Inter-individual divergence in thresholds for detecting opioid effects: Within-subject human laboratory evidence of a testable behavioral phenotype

Variations in inter-individual response to opioid medications has not been well-investigated in prospective, empirical designs or in persons who have no learned experience with opioids or current pain conditions. These analyses categorized response to opioids during rigorous human laboratory experimental conditions. Healthy individuals (N = 75) with little to no prior opioid exposure completed a 5-day residential study wherein they received triple-blinded doses of placebo or oral hydromorphone (2 mg, 4 mg, 8 mg). Outcomes included a series of general and specific visual analog scale (VAS) ratings completed by participants and blinded observers, physiological endpoints, and analgesic responses to laboratory-evoked pain. The lowest dose at which participants endorsed > 20 point change in self-reported “Drug Effect” VAS ratings from baseline was used to define the following opioid sensitivity thresholds: 2 mg (“Low Threshold”, N = 9), 4 mg (“Medium”; N = 29), and 8 mg (“High”, N = 14); a “No Threshold” group (N = 31) did not endorse any effects at any dose. Main effects of sensitivity threshold existed for most participant-reported responses and conformed to threshold categories in dose-dependent ways. In contrast, no main effects of sensitivity threshold were observed for blinded observer ratings, physiological endpoints, or evoked analgesic responses, such that hydromorphone produced dose-dependent opioid agonist effects for all participants that diverged from their self-reported experience. These data provide the most granular assessment of inter-individual differences in opioid response among persons with little or no lifetime opioid exposure or existing pain condition. All participants experienced dose-dependent changes in opioid agonist responses, yet their self-awareness of these effects varied and 30 % of participants endorsed no awareness of opioid exposure at any dose. These data demonstrate a consistent and reliable divergence between the subjective experience of opioids from rigorously-assessed physiological, observable, and analgesic responses. Testable implications of these outcomes are discussed.