Jess H. Lonner, MD, Giles R. Scuderi, MD, and Jay R. Lieberman, MD
Authors’ Disclosure Statement: Work on this review was supported by funding from Pacira Pharmaceuticals, Inc. Dr. Lonner has consulted for and received royalties from Zimmer Holdings, Inc. and Blue Belt Technologies, consulted for CD Diagnostics, Inc., and been a shareholder of Blue Belt Technologies and CD Diagnostics, Inc. Dr. Scuderi has consulted for and received royalties from Zimmer Holdings, Inc., consulted for Medtronic Inc. and ConvaTec, and received institutional research support from Pacira Pharmaceuticals, Inc. Dr. Lieberman has consulted for and received royalties from DePuy, Inc. and consulted for Amgen, Inc. and Arthrex, Inc.
Liposome bupivacaine has dose-proportional pharmacokinetics.50 Presence of a small amount of extra-liposomal bupivacaine in the formulation leads to a bimodal pharmacokinetic profile, with an initial peak serum concentration about 1 hour after administration, followed by a second peak within 12 to 36 hours (Figure).50
Maximum amount of liposome bupivacaine approved for single administration is 266 mg (packaged as 20 mL of a 1.3% solution). However, product labeling includes safety data associated with doses of 532 mg or less.14 The appropriate volume to be used should be based on the amount required to cover the surgical area. Liposome bupivacaine may be expanded with preservative-free normal (0.9%) sterile saline to a total volume of 300 mL: 20 mL liposome bupivacaine plus 280 mL or less diluent, with final concentration of 0.89 mg/mL (1:14 by volume).14
A 25-gauge or larger bore needle should be used to slowly inject liposome bupivacaine into soft tissues of the surgical site, with frequent aspiration to check for blood to minimize risk for intravascular injection.14 Total volume used and fraction injected in specific regions of the surgical site depend on the procedure. For example, a TKA study used 266 mg diluted to a total volume of 60 mL, with 8 mL infiltrated to the area around the medial capsule, 8 mL around the lateral capsule, 12 mL around the posterior capsule, 8 mL around the peripatellar area, 12 mL into the capsulotomy incision, and 12 mL into the subcutaneous tissue on each side of the incision.51
Efficacy
Multiple Surgical Settings. The efficacy of liposome bupivacaine, either alone or as a component of a multimodal analgesic regimen, has been evaluated in a series of 10 phase 2 and 3 studies (8 active-controlled, 2 placebo-controlled) involving 823 patients undergoing TKA, bunionectomy, hemorrhoidectomy, inguinal hernia repair, or mammoplasty.52 Patients received a single liposome bupivacaine dose ranging from 66 to 532 mg.52
Combined analyses of efficacy data from these studies found that liposome bupivacaine–based multimodal analgesic regimens produced postsurgical analgesia for up to 72 hours, increased time to first use of opioid rescue medication after surgery, and reduced total amount of postsurgical opioid consumption versus placebo.52
Compared with standard of care, liposome bupivacaine has been shown to provide effective analgesia in open-label studies in patients undergoing open colectomy,53 laparoscopic colectomy,54 and ileostomy reversal,55,56 as reflected in assessments of postsurgical opioid consumption, LOS, and hospital costs. It has also been studied when administered by infiltration into the transversus abdominis plane (TAP) in patients having laparoscopic prostatectomy and open abdominal hernia repair.57,58
Orthopedic Surgery. In a phase 2 randomized, double-blind, dose-ranging study, TKA patients (N = 138) received bupivacaine HCl 150 mg or liposome bupivacaine 133, 266, 399, or 532 mg administered by local infiltration into the capsulotomy incision and on either side of the incision before wound closure.51 Postsurgical rescue analgesia was available to all patients. Cumulative pain intensity scores with activity (primary efficacy measure) were not statistically different between liposome bupivacaine groups and the bupivacaine HCl group through postoperative day 4. Mean scores in the liposome bupivacaine 266-, 399-, and 532-mg groups were numerically lower than for those treated with bupivacaine HCl on postoperative days 2 to 5, with all doses of liposome bupivacaine having a statistically significant lower pain score at rest on day 5. There were no statistically significant differences across treatment groups with respect to total amount of postsurgical opioids used.
In a phase 3 randomized, double-blind study of TKA patients (N = 245), liposome bupivacaine 532 mg administered into the surgical site was compared with bupivacaine HCl 200 mg for postsurgical analgesia.52 Rescue analgesia was available to all patients. No statistically significant between-group differences were found with respect to postsurgical cumulative pain scores through 72 hours (primary efficacy endpoint).
In a single-center retrospective TKA study, postsurgical outcomes in a patient cohort that received intraoperative periarticular infiltration with liposome bupivacaine 266 mg (n = 65) were compared with a cohort that received infiltration with a combination of ropivacaine 400 mg, morphine 5 mg, and epinephrine 0.4 mg (n = 85).59 Patient-reported postsurgical pain scores were similar in the 2 treatment groups during the first 24 hours after surgery and at discharge. Mean (SD) pain scores during hospitalization after the first 24 hours until discharge were significantly (P = .04) higher in the liposome bupivacaine group, 4.9 (1.4), than in the periarticular group, 4.4 (1.6). There was no significant difference between the 2 treatment groups in postsurgical opioid use. The study demonstrated no advantage to using liposome bupivacaine injections with respect to pain relief, but it was a retrospective review in which pain scores were obtained from electronic medical records. It is essential that liposome bupivacaine be compared with intra-articular injections in well-designed randomized trials.
