Health Care Systems: Responsibilities and Resilience.

Opioid use disorder (OUD) is a major public health issue that has led to unprecedented morbidity and mortality in the last two decades. OUD can be conceptualized as a reward deficit and stress surfeit disorder (), characterized by increased tonic and cue-induced stress during the more severe stages of OUD (). Indeed, perceived stress due to opioid withdrawal symptoms, or even the anticipation of opioid withdrawal symptoms, drives continued opioid use for many individuals who have moderate to severe OUD (). Opioid withdrawal is often treated with a short-term buprenorphine taper (e.g., decreasing doses of buprenorphine over the course of several days) with the long-term goal of maintaining individuals on oral or extended-release naltrexone; this is a clinically challenging situation that can be stressful for patients and is marked by somewhat high rates of treatment attrition (). Moreover, there is relatively little research on biological and patient-reported indices of stress during the opioid withdrawal period. The hypothalamic-pituitary-adrenal (HPA) axis and extended amygdala are hypothesized to be key drivers of the biological stress response among persons with OUD (). The HPA-axis is a neuroendocrine system that regulates numerous physiological responses to stressors, including metabolic, immune, and autonomic nervous system activation. HPA-axis output follows a diurnal pattern that can be observed in humans by measuring systemic cortisol through blood or saliva samples (; ). Cortisol levels naturally vary throughout the day in a diurnal pattern that is relatively predictable; normative cortisol trajectories are characterized by a robust cortisol awakening response, and a steep negative diurnal slope coupled with low bedtime levels (). Transient elevations of cortisol can occur following exposure to environmental stressors. Thus, alterations in total daily cortisol and/or the shape of the diurnal curve can often serve as biomarkers of physiological stress in disorders such as insomnia and major depression (e.g., flattening of the diurnal cortisol slope). There is a substantial body of literature illustrating the changes in cortisol and HPA-axis activity that can occur among individuals with OUD. Consistently elevated total daily cortisol was associated with increased risk for relapse to opioids following discharge from residential treatment (), and a human laboratory study revealed a blunted cortisol response during an acoustic startle paradigm in persons with OUD compared with healthy controls (). The cortisol response to opioid withdrawal, a defining feature among individuals with OUD, has likewise been observed across a number of human studies, consistently finding a correlation between opioid withdrawal severity and increases in cortisol levels (, , , , ). Further, Shi and colleagues explored changes in cortisol levels between heroin-dependent individuals who started on methadone versus those started on non-opioid agonist therapy, finding that cortisol levels were higher in the non-opioid agonist group (). These data suggest that OUD is associated with alterations in HPA-axis function and response to external stressors and that reregulation of the HPA-axis could serve as therapeutic mechanism for OUD medication development.