Novel Therapeutics for Treating Opioid Use Disorder

PROJECT SUMMARY Opioid Use Disorder (OUD) is a prevalent issue in the United States, characterized by the chronic misuse of opioids, resulting in severe consequences such as fatal overdoses, infectious diseases, increased crime rates, and socioeconomic burdens. Despite the availability of treatment options, OUD remains a significant global challenge. The current FDA-approved therapies for OUD include methadone, buprenorphine, and naltrexone. However, these treatments have limitations, including failure to treat all OUD patients, frequent clinic visits, and low retention rates. To address these challenges, this project aims to develop and explore alternative approaches fordrug delivery that can optimize therapeutic outcomes for individuals with OUD. Specifically, this proposal investigates the therapeutic potential of Nor-Levo-α-acetylmethadol (nor-LAAM). Nor-LAAM is an active metabolite of Levo-α-acetylmethadol (LAAM), an FDA-approved drug to treat OUD. LAAM is a high- efficacy agonist at Mu Opioid Receptors (MOR) and was administered orally three times a week, showing promising results in reducing opioid-positive urine tests, incarceration rates, and prolonged abstinence. However, it was reported that LAAM is associated with cardiovascular risks, specifically QT prolongation and torsades de pointes (TdP). Previous studies have shown that QT prolongation is primarily attributed to the parent drug LAAM itself rather than its metabolite nor-LAAM, as nor-LAAM exhibits a higher IC50 of 12 μM to inhibit HERG potassium channels compared to 3 μM of LAAM. Additionally, nor-LAAM is more potent at MOR than LAAM. This proposal involves utilizing biodegradable polymers to develop nor-LAAM-loaded polymeric microparticles (Nor-LAAM-MP) with in vitro sustained release capabilities (≥1 month) suitable for subcutaneous administration to treat OUD. We hypothesize that these microparticles will enable a controlled release of nor-LAAM, thereby reducing dosing frequency and drug dose and enhancing patient adherence while mitigating the risk of drug-related adverse effects and potential toxicities. We plan to conduct pharmacokinetics, efficacy, and safety studies. By completing this project, we can enhance our understanding of the therapeutic potential and safety profiles associated with nor-LAAM-MP for treating opioid use disorder.