Brain and Pain (BaP): Understanding the Central Mechanisms of Pain to Improve Management of Patients With Refractory Chronic Pain
Phase: NA
Conditions: Chronic Pain
Sponsor: University of Santiago de Compostela

 
 
 
Brain and Pain: Understanding the central mechanisms of pain to 
improve management of patients with refractory chronic pain 
Research centre and investigator details: 
Research institution: Universidade de Santiago de Compostela 
Research centre: Brain and Pain research group (BaP) 
Address line: Campus Vida, Calle Xosé María Suárez Núñez, s/n, 15782 
City: Santiago de Compostela 
Postcode: 15705 
Country: Spain 
Principal researcher: Carrillo de la Peña, María Teresa 
Collaborating researchers: González Villar, Alberto; Sanmartín Veiga, Noelia; Fernández 
Feijoó, Fátima; Vázquez Millán, J. Antonio; Gil Ugidos, Antonio; Carceller Ruiz, José 
Javier; López País, Pablo; Mayo Moldes, Mónica. 
Contact emails: mteresa.carrillo@usc.es and joseantonio.vazquez.millan@rai.usc.es  
Index of contents 
1. Justification of the project and theorical framework ............................................. 2 
2. Objectives and hypothesis ..................................................................................... 6 
3. Study design .......................................................................................................... 7 
4. Sample and recruitment ......................................................................................... 8 
5. Description of the treatment ................................................................................ 11 
6. Evaluation protocol and follow-up ...................................................................... 13 
7. Data analysis plan ................................................................................................ 21 
8. Chronogram ......................................................................................................... 24 
9. Security and ethical-legal issues .......................................................................... 26 
10. References .......................................................................................................... 29 

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1. Justification of the project and theorical framework 
Chronic pain is one of the most important public health priorities of the 21st century 
(Langley et al., 2011; Dueñas et al., 2015). It is estimated that about 19-25% of adult 
Europeans suffer from chronic pain of moderate to severe intensity, with increased 
prevalence as population ages (Breivik et al., 2006). Management of chronic pain implies 
an enormous economic burden for public health systems, and continues to be a challenge 
for healthcare providers, due to the inefficacy of current treatments (Leadley et al., 2012). 
Conventional management of chronic pain is based on a combination of 
pharmacological and non-pharmacological therapies including oral nonsteroidal, anti-
inflammatory drugs, intra-articular injections, physical therapy and opioid analgesics 
(Hochberg et al., 2012; Chaparro et al., 2014). However, these options have only 
demonstrated a partial efficacy and their benefits usually decrease over time (due to 
therapy tolerance, disease progression, and/or neural sensitization of pain-related neural 
structures), in addition to the adverse effects which accompany these therapies and 
counteract their benefits (Reinecke et al., 2015). 
Refractory, pharmaco-resistant patients are a challenge for multiple medical 
departments, and it becomes necessary to consider alternative strategies (Leadley et al., 
2012). To do so, we propose a shift from a disease-oriented to a mechanism-based 
management strategy of chronic pain. Chronic pain is a complex sensory and emotional 
experience that varies widely among people, depending on the context, individual 
construct of pain, and physiological state (Bushnell et al., 2013). It is defined as a 
persistent (lasting beyond 3 months) and maladaptive response, without the protective 
function of acute nociceptive pain (Treede et al., 2015; Merskey & Bogduk, 2012). 
Although chronic pain diseases are very heterogeneous in terms of aetiology and 
clinical manifestations, they may share similar pathophysiological mechanisms related to 
the processing and inhibition of pain. Thus, multiple studies confirm that chronic pain 
sufferers tend to present a pattern of increased excitability to pain, and limited central 
analgesic regulation relative to healthy controls (Staud et al., 2008; Potvin & Marchand, 
2016; Kosek & Ordeberg, 2000). 
Therefore, constructing a mechanism-based management strategy of chronic pain 
requires to find techniques which target the brain processing of nociceptive signals and 
the central nervous dysfunctions present at chronic pain patients (Macfarlane et al., 2017). 

Brain and Pain (BaP): Efficacy of home-based tES to treat chronic pain 
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In this vein, non-invasive brain stimulation (NIBS) techniques have become the forefront 
of novel experimental treatments of chronic pain. Those techniques have proved to be 
capable of modulating brain activity without surgical interventions and offer new 
methods to modulate pain-related brain activity in order to reduce pain suffering (Zortea 
et al., 2019), thus becoming an interesting alternative to traditional therapeutic 
approaches. 
One of these techniques for brain stimulation is the transcranial Electrical 
Stimulation (tES).  By applying a low current over the motor cortex through the scalp, 
this technique can excite or inhibit the neural activity, thus modulating brain processes 
like pain perception (Nitsche & Paulus, 2000; Nitsche et al., 2008). The most frequently 
used tES technique is transcranial Direct Current Stimulation (tDCS). It consists of 
the application of a constant low-intensity current (1-2 mA) usually through 2 electrodes 
(anode and cathode) placed on the scalp. This stimulation induces relatively sustained 
changes in cortical excitability and neuroplasticity (Paulus, 2003). More recently, 
transcranial Alternating Current Stimulation (tACS) has been used to modify cortical 
functioning (Fröhlich et al., 2015). 
Transcranial electrical stimulation may be a key component for correcting defective 
central pain generating mechanisms. tDCS has been suggested to induce anti-nociceptive 
effects on experimental pain and have pain-relieving effect in different clinical 
conditions, using anodal stimulation over the precentral region contralateral to pain 
(Santos-Portilla et al., 2013). Although different cortical brain targets have been tested, 
the stimulation of primary motor cortex (M1) appears the most effective cortical target in 
chronic pain patients and their clinical improvements last beyond the time stimulation, 
probably due to solid neuroplastic modifications (Lima & Fregni, 2008). This finding is 
consistent with the hypothesis that cortical networks play a key role in pain processing 
and that the primary motor cortex (M1) may be a gateway to deep pain-related networks 
such as the thalamic nuclei and the cingulate gyrus (Baliki et al., 2008; Maarrawi et al., 
2007). Evidence for pain reduction through M1 tDCS has been reported for chronic pain 
manifestations as diverse as pelvic pain, spinal cord pain, cancer, diabetic neuropathy, 
low-back pain, temporomandibular disorders, and migraine, among others (Lefaucheur, 
2016). 
Transcranial electric stimulation (tES) has several advantages: it is portable, non-
invasive, engineered from low-cost components, has minimal adverse effects, is well 

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tolerated, easy to use, and multiple animal and clinical studies confirm its safety at low 
intensities. Recently, a compendium of experts on tDCS released a review covering more 
than 18,000 stimulation sessions (≈8,000 patients) in which no significant adverse events 
were reported for multiple populations (Antal et al., 2017). 
Nevertheless, there are some gaps in this field. First, the evidence of its efficacy for 
pain relief is still limited, as recent Cochrane reviews on the effectiveness of tDCS in 
chronic pain concluded that the evidence available is not solid enough (O’Conell et al., 
2014; 2018). Most current studies still have significant biases (not blinded or placebo-
controlled), poor methodological quality (insufficient number of sessions, no follow-ups) 
and small sample sizes.  
Second, previous studies have exclusively focused in tDCS, without paying attention 
to tACS. In the unique previous clinical trial with chronic low back pain patients, Ahn et 
al. (2019) found significant correlation between alpha power and pain. Interestingly, 
stimulation with tACS significantly enhanced alpha oscillations in the somatosensory 
region, and this increase was correlated with pain relief. Therefore, tACS demonstrate 
having the potential to relief pain, but it also can help to clarify the mechanism by which 
tES can modify cortical networks involved in pain (Woods et al., 2016; Peng & Tang, 
2016). 
Furthermore, no alternatives to the hospital delivery of this treatment have been 
explored. Although the tES equipment can be controlled remotely and thus allows home-
based interventions. At-home interventions are positively perceived by the patients, as 
they reduce the time involved in treatment and visits to medical centres, favouring self-
management of the disease and reducing the burden on family members; also, they 
increase the efficiency of the professionals, who can attend several patients at the same 
time. 
As we stated before, we are particularly interested in delving into the 
pathophysiological mechanisms which are associated with chronic pain. Therefore, this 
clinical trial aims to evaluate the changes in these mechanisms due to the treatment with 
transcranial electrical stimulation. To this end, we will use two quantitative sensory tests 
(QST) to assess central nervous dysfunctions in processing and inhibition of pain in 
clinical population, namely Conditioned Pain modulation (CPM) and Temporal 
Summation of Second Pain (TSSP).  

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Conditioned Pain Modulation 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; Yarnitsky et 
al., 2010; Willer et al., 1984); whereas TSSP occurs when repeated noxious stimuli over 
the same corporal area amplifies pain sensations, probably due to a central sensitization 
derived from the enhanced response of dorsal horn neurons to repetitive nociceptive 
signals from C-fibers (Dickenson, 1997). Concerning CPM response, approximately 70% 
of chronic pain patients display a large and statistically significant reduction in their pain 
inhibition system relative to healthy controls, as evidenced in a meta-analysis by Lewis 
et al (2012). At the same time, various studies have found greater TSSP in chronic pain 
patients relative to healthy controls (Staud et al., 2001; Arendt-Nielsen et al., 2010; 
Petersen et al., 2015) 
Altogether, the existing evidence supports that both CPM and TSSP could act as 
biomarkers of endogenous pain modulation to distinguish chronic pain patients. In fact, 
the efficiency of these endogenous modulatory pain systems could serve as a predictor of 
treatment outcomes with tES. 
Lastly, the study of brain electrical activity recordings (EEG) in resting state and in 
response to noxious stimuli may also help to characterize the brain processing of 
nociceptive stimuli and how these signals are amplified or mitigated (González-Villar et 
al., 2019). For this reason, another purpose of this research is to evaluate the changes in 
neural patterns which occurred in chronic pain patients after transcranial electrical 
stimulation treatment. Specifically, 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 (Hu et al., 2013; Liberati et al., 2017; Fallon et al., 2018), namely 
Theta (≈4-7 Hz), Alpha (≈8-12 Hz) and Gamma (≈35-70 Hz). Brain activity will be 
recorded both in resting-state (Fallon et al., 2016; Choe et al., 2018) and in response to 
painful heat and cold stimulation (De Keyser et al., 2018; De Tomasso et al., 2014, 2017). 
 
 

Brain and Pain (BaP): Efficacy of home-based tES to treat chronic pain 
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2. Objectives and hypothesis 
The main objective of this clinical trial is to test the efficacy of two different transcranial 
electrical stimulation techniques (tES) to modify dysfunction of central modulatory 
mechanisms of pain, and to improve symptoms and quality of life in refractory chronic 
pain patients. 
In this vein, we hypothesize that transcranial electrical stimulation procedures will be 
more effective than sham to improve pain and related symptoms. Besides, central 
biomarkers of pain processing and modulation (i.e., CPM, TSSP and EEG) will be useful 
to predict the patient response to treatment and thus, the efficacy of these tES procedures. 
Based in these principal ideas, we propose the following secondary or specific 
objectives: 
A. To analyse the relationship between the studied biomarkers and clinical pain 
characteristics of patients (intensity, location, frequency, duration, daily 
interference caused by pain). 
B. To stratify patients and propose profiles based on the selected biomarkers, which 
may be useful to improve diagnosis and to guide individualized treatment plans. 
C. To develop home-based treatment schemes for patients with refractory chronic 
pain. We will assess if tES procedures are safe, feasible and acceptable for the at-
home management of this medical condition. 
D. To test if tES techniques are self-manageable by patients and to observe the impact 
of this treatment in the caregiver-burden declared by the reference person. 
E. To test the efficacy of tDCS (Direct current) versus tACS (Alternant current) to 
modify dysfunction of central endogenous analgesia (i.e., CPM and TSSP) and to 
reduce pain and related symptoms in the patients, in a placebo-controlled clinical 
trial. 
F. To analyze how the different tES techniques (tDCS and tACS) affect brain 
oscillatory activity, and to test if the changes in oscillatory activity are related to 
pain relief. 
G. To test the power of the biomarkers/patients’ stratification to predict treatment 
efficacy and to identify the characteristic of best responders patients. 

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H. To assess the effect of sex/gender and other modulator variables (age, disease 
duration, medication, lifestyle, mood…) on all the analyses (central biomarkers, 
patients’ stratification, response to treatment…). 
3. Study design 
The research is classified as a double-blinded, randomized clinical trial with one control 
group which receive a sham stimulation. 
The transcranial electrical stimulation intervention is considered the independent 
variable, which contains three different conditions or categories differentiated by the type 
of stimulation used. These conditions define the three groups of treatment: 
1) Transcranial direct current stimulation (tDCS), which induces a continuous 
current over the left primary motor cortex (M1). Current intensity is set at 2mA 
and it is applied for 20 minutes, with ramp-up and ramp-down of 15 seconds at 
the beginning and end of the stimulation period. 
2) Transcranial alternat current stimulation (tACS), which induces an alternant 
current over somatosensory cortical region. Current intensity is set at 10-Hz and 
it is applied for 20 minutes, with ramp-up and ramp-down of 15 seconds at the 
beginning and end of the stimulation period.  
3) Sham stimulation, which acts as a placebo-control group. It uses the same 
montage as the previous ones, but it does not emit any kind of current. The 
position of electrodes will be similar to the previous conditions, but the current 
will be just activated during the ramp-up and ramp-down moments. 
Chronic pain patients are randomly assigned to one of these groups, although the 
active stimulation conditions agglutinate the 80% of sample (40% tDCS; 40% tACS), 
whereas the control group contains by the remaining 20%. 
As dependent variables, we consider the assessed clinical symptoms, mainly pain 
characteristics (including intensity, location, frequency, duration and daily interference 
caused by pain), fatigue, depression/anxiety, sleep quality, physical functioning and life 
quality, following the guidelines proposed by the Initiative on Methods, Measurement, 
and Pain Assessment in Clinical Trials (IMMPACT; Dworkin et al., 2005). 

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Besides, as far as we aim to assess the efficacy of tES techniques to restore the 
potential dysfunctions in processing and modulation of pain in patients, central 
biomarkers as Conditioned Pain Modulation (CPM), Temporal Summation of Second 
Pain (TSSP) and EEG are also included as dependant variables. Thus, we try to identify 
any change in these variables which could be attributable to the intervention. 
The intervention and evaluation protocols are more in-depth defined in the following 
sections. 
4. Sample and recruitment 
For planning the sample size for this research, we used Gpower (v.3.1.9.2) software. 
Sample size was estimated for repeated measures ANOVA with three groups (tDCS, 
tACS, Sham) and two measurements (pre-treatment vs. post-treatment). Statistical power 
(SP) was predetermined a priori with a value of SP=0.99 (α=0,01) to increase the validity 
of the subsequent analysis and ensure that we do not miss any statistically significant 
result. 
We based the calculation on the data extracted from the meta-analysis by Zortea et 
al. (2019), who reported a moderate effect size for reduction of pain levels (F=0.68) in 
chronic non-cancer pain patients using the tDCS montage stimulating M1. These results 
were obtained after comparing 380 patients receiving  active tDCS versus 381 who were 
given Sham stimulation. 
Assuming this moderate effect size and the rest of described parameters (SP=0,99), a 
total of 21 patients would be large enough to detect statistically significant changes in the 
whole sample. However, it cannot be ignored the non-despicable drop-out rates of this 
patient profile, corroborated by the own researchers in previous investigations. Besides, 
we are interested in assessing the effect size of the tDCS intervention among the different 
categories or types of chronic pain, just as defined by the ICD-11 (Treede et al., 2015), 
and that requires to create big enough comparable groups. For these reasons, we decided 
to recruit a larger number of participants, thus stablishing the sample size in 120 patients 
with refractory chronic pain.  
Concerning this research, pain is defined as refractory, regardless of etiology, when 
it meets the two following conditions. First, multiple evidence-based biomedical therapies 

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used in a clinically appropriate and acceptable fashion have failed to reach treatment goals 
that may include adequate pain reduction and/or improvement in daily functioning or 
have resulted in intolerable adverse effects. Second, pain persists even after psychiatric 
disorders and psychosocial factors that could be influencing treatment outcomes have 
been assessed and appropriately addressed. 
Epidemiological studies have consistently reported higher prevalence rates of  
chronic pain syndromes among women, compared to men (Jiménez-Trujillo et al., 2019; 
Cimas et al., 2018). As we intend to create a feasible and useful tool for clinical practice, 
these gender differences must also be considered when designing the recruitment plan 
and deciding the sex distribution of the sample. As we aim to assess the influence of 
sex/gender in tDCS treatment efficacy and central pain modulation mechanisms, we will 
recruit both male and female patients, although the latter will represent about 70% of the 
total sample, in accordance with clinical reality; whereas males will represent at least the 
30% of the selected patients, in order to improve and facilitate subsequent comparative 
analysis. The inclusion criteria applied for the selection of patients are the following:  
• 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. 
Participants are allowed to continue with their usual pharmacological regimen, but it 
must have been stable during the two months previous to the enrolment, and it must not 
suffer modifications during the whole research period. We will account for the potential 
effects of some drugs over the efficacy of tDCS/tACS treatment (McLaren et al., 2017), 
making a registry of patients pharmacological prescriptions to consider them in further 

Brain and Pain (BaP): Efficacy of home-based tES to treat chronic pain 
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analysis. Rejecting patients who consume medicaments which can apparently interfere 
with tDCS/tACS effects would not be a well-balanced alternative and would result in a 
huge loss of participants, since some of these drugs are included as priority treatment for 
many chronic pain conditions. As far as the exclusion criteria are concerned, they are 
exposed below: 
• 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 (pacemaker, 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. 
For recruitment phase, we count on the collaboration of three physicians from the 
Public Health System who work in regional specialized units for the treatment of pain. 
They will inform those patients who match the inclusion criteria about the existence and 
nature of the research, offering them the possibility of participating in. Patients who show 
interest are required to sign an initial consent which allows principal researchers to get in 
touch with them by telephone. At that moment, patients will be given a more in-depth 
explanation about the clinical intervention and their implications; researchers will also 
check that the patient comply with inclusion criteria and he/she does not meet any 
exclusion criteria. 
Those patients who agree to receive the treatment are summoned to a face-to-face 
session at the research group laboratory. At this stage, patients must sign the informed 
consent to participate in the research and right after the pre-evaluation protocol is 
implemented. 

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In another vein, this research also seeks to determine whether the home-based 
treatment approach is feasible to be applied by patients themselves and how it affects to 
the caregiving workload for the reference person1. To this end, in the initial phone call 
patients will be asked for identifying that caregiver figure in their own life, in case it 
effectively exists. Caregiver is defined as the person who worries about the patient’s 
health condition, helps them in daily chores and, in sum, is in charge of covering their 
emotional and material needs (Bookman & Harrington, 2007). 
Identified caregivers are invited to a brief face-to-face interview to evaluate their 
burden and health status. Given the exploratory character of this purpose, we do not set a 
priori sample size for caregivers, although the question about the caregiver will be 
formulates to all the patients. 
5. Description of the treatment 
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. This is possible because the devices have an Internet wireless 
connection and send the data obtained to an online platform, only accessible to the 
principal researchers. 
From pre-stimulation set-up, to during stimulation monitoring, to post-stimulation 
confirmation, the device provides an intuitive and clear indication of electrode contact 
quality, facilitating the proper adjustments to ensure a successful stimulation. In case 
stimulation is aborted or interrupted, impedance is abnormal, or other faults are detected, 
the system will automatically abort or alter stimulation and the incident details stored. 
This system also allows researchers to supervise the treatment compliance. 
 
1 It must not be overlooked that patients with chronic pain can find difficulties/limitations to 
accomplish the basic daily tasks and thereby be partially dependant (Meulders, 2019; Zale et al., 2013) 

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Besides, these devices uses a software which allows a double-blinded procedure. Nor 
the researchers neither the participants will know what kind of stimulation is receiving 
each of them. 
The intervention plan comprises fifteen stimulation sessions applied with a daily 
frequency during an uninterrupted period of time which convers just over two weeks. 
Thus, sessions will be scheduled for each patient before the beginning of the treatment, 
arranging with the patient the hour frame for stimulation. Stimulation parameters/sites for 
each condition will be as follows:  
• Transcranial direct current stimulation (tDCS). Current intensity of 2mA 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. 
• Transcranial alternant current stimulation (tACS). Following the design 
stablished by previous studies (Ahn et al., 2019), two electrodes will be placed at 
F3 and F4 and connected together for 10-Hz tACS (or the frequency which shows 
best sensitivity or specific), 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. 
• Sham stimulation. 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. 
At the second pre-treatment evaluation session, patients will receive the portable 
stimulator with the properly explanations about its functioning. It is planned to make a 
training stimulation session during this visit to ensure that patients are able to connect and 
manage the device. 

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6. Evaluation protocol and follow-up 
6.1. Evaluation phases 
Regarding the evaluation protocol, pre-treatment assessment is divided in two different 
sessions, separated by two weeks. 
After obtaining their contact number from physicians, researchers maintain a first 
phone talk with the proposed participants to ensure they not comply with any exclusion 
criterion. During this brief interview, the first meeting with patients is also scheduled, 
according to their availability. 
The first face-to-face session is intended to initiate the pre-evaluation process and it 
takes place fifteen days before starting the treatment. After signing the informed consent, 
participants will complete an exhaustive assessment protocol which includes an interview 
about their health status and clinical history, a set of quantitative sensory tests (Pain 
thresholds, CPM, TSSP) and some other questionnaires to assess psychosocial variables. 
From this point to the end of the post-treatment evaluation, patients are required to 
complete a daily online survey about their symptoms and health condition. Moreover, 
patients will be given a wristband actigraph which should wear during the whole research 
period (except follow-up), in order to monitor their physical activity and sleep patterns. 
The next evaluation will take place two weeks after the first one. During this period, 
participants are required to complete a daily online survey about their symptoms and 
health condition. Moreover, they are given a wristband actigraph which allows to monitor 
their physical activity and sleep patterns. 
At the second session, patients will complete electroencephalographic records in 
different conditions and tasks, some of which include painful stimuli. Furthermore, we 
will collect additional clinical features through validated questionnaires and may also 
repeat the quantitative sensory testing. Caregivers of chronic pain patients will also be 
invited to this appointment to maintain an interview with researchers, which aims to 
determine their health status and the stress-related to the caring tasks. 
Finally, researchers will give the participants the portable stimulator to apply the 
tDCS/tACS treatment, with the properly explanations about its functioning. It is planned 
to make a training stimulation session during this visit to ensure that patients are able to 

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connect and manage the device; researchers will also be available to make a video-call to 
assist the participant in the first stimulation session. 
After completing the treatment period, participants are summoned to other two 
evaluation sessions with the same structure and assessment tools as in pre-treatment 
phase; in case of the daily measurements, the comparison is made between the average of 
the pre-treatment period and that of the post-treatment period. Therefore, differences 
observed between these two time-measurements are considered as index of the treatment 
efficacy. At the post-evaluation session, participants will also answer some questions 
about the satisfaction with the treatment and self-perceived usefulness/improvement. 
Finally, in order to assess the long-term improvement derived from tES, we will 
contact participants by phone in order to invite them to a follow-up session six months 
after finishing the treatment. All questionnaires and sensory tests will be applied in the 
same way, except for daily numerical rating scale. Differences between these results and 
those obtained in pre-evaluation and post-evaluation will be analysed. 
6.2. Evaluation methods and assessment tools 
The following section provides a more in-depth description about the methodology used 
to evaluate the patients and their characteristics. The assessment process includes a 
compendium of questionnaires about clinical and psychosocial characteristics, several 
quantitative sensory tests and EEG records in diverse conditions.  
Regarding the first face-to-face session, we collect relevant sociodemographic data 
to characterize the sample (e.g., sex, age, occupation, dependency certificate), which does 
not enable to know the personal identity. The interviewers also inquire about medication 
and lifestyle questions, such as smoking, alcohol consumption, drug use and physical 
activity. Patients may also be requested to execute some short physical tasks (for example, 
Stais Climb Test) to obtain a performance-based index of their physical function (Dobson 
et al., 2013). We also question about the type and onset of chronic pain, and whether 
he/she has been diagnosed with other relevant medical or psychiatric conditions. 
Clinical features and health condition are assessed using the translated version of 
reliable and validated questionnaires for Spanish chronic pain population. At this initial 
stage, we focus on assessing relatively stable measures: 

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• Multidimensional Pain Inventory (MPI; Kerns et al., 1985; Pastor et al., 1995). It 
serves as a general index about the severity of the disease by asking for pain 
intensity, daily interference, self-perceived control over pain and perceived 
support from significant others. 
• Short Form Health Survey SF-36 (Vilagut et al. 2005). World widely used, this 
questionnaire provides a complete picture of the participant health state, including 
subscales about vitality, mental health and physical, emotional and social 
functioning, among others. 
We will also perform the quantitative sensory testing, which consists of the pain 
thresholds and the above-mentioned procedures to assess abnormalities in endogenous 
modulatory pain mechanisms, namely Conditioned Pain Modulation (CPM) and 
Temporal Summation (TSSP).  
Pain thresholds are defined as the minimum intensity which must reach a stimulus to 
become in painful, as perceived and reported by the own person. Pressure pain threshold 
will be calculated using a digital handhold algometer (Wager Force One Model) which 
puts progressively heavier pressure over the skin surface. Heat pain threshold is obtained 
with a computerized thermal stimulator which progressively enhances the temperature of 
the skin with a small contact metal plate. In both cases, pressure and temperature increases 
to a constant pre-fixed rate, until the participant press a button to indicate she/he starts to 
feel pain. Pressure pain threshold is measured in kPa, whereas heat pain threshold is 
stablished as the temperature in degrees Celsius. 
Although the specific CPM and TSSP protocols are not completely defined yet, we 
count with a wide catalogue of usually used instruments and equipment to perform these 
tests (Fernandes et al., 2019; O’Brien et al., 2018) 
Conditioned Pain Modulation requires of two different painful stimuli applied in 
heterotopic body areas; thus, the conditioning stimuli (CS), tonic in nature, reduces the 
pain sensations from the phasic test stimuli (TS). As CS, we will use the ischemic pain 
produced by pressure cuff and/or the cold pressor test, which means the participant have 
to immerse their non-dominant hand into cold water. Regarding TS, we opt for the same 
procedures as to calculate the pain thresholds (i.e., digital handhold algometer and thermal 
stimulator), given that we aim to compare these isolated thresholds with those obtained 

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while the CS is present. The difference between these two measures is stablished as the 
CPM index. 
Tentatively, Temporal Summation of Second Pain (TSSP) will be evoked with the 
thermal stimulator. After stablishing the parameters which corresponds to a medium pain 
level (5/10 NRS) for each participant, it will be applied ten repetitive pulses with that 
temperature over the skin, separated by two and a half seconds. Patients have to rate the 
pain intensity which produces the first, fifth and last stimuli. The difference in pain 
intensity between the first and last pulse is stablished as the TSSP index. 
Finally, we will explain the daily assessment plan to patients, which starts at this point 
(i.e., fifteen days before the treatment onset) and continues until fifteen days after the 
stimulation sessions have finished. Every day during this period, participants will be 
requested to complete a brief online survey to track the intensity of their symptoms and 
obtain a more reliable measure. These questionnaires will be sent to patients by phone 
message, after getting permission from participants. 
Specifically, the daily survey consists of several Numerical Rating Scales (NRS) of 
eleven points (0-10) which ask about the intensity and unpleasantness of pain, 
interference, fatigue and medication usage, among others. During treatment period, 
participants can also report any side effect of stimulation through these questionnaires. 
For each symptom, we will obtain an average of measures obtained before starting the 
treatment, other average with measures during the treatment and one last average for post-
treatment phase (e.g., fifteen days after finishing the intervention). 
Moreover, patients will be given a wristband actigraph which should wear during the 
whole research period. These devices are capable of detecting the sedentary and activity 
bouts, as well as the intensity of these last ones, the raw acceleration and the distance 
walked every day. Besides, actigraphs can also measure the total sleep time, the sleep 
latency and the awakenings after sleep onset. Thanks to this actigraphy technology, 
physical functioning and sleep patterns will be effectively daily evaluated. 
Thus, by the day of the second evaluation session, we will have already obtained a 
set of daily measures whose average will serve as a reliable clinical baseline. In this 
second appointment, as part of the potential biomarkers of chronic pain, we will register 
the electroencephalography (EEG) of the patients during various conditions (Davis et al., 
2017). Firstly, EEG will be assessed during a resting state to capture spontaneous brain 

Brain and Pain (BaP): Efficacy of home-based tES to treat chronic pain 
17 
 
activity, the spectral power of the oscillations and inter-site phase connectivity (Ploner et 
al., 2017). Secondly, we will analyse wave components of the contact heat evoked 
potentials (CHEPs) to obtain a neural correlate of the painful stimuli processing. For last, 
in order to study the modulatory role of attention in pain perception, we propose to obtain 
the evoked potential derived from a TSSP protocol, both paying exclusive attention to 
pain and during a simple cognitive task. 
Besides, we will repeat the same procedure of quantitative sensory testing to ascertain 
its reliability. Finally, the following questionnaires will be used to get an accurate measure 
of some key symptoms and problems which usually accompanies chronic pain: 
• Hospital Anxiety and Depression Scale (HADS; Cabrera et al., 2015). It 
represents a really useful tool to assess mood state and screen for depressive or 
anxiety disorders, which frequently cooccurs with chronic pain. 
• Modified Fatigue Impact Scale (MFIS; Duarte et al., 2017; Kos et al., 2005), 
which accounts for the physical, emotional and social components of fatigue. 
Fatigue usually accompanies chronic pain conditions and results in great 
limitations for the daily functioning of patients. 
• Pittsburgh Sleep Quality Index (PSQI; Macías & Royuela, 1996). This inventory 
inquiries into several areas about the sleep patterns, such as the related disorders, 
the self-perceived quality or the time passed until falling asleep. 
• Zarit Burden Interview (Martín et al., 1996). This instrument is used with the 
principal caregivers of the patients to assess the stress and negative feelings 
associated with the caring tasks. Thus, it represents the core of the evaluation 
protocol for caregiver, and it intends to pay attention to this figure but also to add 
information about the patient autonomy. 
In sum, all the proposed questionnaires assess relevant clinical variables which are 
expected to be improved by tES treatment. Therefore, changes observed in them between 
pre- and post-evaluation will be subjected to statistical analysis and taken as efficacy 
indices of treatment. 
However, there are some other variables which, despite not expecting to be modified, 
could influence the treatment outcomes for better or worse. We refer to social support, 
self-perceived stress, catastrophizing thinking and beliefs about controllability of pain 

Brain and Pain (BaP): Efficacy of home-based tES to treat chronic pain 
18 
 
(Adams & Turk, 2015; Keefe et al., 2004; Jensen et al., 2011). Thus, these factors must 
be taken into account when assessing the efficacy of tES intervention and we intend to 
account them as covariates in statistical analysis. 
Changes observed in criteria variables between pre- and post-evaluation must be 
equal or higher than the 30%, in order to ensure their clinical significance. It means that 
the improvement observed in self-reported questionnaires and in sensory testing (except 
for EEG) have to achieve or surpass the 30% of the original outcome. The direction of 
these differences depends on the specific scale; for example, it is expected a reduction in 
the global MPI score after treatment, but also a rise in pain thresholds. In the case of EEG, 
the analysis pre-post treatment are only subjected to the statistical significance. However, 
changes in brain activity patterns attributed to the tES will be tried to relate with 
improvement in clinical features. 
Although all explained measurements are considered as success criteria of treatment, 
we selected pain intensity as the primary end point, taken as the average obtained from 
daily numerical rating scale. In this sense, participants will be classified into responders 
when they report, at least, a 30% decrease in their pain intensity. The rest of the variables 
are taken as secondary end points and are also regarded as treatment-efficacy indexes, 
basically the pain thresholds, life quality, physical functioning, interference caused by 
pain, pain unpleasantness, sleep quality, depression/anxiety, fatigue, caregiver burden and 
CPM/TSSP responses. 
 

Brain and Pain (BaP): Efficacy of home-based tES to treat chronic pain 
19 
 
Table 1: End points of the clinical trial and their respective evaluation instruments 
End points 
Assessment tools 
Primary end point 
Pain intensity 
Numerical Rating Scale of eleven points 
(0-10 NRS). Average obtained from daily 
self-reports during the fifteen days before 
treatment and the fifteen days after 
treatment. 
Secondary end points 
Global severity of chronic pain syndrome  
Global and subscales scores of 
Multidimensional Pain Inventory (MPI). 
Interference caused by pain in daily living 
Subscale score of Multidimensional Pain 
Inventory (MPI). 
Numerical Rating Scale of eleven points 
(0-10 NRS). Average obtained from daily 
self-reports during the fifteen days before 
treatment and the fifteen days after 
treatment. 
Pain thresholds 
Pressure pain threshold using a digital 
handheld algometer, measured in kPa. 
Heat pain threshold using thermal 
stimulator, measured in degrees Celsius. 
Life quality 
Short Form Health Survey SF-36 
Physical functioning 
Daily recorded physical activity using 
actigraphy technology. 
Subscales scores of Multidimensional 
Pain Inventory (MPI) 
Sleep quality 
Pittsburgh Sleep Quality Index (PSQI) 

Brain and Pain (BaP): Efficacy of home-based tES to treat chronic pain 
20 
 
Daily recorded sleep quality using 
actigraphy technology. 
Pain unpleasantness 
Numerical Rating Scale of eleven points 
(0-10 NRS). Average obtained from daily 
self-reports during the fifteen days before 
treatment and the fifteen days after 
treatment. 
Mood and emotional functioning 
Hospital Anxiety and Depression Scale 
(HADS) 
Numerical Rating Scale of eleven points 
(0-10 NRS) for assessing daily anxiety. 
Average obtained from daily self-reports 
during the fifteen days before treatment 
and the fifteen days after treatment. 
Fatigue 
Modified Fatigue Impact Scale (MFIS) 
Numerical Rating Scale of eleven points 
(0-10 NRS). Average obtained from daily 
self-reports during the fifteen days before 
treatment and the fifteen days after 
treatment. 
Caregiver burden 
Zarit Burden Interview (ZBI) applied to 
the identified reference person in charge 
of caring the patient 
Endogenous pain inhibition response 
Score obtained from Conditioned Pain 
Modulation (CPM) procedure 
Endogenous pain facilitation response 
Score obtained from Temporal 
Summation of Second Pain (TSSP) 
procedure 

Brain and Pain (BaP): Efficacy of home-based tES to treat chronic pain 
21 
 
Global satisfaction with treatment and self-
perceived improvement 
Ad-hoc designed questionnaire 
7. Data analysis plan 
First of all, we will perform reliability analysis on sensory measures, such as pain 
thresholds, CPM and TSSP magnitudes. The Intraclass Correlation Coefficient to stablish 
the degree of association and agreement among the two scores obtained for each test. 
After applying the pertinent filters to EEG records and once the descriptive analyses 
of the sample have been done, we will observe the correlation of the CPM/TSSP response 
and the EEG registry with the clinical features of the sample, taking into account just the 
pre-treatment evaluation. In order to reinforce the results, we may add Linear regression 
analysis to verify whether the dysfunctions in central modulatory mechanisms and brain 
processing of painful stimulus (CPM, TSSP, EEG) can act as predictors of the symptoms 
severity of chronic pain patients. 
Besides, we will conduct simple ANOVA analyses to compare these indexes of pain 
processing and modulation (CPM, TSSP, EEG) between specific groups of patients, 
divided by type/origin of chronic pain and sex. We reserve the possibility of making 
Cluster analyses in the basis of the mentioned central biomarkers, following by an 
ANOVA comparison of clinical features between the emerged groups. 
Besides, participants will be classified into CPM and TSSP respondents or no-
respondents taking into account their results in these sensory tests. Those patients who 
report a significant increment in pain thresholds will be considered respondents; whereas 
the opposite applies for TSSP, as it must be detected a significant increasement in 
perceived pain intensity in the last pulse compared to the first one. Depending on the 
proportions observed, it could be useful to divide TSSP respondents based on the degree 
of the pain sensitization. Regarding this sample division, we can compare the clinical 
profile of respondents and non-respondents patients using Chi square statistic. 
As far as intervention efficacy is concerned, qualitative analyses will focus on 
differentiating the patients who effectively respond to treatment (Treatment-respondents) 
from those who do not improve (Non-treatment-respondent). Respondents are those 

Brain and Pain (BaP): Efficacy of home-based tES to treat chronic pain 
22 
 
participants whose improvement in a certain clinical variable are equal or higher than the 
30%; whereas non-respondents are all those who do not comply with this criterion. This 
variation is extracted from the comparison of pre- and post-treatment measurements. 
Therefore, for each of the endpoints, we will obtain a number/percentage of 
respondents and non-respondents. Using the Chi-square test, we will compare the 
proportion of respondents between treatment groups to identify the most efficacious 
stimulation procedure. A separated analysis will be done for each described endpoint, 
which define what a respondent is. 
The main quantitative statistical analyses to assess the efficacy of transcranial 
electrical stimulation techniques consist of ANOVA-tests of repeated measures with three 
groups. Time-measures for each of the above-mentioned endpoints are taken as 
intragroup variables (pre vs. post), whereas intergroup measures refer to the received 
stimulation or treatment (tDCS vs. tACS vs. Sham). Thus, both clinical variables (for 
example, pain intensity, fatigue, sleep quality, disease severity and interference) and 
potential biomarkers (including brain oscillatory activity registered by EEG, CPM and 
TSSP response) are considered as intragroup variables. 
Those covariates which show a significant correlation with clinical outcomes will be 
also included in their correspondent ANOVA analysis. These potential covariates are 
basically age, self-perceived stress, social support, catastrophism and medication intake. 
All these statistical analyses will be repeated in separated groups of patients, created 
in the basis of sex, type and duration of chronic pain, among other characteristics. The 
objective is to assess whether the clinical outcomes depend on sex or diagnosis, as each 
tES could be more effective for specific diseases. 
CPM/TSSP response and EEG pattern observed before the tES application are also 
regarded as potential predictors of the treatment efficacy. Thus, the pre-treatment indexes 
of these biomarkers will be used as independent variables in Linear regression models, 
which includes the clinical improvement in each endpoint as dependent measure. The 
procedure will be repeated with Logistic regression analysis stablishing the respondent 
vs. no-respondent categories as dichotomic variable. 
For last, we will register and assess the percentage of dropouts with their respective 
motives, in order to obtain an index of the feasibility of home-based tES approach. Client 

Brain and Pain (BaP): Efficacy of home-based tES to treat chronic pain 
23 
 
satisfaction index and caregiver interview will also include questions about the capability 
of participants to manage with tES devices, data which will be qualitatively analysed. 
 
 

Brain and Pain (BaP): Efficacy of home-based tES to treat chronic pain 
24 
 
8. Chronogram 
WORKING PLAN (WP) 
TASK  
 
 
 
 
 
\ MONTH 
3 6 9 12 15 18 21 24 27 30 33 36 
WP1. Development and selection of assessment and monitoring tools for refractory chronic pain patients 
Task 1.1. 
Review of the literature and identification of the most 
common and important variables used as outcomes in 
clinical trials with chronic pain population. 
 
 
 
 
 
 
 
 
 
 
 
 
Task 1.2. 
Selection of valid and reliable instrument to assess pain 
and the relevant clinical domains identified in the 
previous phase. 
 
 
 
 
 
 
 
 
 
 
 
 
Task 1.3. 
Transfer of chosen instruments into a digital format to 
be applied through an electronic application to facilitate 
data collection and codification. 
 
 
 
 
 
 
 
 
 
 
 
 
Task 1.4. 
Contact with technology companies and acquisition of 
portable tES equipment, actigraphy devices and 
stimulators for quantitative sensory testing. 
 
 
 
 
 
 
 
 
 
 
 
 
Task 1.5. 
Review of the literature and definition of quantitative 
sensory tests (CPM/TSSP) and EEG protocols. 
 
 
 
 
 
 
 
 
 
 
 
 
Task 1.6. 
Preparing of application and obtaining the Ethical 
Committee approval 
 
 
 
 
 
 
 
 
 
 
 
 
Task. 1.7. 
Familiarization of researchers with purchased devices 
and conducting pilot tests to ensure their correct 
performance/operation. 
 
 
 
 
 
 
 
 
 
 
 
 
WP2. Recruitment and first evaluation of chronic refractory pain patients: Pre-treatment phase 
Task 2.1. 
First contact and recruitment of participants by 
physicians from Public Health System. 
Task 2.2. 
Telephone contact with participants to explain the 
nature of the project and arrange a face-to-face 
assessment session. 

Brain and Pain (BaP): Efficacy of home-based tES to treat chronic pain 
25 
 
Task 2.3. 
First pre-treatment assessment session: Signing of 
informed consent, application of pre-selected 
questionnaires and sensory tests. 
Task 2.4. 
Daily assessments of clinical variables during the 
fifteen days following pre-treatment assessment session 
using actigraphy technology and electronic surveys, 
remitted to patients through phone messages. 
Task 2.5. 
Second pre-treatment assessment session: Application 
of pre-selected questionnaires, sensory tests and EEG 
registry. Delivery of tES devices and the correspondent 
explanation. 
WP3. Home-based treatment with tES for chronic refractory pain patients 
Task 3.1. 
Daily Transcranial electrical stimulation sessions during 
fifteen consecutive days. 
Task 3.2. 
Remote monitoring and compliance surveillance of the 
tES sessions from principal researchers. 
Task 3.3. 
Daily assessments of clinical variables and side effects 
during treatment period using actigraphy technology and 
electronic surveys, remitted to patients through phone 
messages. 
WP4. Evaluation of the efficacy of tES intervention for chronic refractory pain patients: Post-treatment phase 
Task 4.1. 
Post-treatment assessment session: Application of the 
same tests as in pre-treatment evaluation, adding 
satisfaction and self-perceived improvement scales; and 
devolution of tES devices. 
Task 4.2. 
Daily assessments of clinical variables during the fifteen 
days following post-treatment assessment session using 
actigraphy technology and electronic surveys, remitted 
to patients through phone messages. 
Task 4.3. 
Follow-up assessment session: Application of the same 
tests as in previous evaluations six months after 
finishing the tES treatment. 

Brain and Pain (BaP): Efficacy of home-based tES to treat chronic pain 
26 
 
WP5. Statistical analyses of the clinical trial data, discussion of results and writing of reports 
Task 5.1. 
Data analysis of pre-treatment evaluation results: Pain 
processing and modulation indexes (CPM, TSSP, EEG) 
and correlations with clinical features of patients. 
Task 5.2. 
Data analyses of immediate tES effects/outcomes and 
potential predictors of treatment efficacy. 
Task 5.3. 
Data analyses of long-term tES effects/outcomes. 
Task 5.4. 
Group discussions about the available results. 
Task 5.5. 
Writing reports and dissemination of results for 
scientific community. 
9. Security and ethical-legal issues 
We are committed to adhere to all relevant international, EU and national legislation and 
guidelines relating to the conduct of clinical studies. Since our research involves human 
samples, we will organize a preliminary seminar on ethics questions to guarantee respect 
for research participants and the appropriate behaviour of the involved researchers and 
clinicians in regard to the health and welfare of the participants. 
The purchased transcranial electrical stimulation devices have obtained the CE 
Certificate for research use, and in some countries, for clinical use as an off-label 
treatment. This certificate warrants the compliance with European standards about the 
security offered by the equipment.  
For research, in most countries, only IRB/Ethical Committee approval is required, 
since the studies using tDCS are considered to be of minimum risk, provided that the 
exclusion criteria are strictly applied (i.e., intracranial ferromagnetic devices or implanted 
stimulators; antecedents of, or active epilepsy; history of neurosurgery, traumatic brain 
injury with loss of consciousness, and/or cortical lesion). Researchers are committed with 
ascertaining that every single enrolled patient complies with all the inclusion criteria and 
he/she does not match the exclusion criteria, in order to ensure that there is no health 
condition or circumstance which advises against participating in the study. 

Brain and Pain (BaP): Efficacy of home-based tES to treat chronic pain 
27 
 
As explained above, no significant adverse events have been reported by a 
comprehensive review covering more than 18.000 stimulation sessions and 
approximately 8.000 patients (Antal et al., 2017). Thus, at present, most IRB committees 
approve tDCS treatments based on the promising data already available, without major 
concerns or obstacles. At the time of uploading this document, we have already obtained 
the approval from the competent Ethical Committee (Research Ethical Committee of 
Santiago-Lugo; Registry Code: 2021/021). 
This project is developed following the requirements of Helsinki Declaration (1964) 
and subsequent assembly ratifications (Tokyo, 1975; Venezia, 1983; Hong Kong, 1989; 
West Somerset, 1996; Scotland, 2000; Seoul, 2006; Fortaleza, 2013) about the ethical 
principles for medical investigations involving human beings; as well as the national-
scope guidelines collected in the RD 1090/2015, about clinical trials and medical praxis. 
As in any other randomized clinical trials, a percentage of participants will be 
assigned to a Sham condition. Patients will be aware about this fact before the start of the 
study although, as for the researchers, patients will not know which was their treatment 
group until the end of the trial. Given that participants will be randomly assigned to one 
of the groups, we guarantee that there is no discrimination based on gender, race, sexual 
orientation or any other individual characteristic. Besides, patients in the placebo group 
will continue to receive their regular treatment and, in addition, due to their participation 
in the study, will receive day-to-day attention on their health state evolution. 
As far as the data processing is concerned, researchers will not ask for personal 
information which could reveal the identity of the patients, thus maintaining anonymity. 
We are committed to respect the European and national legislation about Personal Data 
Protection, whose highest authorities refers to the Regulation (EU) 2016/670 of the 
European Parliament and of the Council, of 27 April 2016, on the Processing and 
Protection of Personal Data and the Spanish law called Ley Orgánica 3/2018, de 5 de 
diciembre, de Protección de Datos Personales y garantías de los derechos digitales. 
The research centre is responsible for the data treatment and processing. Data 
collected will be exclusively used for the objectives described in this investigation 
protocol and maintained during the strictly necessary time to purchase those objectives. 
The nature and objectives of the research will be perfectly explained and clarified to the 
participants and they will have to sign an informed consent before their enrolment. 

Brain and Pain (BaP): Efficacy of home-based tES to treat chronic pain 
28 
 
Each participant will be assigned with a code at the beginning of the study which 
does not allow to discover their identity. These codes will be current during the whole 
trial, thus patients will introduce it in questionnaires and daily surveys instead of any 
other personal data, such as name or surname. Therefore, data collected from participants 
will be saved in a password-protected file which will not contain any identifying 
information. During the data analyses phase, researchers will just have access to the 
participant code, without knowing the identity of the data which they are working it. 
Nevertheless, we intend to make a daily surveillance of the patient progress, as well 
as to facilitate the contact with research responsible in case of any inconvenient emerges. 
For that reason, during the effective period of trial, from pre-treatment phase until post-
treatment end, we will keep in touch with patients via telephone with a daily frequency. 
These conditions will be perfectly explained to the patients and the informed consent 
includes a clause to ensure that they give their authorization to be contacted by phone 
messages from researchers, limited to the clinical trial period. Only researchers who 
collaborate with the investigation will have access to the participants telephone number 
and these data will not be transferred to third parties under no circumstances. Telephone 
number will be just associated with the code given to the participant at the beginning of 
the trial. 
Those participants who give their consent to, will be called and invited to the follow-
up face-to-face assessment session six months after finishing their treatment to inquire as 
the long-term stability of accomplished clinical improvement. In any case, whether they 
decide to come or not, their phone number will be deleted and inaccessible once the 
investigation have finished. 
 
 

Brain and Pain (BaP): Efficacy of home-based tES to treat chronic pain 
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