hospital stay was 17.3 (IQR 8.3–30.5) mg. The consumption of opiates was not statistically different (P = 0.39) between cohorts. For each group, there were three patients who needed no postoperative opiates. The consumption of opiates was also measured for each 8-hour period after the end of anesthesia, and no difference was seen between the two cohorts for any period (Fig. 2). With regard to our secondary outcomes, no difference was observed between the two treatment arms. The pain scores for each patient were averaged over the entire hospital stay, yielding a single mean pain score per patient that was compared between the two groups. The median pain score for the entire hospital stay was 3.75 (IQR 2.5–4.6) for the liposomal bupivacaine group versus 3.9 (IQR 3–4.75) for those who received 0.25% bupivacaine (P = 0.23) (Fig. 3). The pain scores were also compared between the two groups for each 8-hour interval, with no differences seen (Fig. 4). Regarding the time to first opioid use after surgery, the median time for the liposomal group was 261 (IQR 103–450) minutes compared with 305 (IQR 66–383) minutes for the 0.25% bupivacaine cohort
(P = 0.73). The median duration of hospital stay was the same for each cohort at 1 (IQR 1–2) day (P = 0.69). Given the lack of difference between the two groups, a subgroup analysis was performed for those patients who underwent laparoscopic renal surgery, with the hypothesis that these patients may experience more pain. For those patients undergoing renal surgery, the median consumption of opiates measured in intravenous morphine equivalents during the hospital stay was 15 (IQR 6.7–37) mg for liposomal bupivacaine (n = 68) and 21 (IQR 10.1–33.1) mg for 0.25% bupivacaine (n = 64). This was not significantly different (P = 0.30). Similarly, the median pain scores did not differ between the two groups (3.8 [IQR 2.6–4.9] and 4.3 [IQR 3.2– 5.1] for liposomal bupivacaine and 0.25% bupivacaine, respectively; P = 0.13). Discussion
Liposomal bupivacaine has been demonstrated in other studies to reduce postoperative pain and narcotic consumption.3–6 Contrary to other trials, however, the results of this prospective, patient-blinded, randomized trial demonstrate no significant clinical or measurable analgesic differences between liposomal bupivacaine and 0.25% bupivacaine when infiltrated around the incisions during laparoscopic urologic surgery. Several explanations may account for this lack of benefit between the two groups. Laparoscopic port site and extraction incisions are frequently smaller and undergo less retraction force than standard open surgical incisions and are
Table 2. Baseline Characteristics Liposomal bupivacaine Age Sex (n=) Male Female Race (n=) Hispanic White African American Asian/Pacific Islander Unknown BMI (kg/m2) ASA score EBL (mL) Operative time (minutes) Number of ports per patient 15 mm 12 mm 8 mm 5 mm Total port sites per patient Prostate weight (g) Renal/upper tract surgery (n=) Renal tumor size (cm) Robot-assisted prostatectomy (n=) Kidney morcellation (n=) Incision length >3 cm (n=)
0.25% bupivacaine
P value
62 (52–68)
63 (53–69)
0.510
63 (65%) 34 (35%)
57 (60%) 37 (40%)
0.238
55 32 6 1 3 28.2 3 75 159 0 2 2 1 5 42 68 4.8 25 31 7
(57%) (33%) (6%) (1%) (3%) (25.5–32.8) (2–3) (30–200) (95–204)
45 41 5 0 3 28.9 3 50 157
(48%) (44%) (5%) (0%) (3%) (25.6–34.8) (2–3) (30–175) (93–220)
0.532
0.363 0.198 0.383 0.927
(0–1) (1–3) (0–3) (0–3) (3–6) (34–49) (70%) (2.8–6.4) (26%) (32%) (7%)
0 2 2 1 5 39.5 64 4.4 24 25 6
(0–1) (1–3) (0–4) (0–3) (3–6) (31–47) (68%) (2.9–6) (26%) (27%) (6%)
0.430 0.382 0.691 0.915 0.388 0.362 0.765 0.991 1 0.449 0.774
Categorical variables are represented with their count and percentage. Continuous variables are represented with their median and interquartile range except for number of ports per patient, which are shown as median and range. BMI = body mass index; ASA = American Society of Anesthesiologists; EBL = estimated blood loss.
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FIG. 1. Total opioid consumption. The box plot demonstrates the median with interquartile range (IQR). The whiskers represent 1.5 times the IQR or the range, whichever is the least distance from the IQR. Outliers are data beyond these values and denoted by small circles.
routinely noted to cause less postoperative discomfort.16–18 Therefore, the decreased level of pain associated with laparoscopic incisions may explain why local anesthesia provides little or no additional pain relief. Moreover, the specific use of local anesthetics for laparoscopic surgical site infiltration has been evaluated in several previous studies with equivocal results, and further raises the question of the utility of local anesthesia for laparoscopic incisions.19–22 Furthermore, the large variability in postoperative pain perception within each group makes it difficult to observe a statistically significant difference between the two groups. In addition, patients with chronic pain and/or preoperative opioid analgesic use were not excluded, thus theoretically increasing the variability in opioid consumption within each group. The strengths of this study include the randomized, prospective, and patient-blinded design. This study is also the first to evaluate the use of liposomal bupivacaine in laparoscopic
surgery. Furthermore, the surgeries and postoperative care were performed by two high-volume surgeons with similar and standard operative techniques that improve the generalizability of the findings. In addition, standardized order sets were used at each hospital in attempt to minimize variability in opiate dosing. Lastly, the use of PCA devices and NSAIDs were not allowed to exclude the effect of adjunctive pain management regimens. Limitations of the study include a heterogeneous patient population that underwent a variety of laparoscopic urologic surgeries. Furthermore, the variability in opiate consumption within the study population as well as insufficient statistical power may preclude the ability to detect a small difference between the two groups. Moreover, the study comprised patients with a relatively short hospital stay (mean = 40 hours), and we were unable to accurately assess outpatient opiate consumption. With the 72-hour duration of liposomal bupivacaine, a difference between the groups may have been
FIG. 2. Opioid consumption in 8-hour intervals. The box plot demonstrates the median with interquartile range (IQR). The whiskers represent 1.5 times the IQR. Outliers are data beyond these values and denoted by small circles.
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FIG. 3. Pain score averaged over entire hospital stay. The box plot demonstrates the median with interquartile range (IQR). The whiskers represent 1.5 times the IQR or the range, whichever is the least distance from the IQR. Outliers are data beyond these values and denoted by small circles.
observed if opiate consumption had been monitored after discharge from the hospital. Another shortcoming is the tendency for patients with worse pain to have more pain scores recorded by the nursing staff. We attempted to counter this effect by assessing pain scores with every set of vital signs, to ensure consistency within and between study groups. Lastly, although the dosage determination for 0.25% bupivacaine was standardized based on patient weight to achieve the maximum dosage (2 mg/kg or 150 mg), the actual number of patients who received less than 60 mL of 0.25% bupivacaine was not recorded. While clinical efficacy is the principal aim of any healthcare intervention, it is also important to consider the costs associated with the use of any new technology. The average wholesale price of liposomal bupivacaine is $285 per 20 mL vial while 0.25% bupivacaine costs $1 to $3 per vial. Given the recent increased awareness and scrutiny of healthcare costs,
from a comparative effectiveness perspective, the use of liposomal bupivacaine for local infiltration during laparoscopic urologic surgery is not cost-effective. Further studies are under way to address whether liposomal bupivacaine offers advantages for procedures that typically produce more postoperative pain or in regional anesthetic applications. Conclusion
The benefit of liposomal bupivacaine has been demonstrated for inguinal hernia repair, total knee arthroplasty, hemorrhoidectomy, breast augmentation, and bunionectomy. These data suggest, however, that for laparoscopic urologic surgery, liposomal bupivacaine provides no clinical benefit compared with 0.25% bupivacaine. Given these findings, the increased cost associated with liposomal bupivacaine does not justify its routine use in laparoscopic urologic surgery. The potential
FIG. 4. Pain score in 8-hour intervals. The box plot demonstrates the median with interquartile range (IQR). The whiskers represent 1.5 times the IQR or the limits of the scale (0–10). Outliers are data beyond these values and denoted by small circles.
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benefit of liposomal bupivacaine during procedures typically associated with more pain should be evaluated with future clinical trials before widely adopting this local anesthetic. Acknowledgments
This work is attributed to the San Antonio Uniformed Services Health Education Consortium. An abstract has been published by the Society of Government Service Urologists at the Annual Kimbrough Meeting, January 16, 2014. This research was also presented at the European Association of Urology Annual Congress, March 22, 2015, and at the American Urological Association Annual Meeting, May 17, 2015. Institutional support was provided by Methodist Healthcare System and Baptist Health System. We would like to thank the nursing and ancillary staff at Methodist Healthcare System and Baptist Health System for their dedication to patient care and quality research. We would also like to thank the Wilford Hall Medical Art Department for assistance with graphic design. Author Disclosure Statement
No competing financial interests exist. References
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Address correspondence to: Richard B. Knight, MD 48th MDG, RAF Lakenheath PSC 41 Box 375 APO, AE 09464-0004 E-mail: [email protected]
Abbreviations Used FDA ¼ Food and Drug Administration IRB ¼ Institutional Review Board NSAID ¼ nonsteroidal anti-inflammatory drug PCA ¼ patient-controlled analgesia
