A Randomized, Double-blind, Active Controlled, Single-center Study to Evaluate the Efficacy of EXPAREL vs. Bupivacaine HCl Administered as Combined Sciatic (in the Popliteal Fossa) and Saphenous (in the Adductor Canal) Nerve Blocks for Postsurgical Analgesia in Subjects Undergoing Total Ankle Arthroplasty

EXPAREL® is a long-acting local anesthetic specifically developed to provide extended postsurgical pain relief from a single-dose administration, thereby reducing or eliminating the need for indwelling catheters and minimizing reliance on supplemental opioid medications. It is currently indicated for single-dose infiltration to produce local analgesia in patients aged 6 years and older, as well as for regional analgesia via interscalene brachial plexus, sciatic (in the popliteal fossa), and adductor canal nerve blocks in adults. Pain following surgery is common, often peaking in the initial postoperative days, and if inadequately managed, it can delay healing, impair mobilization, prolong hospital stays, and increase the risk of complications and healthcare costs. Despite the prevalence of multimodal analgesic strategies-including the use of local anesthetics and systemic opioids-opioids remain a mainstay for moderate to severe postsurgical pain. However, their use is often limited by adverse effects such as respiratory depression, nausea, vomiting, pruritus, constipation, somnolence, and urinary retention. These complications not only reduce patient satisfaction and recovery but also increase medical intervention and resource use, making opioid-sparing alternatives clinically and economically attractive.

EXPAREL addresses this need by leveraging a proprietary multivesicular liposome (pMVL) drug delivery system that encapsulates bupivacaine at a concentration of 13.3 mg/mL within microscopic spherical vesicles. These vesicles-composed of naturally occurring or bioanalogous lipids-release bupivacaine gradually over time through lipid membrane reorganization and diffusion, thereby extending its duration of action well beyond the 6-8 hours typical of conventional bupivacaine formulations. The liposomal technology used in EXPAREL is based on the same pMVL platform found in the FDA-approved product DepoCyt®, though EXPAREL's lipid formulation has been modified for local anesthetic use. Since its initial FDA approval in 2011 for surgical site infiltration and the subsequent expansion of its indications in 2018 to include various nerve blocks, EXPAREL has been administered to approximately 14 million patients in the U.S., highlighting its growing adoption in clinical practice.

The rationale for the current study stems from the need to optimize postsurgical pain control in patients undergoing total ankle arthroplasty, a procedure associated with significant postoperative pain. This randomized, double-blind, active-controlled, single-center trial will evaluate the efficacy of EXPAREL when used in combination with bupivacaine HCl as part of a combined sciatic (popliteal fossa) and saphenous (adductor canal) nerve block regimen. Specifically, the intervention group will receive 20 mL EXPAREL (266 mg) admixed with 20 mL of 0.25% bupivacaine HCl (50 mg), while the control group will receive 40 mL of 0.25% bupivacaine HCl (100 mg), with each agent administered in equal volumes to the respective nerve sites. The objective is to determine whether the EXPAREL-based regimen provides more effective and longer-lasting analgesia compared to bupivacaine HCl alone, thereby enhancing recovery, reducing opioid consumption, and improving overall patient outcomes in a high-pain surgical population.