Clinical validation of a non-invasive electrodermal biofeedback device useful for reducing chronic perceived pain and systemic inflammation

This study was performed to evaluate the clinical applications of a new non-invasive electrodermal biofeedback device, which would be potentially useful in reducing perceived pain levels and chronic systemic inflammation. According to the definition of the International Association for the Study of Pain (1986) and the World Health Organization (WHO), pain “is an unpleasant sensory and emotional experience associated with tissue damage, either ongoing or potential, or described in terms of damage”. Pain represents a composite of (a) a perceptive component (nociception), i.e., the sensorial modality that allows reception and transmission of stimuli potentially harmful to the organism and to the central nervous system, and (b) an experiential part which is the psychological state connected to the perception of an unpleasant feeling. Thus, pain is a defense reaction and, therefore, physiologically a vital symptom, as it represents a warning signal to the brain of tissue injury, essential to avoid or minimize damage. The pain becomes pathological when it is maintained over time, losing its initial teleology and becoming a disease, i.e., a chronic pain syndrome [1]. Pain is thus a fundamental function for the survival of the individual, with pain-sensing receptors able to identify various types of dangerous stimuli, mechanical, chemical, and thermal.

Epidemiologic investigations [2, 3] were conducted in various European countries, including Italy. In the latter country, chronic pain afflicts 1 in 4 people (about 15 million Italians), for an average period of 7.7 years, while 1/5 patients had been suffering from pain for over 20 years. These data highlight the magnitude of the problem, which is particularly impactful in patients with chronic diseases, such as rheumatoid arthritis, osteoarthritis, fibromyalgia, osteoporosis, chronic headaches, irritable bowel syndrome, and cancer. A recent study was performed in 13 European countries via interviews and follow-up over time in patients suffering from chronic non-cancer pain. Of these patients, 47% complained of severe intensity pain with a duration longer than 2 years [4].

The chronic pain present in degenerative, neurological, and oncological diseases, especially in their advanced and terminal stages, assumes the characteristics of systemic or global pain and is linked to major physical, psychological, and social changes, as highlighted in the WHO documents [5]. It is important always to carefully evaluate pain when treating it, because each individual reacts uniquely to a specific painful stimulus, based on previous experiences and different individual threshold levels. Pain is an unpleasant subjective experience and usually has an emotional component. Pain is measured using official scales validated by international clinical trials [6, 7]. Pain assessment is performed by asking the patient to assign a score corresponding to the tested pain. The Numeric Rating Scale (NRS) for pain is based on the use of a scale consisting of 11 degrees from 0 to 10, where 0 corresponds to the total absence of pain and 10 represents the worst pain imaginable by the patient [8, 9]. The different scales employed for pain assessment cannot, among themselves, be formally compared; generally, however, NRS is accepted as a reliable procedure.

Inflammation is a defense mechanism of the body whose goal is the elimination of the cause of the injury and the subsequent repair of the damaged tissues; it is a necessary protection mechanism; however, the persistence of even a low-grade chronic inflammatory state is a common feature of a wide range of chronic disorders and/or diseases. Low-grade chronic systemic inflammation is a widespread and rapidly increasing human disease state, linked to the modern lifestyle and environmental pollution. Low-grade inflammation has several causes, some being chronic stress, overweight/obesity, sedentary life, bad nutrition, loss of circadian rhythmicity, and poor sleep. Thus, it is a systemic inflammatory process strongly correlated with type of feeding (excessive caloric intake, latent metabolic acidosis, excessive production of insulin, imbalance of fatty acids, lack of CoQ10 and L-carnitine, and excess positive potential renal acid load (PRAL) (pro-inflammatory food), scarce or absent physical activity, chronic stress, sleep deprivation, and alterations in biological rhythms. The chronic low-grade systemic inflammation manifests with a constellation of “non-specific” symptoms (medically unexplained symptoms, MUS) that include asthenia, fatigue, daytime sleepiness, nocturnal insomnia, irritability, and difficulty in concentration. Over time, its failure to correct promotes numerous disease states, including obesity, type 2 diabetes mellitus, malignant neoplasms, and neurodegenerative diseases (in particular Alzheimer’s disease, multiple sclerosis, and Parkinson’s disease). It involves the extracellular matrix and the cells of all the tissues and organs of the body. Chronic or autoimmune persistent inflammation also leads to increased acute phase reactants, in particular of C-reactive protein (CRP). This protein is produced by the liver and secreted into the bloodstream. As the plasma concentration of CRP increases within a few hours from the beginning of an inflammatory reaction, it is particularly useful to monitor its course [10]. An increase in circulating CRP levels simply reflects an ongoing inflammatory state; this increase may be non-specific with respect to an inflammation site. Usually, in healthy subjects, CRP levels are lower than 5 mg/L [11], while, on average, they are higher in women than in men and rise with aging [12].

In the presence of chronic inflammation with altered hydroelectrolytic conditions of the extracellular environment (increase in extracellular water [ECW], loss of intracellular potassium [increase in serum potassium]), the cell membrane resting potential decreases to values less than − 70 mV, with a time trend towards 0 mV. The consequences of these changes are (a) a decrease in the ability to reach the threshold potential, (b) a reduction of the frequency of action potential, and (c) a net decrease in local and systemic hydroelectrolytic regulatory capacity with reduced functional, reparative, or conservational activities. Restoration of membrane potential and, therefore, of the normal hydroelectrolytic condition is necessary to overcome the state of chronic allostasis or, more accurately, cacostasis. Whatever method is used, there are action potentials when an externally applied stimulus has sufficient amplitude and duration to cause an ionic flow through the cell membrane and to raise its potential above the threshold value.

The RegMatEx electrodermal device uses the principle of biofeedback of the measured systemic basic and stimulated potential, which allows evocation of a greater frequency than that in the basal state of chronic inflammatory allostasis or cacostasis, inducing cellular repolarization (− 70 to − 90 mV) and stimulating the biofeedback processes of the autonomic nervous system. We hypothesized that stimulating cellular repolarization lowers pain and inflammatory processes by contributing to the control of intra- and extracellular hydroelectrolyte balance.

Chronic stress and inflammation in adults have been associated with MUS, including pain and increased extracellular water, abdominal obesity, osteosarcopenia, a flattened salivary cortisol rhythm, and elevated circulating CRP concentrations [13, 14]. We have hypothesized that the MUS are, in fact, a combination of stress and “sickness syndrome,” manifestations elicited by sustained activation of the stress system and the immune and inflammatory reaction [15]. The subjects included in this study had as predominant manifestations hyperalgesia and frank pain, both products of the interaction between immune mediators and the peripheral and central nervous system.

The use of the electrodermal biofeedback RegMatEx device in our subjects was associated with reduced pain perception and decreased chronic systemic inflammation, with stability over time. This did not occur in the placebo-treated group. The symptomatology of the treated patients significantly improved in terms of pain relief shown in the NRS pain test, and this was accompanied by reported improvements in mobility, mood, and quality of life. Thus, the RegMatEx electrodermal biofeedback procedure is a non-invasive and easy to use therapeutic method, free of side effects and with high patient acceptability, excellent efficacy and duration of effect, and therefore a valuable tool in the treatment of chronic pain and inflammation.

There may be conditions that can lead to lower therapeutic performance in terms of effectiveness of the above method over time. On the other hand, the technique has limitations in the following situations: (a) inaccurate reading of electrical tissue potentials due to poor water turnover (less than 2% of body weight) or with very low total body water (less than 45%), (b) reduced ion exchange from chronic use of anti-inflammatory drugs, and (c) low presence of electrolytes essential for the maintenance of action potentials due to the chronic use of diuretics (low induction of action potentials due to loss of electrolytes).

In conclusion, the electrodermal biofeedback RegMatEx device produced significant results in reducing subjective pain and objective chronic inflammation. After a 3-week cycle of six biofeedback treatments, the symptomatology of the patients significantly improved.

Simultaneously, the concentrations of circulating C-reactive protein were decreased. The RegMatEx electrodermal biofeedback device is thus a valuable tool in the treatment of both physical and mental pain related to chronic stress and inflammation. Given the validity of this method, other applications can be envisioned, both in disease and health. We have now extended this study by following the patients with the Health Questionnaire EQ-5D-5 L and with the perceived stress scale. In these patients, using a different device, namely, “PPG Stress Flow,” we are also examining heart rate variability, vagal tone, and the balance between the sympathetic and parasympathetic systems over a long period of time. It is noteworthy that vagal tone exerts systemic anti-inflammatory actions and could explain our findings, at least partially [16].