Stress and Opioid Misuse Risk: The Role of Endogenous Opioid and Endocannabinoid Mechanisms

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Abstract Indiscriminate prescribing of opioids for chronic pain management has contributed to the current opioid crisis. While opioids work well at stable doses for some patients, others experience poor pain relief with significant risks of developing iatrogenic opioid use disorder (OUD). Similar risks may occur in the context of extended postoperative pain management using opioids following major surgery. Ability to predict this risk/benefit balance for individual patients is limited by inadequate understanding of mechanisms influencing opioid responses and risks. To address this gap, our prior funded work has systematically evaluated mechanisms contributing to differential opioid responses. We have shown that: 1) chronic pain patients at increased risk of opioid misuse experience greater analgesia and subjective reinforcing effects of opioid analgesics (e.g., drug liking, desire to take the drug again), 2) low endogenous opioid (EO) function predicts greater analgesic responses to opioid analgesics (replicated across two studies), and 3) that low EO function and endocannabinoid (EC) levels together predict greater subjective opioid reinforcing effects. Our data are consistent with a reinforcement model in which differential opioid responding related to low EO and EC function may enhance risk of OUD. Stress is a known predictor of risk for OUD, but mechanisms are not well understood. EO and EC activity are however both known to inhibit stress responses. This project integrates diverse literatures and will test in 120 chronic low back pain patients a novel mechanistic model in which elevated stress, via links to low EO and EC activity, contributes to patterns of differential opioid responding that will enhance OUD risk via elevated opioid reinforcing properties. Primary aims are: 1) to determine whether stress-related measures are associated with analgesic and misuse-relevant subjective responses to placebo- controlled oxycodone administration, and 2) evaluate associations between stress-related measures and both EO function and EC levels, and test whether EO and EC mechanisms mediate associations between stress- related measures and oxycodone responses. This project will assess stress at multiple levels (subjective, cardiovascular reactivity to two controlled stressors, and pain-relevant heart rate variability [HRV] stress markers) with quantitative assessment of EC levels, and assessment of EO function and opioid agonist subjective and analgesic responses based on randomized, placebo-controlled crossover administration of naloxone (for EO) and oxycodone (opioid responses). Laboratory stress measures will be validated using EMA electronic diary assessment of stress. Results will provide unique mechanistic knowledge of mechanisms contributing to known associations between stress and OUD risk, in line with the goals of PAS- 18-624, and highlight a novel and clinically-pragmatic HRV measure that might predict risk-enhancing differential opioid responses before initiating opioid therapy.