Association of Low Doses of Naltrexone and Transcranial Direct Current Stimulation in Fibromyalgia: Randomized Clinical Trial, Blind, Controlled With Placebo
Phase: PHASE2
Conditions: Fibromyalgia
Sponsor: Centro Universitario La Salle

 UNIVERSIDADE LA SALLE 
Postgraduate Program in Health and Human Development 
Research Line: Pathological Process 
 
 
 
 
 
 
 
 
 
 
Research Project 
 
 
Association of low doses of naltrexone and Transcranial Direct Current 
Stimulation in fibromyalgia: randomized clinical trial, double blinded, 
controlled with placebo 
 
 
 
 
 
Profa. Dra. Andressa de Souza 
 
 
 
 
 
 
 
 
Canoas 
2019 

ABSTRACT 
Fibromyalgia (FM) is a syndrome of chronic pain, which its physiopathology seems to involve 
alteration on the cortical system responsible for the processing of pain. Currently, the treatment 
for fibromyalgia became a big challenge, inasmuch as the available medicines present adverse 
effects that limit the adhesion of the same. Objectifying to modulate these altered circuits, 
Association of low doses of naltrexone and Transcranial Direct Current Stimulation (tDCS) 
have showed promising results for its capacity of reducing the pain in these patients. Besides 
that, the use of low doses of naltrexone at FM showed analgesic effects, which looks like 
interesting according to the pharmacodynamics profile of this medicine, being the probable 
mechanism of action the up regulation of opioids receptors and consequently the increase of 
endogenous opioids. Aiming to evaluate if the previous use of low doses of naltrexone 
potentiate analgesic effect induced by the tDCS in patients with fibromyalgia; it is proposed to 
evaluate the changes on the level psychophysical and neuroendocrine through evaluation with 
psychophysical pain tests, and levels of neurotrophins and serum cytokines. It will be conduced 
a randomized clinical trial, double blind, parallel, controlled with sham and placebo. It will be 
included 92 women between 18 and 65 years with confirmed diagnosis of fibromyalgia and 
pain evaluated as bigger than six in the Visual Analog Scale (VAS) at the last three months. All 
patients will sign an Informed Consent Questioner. Each patient will be randomized to receive 
21 days of low doses of naltrexone or placebo, followed by 5 consecutive sessions of tDCS or 
sham-tDCS. We will evaluate the changes on pain after intervention, and we will study your 
association with the psychophysical profile of pain and serum neurotrophins, that might have 
predictive response function. 
 
Key Words: fibromyalgia, low doses of naltrexone, Transcranial Direct Current Stimulation 
INTRODUCTION 
 
The chronic pain is a maladaptive process that manifests as a dysfunction of the nervous 
system. It causes considerable negative impact on the individual and the society, it onerous the 
health system affecting more than 20% of global population, allied to the incapacity, work 
departures and early retirement (Saastamoinen et al., 2012; Hecke, Torrance and Smith, 2013). 
Although the multiples mechanisms physiopathogenics that unleash and sustain this process are 
known, it is not clear the real impact of the therapeutic strategies on the mechanisms of 
neuroplasticity on the neuromatrix of pain. Among the conditions of chronic pain of hard 

treatment there is the fibromyalgia, characterized by musculoskeletal generalized pain, 
accompanied by fatigue, sleep alterations and humor (Wolfe, 2016). Sleep disturbances, 
depression e symptoms of fatigue, constitute the fibromyalgic syndrome (Russel and Raphael, 
2008), that affects between 1-2% of the population, being more frequent in women (Bannwarth, 
2009; Mas et al., 2008; McNally, Matheson and Bakowsky, 2006). Fibromyalgia courses with a 
deep impact on the activities and productivity in the daily life of the individual (Hawley and 
Wolfe, 1991; Martinez et al., 1995). More than one-third of the patients are forced to reduce the 
work journey or the level of work physically exigent, involving additional costs to the society in 
general. At USA, for example, 15% of population with fibromyalgia is retired due to disability 
(Russell, 2011). 
The physiopathology model more accepted considers that there is an imbalance between 
the nociceptive process and the physiologic control of pain (Yunus, 2007). According to this 
model, there is a global decrease on the inhibitor routes of pain; allowing, that way, the stimuli 
of low intensity or non-nociceptive to be processed on pre-cortical structures and cortical 
involved on the affective and cognitive process of pain, increasing the painful perception 
(Burgmer et al., 2009). Based on this theory, the therapeutic approaches, aiming the modulation 
of the central nervous system, can be beneficent. Anticonvulsant drugs, that block up the sodium 
channels, for example, phenytoin, topriamate, carbamazepine, lamotrigine, increases the motor 
threshold; and agonists GABAergics, such as diazepam, reduce the signal of intracortical 
facilitating neurons potentiating the intracortical inhibition (Chen et al., 1997; Manganotti et al., 
1990; Ziemann et al., 1996). Based on clinical works that demonstrate reasonable evidence, the 
antidepressant and anticonvulsant are recommended options for the fibromyalgia treatment 
(Arnold, 2006; Harris and Clauw, 2008). However, the use of anticonvulsants induces the 
depression of the central nervous system (CNS), leading the patients to present somnolence, 
mental confusion or imbalance. These central side effects are frequent (Chizh et al., 2007), 
because of this it is necessary the investigation of new options of treatment, wheter 
pharmacological or not pharmacological.  
A therapeutic option that is still in study for the treatment of fibromyalgia is the use of 
low doses of naltrexone (Younger et al., 2013). Antagonist of the opioid receptors, naltrexone is 
used on the treatment of dependence on opioids and alcohol (Haber et al., 1997). Its structure and 
action mechanism are similar to the antagonist opioid, naloxone. However, naltrexone shows a 
greater bioavailability on oral and greater time of half-life (Verebey et Mulé, 1975). Naltrexone 
acts blocking opioids receptors leading to a compensatory increase on the production of 
endogenous opioids that activate the kappa opioids receptors. The activation of kappa receptors 

induces the anti-inflammatory effect, decreasing the IL-6 levels and neutrophils migration (Dan 
Segal et al., 2013). 
Another mechanism potential for the effects of the use of low doses of naltrexone, 
happens by the antagonism on non-opioids receptors, such as Toll like Receptor 4 (TLR4) (Brown 
and Panksepp, 2008), found on macrophages. The blocking of TLR4 inhibits the release of 
cytokines pro-inflammatory, P substance, nitric oxide, excitatory amino acids and TNF 
conducing to negative regulation of the expression of the chemokine receptor and the adhesion 
molecule (Jarred et al., 2014). 
Besides these mechanisms, studies in animals (Tempel, Gardner e Zukin, 1985) shows 
that the daily administration of naltrexone induces up-regulation of opioids receptors, reaching 
its high effect in 8 days of treatment.  The therapy increased by 1,9 times the concentration of 
encephalic opioids receptors.  The "up-regulation" induced by naltrexone happens, mainly, in 
receptors of subtype mu and delta, without changing significantly the density or affinity of kappa 
or sigma receptors. In the expected form, the chronic therapy with naltrexone increases the 
analgesia induced by morphine, that turns back to its basal approximately 6 day after the 
suspension of naltrexone. 
Therefore, the use of low doses of naltrexone seems to be an interesting therapeutic from 
the pharmacodynamic point of view e also related to the adverse effects. Moreover, considering 
that most of fibromyalgics patients respond just partially to the treatment and that its 
neurophysiological effect is poorly known, a greater understanding of the effect of the 
therapeutics on the neuromatrix of pain, constituted by multiples centers of cortical and 
subcortical domain, could provide a better base of understanding to the diagnostic and therapeutic 
process.   
Considering the importance of the searching of new therapeutic options for the treatment of 
Fibromyalgia, non-invasive techniques of cerebral stimulation can represent a promising focus 
of study. A neuromodulator technique has been studied for the treatment of chronic pain is the 
transcranial direct current stimulation(tDCS) (Boros et al., 2008; Floel et al, 2008; Fregni et al., 
2006a; Fregni et al., 2006b; Hummel and Cohen, 2005; Wagner et al., 2007; Nitsche et al., 2003a; 
Nitsche et al., 2003b). It has been shown that this technique induces significant currents on 
cortical areas that induces alterations on the cortical excitability. These changes on excitability 
can be explained by synaptic changes and direct effects on the neuronal spontaneous activity 
(Boros et al., 2008). The changes of long duration on the excitability resemble in long term to 
the potentiation and depression, such as alterations of intensity of glutamatergic synapses (Boros 
et al., 2008; Nitsche et al., 2003a; Nitsche et al., 2003b; Nitsche et al., 2001; Nitsche et al., 2000). 
The duration of the effects depends on the time of the stimulation and can remain for more than 
one hour after stimulation (Medeiros et al., 2012). Because the mechanisms of action of tDCS 
induces a alteration on the neuronal spontaneous activity, the use of this technique combined to 
the drug effects on the matrix of pain can amplify the therapeutic effects. 

tDCS modulates the cortical excitability by the application of a continuous current of 
low intensity (1-2mA) directed to the scalp by cathodes and anodes electrodes. The current 
reaches the cerebral cortex, producing hyperpolarization or depolarization of the potential of 
axonal membrane. Evidences have shown that this method of neuromodulation  can 
change 
neural cortical e subcortical network (Medeiros et al., 2012).  The use of tDCS on the treatment 
of pain has as theoretic and empiric support the reducing of pain and changing of 
neurophysiological report of the painful experience (Fregni, Freedman and Pascual-Leone, 2007; 
Zaghi et al., 2011). The tDCS stimulating the motor cortex is a non-invasive technique, of low 
cost and easy application and it has demonstrated efficacy on the treatment of pictures that curses 
with chronic pain. These properties characterize it as a promisor technique on the therapeutic 
scenario of many kinds of pain.  
The tDCS effects are from dependent polarity, whose anodic stimulation induces 
cortical excitability and the cathodic stimulation, reduces. The effects are explained by the 
depolarization or hyperpolarization of the membrane, respectively. The kind of answer is bound 
to the stimulated area (Raghavan, Eldabe and Strachan, 2008). This effect is additive to the 
repetition of the stimulation courses. The lasting effect is due to the increase of the pre-synaptic 
activation and positive regulation of the synaptic mediated tonus by NMDA receptor, depending 
on protein synthesis, on modifications on the cyclic AMP intracellular and on calcium 
intracellular influx. These processes are part of the long-term potention,- LTP and long-term 
depression - LTD (Liebetanz et al., 2006). Experimental studies developed on a partnership with 
Brazilian laboratory demonstrated that, in animal models, the analgesia promoted by tDCS is 
mediated by opioid pathways, noradrenergic, serotoninergic, adenosinergic and canabinoids, on 
central and peripheral circuits (unpublished data).  It is about, therefore, of a non-
pharmacological technique, that acts modulating different endogenous systems to promote 
therapeutic effects. 
As explained, the fibromyalgia courses with an alteration on the nociceptive system.  
The tDCS, by means of various mechanisms, could play a role by lowing the pain on those 
patients, being its clinical significance still a study subject. In consideration to the involvement 
of the opioid system both in the physiopathology of fibromyalgia, and on the tDCS action 
mechanisms, we propose to realize a “conditioning” of this system using naltrexone. As 
previously explained, low doses of naltrexone induces up-regulation of the opioids receptors.  
This induction would let the endogenous opioid system (responsible for the inhibition descending 
of pain, among others) with more exposition receptors, ready to be activated by tDCS. 
To understand the effect of different therapeutic approaches on the neuroplasticity 
cerebral processes, added to the resources that operationalize this measure by physiological 

parameters, evaluation of the inflammatory marker levels, such as interleukins and neurotrofines 
like BDNF seems to be complementary. Besides the advantages to the patients and public safes, 
this is study may provide a new therapeutic option, which effect on the neurobiological processes 
in real time is still incipient on clinical research. In the study of pain, this association of different 
therapeutic modality allows to understand the complex integration of different structures  that 
constitute the pain matrix, in reference of perception, modulation and therapeutic.  
On the process of markers evaluation, it may be bound to the treatment course, directly 
or indirectly, once that the painful episodes courses with stress and IL-1 is a critic mediator of 
stress adaptive answer. It induces the activation of the hypothalamic axis adrenal hipophysis, at 
least in part, by changing on the hypothalamic noradrenergic neurotransmission. This way is 
mediated by IL-1β, that activates proto-oncogenes c-fos on the cellules producers of 
corticotrophin releasing hormone(CRH) of the paraventricular nuclei, by the spinal 
noradrenergic projections. Besides that, the peripheral IL-1 can stimulate the nucleus of the 
lonely tract, the ventrolateral medulla and the locus ceruleus to secrete noradrenaline, which, in 
turn, increases hypothalamic IL-1by microglia. This relation between cerebral IL-1 and the 
noradrenergic system seems to be bidirectiona. IL-1 also induces hyperalgesia and depressive 
symptoms, even in the absence of inflammation (Markus et al., 2003; Lorton et al., 2008). The 
BDNF is a neurotrophin that regulates the integrity and differentiation of neurons during its 
development, is also involved in many functions on the adult life, including the neuronal 
plasticity process.  The BDNF expression on the CNS I modified by many impairments, such as 
stress, ischemic, hypoglycemia, depression, etc. It also can work in adaptive essential 
mechanisms, playing a crucial role on the synaptic potentiation process of long duration, 
neuroplasticity mechanism fundamental to unleash and sustain the pain memory process. The 
growth of BDNF increases the LTP, while the reduction of its levels attenuates this phenomenon. 
With this, it is observed that chronic painful condition depends on a long time process (Patterson 
et al. 1996; Kossel et al., 2001). 
Considering what was exposed, the hypothesis of this study is that the previous use of 
low doses of naltrexone potentiate the analgesic effects of tDCS, by positive regulation of opioids 
receptors in female fibromyalgic patients. 
 
 
 

OBJECTIVE 
 
Primary Objective: evaluate the effect of low doses of naltrexone followed by tDCS for the 
treatment of pain in patients with fibromyalgia.  
 
Secondary Objectives: 
1. Measure the effect of low doses of naltrexone followed by tDCS on pain of patients with 
fibromyalgia, evaluated by Visual Analogue Scale 
2. Study if the effect of this association present some impact on the quality of life and 
psychological factors of these patients, evaluated by the Fibromyalgia Impact 
Questionnaire, Beck Depression Inventory, State-Trait Anxiety Inventory, Pain 
Catastrophizing Thought and Profile of Chronic Pain 
3. Study if this association induces changes on the nociceptive system, when evaluated by 
Pain Pressure Threshold (PPT) and Conditioned Pain Modulation 
4. Evaluate if the effect of this association induces changes in possible serum biomarkers of 
neuroplasticity (BDNF) and cytokines. 
 
 
 

MATERIAL AND METHODS 
Design: Randomized clinical trial, double-blind, parallel, controlled. 
Randomization and blinding: randomization table will be generated by a website 
(www.sealedenvelope.com), creating a list of randomization, using randomization in blocks with 
size equal to 8.The codes of randomization will be placed in sealed brown envelopes, it will be 
randomized in four groups:  
1. tDCS + Placebo  
2. tDCS + low doses of naltrexone  
3. tDCS-Sham + Placebo  
4. tDCS-Sham + low doses of naltrexone 
Evaluators and patients will be blinded. The blinding will be kept in wall stages of the 
study. To evaluate the conservation of the tDCS blinding, at the end of 5 (five) sessions the patient 
will be inquired about the type of intervention that believes to have received (tDCS active or sham) and 
about the degree of safety on the answer, using a standardized questionnaire. The same will be realized 
to evaluate the blinding of naltrexone. 
 
Follow-up 
The patients will be evaluated for one week after the last intervention, to rate the effects 
after stopping the use of naltrexone and tDCS.  
 
Inclusion Criteria: Provide an informed consent to participate on the study; women with age 
between 18 and 65 years; medical diagnoses of fibromyalgia according to the American College 
of Rheumatology criterion (2010); know how to read and write; pain evaluated as bigger than six 
at the last 3 months on the Visual Analogic Scale; treatment of chronic use stable on the last 3 
months;  

Exclusion Criteria: Be using opioid drugs; pregnancy or non-use of contraceptive method; history 
of alcohol or drugs abuse on the last 6 months; historic of neurologic pathology; history of cardiac 
arrhythmia and use of drugs that change the vascular answer (adrenergic blockers, vasodilators); 
history of cranial traumatism moderated or severe; history of neurosurgery; systemic 
decompensated disease, and chronic inflammatory disease (Lupus, rheumatoid arthritis, Sjogren 
Syndrome, Reiter Syndrome);  history of hypothyroidism non compensated; personal history of 
cancer, passed or in treatment. 
 
Evaluation: after the realization of the Informed Consent Questioner, it will be applied the 
following proceeds: 
- Sociodemographic Questionnaire 
- Visual Analogue Scale for Pain (VAS) 
- Beck Depression Inventory (BDI-II) 
- Fibromyalgia Impact Questionnaire (FIQ) 
- State-Trait Anxiety Inventory (STAI) 
- Pain Catastrophizing Scale (PCS) 
- Blood samples for BDNF (Brain Derived Neurotrophic Factor) 
- Pain Pressure Threshold (PPT) 
- Conditioned Pain Modulation (CPM) task 
As the randomization, the participant will receive 21 days of treatment with low doses of 
naltrexone (or placebo) and more 5 days in sequence of low doses of naltrexone combined with 
tDCS, 5 sessions of allocated intervention.  During each session, the patient will be inquired 
about the perception of the pain with the Visual Analog Scale and about the presence of adverse 
effects, according to a standardized questionnaire. At the day of the last allocated session, the 
patient will be submitted to the same initials questionnaires and evaluations, except the 
demographic questionnaire.  

 
Measurement of Outcomes  
Measurement of Outcome by clinical parameters: Pain – The pain will be measured 
by the Visual Analog Scale (EAV) of 100 mm, whose zero corresponds to no pain and 100 to a 
lot of pain  
CPM, Conditioned Pain Modulation: it will be measured as a difference on the pain 
score between two tests of painful stimulus, first applied on baseline and also, concomitantly 
with the conditioning painful stimulus produced by the non-dominant hand immersion on the 
water with temperature between zero and 1,5°C for 30 seconds.  
Pain Pressure Threshold (PPT): measured using the electronic algometer with a 
rubber probe with 1 cm2 applied on the right forearm. The researcher will touch the rubber probe 
slowly increasing the pressure, instructing the patient to report verbally as soon as feel the pain 
first sensation. 
 
Laboratory Outcomes 
It will be measured before the first allocated intervention session, and at the end of the 
last session, and it will be included the BDNF levels. The blood will be centrifuged, the 
supernatant will be aliquot and stored in a freezer at the research room at Clínicas Integradas 
Unilasalle, for posterior analysis, that will be realized by the ELISA technique, according to the 
manufacturer instructions. 
 
Interventions 
Low doses of naltrexone: the biggest clinical trial published until now (Younger et al., 
2013) using low doses of naltrexone in patients with fibromyalgia, used a dosage of 4,5 mg VO 
each day. This dosage has been previously descripting in pilot studies (Younger and Mackey, 
2009) and observational on fibromyalgia (Noon et al., 2016). Therefore, the pharmacological 

intervention will be consisted by the use of low doses of naltrexone (4,5mg lonely daily dose), 
for 26 days, being 21 days just naltrexone and 5 days subsequent combined to tDCS. 
Naltrexone’s placebo: the placebo will be produced by a manipulation pharmacy. It 
will be a capsule of the same color as naltrexone; however, the excipient utilized will be amid.  
 
tDCS: The proceed will begin with the placing of a anodal electrode on the superjacent 
scalp of the primary motor cortex (contralateral to the dominant cortex), the cathode will be on 
the contralateral supra-orbital area. The size of the electrodes will be 35cm². The utilized current 
will be 2 mA applied for 20 minutes. A stimulator of constant current moved by battery will be 
used (tDCS device Soterix 1X1) (Fregni et al., 2006a, Fregni et al., 2006b). It will be done 5 
sessions of stimulation, as reported in previously publications for the Fibromyalgia analgesia 
(Valle et al., 2009). 
tDCS sham: the current will be applied just for 30 seconds. The patients can perceive 
the same sensation of the initial stimulation, but they will not receive current for the remaining 
period. Analogously to tDCS, it will be realized 5 sessions of sham stimulation. 
 
tDCS Potential Adverse Effects: It will be used a standardized questionnaire of adverse 
effects. 
 
Statistical Analysis  
The comparison between the groups of average of the variable at baseline will be 
realized a one-way ANOVA, when the variables present normal distribution or equivalent test 
for statistics non-parametric. The comparison of the variables outcomes over the time will be 
done repeated measures ANOVA on a mixed linear model from fix effect, with adjust to the 
levels of baseline and possible confounders. Having the intervention group as factor and time as 
repeated measure to the outcome variables. It will be used the Bonferroni post hoc test to 
multiples comparisons to detect differences between groups in any of the measurements 

moments. The level of significance will be P<0.05, with respective adjusts to multiple 
comparisons. The analysis will be processed using SPSS 20.0 version (SPSS, Chicago, IL).  
 
Ethics: The study follows the established conditions at 466/12 Resolution from Conselho 
Nacional de Saúde (CNS) and will be registered on the international platform 
www.ClinicalTrials.gov.  
 
MAIN SCIENTIFIC, TECHNOLOGICAL OR FROM INOVATION CONTRIBUTIONS 
OF THE PROPOSE 
As bigger goal, we look up to strengthen the activity of academic cooperation between 
the Post-graduation Program in Health and Human Development with excellence global centers 
of this investigation area. The concretization of this study can have applicability in other 
conditions mentioned above to understand physiological, physiopathological aspects, predict and 
evaluate outcomes until then only inferred by means of depressive and anxiety symptoms. 
Besides that, we look for contribution with the development of post-graduation and research 
group involved, collaborating both qualitatively and quantitatively with the scientific and 
technological development of the country. It is intended to help on the fortification of the 
international competitiveness of the Brazilian research by innovation and regional development, 
in a local, regional and international development policy. In addition to enable a improvement 
on the patient care that suffer with pathologies that demand high costs from the Brazilian health 
public system.  
 
 
 
 
 
 
 
DETAILED BUDGET 
Prof. Andressa already own all equipment at your disposal to execute the project, the materials 

that has to be acquired are going to be provided by external research edicts or from own financing. 
 
Spend – Consumption Material (Values are described in Reais) 
Specification 
Quantity 
Unit Cost 
Total Cost 
Kit ELISA BDNF human 
01 
4.800,00 
4.800,00 
Kit ELISA IL1-beta human 
01 
4.800,00 
4.800,00 
Saline 9% 250 Ml 
92 
1,70 
156,40 
Alcohol PA 
1 
68,50 
68,50 
Cotton 
2 
5,95 
11,90 
Rechargeable batteries for the tDCS– 
AA with 4 units 
2 
84,00 
168,00 
Prints of questionnaires and TCLE 
1000 
0,20 
200,00 
TOTAL VALUE 
 
 
10.204,80 
 
Capital – Permanent Material (Values are described in Reais) 
Specification 
Quantity 
Unit Cost 
Total Cost 
Notebook 
1 
R$ 1.800,00 
R$ 3.100,00 
Pressure 
Algometer 
(Algomed) 
1 
R$ 13.000,00 
R$ 13.000,00 
Total 
R$ 16.100,00 
 
 
 
 
ACTIVITY SCHEDULE 
 
Year/ Activity 
Schedule divided by trimester   
2017 
1º 
2º 
3º 
4º 

Patients call and application of the inclusion and exclusion 
criteria 
 
 
 
X 
Randomization and data collect 
 
 
 
X 
Data typing 
 
 
 
X 
2018 
1º 
2º 
3º 
4º 
Patients call and application of the inclusion and exclusion 
criteria 
X 
X 
X 
X 
Randomization and data collect 
X 
X 
X 
X 
Data typing 
X 
X 
X 
X 
2019 
1º 
2º 
3º 
4º 
Patients call and application of the inclusion and exclusion 
criteria 
X 
X 
X 
X 
Randomization and data collect 
X 
X 
X 
X 
Data typing 
X 
X 
X 
X 
Statistics Analysis 
 
 
X 
X 
2020 
1º 
2º 
3º 
4º 
Write and Submission of scientific articles and reports.  
X 
X 
X 
X 
 
All activities are occurring according what was planned  
 
 

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TERMO DE CONSENTIMENTO LIVRE E ESCLARECIDO 
NOME DO ESTUDO: Efeitos da combinação de baixas doses de naltrexona e Estimulação Elétrica Transcraniana 
na fibromialgia: ensaio clínico randomizado, cego, controlado com placebo. 
Número do protocolo:________________________________  
Instituição: Universidade La Salle – Clínicas Integradas 
Pesquisador Responsável: Dra. Andressa de Souza – 51 981975718  
Você está sendo convidado para participar, como voluntária, em uma pesquisa. Após ser esclarecida sobre as 
informações a seguir e retirado todas as suas dúvidas sobre a pesquisa, no caso de aceitar fazer parte do estudo, 
assine ao final deste documento, que está em duas vias. Uma delas é sua e a outra é do pesquisador responsável. 
1. OBJETIVO DO ESTUDO 
Avaliar o efeito do tratamento da dor por meio da utilização do medicamento naltrexona e da aplicação de corrente 
contínua de baixa intensidade sobre a cabeça (ETCC - figura 1), à pesquisa de marcadores de resposta em pacientes 
com fibromialgia. Os efeitos destas intervenções serão avaliados por meio de exames de sangue, percepção da dor 
por estímulos leves que produzem as sensações de calor e a pressão. Haverá perguntas sobre os seus sentimentos, 
nível de dor e pensamentos que lhe aparecem na cabeça durante o tratamento. 
 
Figura 1. ETCC. 
2. EXPLICAÇÃO DOS PROCEDIMENTOS 
Para participar da pesquisa, será necessário que a senhora responda várias perguntas antes, durante e após os 
procedimentos. O estudo ocorrerá ao longo de sete visitas. A sua participação é voluntária. Se concordar, serão 
aplicados os questionários e daremos início ao estudo. Na continuação, serão explicados os procedimentos realizados 
em cada visita: 
 Na primeira visita serão realizadas: coleta de sangue, questionários e testes da sensibilidade à dor. A coleta da 
amostra de sangue avaliará a produção de marcadores sanguíneos relacionados a sensação de dor. O sangue será 
coletado antes de se iniciar os procedimentos na primeira visita. O volume de sangue será de 10 ml a cada coleta, o 
equivalente a duas colheres de sopa. Depois, serão realizados questionários para verificar a qualidade do sono, 
características de sintomas de tristeza, nível  de dor, ansiedade  e os  pensamentos relacionados à dor. Nos testes de 
senbilidade à dor, será colocado um equipamento que produz estímulos leves de sensações de calor e de pressão, 
através de um aparelho que será posicionado no seu braço. Nesta primeira visita você receberá um pote com 26 
cápsulas do medicamento naltrexona, que a senhora deverá utilizar uma cápsula por dia, pela manhã. A senhora 
deverá utilizar esse medicamento por 21 dias e retornar para avaliação no 22º dia. Se a senhora sentir qualquer 
incomodo com o uso do medicamento, deverá entrar em contato imediatamente com o pesquisador do estudo. Esta 
visita terá duração aproximada de uma hora. 
Na segunda visita, serão realizados os mesmos questionários e testes da primeira visita, além da coleta de 
sangue. Finalmente, será realizada a primeira sessão com a estimulação trancraniana de corrente contínua (ETCC), 
com aplicação de uma corrente elétrica fraca na sua cabeça por 20 minutos, como será explicado no item Sessões de 
ETCC. Após a estimulação serão feitos testes para avaliar a dor ou desconforto e pesquisa de aparição de efeitos 
adversos.  Estima-se que o tempo para cada uma destas visitas seja de uma hora. 
 

Na terceira à quinta visita será realizada a sessão de ETCC e a pesquisa de aparição de efeitos adversos.  
Estima-se que o tempo para cada uma destas visitas seja de 40 minutos. 
Na sexta visita, serão realizados os mesmos questionários e testes da primeira visita, além da coleta de sangue. 
Será realizada a sessão com a estimulação trancraniana de corrente contínua (ETCC). Após a estimulação serão feitos 
testes para avaliar a dor ou desconforto e pesquisa de aparição de efeitos adversos.  Estima-se que o tempo para cada 
uma destas visitas seja de uma hora. 
Na sétima visita ocorrerá sete dias após a última dose do medicamento e última sessão de ETCC, então serão 
realizados os mesmos questionários e testes da primeira visita, além da coleta de sangue, afim de verificar os efeitos 
após cessar o uso do tratamento. Estima-se que o tempo para cada uma destas visitas seja de 40 minutos. 
3. MEDICAÇÃO - NALTREXONA 
A naltrexona é um medicamento que em baixas doses tem sido estudada para o tratamanento da fibromialgia. Neste 
estudo você poderá receber a medicação verdadeira, naltrexona 4,5mg, ou placebo. Nem o participante da pesquisa, 
nem os profissionais responsáveis pela condução dos testes saberão qual tipo de tratamento. 
4. SESSÕES DE ETCC 
Neste estudo, as sessões serão realizadas conforme o protocolo. Será composto por dez sessões, nas quais iremos 
utilizar eletrodos (“borrachas umedecidas”) que serão colocados na sua cabeça, através dos quais passarão uma 
corrente elétrica de baixa intensidade. No grupo “sham”, a sessão será realizada com os mesmos equipamentos que 
não emitirão nenhum estímulo. Se concordar em participar do estudo, terá que cooperar em todas as etapas do 
mesmo. Nem o sujeito de pesquisa, nem os profissionais responsáveis pela condução das sessão de ETCC saberão 
qual tipo de tratamento (ativo ou “sham”) a senhora estará recebendo. 
 
3. GRUPOS DE PESQUISA 
Após um sorteio utilizando um site na internet, você será alocado em um dos 4 grupos de tratamento: 
1. ETCC + Medicação verdadeira 
2. ETCC + Placebo 
3. ETCC-Sham + Medicação verdadeira 
4. ETCC-Sham + Placebo 
 
5. POSSÍVEIS RISCOS E DESCONFORTOS 
Um possível desconforto poderá ser sentido, por algumas pessoas, na coleta de sangue, pois implica uma picada que 
poderá gerar uma mancha roxa no local, que desaparecerá em poucos dias. Durante a aplicação da estimulação 
poderá ocorrer vermelhidão, sensações de coceira, leve formigamento no local onde serão colocados os eletrodos. 
Com os questionários você poderá se sentir desconfortável ao responder alguma pergunta pessoal ou sobre o seu 
estado de saúde e qualidade de vida. Nos testes de sensibilidade à dor você poderá sentir um desconforto na região 
local do braço e apresentar alguma vermelhidão, que deverão desaparecer em pouco tempo. Em relação ao uso do 
medicamento, você poderá apresentar os seguintes efeitos adversos: nausea, cefaleia, visão turva e alterações do 
humor, que podem ocorrer em aproximadamente 1% da população. 
6. POSSÍVEIS BENEFÍCIOS DESTES ESTUDOS 
Você poderá não beneficiar-se diretamente da participação neste estudo pois, embora a naltrexona e a ETCC ETCC 
visem diminuir a dor e melhorar a qualidade de vida, 5 sessões de ETCC podem diminuir a dor mas por um tempo 
de duração limitado a semanas. Porém, com os resultados deste estudo poderemos obter informações importantes 
sobre o quanto esta terapia poderá beneficiar outros pacientes com quadros de dor semelhantes ao seu, ou você 
mesma num futuro próximo. 
7. EXCLUSÃO DO ESTUDO 
O investigador responsável poderá ao longo do estudo considerar o seu afastamento da pesquisa, caso seja verificado 
que você não preenche adequadamente os critérios necessários ou seja verificado que a pesquisa possa adicionar 
outros riscos para você . 

 
8. DIREITO DE DESISTÊNCIA  
Sua participação é totalmente voluntária, e você pode desistir de participar a qualquer momento da pesquisa, sinta-
se à vontade. Sua decisão de não participar ou de deixar a pesquisa depois de iniciada não prejudicará a atenção 
recebida nas clínicas integradas da La Salle.  
9. PRIVACIDADE 
Os pesquisadores se comprometem em manter a confidencialidade dos dados. Todas as informações obtidas deste 
estudo poderão ser publicadas com finalidade científica, preservando os dados de identificação dos participantes. 
10. CONTATO DOS PESQUISADORES 
Caso você tenha alguma dúvida poderá entrar em contato com o pesquisador responsável por este estudo: Profº Dra. 
Andressa de Souza, através do telefone 981975718. Ou, poderá contatar o Comitê de Ética e Pesquisa da 
Universidade La Salle, pelo e-mail: cep.unilasalle@unilasalle.edu.br 
11. RESSARCIMENTO DE DESPESAS 
Você não terá despesas com a sua participação na pesquisa e não será remunerada por ela. 
12. CONSENTIMENTO 
Este termo de Consentimento Livre e Esclarecido será assinado em duas vias, uma para você e uma via será 
arquivada pelo pesquisador. Desta forma, declaro ter lido – ou me foi lido – as informações acima antes de assinar 
este Termo. Foi-me dada ampla oportunidade de fazer perguntas, esclarecendo plenamente minhas dúvidas. Por este 
instrumento, torno-me parte, voluntariamente, do presente estudo. 
 
Nome do participante: _______________________________________________________________ 
Assinatura do participante: ___________________________________________________________ 
Nome do pesquisador: _______________________________________________________________  
Assinatura do pesquisador: ___________________________________________________________  
 
Porto Alegre, _______  de ________________________   de _____.