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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. [ABSTRACT FROM AUTHOR]

Introduction: Studies have shown that genetic variation and environmental factors are associated with individual differences in therapeutic efficacy and side effects of opioids. However, the focus of these studies has been on a single factor of single-nucleotide polymorphisms (SNPs) or haplotypes, for which results have rarely been validated. For complex traits, such as cancer pain and opioid response, interactions between multiple genetic variation and environmental factors need to be considered to explain the opioid individual differences. Methods: We conducted an exploratory two-stage cross-sectional study with 1027 Chinese patients who were taking strong opioid medications for their cancer pain, and genotyped 110 SNPs to explore the association of SNPs, haplotypes, gene–gene and gene–environment interactions with opioid dose, pain relief, and opioid-induced constipation. Results: Due to the failure to meet Benjamini–Hochberg criteria in the discovery stage or to be validated in replication stage, no association was found between SNPs, haplotypes, paired SNP–SNP interactions or multi-dimensional gene–gene interactions and opioid response. However, for gene–environment interactions, optimal models have been constructed in all phenotypes of opioid response. Conclusions: This study reveals for the first time that construction of multidimensional gene–environment interactions enables better interpretations of the effect of genetic variation and environmental factors on the opioid response in patients with cancer pain. Trial registration: Chictr.org.cn, identifier, ChiCTR2000033576. [ABSTRACT FROM AUTHOR]