Human pain is a complex and multifaceted phenomenon(1) that is controlled by multiple systems in the human body (2). These systems work together to process, interpret and respond to pain (3).The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage" (4) This experience evokes an integrated response from the various systems associated with pain.This integrated response to the phenomenon of pain occurs in a more complex way at the level of the cortex where pain is consciously perceived, such as the primary somatosensory cortex, the primary motor cortex and supplementary motor cortex, the secondary somatosensory cortex, the insular cortex, the anterior cingulate cortex and the thalamus (5,6). Also at an unconscious level, but more central, is the emotional regulation of pain, which is linked to the limbic system, where the experience of pain acquires an individual component linked to the emotions and experiences of the individual themselves, such as memory and fear in the amygdala, hippocampus and subcortical structures, including the basal ganglia (6,7).In addition, there are some systems that are particularly important in pain regulation, namely the immunological system, the endocrine system and the descending noradrenergic system. Despite today's deeper understanding of pain mechanisms, there is still a lack of solutions for more complex conditions. The role of the autonomic nervous system (ANS) in pain modulation with the different systems involved in pain, such as the immunological system, the endocrine system and the descending noradrenergic system, is becoming increasingly clear and there is an urgent need to develop solutions for effective modulation of the ANS with a focus on pain (9). From this perspective, neuromodulation of the ANS appears to be a potentially supportive solution for the modulation of pain, in particular non-invasive neuromodulation of the autonomic nervous system NESA, which has been shown to be effective for pain in chronic pathologies such as multiple sclerosis (8).The need arises for effective non-pharmacological treatments, based on electrical neuromodulation, and backed by scientific evidence to support their use for pain. In this sense, previous studies have shown that microcurrent technologies for prefrontal and primary motor cortex modulation such as transcranial stimulation (tDCS) combined with peripheral stimulation (9) or vagal stimulators (VNS) (10) have demonstrated benefits on different aspects of pain, headaches, chronic pain in diverse populations (11). However, science is advancing and other types of specific microcurrent are emerging for autonomic modulation targets that are more comfortable for the patient, with no side effects and an easier application, such as non-invasive neuromodulation NESA (12). It is therefore necessary to explore the field of work of NESA microcurrents so that they can be used to modulate pain through the autonomic nervous system.Subsections relevant for the subject.The immune system influences the release of substances such as pro-inflammatory cytokines, which sensitize pain receptors and pathways and thus increase the perception of pain (13). The immune system also plays a role in reducing pain levels in the process of tissue recovery (14). The regulation of the immune system, pain and inflammation is largely mediated by the ANS and its different divisions such as the sympathetic, parasympathetic and enteric branches (15). This deregulation can be observed in autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis, where changes in the ANS are associated with increased inflammation. As a result of these increased inflammatory levels, there is a dysfunctional interaction between the ANS and the gut microbiota with direct effects on the homeostasis of inflammation (14,15). A study with individuals with rheumatoid arthritis showed a strong correlation between the increase in sympathetic activity due to muscle sympathetic nerve activity and the painful symptoms of these patients (16).The endocrine system also has an influence on pain regulation via hormones that influence pain perception (17,18). The hypothalamic-pituitary-adrenal axis (HPA axis) and cortisol is an important hormonal regulatory system that is also of great importance for the regulation of pain by regulating cortisol levels. Elevated cortisol levels following acute stress can facilitate the consolidation of fearbased emotional memories and cause a sensitized physiological response to stress. However, prolonged stress or situations of constant or exaggerated physical pain can increase sympathetic and neuroendocrine activity, decrease cortisol levels, and perpetuate generalized pain and inflammation (19). The increase in cortisol levels is accompanied by an increase in adrenaline levels associated with acute pain or stress, which can transiently alter pain perception (14). This type of response is often associated with the "fight or flight" response, which can temporarily reduce pain sensitivity (20). However, prolonged chronic stress leads to a functional change in the ANS that impairs pain regulation, such as in fibromyalgia (21,22) and central sensitization (23).Pain modulation also depends on an important system such as the descending noradrenergic system, its relationship with the periaqueductal gray matter (PAG) and the reticular formation of the brainstem (24). The PAG is also involved in risk assessment and threat response and contributes to defensive behaviors related to negative events. These pathways lead to learned aversive behaviors through the involvement of sympathetic responses, motor responses, and emotional responses characteristic of acute and chronic pain (25). Some structures are particularly important for the development and maintenance of...