Non-Opioid Treatments for Opioid Use Disorder: Rationales and Data to Date.

Opioid use disorder (OUD) represents a major public health problem that affects millions of people in the USA and worldwide. The relapsing and recurring aspect of OUD, driven by lasting neurobiological adaptations at different reward centres in the brain, represents a major obstacle towards successful long-term remission from opioid use. Currently, three drugs that modulate the function of the opioidergic receptors, methadone, buprenorphine and naltrexone have been approved by the US Food and Drug Administration (FDA) to treat OUD. In this review, we discuss the limitations and challenges associated with the current maintenance and medication-assisted withdrawal strategies commonly used to treat OUD. We further explore the involvement of glutamatergic, endocannabinoid and orexin signaling systems in the development, maintenance and expression of addiction-like behaviours in animal models of opioid addiction, and as potential and novel targets to expand therapeutic options to treat OUD. Despite a growing preclinical literature highlighting the role of these potential targets in animal models of opioid addiction, clinical and translational studies for novel treatments of OUD remain limited and inconclusive. Further preclinical and clinical investigations are needed to expand the arsenal of primary treatment options and adjuncts to maximise efficacy and prevent relapse.