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Currently available local anesthetics approved for single-injection peripheral nerve blocks have a maximum duration of <24 hours. A liposomal bupivacaine formulation (EXPAREL®, Pacira Pharmaceuticals, Inc., San Diego, CA), releasing bupivacaine over 96 hours, recently gained Food and Drug Administration approval exclusively for wound infiltration but not peripheral nerve blocks.Bilateral single-injection femoral nerve blocks were administered in healthy volunteers (n = 14). For each block, liposomal bupivacaine (0–80 mg) was mixed with normal saline to produce 30 mL of study fluid. Each subject received 2 different doses, 1 on each side, applied randomly in a double-masked fashion. The end points included the maximum voluntary isometric contraction (MVIC) of the quadriceps femoris muscle and tolerance to cutaneous electrical current in the femoral nerve distribution. Measurements were performed from baseline until quadriceps MVIC returned to 80% of baseline bilaterally.There were statistically significant dose responses in MVIC (0.09%/mg, SE = 0.03, 95% confidence interval [CI], 0.04–0.14, P = 0.002) and tolerance to cutaneous current (−0.03 mA/mg, SE = 0.01, 95% CI, −0.04 to −0.02, P < 0.001), however, in the opposite direction than expected (the higher the dose, the lower the observed effect). This inverse relationship is biologically implausible and most likely due to the limited sample size and the subjective nature of the measurement instruments. While peak effects occurred within 24 hours after block administration in 75% of cases (95% CI, 43%–93%), block duration usually lasted much longer: for bupivacaine doses >40 mg, tolerance to cutaneous current did not return to within 20% above baseline until after 24 hours in 100% of subjects (95% CI, 56%–100%). MVIC did not consistently return to within 20% of baseline until after 24 hours in 90% of subjects (95% CI, 54%–100%). Motor block duration was not correlated with bupivacaine dose (0.06 hour/mg, SE = 0.14, 95% CI, −0.27 to 0.39, P = 0.707).The results of this investigation suggest that deposition of a liposomal bupivacaine formulation adjacent to the femoral nerve results in a partial sensory and motor block of >24 hours for the highest doses examined. However, the high variability of block magnitude among subjects and inverse relationship of dose and response magnitude attests to the need for a phase 3 study with a far larger sample size, and that these results should be viewed as suggestive, requiring confirmation in a future trial.