## 4 Discussion
### Interpretation and Implications
However, long-term changes to pain sensitivity can be caused by a plethora of biopsychosocial factors other than the used training paradigm, further complicating the interpretation of such results [20]. Large-scale research integrating all such factors is needed [70]. The absence of any differences in the inflammatory responses between the two groups both at rest and postexercise challenges the hypothesis of a general, more pronounced pro-inflammatory state in persons with CNSLBP. Altered systemic levels of pro- or anti-inflammatory biomarkers have been widely discussed in the literature. A recent systematic review by [PERSON] et al. showed no differences in IL-6 and TNF-\(\alpha\)[22] between persons with CNSLBP and HCs, while [PERSON] et al. and [PERSON] et al. found positive correlations of IL-6 and TNF-\(\alpha\) with the presence of nonspecific low back pain [27; 71]. As the latter reviews included both acute and chronic low back pain, specific categorizing of the timing of clinical pain (i.e., acute/chronic) seems imperative to correctly evaluate such outcomes. Furthermore, the current evidence remains limited and of low methodological quality, postulating the need for additional supportive data to facilitate more in-depth analyses. Given these mixed findings, future research might also focus on the importance of extensive phenotyping of persons with CNSLBP to identify specific subgroups with an inflammatory-driven pain mechanism [72]. Such tailored approaches may help uncover the subset of patients for whom inflammation actually plays a significant role [73]. In other fields of musculoskeletal pain research, it has been demonstrated that there is a substantial inter-person variability in inflammatory markers [74; 75], and evidence suggests that this variability might be able to guide therapy [76]. Moreover, while IL-6 and TNF-\(\alpha\) were selected as key inflammatory markers due to their more established relevance in exercise and chronic pain, the importance of assessing additional markers such as IL-1\(\beta\), CRP, and IL-10 should also be recognized [22; 71; 77]. As such, future research might aim to include a broader range of biomarkers to evaluate a broader inflammatory profile and provide a more detailed understanding of the inflammatory response to high-intensity exercise in chronic pain populations. The findings from the current study regarding HIIT and MICT responses indicate that neither exercise protocol significantly affected the inflammatory markers within CNSLBP. This was an unexpected outcome as, at least in HCs, the impact of acute exercise on systemic IL-6 levels has been demonstrated [78; 79] and in high-intensity (interval) exercise conditions [80; 81; 82]. Furthermore, baseline values of IL-6 and TNF-\(\alpha\) in both groups (but especially in the HCs) were much higher than reported in the literature [83; 84]. However, as high variability in inflammatory biomarkers has been noted in general, which can even increase in chronic pain [71; 85], it is unclear if this affected the outcome. Finally, the observed correlations between specific pro-inflammatory markers and cuff algometry outcomes suggests a link between inflammation and pain sensitization in CNSLBP. This association has been widely studied in animals [86] and has only just recently been confirmed in humans [87]. But, due to the lack of broader significant correlations, the current results remain speculative, and other variables not included in this study could heavily influence this relationship. Through correcting for either age and BMI or DASS-21 and PSQI outcomes, we were able to show that the latter strongly impacted the association between systemic inflammation and pain sensitivity. Hence, we believe that the positive correlation found in this analysis should at this moment be interpreted with caution. A more inclusive evaluation of psychological factors confounding this relationship seems essential.