Acute pain antagonizes the anti-inflammatory effects of opioids

Accumulating evidence suggests that pain and opioids separately induce changes to the activity of innate immune system. What has not been explored is the degree to which acute pain and opioid analgesics act together to influence markers of inflammation. The purpose of this study was to characterize pro-inflammatory responses to acute pain and opioid analgesia, separately and together, in healthy control subjects. The study was designed to compare molecular inflammatory signaling (unstimulated nuclear factor (NF)B expression) and cellular cytokine markers of inflammation (interleukin-6, IL6; soluble tumor necrosis factor receptor II, TNFRII; interleukin-1 receptor antagonist, IL1ra;) in healthy individuals (n=23, 11 female) following randomly ordered experimental sessions of: opioid-only (IV fentanyl 1mcg/kg), pain-only (cold-pressor), pain+opioid, or a control (resting) condition. Blood samples were obtained before, during and three hours after experimental sessions. The study received full and continuous approval from the UCLA Institutional Review Board. Expected physiological effects of pain and opioids on sympathetic and nociceptive systems were observed. Opioid alone trended toward decreases in the levels of the majority of inflammatory markers examined, and significantly so in the case of the cytokine receptor TNFRII (p=0.005). However, neither short-term responses in the pain-only nor pain+opioid conditions differed from control responses. Inconsistent with previous in investigations, experimental pain did not result in significant changes in immune markers, with patterns of response to pain similar to those of controls. However, acute opioids had consistent depressant effects on inflammatory systems, depressing markers with pro-inflammatory effects. Interestingly, across subjective and immune measures, opioid effects were reversed or antagonized by the presence of experimental pain. That pain may protect the patient from the immune consequences of opioid administration is a novel and intriguing finding.