Home-based Transcranial Stimulation in the Treatment of Patients With Refractory Chronic Pain

Brain and Pain (BaP): Understanding the Central Mechanisms of Pain to Improve Management of Patients With Refractory Chronic Pain

Spanish Ministry of Science and Innovation (Funding support), Health Research Institute of Santiago de Compostela - IDIS (Recruitment support), Fundación Biomédica Galicia Sur (Recruitment support)

Refractory chronic pain represents a serious and limiting health condition which does not respond to standard pharmacological therapy. Thus, it emerges the necessity of new techniques to treat these group of diseases, such as the transcranial electrical stimulation (tES). This procedure induces a low-intensity electrical current through the scalp to modify the excitability of brain cells, thus facilitating changes in neural networks which may be dysfunctional in some chronic pain patients. The main objective of this research is to test the efficacy of two tES techniques, differentiated by applying direct or alternant electrical current, to reduce the pain intensity and to increase pain thresholds of these patients. Besides, intervention is implemented at home for patients themselves thanks to a portable and convenient stimulator device, after one training session provided by technicians. Researches can supervise the compliance of the treatment remotely, as the stimulator has a permanent connection with their computers. A home-based approach means a more comfortable and accessible treatment alternative for patients, since they do not have to attend to clinics everyday to receive the stimulation; the advantages become even more relevant in the pandemic context, since the risk of being infected is radically minimized. Despite the main purpose is to test the efficacy of tES to improve the pain suffered by patients, many other areas are considered as secondary end points for being intrinsically linked or affected by the disease, such as the interference in daily tasks provoked by pain, mood disorders (depression/anxiety), fatigue, life quality, physical functioning and sleep quality; these last two variables are measured with actigraph wristwatches, apart from specific questionnaires. Lastly, endogenous modulatory pain mechanisms are examined through sensory tests, namely Conditioned Pain Modulation and Temporal Summation of pain.

This work aims to provide answers to the refractory chronic pain challenge. Pain is defined as refractory when multiple evidence-based biomedical therapies have failed to reach treatment goals that may include adequate pain reduction and/or improvement in daily functioning, even after appropriately assessing and addressing those psychosocial factors that could influence pain outcomes. In this sense, on the one hand, the study focus on detecting central biomarkers of pain modulation and processing which will contribute to improving knowledge of the mechanisms of pain chronification and the diagnosis procedure. On the other hand, given the low efficacy of pharmacological or non-pharmacological therapies for the patients studied, the efficacy of new therapeutic alternatives (tES) is explored. In short, the project will allow the transfer of knowledge to clinical practice in several aspects, such as diagnosis or treatment. Therefore, the research aims to test the role of defective central pain modulation/processing as explanatory mechanisms for chronic pain. A second main objective is to test the efficacy of transcranial electric stimulation (tES) to modify dysfunction of central mechanism of pain, and to improve symptoms and quality of life in refractory chronic pain patients. To achieve this, the investigators will select valid and reliable instruments to assess pain and comorbid symptoms in chronic pain patients and the most sensitive outcome measures to assess tES treatment efficacy. Sensory testing paradigms, namely Conditioned Pain Modulation, Temporal Summation of Second Pain and pain-related evoked potentials using electroencephalographic recordings, will act as biomarkers which are proposed to correlate with the severity of the chronic pain disease or some of their symptoms, and also as predictors of the treatment outcome. Total sample includes 120 patients with refractory pharmaco-resistant pain, attended at the Pain Units of two Public Galician Hospitals (36 male, 84 female). The study is expected to contribute to detection and preventive measures of future pain, and diagnosis of chronic pain disorders, improving prognosis and development of feasible patient-centered interventions, providing new directions for future research on pain.

Transcranial electrical stimulation, Fibromyalgia, Arthritis, Arthrosis, Low back pain, Migraine headaches, Anxiety disorders, Depression, Chronic fatigue, Sleep disorders, Pain assessment, EEG

Participants will be randomly assigned to one of three treatment groups (40% active tDCS; 40% Active tACS; 20% Sham). Patients receiving sham stimulation will act as the control group.

Portable devices for applying the transcranial electrical stimulation are equipped with a software which allows a double-blinded procedure. The same computer program is in charge of randomly allocating patients to one of the three treatment groups. Thus, nor the researchers neither the participants will know what kind of stimulation is receiving each of them.

Fifteen stimulation sessions applied with a daily frequency during an uninterrupted period of time which comprises just over two weeks. Current intensity of 2mA is applied during 20 minutes at the left M1, with anodal electrode placed in C3 and cathodal in FP2, following the International 10-20 EEG System. Ramp-up and ramp-down comprises 15 seconds at the beginning and end of the stimulation period.

Fifteen stimulation sessions applied with a daily frequency during an uninterrupted period of time which comprises just over two weeks. Two electrodes will be placed at F3 and F4 and connected together for 10-Hz tACS (or the frequency which shows best sensitivity or specificity), and one electrode at Pz will be the return electrode. This setting is used to stimulate the somatosensory cortical region. Stimulation will last for 20 minutes, with a ramp-up and ramp-down of 15 seconds at the beginning and end of the session.

The electrode montage will be either the tDCS (for half of the participants) or the tACS montage (for the other half), and we will just apply the current at the ramps terms, but no current in the interval between the ramps which practically comprises the whole session. As for the two other group, fifteen sham stimulation sessions will be daily scheduled in a non-interrupted period of two weeks.

By applying a low current over the cortex through the scalp, this technique can excite or inhibit the neural activity, thus modulating brain processes like pain perception and inducing relatively sustained changes in cortical excitability and neuroplasticity. Home-based transcranial electrical stimulation device consists of a custom headgear with fixed electrode sites and built-in cabling made for a simplistic setup for tDCS/tACS stimulation. Systems are equipped with strict dose control feature that provide reliable control over the intensity and timing of stimulation, turning these devices into a feasible and safe clinical alternative. The equipment is specifically designed for easy and simplistic self-setup and allows the researchers to remotely check the position of electrodes and also monitor the stimulation session.

Participants must evaluate the intensity of their pain using an online version of a Numerical Rating Scale of eleven points (0-10), so that the higher the score is, the worse the pain is.

Pre-treatment measure is the average of pain intensity of fifteen days previous to treatment; whereas the post-treatment measure is the average of fifteen days after treatment have finished

Composed index about the gravity of the chronic pain condition, taking into account several parameters as social and professional limitations due to pain, frequency and intensity of pain crisis, among others. The severity of chronic pain syndrome is assessed with global and subscales scores of Multidimensional Pain Inventory (MPI). Higher scores are indicative of worse health condition.

Participants will complete MPI one or two days before the treatment onset, and one or two days after treatment ending.

Pressure pain threshold is defined as the minimum force necessary to induce pain in the participant, measured using a manual algometer and operationalized in kPa.

Pressure pain thresholds will be assessed in face-to-face laboratory sessions, which would take place one or two days before the treatment onset and one or two days after treatment ending.

Heat pain threshold is stablished as the temperature, measured in degrees Celsius, at which participant starts to feel pain, using a thermal stimulator.

Heat pain thresholds will be assessed in face-to-face laboratory sessions, which would take place one or two days before the treatment onset and one or two days after treatment ending.

Subscales of Multidimensional Pain Inventory (MPI) are used to evaluate whether patients usually leave undone or are not capable to do some daily activities and tasks due to the pain they suffer from. The test consists of a numerical rating scale of seven points (0-6), so that the higher the score is, the more pronounced is the interference due to pain.

Pain interference will be assessed in face-to-face laboratory sessions, which would take place one or two days before the treatment onset and one or two days after treatment ending.

General health status considering physical, emotional and social functionality, as well as physical and mental health. Life quality is measured using the Short Form-36 Health Survey (SF-36). Higher scores are indicative of better health condition.

Life quality will be assessed one or two days before the treatment onset and one or two days after treatment ending.

Estimations about daily energy expenditure, based on sedentary and activity bouts are recorded with wristband actigraphs which participants must wear during the whole research period.

Sleep habits of participants and the degree in which they perceive that sleep as restorative. Sleep quality is measured using the Pittsburgh Sleep Quality Index (PSQI), a self-rated questionnaire which assesses sleep quality and disturbances over a 1-month time interval. Higher scores are indicative of poorer sleep quality.

Participants will complete PQSI at two time-points, this is, one or two days before the treatment onset and one or two days after treatment ending.

Sleep habits of participants, as total sleep time. This sleep parameter is measured using the data recorded for wristband actigraphs which participants must wear during the whole research period.

Wristband actigraph are given to patients fifteen days before the treatment onset, so sleep habits are monitorized since that moment, until fifteen days after treatment have finished

Affective component of pain, which refers to the discomfort or distress which pain provokes in patients. Participants must evaluate the discomfort produced by pain using an online version of a Numerical Rating Scale of eleven points (0-10), so that the higher the score is, the more stressful the pain is.

Pre-treatment measure is the average of pain unpleasantness obtained from fifteen daily assessments previous to treatment; whereas the post-treatment measure is the average obtained from the fifteen days after treatment have finished

Depressive and anxiety symptomatology which can concur with chronic pain conditions. Mood alterations are measured using the Hospital Anxiety and Depression Scale (HADS). Higher scores are indicative of a worse mood state.

Participants will complete HADS at two time-points, this is, one or two days before the treatment onset and one or two days after treatment ending.

General anxiety level are evaluated with a daily frequency using an online version of a Numerical Rating Scale of eleven points (0-10), so that the higher the score is, the higher the anxiety level is.

Pre-treatment measure is the average of anxiety levels obtained from fifteen daily assessments previous to treatment; whereas the post-treatment measure is the average obtained from the fifteen days after treatment have finished

Tiredness which may result in difficulties to perform physical or psychological tasks. Fatigue and its consequences are measured using the Modified Impact Fatigue Scale (MFIS). Numerical Rating Scales of eleven points (0-10) are also used to assess daily fatigue levels. In both cases, higher scores are indicative of a greater fatigue.

Fatigue is registered with a daily frequency since the fifteen days before the treatment onset, until fifteen days after treatment ending. Participants will complete the MFIS at two time-points, this is, one or two days before and after treatment.

Stress levels which are subjected the caregivers of chronic pain patients are evaluated through the Zarit Burden Interview (ZBI) to assess if tES treatment means a reduction in burden derived from caring tasks. Higher scores are indicative of a more pronounced caregiver burden.

Caregivers are invited to a face-to-face interview with researchers one or two days before the treatment onset and one or two days after treatment ending.

Patients are asked to rate their satisfaction with the tES treatment and whether they believe it has helped to improve their health status, using an ad-hoc designed questionnaire.

Inhibitory pain system will be assessed through the Conditioned Pain Modulation (CPM) paradigm, which consists of the reduction of the pain provoked by a given noxious stimulus (i.e., test stimulus) when another painful stimulus (i.e., conditioning stimulus) is applied to a remote area (i.e., pain inhibits pain). Tentatively, we will use the cold water immersion of the non-dominant hand as conditioning stimuli; whereas the test stimuli will be the pressure pain thresholds using a digital handhold algometer, which puts progressively heavier pressure over the lateral area of dominant forearm. Differences in pressure pain threshold between the standard condition and when the CS is applied is assumed as an index of pain inhibitory response. Negative values are indicative of a greater pain inhibitory response.

CPM procedure will be performed at two time-points, this is, one or two days before and after treatment, in order to assess if tES treatment is capable of restoring any dysfunction in this inhibitory pain network.

Amplifier pain system will be assessed through the Temporal Summation of Second Pain (TSSP) paradigm, which consists of the augmentation of subjective pain sensations due to the application of repeated noxious stimuli over the same corporal area, even when those stimuli are equal in terms of intensity and duration. Positive values are indicative of a greater pain facilitation score.

TSSP procedure will be performed at two time-points, this is, one or two days before and after treatment, in order to assess if tES treatment is capable of restoring any dysfunction in this facilitatory pain network.

Using the electroencephalography, we will capture the brain default mode network of chronic pain patients. Besides, we will register the evoked potentials elicited by diverse types of noxious heat-stimuli, as they may be reflecting how nociceptive signals are processed by brain. We purport to make a time-frequency and connectivity analysis of the EEG paying special attention to those key frequency bands involved in nociceptive perception, such as theta, alpha and gamma bands.

EEG will be registered at two time-points, this is, one or two days before and one or two days after treatment.

Inclusion Criteria: Suffering a chronic pain condition of non-cancer nature. Those patients who report chronic pain even after overcoming an oncological process are suitable to participate, but only if they have received the definitive medical discharge and have been free from radiotherapy/chemotherapy for at least twelve months. Adult subjects (18-65 years old). Subjects able to provide informed consent to participate in the study and to self-report pain. Existing chronic pain which reaches an intensity of at least 4 on a 0-10 Numeric Rating Scale (NRS) on average over the past 3 months prior to enrolment. Pain intensity of at least 5 on a 0-10 NRS over the week prior to enrolment. Diagnosis of pharmaco-resistance to analgesic drugs across the WHO ladder. Pharmacological regimen have kept stable for at least two months previous to the enrolment, and it must not suffer modifications during the whole research period. Exclusion Criteria: Chronic pain derived from current cancer disease. Pregnant women or women in fertile age not having efficacious contraception during the whole period of the study. History of alcohol or drug abuse within the past 6 months as self-reported. Suffering from unstable medical conditions (e.g., uncontrolled diabetes, uncompensated cardiac issues, heart failure or chronic obstructive pulmonary disease). Intracranial ferromagnetic devices or implanted stimulator (basal ganglia stimulator, vagus nerve stimulation). Antecedents of, or active epilepsy. History of neurosurgery, psychiatric diseases other than anxiety or depression, traumatic brain injury with loss of consciousness, and/or cortical lesions.

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