Cytokine Expression in Cancer Survivors Suffering From Chronic Pain: A Systematic Review

Background: Chronic cancer -related pain remains underdiagnosed and undertreated, although it affects 40% of cancer survivors. Recent insights suggest that cytokine signaling between immune, neuro, and glial cells contributes to chronic pain. Objectives: This study systematically reviewed cytokine levels and their relation to chronic cancer -related pain and, additionally, investigated differences in cytokine levels between cancer survivors with and without chronic pain. Study Design: Systematic review. Methods: This systematic review was conducted and reported following the Preferred Reporting Items for Systematic Reviews and Meta -Analysis guidelines (PRISMA). The study conducted a systematic literature search in the databases PubMed, Web of Science, and Embase for articles examining cytokine levels and pain experience at a time point of a minimum of 3 months post -cancer diagnosis. Pain experience was categorized into a total pain score, pain intensity, and pain interference. The risk of bias was assessed using the Newcastle Ottawa Scale. Results: Eight articles were included, investigating 6 cancer types and 30 cytokines. Moderate evidence was found for pro -inflammatory cytokine IL -6 to be correlated with pain intensity, of which higher levels are observed in cancer survivors experiencing chronic pain compared to pain -free survivors. Moderate evidence was found for TNF-alpha to be not correlated with any pain experience, which is similar for anti-inflammatory cytokines IL -8 and IL -10 with pain intensity. For the remaining 26 cytokines and pain outcomes, only limited evidence was found for an association or alteration. Limitations: The number of included studies was small. Overall, studies showed a moderate risk of bias, except one indicated a high risk of bias. Conclusion: More standardized post -cancer treatment studies are warranted to confirm these results and explore associations and alterations of other cytokines. Nonetheless, moderate evidence suggests that elevated levels of IL -6, in contrast with TNF-alpha levels, are correlated with pain intensity in cancer survivors experiencing chronic pain compared to painfree survivors.