Novel Pharmacotherapeutics for Opioid Addiction

Abstract

This thesis investigates novel pharmacotherapies for opioid use disorder using rodent models, with a focus on oxycodone. It explores the therapeutic pipeline, revealing a significant emphasis on cannabinoid receptor targeting compounds, particularly CBD. The research delves into CBD's impact on oxycodone withdrawal symptoms and analgesic efficacy, alongside evaluating the CB1 receptor's potential in alleviating withdrawal symptoms, using mouse models. Additionally, it assesses the clinical stage therapeutic, KNX100, for opioid use disorder, utilising rat self-administration models. Findings suggest that CBD alleviates opioid withdrawal-induced gastrointestinal symptoms but exhibits limited effects on negative affective symptoms. Furthermore, the thesis demonstrates that negative allosteric modulation of the CB1 receptor may not significantly impact withdrawal symptoms, with results confounded by sedation or lacking specificity to withdrawal. This thesis discovered a dangerous drug-drug interaction between CBD and oxycodone, wherein CBD delays oxycodone metabolism, prolonging analgesic efficacy in the short term but potentially increasing the risk of side effects like respiratory depression. In the long term, this interaction accelerates the development of tolerance to oxycodone’s analgesic effects. Moreover, the thesis demonstrates the potential of KNX100 in alleviating negative affective withdrawal symptoms and reducing craving, crucial factors contributing to relapse. Addressing sex bias in research and challenges in translating preclinical neuroscience research, the thesis advocates for inclusive research, employing more translatable animal models, and refined diagnostic criteria. Overall, this thesis contributes to advancing safer, more effective therapies for combating the opioid epidemic, offering renewed hope to individuals affected by opioid use disorder.