# Whole-Body Cryostimulation in Fibromyalgiaia: A Scoping Review
## 4 Discussion
### Molecular Effects of WBC in FM  
The pathogenesis of FM not only includes pain sensitivity, pain inhibition, or pain amplification, but also an imbalance of pro- and anti-inflammatory cytokines, genetic predisposition, and environmental triggers such as mechanical/physical trauma or injury and psychosocial stressors that ultimately leads to pain and impaired pain processing.  
There is growing evidence of neuroinflammation in FM. Several pro-inflammatory cytokines, including TNF-\(\alpha\), IL-1\(\beta\), IL-6, and tumor necrosis factor \(\alpha\) (TNF-\(\alpha\)), have been found to be elevated in animal models of neuropathic pain and in the cerebrospinal fluid (CSF), peripheral tissues, and blood of patients with chronic neuropathic pain conditions [75]. In addition, pharmacologically lowering or blocking of these pro-inflammatory cytokines has been demonstrated to prevent, reduce, or reverse pain (allodynia and hyper-algesia) in both animal models and clinical studies [76].  
Thus, the imbalance of pro- and anti-inflammatory cytokines is assumed to play a role in the induction and maintenance of pain and the occurrence of many of the clinical features of FM (such as swelling, dysesthesia, skin manifestations, fluid retention, and increased levels of fibronectin, which is a tissue marker of endothelial activation) as a result of a neuroinflammatory condition that gives rise to descending pathways that influence predominant symptoms, such as pain, fatigue, and cognitive impairment. In addition, environmental triggers, stress, and emotions are the upstream driving mechanism of neurogenic inflammation in FM [77].  
Therefore, the likelihood that FM may have an imbalance in cytokine production and secretion has been confirmed. [PERSON] et al. showed that FM patients have higher serum levels of IL-1 ra, IL-6, and IL-8, and higher plasma levels of IL-8, compared to controls [78], while two studies of [PERSON] et al. showed how WBC affects the inflammatory status by inducing an imbalance towards the anti-inflammatory side [55; 56]. Consecutive sessions of cryotherapy increased levels of IL-6, which can act both as a pro-inflammatory and anti-inflammatory cytokine, and IL-10, an anti-inflammatory cytokine, and lowered the IL-1\(\alpha\) levels. Furthermore, WBC appears to improve the oxidative status already after a limited number of sessions, in a dose-dependent way [58; 59].  
[PERSON] et al. integrated the clinical effects with the molecular effects of WBC [37]. In parallel with changes in disease activity and pain reduction, patients with FM showed a significantly different response to WBC compared with healthy controls in terms of changes in IL1, -6, -10, and TNF-\(\alpha\) over time to WBCs. FM patients had higher levels of IL-1, -6, -10, and TNF-\(\alpha\) at baseline compared to healthy subjects. IL-1, IL-6, and IL-10 levels decreased significantly after three and six sessions and stabilized up to three months after discontinued WBC treatment. Interestingly, IL-6 levels returned to baseline after three months only in healthy controls and showed significantly decreased IL-6 levels at each reading point compared to baseline. WBC had no effect on TNF-\(\alpha\) levels, neither in FM patients nor in healthy controls.  
Therefore, even if the levels of IL-1, IL-6, and IL-10 in FM patients were higher than healthy controls after 6 WBC sessions and 3 months after the last WBC session, their significant alteration confirms the overall beneficial effects of WBC.