The narrative review aims to shed light on the influence of inflammation in the comorbid chronic pain and major depressive disorder (MDD). This connection is known to be multifactorial, with a dynamic interaction between genetic and epigenetic factors. However, a growing body of evidence has shown that the co-presence of MDD and pain is underlain by immune mechanisms involved in the persistence of the inflammatory process. In particular, the cytokines released following activation of the innate immune system during inflammation cause changes at the endocrine level that result in glucocorticoid resistance, as well as altering the synthesis and metabolism of some central nervous system (CNS) mediators. Cytokines appear to generate neuroinflammation by activating normally protective microglia. Various other mechanisms, including changes in the function of the glutamatergic, GABAergic, and serotonergic systems are also implicated, but inflammation-induced reduction of BDNF (brain-derived neurotrophic factor) appears to be the deciding factor. In turn, neuroinflammation leads to sickness behavior, which is characterized by anhedonia and social withdrawal. This review explored these mechanisms, which may be at the root of comorbid pain and MDD. Although intriguing, however, most available evidence comes from animal studies, and rigorous clinical exploration is warranted.

Our immune system acts to protect us in times of stress and traumatic injury. As part of the immune response, the body produces various cytokines, which mediate or modulate immune functions. Such cytokines include tumor necrosis factor (TNF) and interleukin 6 (IL-6) and IL-17. These cytokines can also act on the nervous system to influence pain perception. TNF-α triggers an inflammatory response and two forms of programmed cell death, apoptosis and necroptosis, depending on the pathological state. For individuals with chronic conditions relating to immune deficiency, the actions of these cytokines can present as chronic pain states, significantly altering quality of life. One attractive potential solution for treating this immune linked pain is by altering signaling pathways of pain-enhancing cytokines. Infliximab and etanercept are TNF inhibitors that are currently on the market for use in the treatment of chronic pain. Secukinumab and tocilizumab serve as IL inhibitors, utilized for a similar purpose. These novel immunotherapies have shown efficacy in numerous clinical studies with acceptable side effect profiles. In this review, we summarize the pharmacological profiles of these drugs and discuss their usage in treating chronic pain.

Interleukin-6 (IL-6) plays a critical role in the pathogenesis of various chronic inflammatory diseases, tracked across numerous fields of research. Despite this, a crucial aspect often overlooked in studies is the differentiation between IL-6 classic-signaling and trans-signaling, leading to potential confounding of their findings; less than half of selected IL-6 studies included differentiation. This review delves into the distinction between IL-6 classic- and trans-signaling and their role in chronic inflammatory diseases and endometriosis. The unique pro-inflammatory nature of IL-6 trans-signaling, contrasted with the anti-inflammatory character of IL-6 classic-signaling, presents significant implications for research methodology, particularly in studies investigating anti-inflammatory interventions or interleukin inhibitors. Diagnostic failure to account for these distinct pathways may inadvertently misrepresent beneficial immune responses or the efficacy of interventions, posing significant challenges in predicting health outcomes. Interventions that do not differentiate these pathways could face reduced efficacy or safety. This review proposes adjustments to research methodologies and stresses the importance of careful interpretation of inflammatory markers in IL-6-related research. Examples of differentiation issues are discussed across the topics of endometriosis and multiple inflammatory diseases. By addressing this methodological issue, researchers could potentially improve patient outcomes, enhance the efficacy of interventions, and contribute to public health advancements.