Potential Utility of Liposome Bupivacaine in Orthopedic Surgery

Another single-center, matched-cohort TKA study (N = 200) compared a liposome bupivacaine regimen with femoral nerve block.⁶⁰ Compared with patients who received femoral nerve block, patients who received liposome bupivacaine reported lower pain intensity scores after surgery and had shorter LOS, reduced costs, and improved knee flexion at follow-up.⁶⁰

Results from 2 other studies were presented at the 2014 meeting of the American Academy of Orthopaedic Surgeons (AAOS). One was a single-center, matched-cohort TKA study (N = 72) comparing infiltration of a single dose of liposome bupivacaine into the surgical site with continuous femoral nerve block.⁶¹ The 2 treatment groups had similar mean postsurgical pain intensity scores on a 0-to-10 visual analog scale, 1.8 for liposome bupivacaine and 2.3 for continuous nerve block (P = NS), but total amount of postsurgical opioids (hydrocodone-equivalent milligrams) was significantly (P < .0001) less in the liposome bupivacaine group (82 vs 177 mg).

The other study presented at the AAOS meeting was a larger, prospective case–control study comparing outcomes between 1000 patients who had total joint arthroplasty (TJA) with liposome bupivacaine and 1000 control patients who had TJA without liposome bupivacaine.⁶² For the control and liposome bupivacaine cohorts, respectively, mean postsurgical pain intensity scores were 2.41 and 1.98 (P < .0001), mean LOS was 2.83 days and 2.66 days (P < .02), and incidence of falls was 1.0% and 0.2% (P = .02). Average per-patient costs were $1246 lower in the liposome bupivacaine cohort.

A pivotal phase 3 placebo-controlled study compared liposome bupivacaine 106 mg with placebo in patients undergoing bunionectomy (N = 193).⁵ Rescue medication was available to all patients. Cumulative pain scores were significantly (P = .0005) lower in the liposome bupivacaine group (125) than in the placebo group (146) through 24 hours after surgery (primary efficacy measure) and significantly (P = .0229) lower (197 vs 220) through 36 hours. Median time to first use of rescue opioids was delayed in favor of the liposome bupivacaine group (7.2 vs 4.3 hours; P < .0001). Mean total number of opioid tablets used within 24 hours after surgery was also significantly lower (3.8 vs 4.7; P = .008), and a larger percentage of patients in the liposome bupivacaine group avoided opioid use altogether through 24 hours (7% vs 1%; P = .04).

Efficacy data for liposome bupivacaine appear promising for relief of pain after joint arthroplasty and other orthopedic procedures but have their limitations. First, no randomized trials have compared liposome bupivacaine with locally injected pain medications (intra-articular injections in TKA or hip arthroplasty). As these injections are quite common now, such analyses are essential. Second, cost-effectiveness studies are needed for orthopedic procedures. Third, most of the published studies were sponsored by the manufacturer of liposome bupivacaine—a situation that raises questions about potential bias. Non-industry-sponsored randomized trials assessing efficacy, safety, and cost-effectiveness are needed.

Safety

Local anesthetics, including liposome bupivacaine, have the potential for central nervous system (CNS) or cardiac toxicity resulting from excessive systemic absorption or inadvertent IV administration.⁶³ However, reported serious CNS or cardiac-related AEs are rare.^63,64

AE Profile. Safety data from 10 phase 2 and 3 studies involving 823 patients who received liposome bupivacaine were evaluated.⁶⁵ Of these patients, 545 received a dose of 266 mg or less (maximum dose approved by the US Food and Drug Administration [FDA]). Liposome bupivacaine was generally well tolerated. Reported AE incidence was 62% (liposome bupivacaine), 75% (bupivacaine HCl), and 43% (placebo). More than 90% of reported AEs were mild or moderate. The most frequently reported AEs were nausea, constipation, and vomiting (liposome bupivacaine, bupivacaine HCl) and nausea, dizziness, and vomiting (placebo).

Serious AEs were reported in 22 (2.7%) of the 823 patients in the liposome bupivacaine group, 24 (5.4%) of the 446 in the bupivacaine HCl group, and 2 (1.1%) of the 190 in the placebo group.⁶⁵ None of the serious AEs in the liposome bupivacaine and placebo groups were considered treatment-related. Six patients in the bupivacaine HCl group had treatment-related serious AEs (hypoglycemia, arthrofibrosis, hemarthrosis, joint swelling, scar, knee arthroplasty).

Cardiac Safety. Possible cardiac effects associated with liposome bupivacaine were evaluated with data from studies conducted during the clinical development program.⁶⁶ One hundred thirty-eight patients participated in the phase 2 safety and efficacy study in TKA. In these patients, a consistent change in mean heart rate (range, +12.2 to +16.5 beats per minute) was found across all liposome bupivacaine doses and with bupivacaine HCl. No clinically relevant changes from baseline in mean electrocardiographic parameters, including QTcF interval (QT interval adjusted using Fridericia’s correction formula), were found. In another analysis,⁶⁷ liposome bupivacaine administered in a single subcutaneous dose (266, 399, 532, or 665 mg) to healthy volunteers did not prolong (vs placebo) QTc interval.