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

doi:10.1016/j.knee.2011.12.004

The Knee

Volume 19, Issue 5, October 2012, Pages 530-536

https://doi.org/10.1016/j.knee.2011.12.004 Get rights and content

Abstract

Introduction

DepoFoam bupivacaine is a novel liposomal formulation of bupivacaine designed to provide prolonged postsurgical analgesia. This dose-ranging study evaluated extent and duration of analgesia following administration of DepoFoam bupivacaine in patients undergoing total knee arthroplasty (TKA).

Methods

Efficacy, safety, and pharmacokinetics of DepoFoam bupivacaine doses of 133, 266, 399, or 532 mg were compared with bupivacaine HCl (150 mg) with epinephrine given as single injections via wound infiltration in TKA patients (N = 138). Primary efficacy measure was AUC of pain intensity scores assessed by numeric rating scale with activity (NRS-A) through Day 4 postsurgery. Other assessments included pain intensity at rest (NRS-R), postsurgical opioid consumption, and safety, among others.

Results

Mean AUC of NRS-A scores through Day 4 were 20.7, 19.5, 18.8, and 19.1 for the 133-mg, 266-mg, 399-mg, and 532-mg DepoFoam bupivacaine groups vs 20.4 for bupivacaine HCl. With DepoFoam bupivacaine 532-mg, differences in NRS-R scores reached statistical significance (P < 0.05) vs bupivacaine HCl on Days 1 and 5 and mean AUC NRS-R scores were significantly lower through Days 2–5; a dose–response trend was demonstrated. Mean rating for blinded care provider's satisfaction with analgesia was significantly higher for DepoFoam bupivacaine 532 mg vs bupivacaine HCl (P ≤ 0.05). Other efficacy measures showed no statistically significant differences.

Conclusion

Exposure to bupivacaine increased in a dose-related manner, as reflected by mean and maximum plasma bupivacaine concentrations, and AUC_0 − ∞. Treatment with DepoFoam bupivacaine 532 mg was associated with statistically significantly greater analgesia while patients were at rest after surgery compared with bupivacaine HCl.

Introduction

Total knee arthroplasty is a frequently performed surgical procedure that causes postsurgical pain of considerable intensity and duration. Inadequate control of pain following total knee arthroplasty has been associated with poor functional recovery [1], whereas appropriate postsurgical pain management contributes to improved healing, faster patient mobilization, shortened hospital stays, and reduced healthcare costs [[2], [3], [4]]. Standard methods of analgesia include administration of parenteral and oral opioids through at least 96 hours postsurgically [[5], [6], [7]]. Other analgesic techniques, such as epidural infusions and continuous femoral blocks, may also be used [8]. However, multimodal analgesia has been established as the preferred method for postoperative pain control [9], [10], and studies have shown that multimodal analgesia that includes infiltration of a local anesthetic administered during total knee arthroplasty provides better postsurgical pain control than monotherapy-based regimens. This approach is also associated with a reduction in the use of opioid analgesics, leading to fewer opioid-related adverse events (AEs) [[8], [11], [12], [13], [14]] such as respiratory depression, hypotension, nausea, vomiting, central nervous system depression, pruritus, and constipation.

Bupivacaine HCl is one of the longest-acting local anesthetics [15] and is commonly administered by local infiltration for postsurgical analgesia. However, the duration of the local analgesic action of bupivacaine HCl is limited, even with the addition of epinephrine to extend the duration of its analgesic effects [[16], [17], [18]]. A formulation of bupivacaine given as a single injection during surgery to provide adequate, continuous, and extended pain relief would minimize postsurgical pain and reduce the consumption of supplemental opioid medications postsurgery, which could lead to earlier patient mobilization.

DepoFoam bupivacaine (marketed as EXPAREL™, Pacira Pharmaceuticals, Inc., Parsippany, NJ, USA) consists of microscopic, spherical, lipid-based particles (the DepoFoam drug delivery system) containing encapsulated drug. DepoFoam bupivacaine is designed to allow diffusion of drug over an extended period of time.

This study was designed to identify a therapeutic dose of DepoFoam bupivacaine in patients undergoing total knee arthroplasty and to further characterize its safety and pharmacokinetic profile. The primary objective of the study was to evaluate the extent and duration of the analgesic effect achieved by a single administration of four dose levels of DepoFoam bupivacaine and bupivacaine HCl with epinephrine given via local infiltration. We hypothesized that administration of DepoFoam bupivacaine would result in greater pain relief than bupivacaine HCl, as reflected in cumulative pain scores with activity through Day 4 after surgery.

Section snippets

Materials and methods

This phase 2, randomized, multicenter, parallel-group, double-blind, dose-ranging study evaluated the efficacy, safety, and pharmacokinetics of four dose levels of DepoFoam bupivacaine compared with 150 mg of bupivacaine HCl/epinephrine (Marcaine® 0.25% with epinephrine 1:200,000, Hospira, Inc., Lake Forest, IL) in total knee arthroplasty. The dose of bupivacaine HCl in this study was selected based on the standard of practice, published clinical studies [7], [13], and the extent of the

Results

Of 144 patients randomized, 138 underwent the surgical procedure, received study treatment, and had at least one postbaseline pain intensity score (full analysis set); of these patients, 134 completed the study and 126 were evaluable for pharmacokinetics analyses (Fig. 1). One patient was randomized to receive bupivacaine HCl but received DepoFoam bupivacaine 133 mg in error. Patient demographics and baseline characteristics are presented in Table 1. Demographics and baseline characteristics

Safety

Overall, 112 (81.2%) of the 138 patients who received study drug reported at least one AE during the study; 83 (79.8%) in the combined DepoFoam bupivacaine groups and 29 (85.3%) in the bupivacaine HCl group. The incidence of AEs stratified by treatment group is summarized in Table 4. The most frequently reported AEs were nausea, constipation, and pyrexia. One patient in the DepoFoam bupivacaine group discontinued participation in the study because of an AE of bipolar disorder. This event was

Discussion

The main goal of this phase 2 dose-ranging study was to identify an appropriate dose of DepoFoam bupivacaine for further study in larger, phase 3 clinical studies in patients undergoing total knee arthroplasty. Though a statistically significant difference in the primary efficacy measure was not attained in this relatively small sample, a single dose of DepoFoam bupivacaine 532 mg administered via wound infiltration trended toward benefit compared with bupivacaine HCl 150 mg on most of the

Conclusion

In this phase 2 dose-ranging study, DepoFoam bupivacaine was shown to be well tolerated, with the majority of AEs mild to moderate in nature and similar to those observed with bupivacaine HCl. At the 532-mg dose, DepoFoam bupivacaine demonstrated robust efficacy, offering an alternative to bupivacaine HCl by potentially expanding the duration of local analgesia effect from under 12 h to up to 5 days. Based on the results of this study, the 532-mg dose level was identified for further evaluation

Source of funding

Pacira Pharmaceuticals, Inc. was the source of funding for this study.

Conflict of interest statement

Dr. Viscusi is a consultant for Pacira Pharmaceuticals, Inc. Dr. Onel is an employee of Pacira Pharmaceuticals, Inc. Drs. Bramlett and Jones report no conflicts. All authors verify that they have fulfilled authorship criteria by making substantial contributions to the conception and design of the study, or acquisition of data, or analysis and interpretation of data; drafting the article or revising it critically for important intellectual content; and providing final approval of the submitted

Acknowledgments

Editorial assistance was provided by Peloton Advantage, LLC, supported by Pacira Pharmaceuticals, Inc.

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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

Abstract

Introduction

Methods

Results

Conclusion

Introduction

Section snippets

Materials and methods

Results

Safety

Discussion

Conclusion

Source of funding

Conflict of interest statement

Acknowledgments

Crit Care Clin

Reg Anesth Pain Med

J Clin Anesth

Reg Anesth Pain Med

Br J Anaesth

Effects of perioperative analgesic technique on the surgical outcome and duration of rehabilitation after major knee surgery

Anesthesiology

A report by the American Society of Anesthesiologists Task Force on pain management, acute pain section

Anesthesiology

Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial

Biometrics

Does postoperative epidural analgesia increase the risk of peroneal nerve palsy after total knee arthroplasty?

Anesth Analg

Comparison of lumbar plexus block versus conventional opioid analgesia after total knee replacement

Anaesthesia

Effects of intravenous patient-controlled analgesia with morphine, continuous epidural analgesia, and continuous three-in-one block on postoperative pain and knee rehabilitation after unilateral total knee arthroplasty

Anesth Analg