Abstract
INTRODUCTION: Recent studies have revealed that inflammation is a key factor in the causation of opioid analgesic tolerance. Opioids can induce a massive release of inflammatory cytokines and disruption of intestinal barrier function by activating Toll-like receptors 2/4 (TLR2/4), eventually resulting to sustained bacterial transmission and persistent systemic inflammation. However, most of the relevant analyses available were conducted at the level of animal experiments. It is necessary to explore the potential association between opioid tolerance and inflammatory cytokines and gut microbiota in patients with cancer pain. METHODS: We retrospectively analyzed cytokines, lymphocyte subsets and blood cells in 186 cancer patients to examine the effect of oral opioids on inflammatory cytokines in patients with moderate to severe cancer pain. The control group constituted tumor patients without cancer pain, while patients with moderate to severe cancer pain taking oral opioids made up the observation group. Fecal samples collected from 25 cancer patients were also analyzed for the composition and diversity of gut microbiota using 16S rRNA sequencing to explore the association between oral opioids and dynamic changes in gut microbiota. RESULTS: Patients with moderate to severe cancer pain taking oxycodone had significantly higher levels of IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ than those in the control group (p < 0.001). The difference in the relative abundance of Lactobacillus (p = 0.025), Anaerostipes (p = 0.034), Megamonas (p = 0.0080), Monoglobus (p = 0.0080), and the Rikenellaceae_RC9_gut_group (p = 0.022) between the opioid and control group was significant. CONCLUSION: Oral oxycodone can cause abnormal changes in cytokine levels and gut microbiota of patients with moderate to severe cancer pain, prompting chronic systemic inflammation. Analgesic tolerance induced by long-term oxycodone use could be closely related to the consistent upregulation of IL-6 and TNF-α levels.