Maladaptive state allocation: an orexin-based framework linking sleep disturbance, chronic pain, and substance use disorder

Sleep disturbance, chronic pain, and substance use disorders are highly prevalent conditions that frequently co-occur and exacerbate one another. Although traditionally studied as distinct clinical entities, growing evidence suggests they share common neurobiological mechanisms. Among these, the orexin (OX; also known as hypocretin) system has emerged as a critical regulator of arousal, motivation, stress responsiveness, and nociception, positioning it as a potential contributor to interactions among sleep, pain, and addiction. In this review, we propose that OX may function as a state-integration network that coordinates behavioral responses to competing physiological and environmental demands. Through widespread projections to brainstem, thalamic, limbic, and mesolimbic circuits, OX transmission dynamically regulates vigilance, salience attribution, pain modulation, and reward-seeking behavior. Under physiological conditions, these actions promote adaptive behavioral prioritization. However, chronic dysregulation of OX transmission may result in maladaptive state allocation characterized by persistent hyperarousal, amplified pain-related salience, and excessive motivational value assigned to drug-associated cues. We synthesize experimental evidence implicating OX-dependent circuits in the pathophysiology of sleep disturbance, chronic pain, and substance use disorder and introduce a conceptual triad model linking these conditions. Within this framework, we propose that sleep loss may increase pain sensitivity and craving, chronic pain may disrupt sleep and promote substance use, and repeated drug exposure may further destabilize sleep and pain regulation, creating a self-reinforcing cycle. Finally, we discuss individual factors that may influence vulnerability to triadic comorbidity and highlight emerging therapeutic approaches targeting the OX system.