Introduction Early diagnosis of acute extremity compartment syndrome is crucial to timely surgical management. Pain is commonly used as an early diagnostic sign for acute extremity compartment syndrome, making regional anesthesia after lower extremity surgery controversial. This randomized study tested whether different concentrations of local anesthetics, or combinations of nerve blocks, would differentially impact the perception of acute extremity compartment syndrome-like pressure and ischemic pain. Methods Healthy volunteers underwent quantitative sensory testing, including determination of pressure pain thresholds and prolonged pressure/ischemic pain in the leg using a variable cuff inflation system. Subjects were randomized to receive (1) adductor canal block alone (ACB), (2) ACB with low-concentration sciatic nerve block (ACB +LC SNB), or (3) ACB with high-concentration SNB (ACB +HC SNB). For the primary outcome, we assessed block-induced increases in pressure threshold to reach 6/10 pain, and compared the degree of increase between the three groups. The main secondary outcome was a comparison of average pain score during a 5 min hold at the 6/10 pressure pain threshold between the three groups. Results All blocks raised pressure pain threshold and decreased ischemic pain, but to variable extents. Specifically, the amount the block increased pressure pain threshold was significantly different among ACB, ACB+LC SNB, and ACB+HC SNB groups (mean±SD: 24±32 mm Hg, 120±103 mm Hg, 159±93 mm Hg; p=0.002), with post hoc testing revealing ACB as less than the other two groups. Similarly, average pain scores during a prolonged/ischemic cuff hold differed among the groups (4.2±1.4, 1.4±1.7, 0.4±0.7; p<0.001), with post hoc testing revealing ACB as significantly higher. Discussion This study suggests the possible utility of titrating regional anesthesia, to provide some analgesia while still allowing acute extremity compartment syndrome detection.