Project Summary Over 14,000 people die of prescription opioid misuse per year. Opioid-based medications are a mainstay of postoperative pain management with approximately 80% of surgical patients receiving opioid prescriptions for postoperative pain management. However, their use is associated with a variety of adverse events such as addiction, respiratory depression, cognitive impairment, nausea, constipation, and death. Surgery is a critical point where patients are at risk of developing or worsening opioid-misuse disorders with upwards of 10% of patients going on to long term use. Additionally, adverse events related to opioids for postoperative pain management are associated with increased cost of care, hospital length of stay, and readmission rates. A safe and effective alternative to opioids for postoperative pain management can provide significant value to the customer, patient, and society alike by reducing opioid-related adverse events and the costs associated with them. Local anesthetics can temporarily control the pain at a surgical site, but the duration is limited to only a few hours, after which pain returns and systemic pain medications (e.g. morphine, oxycodone) are required. If local control of pain at the surgical site can be extended, it could lessen or completely mitigate the need for systemic opioid medication. The current options for long-acting local anesthesia (e.g. liposomal bupivacaine, indwelling catheter-based infusion pumps) are plagued with substantial drawbacks such as inadequate efficacy, high-cost, cumbersome equipment, and risk of complications, which have limited their use and impact. Rebel Medicine has developed a proprietary oil-based gel to deliver local anesthetics over a period of 3 day, mitigating the need for prescription opioid use in the acute post-surgical period. While this formulation has shown extended effect duration in rats, drug loading limitations of the system require larger injection volumes (>3mL) to achieve effective pain management. Lipophilic salts of local anesthetics may provide not only increased solubility of local anesthetics in Rebel’s oleogel delivery system, but may provide additional benefits of increased potency and tunability of drug release from the gel system, allowing for extended pain treatments up to 7 days from a single dose. Our aim for Phase I is to demonstrate our characterized lipophilic bupivacaine oleogel formulation has superior in vivo safety and efficacy over with the current clinical standards in a standardized porcine model. We have an assembled team with demonstrated expertise in medical technology development, drug delivery and material science, pre-clinical analgesic drug evaluation, pharmacokinetic assessment, and pharmaceutical commercialization.