Local anesthesia produced by quaternary lidocaine derivatives: the comparative efficacy and safety of QX-314, QX-572, and QX-222 in mice (2020)
Poorly managed acute pain, particularly postoperative pain, reduces quality of life, delays recovery, and increases financial burden. Current therapeutic regimens focus on nonsteroidal anti-inflammatory drugs and systemic opioids. Unfortunately, these analgesics are associated with notable and potentially life-threatening adverse events. Thus, there is a great need for analgesic alternatives.Local anesthetics are among the most effective non-opioid analgesic options for acute pain. However, conventional agents are limited by their short duration as well as local and systemic toxicity. Previous research at the UBC Hugill Anesthesia Research Centre, showed that the quaternary lidocaine derivative, QX-314, produces long-lasting local anesthesia in animals. However, QX-314 was found to be more toxic compared to its parent compound. The quaternary lidocaine derivatives, QX-572 and QX-222, have not been studied systematically to compare their duration and toxicity. In this thesis, I tested the primary hypothesis that perineural injection of QX-572 and QX-222, similar to QX-314, will produce long-lasting local anesthesia. I assessed nerve blockade in mice and found that QX-572 concentration-dependently produced long-lasting sensory and motor blockade. In contrast, QX-222 produced long-lasting sensory blockade but did not produce extended motor blockade. I determined the order of potency among quaternary lidocaine derivatives to be: QX-572 > QX-314 > QX-222. Additionally, I tested the secondary hypothesis that QX-572 and QX-222 have more favorable local and systemic toxicity profiles relative to QX-314. I found that QX-314 and QX-222 induced myofibre degeneration whereas QX-572 induced ischemic necrosis of the mouse tail. Adverse reactions were observed that manifested as death. To investigate the possibility of systemic toxicity, I developed a novel liquid chromatography tandem mass spectrometry method to measure plasma concentrations of quaternary derivatives. I found that QX-314 and QX-222 were absorbed more readily than QX-572 or lidocaine. The results from this thesis suggest that differences in therapeutic and toxic local anesthetic effects are mediated by structural differences. Overall, the present findings do not unreservedly support the transition of QX-314, QX-572, or QX-222 into human studies for the treatment of acute postoperative pain, however, they illustrate a potentially promising pharmacological avenue for further research and provide insight into quaternary anesthetic pharmacology.