Exploratory analysis of cytokine associations with laboratory-evoked pain and opioid response profiles in healthy human subjects

Background: The association of cytokines, measures of immune function and inflammation, in response to acute pain stressors and opioid medications is not well understood. Methods: This is a secondary, exploratory, and descriptive analysis of a double-blind, randomized, placebo-controlled comparison of the opioid hydromorphone vs placebo in healthy individuals ( N = 86). Participants completed quantitative sensory testing (QST) laboratory-based pain testing and received oral hydromorphone (2, 4, and 8 mg) and placebo doses using a within-subject design. Blood samples were analyzed for interleukins IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, and tumor necrosis factor-α. Quantitative cytokine levels were compared before and after QST, correlated with QST response, and examined as a predictor of subsequent opioid drug response. Results: IL-12 was the only cytokine whose levels changed significantly from pre- to post-QST exposure. Analysis of cytokine change levels pre-/post-QST revealed the magnitude of change in IL-6 was associated with several cold pressor outcomes and that IL-1β, IL-4, IL-10, and IL-13 were each correlated with some but not all cold pressor outcomes. Regression analyses of “pre” QST cytokine levels on subsequent drug ratings found IL-6 was associated with Drug Effects ( p < 0.001) and Good Effects ( p = 0.022). Conclusions: Data are consistent with prior reports that IL-6 is sensitive to acute stressors and provide preliminary support for future prospective studies designed to more thoroughly evaluate how cytokines and/or IL-6 may influence the experience of opioid agonists.