Improving Sleep to Address Co-Occurring Substance Use Disorder and Chronic Pain: Exploring the Potential of the Orexin (Hypocretin) System as a Clinical Target

The present review investigates the potential of the orexin system as a clinical target for co-morbid substance use disorder (SUD) and chronic pain, focusing on improving sleep disturbances, an important shared risk factor. We synthesize current evidence from both human and animal studies and proposes viable future research directions to address existing knowledge gaps. Sleep disturbances significantly contribute to both SUD and chronic pain. The orexin system plays a vital role in sleep–wake regulation, and emerging evidence suggests the orexin system's unique involvement in drug-related reward functioning and pain modulation. Hence, the orexin system presents a unique opportunity to address the complex interplay between SUD, chronic pain, and sleep disturbances. Orexin receptor antagonists, particularly Dual Orexin Receptor Antagonists (DORAs) that are FDA-approved for treating insomnia, show considerable promise as novel treatments for both SUD and chronic pain. The current review highlights orexin system’s complex role in SUD and chronic pain. While preliminary evidence for DORAs in treating SUD and chronic pain is promising, critical gaps remain in limited human clinical trials, long-term effects, safety, abuse liability, and understanding of the orexin system’s underlying mechanisms in both problematic substance use and pain. Future studies should explore appropriate dosing regimens, the potential of different types of orexin antagonists, including Selective Orexin Receptor Antagonists (SORAs) and combined SORA and DORA therapies, and consider individual differences (e.g., sex differences) to realize their full therapeutic potential for co-morbid SUD and chronic pain.