Combining a Candidate Vaccine for Opioid Use Disorders with Extended-Release Naltrexone Increases Protection against Oxycodone-Induced Behavioral Effects and Toxicity.

Opioid use disorders (OUDs) and opioid-related fatal overdoses are a significant public health concern in the United States and worldwide. To offer more effective medical interventions to treat or prevent OUD, antiopioid vaccines are in development that reduce the distribution of the targeted opioids to brain and subsequently reduce the associated behavioral and toxic effects. It is of critical importance that antiopioid vaccines do not interfere with medications that treat OUD. Hence, this study tested the preclinical proof of concept of combining a candidate oxycodone vaccine [oxycodone-keyhole limpet hemocyanin (OXY-KLH)] with an FDA-approved extended-release naltrexone (XR-NTX) depot formulation in rats. The effects of XR-NTX on oxycodone-induced motor activity and antinociception were first assessed in nonvaccinated naïve rats to establish a baseline for subsequent studies. Next, OXY-KLH and XR-NTX were coadministered to determine whether the combination would affect the efficacy of each individual treatment, and it was found that the combination of OXY-KLH and XR-NTX offered greater efficacy in reducing oxycodone-induced motor activity, thigmotaxis, antinociception, and respiratory depression over a range of repeated or escalating oxycodone doses in rats. These data support the feasibility of combining antibody-based therapies with opioid receptor antagonists to provide greater or prolonged protection against opioid-related toxicity or overdose. Combining antiopioid vaccines with XR-NTX may provide prophylactic measures to subjects at risk of relapse and accidental or deliberate exposure. Combination therapy may extend to other biologics (e.g., monoclonal antibodies) and medications against substance use disorders. SIGNIFICANCE STATEMENT: Opioid use disorders (OUDs) remain a major problem worldwide, and new therapies are needed. This study reports on the combination of an oxycodone vaccine [oxycodone-keyhole limpet hemocyanin (OXY-KLH)] with a currently approved OUD therapy, extended-release naltrexone (XR-NTX). Results demonstrated that XR-NTX did not interfere with OXY-KLH efficacy, and combination of low doses of XR-NTX with vaccine was more effective than each individual treatment alone to reduce behavioral and toxic effects of oxycodone, suggesting that combining OXY-KLH with XR-NTX may improve OUD outcomes.