Analgesic Effect of Cathodal tDCS Over Right DLPFC in Subjects With Muscular TMD: a Double Blind Crossover RCT
Condition: Craniomandibular Disorders
MeSH terms: Craniomandibular Disorders
Study type: Interventional

Summary: 
      1. BACKGROUND: Temporomandibular Disorders (TMD) have become part of the daily routine of
           all the health care professionals. Some studies have shown improvement in subjects with
           chronic pain using neuromodulation. Chronic pain is involved with neuronal excitability
           and the excitatory modulation is also being studied to treat chronic pain. Transcranial
           direct current stimulation (tDCS) allows the neuronal membranes to be neuromodulated.
           tDCS can enhance or inhibit the potential actions on the cortex. Studies with animals
           has shown that anodal stimulation modulate the membrane in the way to depolarize which
           results in a long term potential in the stimulated area.

        2. PROBLEM: Most strategies for the treatment of TMDs are local and aim to treat directly
           the cranial-facial muscles, applying kinesitherapy on Temporomandibular joint (TMJ)
           and/or on the jaws and on the occlusion of teeth. Some drugs, such as tricyclic
           antidepressants, that act in the CNS are used in these patients with positive results in
           the beginning of the treatment. However, many patients after using these drugs in a
           daily basis, are refractory to them and do not present an improvement in the pain
           anymore or present several side-effects. Therefore, the investigators want to know if
           tDCS over dorsolateral prefrontal cortex (DLPFC) would have an analgesic effect when
           reaching emotional areas.

        3. HYPOTHESIS: The investigators believe that neuromodulation by tDCS over DLPFC would
           decrease the anxiety level and consequently the muscular hyperactivity that is an
           important etiological factor of TMD. For that, the masseter motor evoked potential (MEP)
           will be used to verify any change.

        4. AIM: To investigate if cathodal tDCS over right DLPFC has analgesic effects in subjects
           with muscular TMD.

        5. METHOD: The investigators will run a three-arm crossover double blind with 15 muscular
           TMD subjects. The group treatments will be cathodal tDCS 1mA, cathodal tDCS 2mA and
           Placebo. To verify selection criteria the investigators will use RDC/TMD, Visual
           analogical scale (VAS) score from 4 to 10 for six months or longer, Inventory of
           state-trit anxiety (ISTA) score more than 42. The outcomes will be VAS, sensory testing,
           Electroencephalogram (EEG) and ISTA.
    

Detailed description: 
      1. INTRODUCTION Pain is among the main complaints of most patients that seek care in a
           hospital or a primary care unit. Temporomandibular Disorders (TMD) patients have become
           part of the daily routine of all the health care professionals. Temporomandibular and
           cranial-facial disorders are so prevalent that, since 1987, the International Headache
           Society holds meetings to classify different types of pain associated with head. This
           resulted in the publication of the Manual of Classification of Headaches - The
           International Classification of Disorders Headache was revised in 2013.

           There are different strategies to treat TMD patients, and the best is chosen depending
           on the type of problem diagnosed or the most suitable strategy according to professional
           experience. Strategies range from advice on lifestyle, psychotherapy, containment of the
           jaw, kinesitherapy, ultrasound, TENS, muscle relaxants plates, allopathic and
           homeopathic therapies and surgical interventions to the temporomandibular joint (TMJ).
           Some of these techniques aim to treat the muscles, others treat the dental occlusion or
           joint structures and there are those whose primary focus is the psycho-emotional
           factors. As The TMDs are due to various factors of muscular, joint, emotional,
           inflammatory, autoimmune or even infectious reasons, the treatment should include
           different therapies during the rehabilitation process, considering the best strategies
           for each patient. Literature has shown that the causes of muscular origin are more
           prevalent in patients with this type of disorder). A systematic review using studies
           with functional brain imaging, showed that, although the majority of disorders are
           associated with muscle pain, this would be secondary to a process triggered by the
           Central Nervous System (CNS). Following this theory, some behavioral studies have shown
           that the TMD, almost always, are related to preexisting psychopathology.

           Chronic pain is involved with neuronal excitability. a study using transcranial magnetic
           stimulation (TMS) found higher threshold in both sides of resting motor cortex with
           lower up regulation responses. Furthermore they found lower responses in the
           intracortical facilitation and inhibition.

           The transcranial direct current stimulation (tDCS) allows the neuronal membranes to
           neuromodulate and it can enhance or inhibit the potential actions on the cortex. Studies
           with animals has shown that anodal stimulation modulate the membrane in the way to
           depolarize which results in a long term potential in the stimulated area. Some studies
           have shown improvement in subjects with fibromyalgia and chronic pain using
           neuromodulation . Some authors suggest anodal tDCS over motor cortex to decrease pain
           while modulating the activity in the neuronal networks responsible for pain, an example
           of that is the thalamus. It also facilitates the descending inhibition of pain. However
           few evidences support the efficacy of tDCS.

           Another montage is tDCS over dorsolateral prefrontal cortex (DLPFC). This area is
           involved with anxiety and depression without direct analgesic effect. A study showed a
           pain level decrease after tDCS over DLPFC in patients with emotional and affective
           troubles. The authors suggested it based on emotional modulation by pain independent
           networks by somatosensory pain perception. A study found anxiety modulation after tDCS
           application over DLPFC using cathodal current on the right side and anodal on the left
           side. This result is just a weak evidence that the tDCS anxiety effect, there is a
           demand to investigate that approach.

           Regarding the parameters the authors have suggested, 1 or 2mA, but the most common and
           more used is 2 mA. There is a discussion about which milliamperage is more appropriate
           when the investigators use cathodal current. A study verified the same results after
           cathodal and anodal 2mA, both increased the motor evocated potential (MEP) whereas 1mA
           cathodal current decreased the cortical excitability. Regarding the risks of side and
           adverse effects a systematic review found just a few adverse effects such as itching,
           tingling and mild headache that lingered after the stimuli was removed. The adverse
           effects depend on the intensity and duration and usually the protocol recommends the use
           of lower intensity (1 or 2mA) during short period of time of 20 or 30 minutes. A
           questionnaire has been utilized to access these effects.

        2. PROBLEM Most strategies for the treatment of TMDs are local and aim to treat directly
           the cranial-facial muscles, applying kinesitherapy on TMJ and/or on the jaws and on the
           occlusion. Some drugs, such as tricyclic antidepressants, that act in the CNS are used
           in these patients with positive results in the beginning of the treatment. However, many
           patients, after using these drugs in a daily basis, are refractory to them and do not
           present an improvement in the pain anymore or present several side effects. Therefore,
           the investigators want to know if tDCS over DLPFC would have an analgesic effect when
           reaching emotional areas and if there are different results with different amplitude.

        3. HYPOTHESIS The investigators believe that neuromodulation by tDCS over DLPFC would
           decrease the anxiety level and consequently the muscular hyperactivity that is an
           important etiological factor of TMD. Using the motor evoked potential the investigators
           will verify if changes will occur after 1mA and 2mA stimulation and if those changes
           will be different when compared.

        4. OBJECTIVES 4.1- GENERAL PURPOSE Investigate if cathodal tDCS over right DLPFC has
           analgesic effects in subjects with muscular TMD.

           4.2- SPECIFICS PURPOSES 1- Evaluate the tDCS effect regarding pain perception and
           pressure threshold; 2- Evaluate if tDCS has any effect on anxiety and stress; 3- Measure
           the masseter MEP pre and post tDCS; 4- Correlate pain intensity with anxiety and
           masseter MEP pre and post tDCS; 5- Compare tDCS effects over pain intensity, anxiety,
           stress and masseter MEP after apply different intensities (1mA/2mA).

        5. BACKGROUND tDCS has shown promising results for the treatment of chronic pain in several
           types of diseases, being a good and non-invasive alternative to treat pain in TMD
           patients. Also, based on studies that showed changes in the brain activity of chronic
           pain patients and on the difficulties faced to treat TMD, there is a need to conduct
           clinical trials using new techniques, such as neuromodulation, to help these patients to
           control their pain. Therefore, tDCS emerges as a new tool to be coupled with other
           effective treatments already used for these patients. Furthermore, the investigators
           think that there is a tie relationship between anxiety and muscular hyperactivity but
           there is no evidence to say that tDCS over emotional areas can decrease anxiety.

        6. MATERIALS AND METHODS 6.1 Sample The IMMPACT (Initiative on Methods, Measurement, and
           Pain Assessment in Clinical Trial) advises an effect size of 0.5 to treat pain disease.
           Using this parameter from G*Power 3.1, with an 80% statistical power, alpha of 0.05,
           measuring six measures of three intervention groups. Therefore a sample size of 15
           subjects with muscular TMD will be utilized. Subjects are from database of Occlusion and
           TMJ Center of Dentistry Faculty of Federal University of Bahia.

      Randomization The subjects will be allocated consecutively to randomization as intervention
      order using the tool from randomization.com website (Dallal GE,
      http://www.randomization.com). The investigators will use the second generation suggested for
      crossover studies.

      6.2 Materials The materials are available on the budget table and the questionnaire is
      annexed.

      6.3 Data Collection Procedure All subjects will be treated using three different
      interventions (groups I1, I2 e I3) respecting the washout period of 7 days to avoid residual
      effects. The intervention order will be determined by randomization per group of
      intervention.

      After COAT institutional authorization, subjects will be contact by phone and asked if they
      want to participate in the study. Those who wish to participate and qualify according to the
      selection criteria after completing the pre-screening questionnaire will be scheduled after
      reading and signing the consent form (2 copies). Women of chill-bearing potential will be
      required to take a urine pregnancy test during screening process. If a subject becomes
      pregnant during the course of the study, she will be withdrawn from the study. At the end of
      the first appointment the subject will take a VAS and ISTA diary home to complete 7 days
      before the baseline evaluation. The investigators will use the average of VAS and ISTA diary
      to get the baseline values.

      During the second visit, all clinical and neurological assessments will be performed before
      and after tDCS stimulation. During the second visit (T2) clinical and neurological
      assessments will be performed. The clinical assessments will be guided by RDC/TMD, pain and
      anxiety diary and by sensory tests (Von Frey monofilaments and algometry/EMG system). The
      neurophysiological assessment will be done using EEG to analyze cortical activity. Each
      patient will be clinically and neurologically assessed before and after the stimulation,
      allowing data to be collected 6 times (T2 to T7) and also at the first visit.

      To group I1, the parameters used in the TDCS will be 1mA with cathodal over the right DLPFC
      and anodal stimulation in the supraorbital contralateral area. With this chosen area the
      investigators aim to reach cerebral regions responsible for anxiety. To group I2, the same
      parameters will be used; however the current will be 2mA. The parameters to group I3, which
      is the control group, will be the same as the active and the device in sham mode. To acquire
      a placebo effect, the current will be used for the first 30 seconds and then reduced
      gradually until zero in 20 seconds. This method has been shown effective in previous studies
      and accepted by the academic community to blind subjects without any type of effects in the
      cortical excitability.

      The current will be applied using 35cm2 electrodes soaked in saline substance (140mMol de
      NaCl water dissolved Mille-Q). The electrodes will be connected in the device driven by a 9v
      batteries and will be regulated by a digital multimeter (EZA EZ 984, China) standard error of
      ±1.5% (Montenegro et al., 2012).

      All subjects will receive just one stimulation session for each type of intervention (I1, I2,
      I3), totaling 3 sessions. After tDCS sessions the subject will answer an adverse effects
      questionnaire. A trained researcher will do each procedure. A researcher responsible for the
      general coordination (E.P.S.) will hold the randomization list and just the responsible for
      the tDCS stimulation would know this information.

      6.4 Study Variables Dependent: Visual Analogic Scale to pain, inventory of state-trit
      anxiety, sensory testing, TMS and EEG.

      Independent: Cathodal tDCS over DLPFC (1mA/2mA) and placebo treatment. 6.5 Data Analysis Data
      will be recorded at an Excel 2010 sheet to be analyzed by a biostatistics professional who
      will not have access to randomization process. To verify improvements after tDCS session from
      each intervention group the investigators will use correlation test, post-hoc (to multiples
      compare), a parametric one-way ANOVA if the data distributions are normal or non-parametric
      if not normal and an intraclass concordance test. The difference among groups will be
      analyzed by a multiple variance analysis (placebo vs. 1mA, Placebo vs. 2mA and 1mA vs. 2mA)
      and p-value will be corrected to multiple compare (Bonferroni) to acquire a 0.05 significance
      level. All data will be analyzed by intention to treat.
    

Intervention name(s): tDCS
Intervention type(s): Device
Intervention description(s): The transcranial direct current stimulation allows the neuronal membranes to neuromodulate and it can enhance or inhibit the potential actions on the cortex. Studies with animals has shown that anodal stimulation modulate the membrane in the way to depolarize which results in a long term potential in the stimulated area
Other intervention name(s): Soterix Medical 1×1 tDCS 1300A
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Temporomandibular; Musculoskeletal Diseases; Electrical Stimulation of the Brain; Prefrontal Cortex