Slow-release non-opioid local anesthetic, AMT-143, does not alter survival after extremity trauma and hemorrhage in rats

Objective: Multiple analgesics are used for acute pain relief in both the military and civilian settings. However, in addition to their ability to relieve pain, medical providers must also be concerned about secondary effects of the analgesics, especially effects on the cardiovascular and respiratory systems when the pain of trauma is associated with hemorrhage. AmacaThera, Inc. has developed AMT-143, a new delivery platform for the FDA-approved anesthetic ropivacaine, a non-opioid sodium channel blocker having both local anesthetic and analgesic effects. AMT-143 is formulated as a slow releasing hydrogel that provides extended release of ropivacaine. Ropivacaine in high doses, like other local anesthetics, can have effects on the central nervous and cardiovascular systems. While a single subcutaneous dose of AMT-143 can be used to localize ropivacaine to the injection site, to provide effective pain relief over an extended period, the effects of this prolonged local concentration of ropivacaine on cardiovascular and respiratory responses after extremity trauma (ET; fibular fracture + hindlimb soft tissue crush injury) and hemorrhage (HEM) are unknown. Hypothesis: We hypothesized that AMT-143 will change cardiovascular responses to HEM by 30% or more and thereby decrease survival. Methods: Male rats were anesthetized with isoflurane and implanted with a telemetry transmitter to measure mean arterial pressure (MAP) and heart rate (HR); buprenorphine sustained release was used to relieve pain associated with surgical procedures. Following 2 weeks recovery, rats were anesthetized, and a carotid catheter was implanted. The next day, rats were briefly anesthetized to perform ET and were allowed to recover 90 min before starting conscious HEM (time = 0-25 min). HEM was either moderate (37%HEM, 37% of total blood volume) or severe (50%HEM, 50% of total blood volume). Rats received either 1) saline vehicle (VEH) or 2) AMT-143 via subcutaneous injection into the injured hind limb at end of HEM (t=25 min). The study continued for 215 minutes (time = 25-240 min). Data are mean ± standard deviation. Results: There were no differences between groups in MAP or HR at either baseline (t = 0 min), end of HEM (t = 25 min), or after VEH/AMT-143 injection (t = 25-240 min) in either the 37%HEM animals or 50%HEM animals. 100% of animals in 37%HEM VEH (n=8) and 37%HEM AMT-143 (n=11) survived. There was no difference (P=0.197) in survival rate between 50%HEM VEH (44.4%, n=9) and 50%HEM AMT-143 (22.2%, n=9). Summary: An analgesic dose of AMT-143 did not affect cardiovascular responses or survival following ET and HEM. Conclusion: AMT-143, a slow-release non-opioid anesthetic, may prove useful in the battlefield or civilian sector to reduce pain locally after traumatic hemorrhage. Congressionally Directed Medical Research Program (CDMRP) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.