(371) Evaluation of Analgesia and Clotting Time of Novel Acetaminophen Analogs

Abstract

Background: Acetaminophen and combinations of acetaminophen with opioids such as oxycodone are widely used in the management of mild to moderate pain. At the upper threshold of therapeutic doses, acetaminophen has a profound negative impact on coagulation that is amplified when combined with oxycodone. Kalyra Pharmaceuticals has developed novel acetaminophen analogs which lack hepatotoxicity. This study demonstrates that these novel acetaminophen analogs demonstrate analgesic activity and less interference on coagulation. These novel analogues therefore present a potentially better option for analgesia in battlefield and surgical scenarios where blood loss and blood clotting is a concern. Methods: Blood was collected in sodium citrate tubes and centrifuged at 1500G for 15 minutes two times to produce platelet poor plasma (PPP). PPP was treated with the novel analogs, acetaminophen, and oxycodone with combinations of each at both the recommended therapeutic dose and at 10X. Activated partial thromboplastin time was used to measure the amount of time needed for blood to clot. Analgesic efficacy of the analogs and acetaminophen was tested using our rat thermal injury model. Rats are tested at peak pain threshold using thermal hyperalgesia behavior by introducing a noxious stimulus to a burn injury and measuring paw withdraw latency. Results: Behavior testing showed a significant reduction in paw withdraw latency indicating the presence of thermal hyperalgesia. Paw withdraw latency increased after administration of acetaminophen analogs or oxycodone demonstrating analgesic efficacy of the new compounds. Our results also demonstrated that acetaminophen, but not the novel analogs or oxycodone, greatly prolonged clotting time. When combined with oxycodone, acetaminophen inhibited the clotting time by eight fold while the analogs had little deviation from un-treated plasma. Conclusion: These findings show that the novel acetaminophen analogs which lack liver toxicity demonstrate analgesic effect and are significantly less inhibitive of coagulation than acetaminophen and acetaminophen/oxycodone combinations.