IV IL-1 receptor antagonist reduces pain sensitivity and enhances brain endorphin release during a standardized, experimental, acute pain challenge: A BESH clinical trial

Abstract

Prescription of opioid analgesic drugs is a major contributing factor to the current opioid epidemic. Novel, effective, non-opioid analgesic interventions are sorely needed to reduce reliance on opioid analgesics. In animal models, Anakinra (IL-1 receptor antagonist) blocks the nociceptive effects of IL-1b, reducing IL-1b - induced pain, morphine tolerance, and morphine hyperalgesia. Opioid-cytokine interactions between IL-1 family cytokines (e.g. IL-1b, IL-1ra) and endogenous brain mu-opioid receptor mechanisms appear to underlie Anakinra's analgesic effects. However, to our knowledge, Anakinra has not been shown effective in humans to reduce acute or chronic pain or to enhance endogenous opioid analgesic activity, posing research gaps to clinical translation of Anakinra's analgesic effects. To that end, we tested the analgesic effect of Anakinra during a standardized, experimental pain challenge in (n = 43) healthy, pain-free human participants using a brief, crossover, placebo-controlled BESH (basic experimental study in human subjects) study design. A subset of subjects completed ¹¹C-CFN (¹¹C-carfentanil) Positron Emission Tomography (PET) imaging of the brain during the pain challenge to show that analgesic effects were associated with underlying brain mu-opioid receptor (MOR) activity. Results showed that Anakinra reduced the extent of pain experienced during the pain challenge while enhancing activity of underlying MORs in the thalamus, insula, nucleus accumbens, cingulate, and caudate. Notably, these brain regions are implicated in modulating perception of the pain experience and in regulating motivation/reward circuitry in response to pain. Results from this project will facilitate follow-up testing of Anakinra's analgesic effects in an expanded clinical trial, responding to a stated need in combatting the current opioid epidemic.

Keywords: Acute Pain; Anakinra; Carfentanil; IL-1ra; Opioid; PET Imaging.