Fibromyalgia (FM) is a medical condition characterized by the combination of complex, sometimes indistinct, symptoms. FM manifestations include chronic widespread musculoskeletal pain and associated fatigue, morning stiffness, sleep disturbances [1,2], depression, anxiety, and cognitive symptoms [3,4], in line with the biopsychosocial model of pain [5], and evidence related to other chronic pain conditions [6,7,8]. In addition, FM is associated with psychological factors, such as neuroticism [9], alexithymia [10], catastrophizing [11], and low health-related quality of life [4], limiting people’s daily activities as well as their social, professional, and recreational activities [12,13]. FM is the third most common musculoskeletal condition and is estimated to affect 0.2 to 6.6% of the adult general western population [14,15]. Due to its persistent and debilitating condition, FM imposes enormous economic burdens on society, as patients with FM have relatively high levels of comorbidities and high levels of health care utilization and cost [16].

Despite predisposing factors (genetic, stressful or traumatic events, viral infections, and obesity), the etiopathogenesis of FM is still not fully unraveled, making its diagnostic and classification criteria confusing. One of the most widely held hypotheses regarding the pathogenesis of FM is central sensitization to pain and deficits in endogenous pain-inhibiting mechanisms. Several studies in patients with FM have shown a lower threshold and tolerance for pain [17,18], hyperalgesia and allodynia [19], a slower cognitive processing speed [20], a cortical or subcortical increase in pain processing compared with healthy subjects [21], and evidence of the presence of polyneuropathy in both small and large fibers [22]. All these symptoms suggest a neurogenic common origin characterized by an imbalance in the levels of neurotransmitters and consequently of the peripheral pro- and anti-inflammatory mediators [23]. Due to lack of agreement regarding its diagnosis, classification and etiopathogenesis, no consistently effective treatments are yet available. In many cases, FM has been seen as a “disease of misconnection” at different levels characterized by lack of specific biomarkers [2,24].

In most cases, the therapeutic approach is characterized by multidisciplinary interventions that include patient’s education, physiotherapy (including physical agents and exercise), pharmacological treatment, and psychotherapy [2]. Therapies for the management of FM are mainly focused on easing patients’ symptoms and improving quality of life [25]. Although some studies have been conducted examining pharmacological and non-pharmacological interventions, treating patients with FM using a multimodal approach appears to be the most effective option even if more trials are needed [26]. Conventional pharmacological therapies usually rely on cyclic or chronic use of antidepressants, muscle relaxants, anti-inflammatories, and antioxidants [27]. Non-pharmacological measures consist of: (i) physiotherapy, including a variety of physical agents and land- or water-based physical exercise, such as aquatic or aerobic-based exercise, strength training (anaerobic exercise), and flexibility training; and (ii) psychotherapy, including cognitive-behavioral interventions, biofeedback, and psychological support [28,29]. With the growing recognition that there are different categories of FM with different clinical features, personalized prescription should be an important target to be achieved among the empirical and constantly evolving approaches that are proposed.

Whole-body cryostimulation (WBC) is a highly effective physical treatment mainly used in sports medicine to relieve pain, inflammatory symptoms, fatigue, and overuse symptoms due to its widely recognized anti-inflammatory and anti-oxidant effects [30]. Presently, it has been used as an add-on therapy in rheumatic (arthritis [30], fibromyalgia [31,32,33,34,35,36,37,38,39,40], and ankylosing spondylitis [41]), neurological (multiple sclerosis [42]) psychiatric (depression) [43], metabolic (obesity) [44], and diabetes [45]. WBC consists of exposure of a part or the whole body to very cold and dry air for generally 2 to 3-min. At present, there are two types of cryostimulation. Partial-body cryostimulation (PBC), where the body, excluding the head, is exposed to a cryogenic fluid injected and vaporized around the body inside a cryosauna, and the whole-body cryostimulation (WBC), performed inside a cryochamber, where the whole body is exposed to cold produced by cryogenic fluids or refrigerants [46]. Given the limited amount of published literature, here adopted studies performed with both a cryochamber and a cryosauna, all reported as “Whole-body Cryostimulation”, despite knowing the different physiological reactions after PBC and WBC due to their large differences in internal temperatures measured with PBC having a higher gradient. The thermal stress elicited by cryostimulation generates vasoconstriction and stimulate the thermal receptors of the dermis by lowering skin temperature, and slowing down nerve conduction in pain fibers, which may be a way that cryotherapy induces an analgesic effect, relieving pain and inflammatory symptoms [47,48]. Moreover, it causes changes in the endocrine, circulatory, neuromuscular, and immunological system [49]. It provides homeostatic autonomic responses of thermogenesis and vasoconstriction by stimulating cold receptors and the thermoregulatory center in the hypothalamus from which efferent signals cause activation of the sympathetic system resulting in vasoconstriction followed by release of noradrenaline. Along with endorphins, norepinephrine modulates pain and slow conduction velocity of sensory nerve fibers such as C fibers, disabling the sensory receptors as well as their connections to proprioceptors [50]. An increase in parasympathetic cardiac control also occurs. Indeed, after cryostimulation, as a compensatory mechanism, downregulation of blood pressure [50], even overnight [51], may result in reduced feelings of fatigue, improved mood, and reduced mental health deterioration with possible positive consequences on depressive states, and improved sleep quality [43]. Recent literature has shown that WBC is immunostimulating and yields an anti-inflammatory response, with a decrease of the pro-inflammatory cytokines and increases of anti-inflammatory mediators [52,53,54,55,56,57]. It also appears to improve the effect on redox balance in a session/treatment number-, age-, and fitness-dependent manner [58], probably through the decrease in the total oxidant production which, consequently, induces antioxidant activity [56,58,59,60,61,62,63]. Thus, due to its widely recognized anti-inflammatory, antioxidant, analgesic, and exercise-mimicking effects [64], WBC is proposed as a promising add-on option in the multidisciplinary treatment of FM, considering also that diffuse inflammation is one of the sub mechanisms of depression [65], and that co-morbid depression is very common among FM patients, with a lifetime prevalence of 62–86% [66]. 

2. Clinical Effects of WBC in FM

3. Molecular Effects of WBC in FM

4. Gene Expression after WBC in FM