Nonpharmacological and pharmacological influences on opioid effects: A review of clinical research findings.

The current opioid crisis underscores the need for continued research on variables that affect opioid self-administration and strategies to alter this behavior. Decades of human behavioral pharmacology studies suggest that a range of nonpharmacological and pharmacological factors influence the effects of opioids. This review focuses on consolidating findings on the influence of experimental conditions on opioid effects, with a particular emphasis on subjective effects and reinforcement. We describe different schedules of reinforcement that have been used in studies of opioid self-administration in humans, and we review the influence of pain, stress, and individual characteristics (eg, sex, genetic factors, and psychiatric comorbidity) on opioid effects. Some pharmacological variables (eg, routes and rates of drug administration, dosing intervals, and state of physical dependence) also are reviewed to highlight the profound influence these variables can have on the subjective and reinforcing effects of opioids. We conclude with commentary on current gaps in and challenges to characterizing opioid effects in behavioral pharmacology experiments and future directions for this area of scientific inquiry. SIGNIFICANCE STATEMENT: This review highlights and summarizes findings on nonpharmacological and pharmacological influences on opioid effects, synthesized from the last several decades of clinical studies. This review focuses on behavioral pharmacology studies that explore the subjective and reinforcing effects of opioids and human research examining individual characteristics that influence opioid effects.