Investigation and Modulation of the Mu-opioid Mechanisms in TMD (in Vivo)

Study Overview
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Brief Summary
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In this study, this team of researchers will investigate the impact of chronic temporomandibular disorder suffering on the endogenous μ-opioid system in vivo, arguably one of the principal endogenous pain modulatory systems in the brain, and its modulation by 10 daily sessions of primary motor cortex stimulation using high-definition transcranial direct current stimulation (HD-tDCS).

Detailed Description
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Approximately 10% of TMD patients will not experience an improvement of their symptoms and around 75% of patients who fail to respond to conservative treatments are also not suitable for TM joint surgery. Initial studies from NIH-NIDCR R56 project using positron emission tomography (PET) with [11C] Carfentanil, a selective radiotracer for μ-opioid receptor (μOR), have demonstrated that there is a decrease in thalamic μOR availability (non displaceable binding potential BPND) in the brains of TMD patients during masseteric pain compared to healthy controls. μ-opioid neurotransmission is arguably one of the mechanisms most centrally involved in pain regulation and experience. Moreover, the thalamus is the major relay structure in the forebrain for (non)-noxious inputs, which will be distributed subsequently to multiple cortical areas for discriminative, cognitive and affective processing. MRI-based reports have found that those findings co-localize with neuroplastic changes in trigeminal pain patients. Conventional therapies are unable to selectively target the thalamus and associated regions, and there is a paucity of data on how to reverse neuroplastic molecular mechanisms when available medications fail. Interestingly, several studies with motor cortex stimulation (MCS) have shown that epidural electrodes in the primary motor cortex (M1) are effective in providing analgesia in patients with central pain and that it occurs via indirect modulation of thalamic activity. Evidently, the invasive nature of such a procedure limits its indication to highly severe pain disorders. New non-invasive neuromodulatory methods for M1, such as transcranial direct current stimulation (tDCS), can now safely modulate the μOR system, providing relatively lasting pain relief in pain patients. Recently, a novel high-definition tDCS (HD-tDCS) montage created by this research group was able to reduce exclusively contralateral sensory-discrimative clinical pain measures (intensity/area) in TMD patients by targeting precisely the M1 region. Therefore, the main goals of this study are: First, to exploit the μ-opioidergic dysfunction in vivo in TMD patients compared to healthy controls; Second, to determine whether 10 daily sessions of noninvasive and precise M1 HD-tDCS have a modulatory effect on clinical and experimental pain measures in TMD patients; and Third, to investigate whether repetitive active M1 HD-tDCS induces/reverts μOR BPND changes in the thalamus and other pain-related regions, and whether those changes are correlated with TMD pain measures. The studies above represent a change in paradigm in TMD research, as this research group directly investigates and modulates in vivo one of the most important endogenous analgesic mechanisms in the brain. The IRB approved study protocol also includes secondary data sets to be used for analysis in study objective #6 only. The data sets are not part of the clinical trial as they were collected during a previous study (NIDCR-R56-DE022637 project [IRBMED #HUM00080911; Dr. Alexandre DaSilva, Principal Investigator]). Participants in HUM00080911 (both Healthy and TMD patients) received no intervention, but underwent the same Baseline, MRI and PET protocol. This secondary data will not be represented in the Adverse Event or final enrollment total for this clinical trial. However, the data will be analyzed in a meta-analysis addressing secondary objective #6 only. These data sets will not be used to analyze any primary study objectives, nor change the terms of the clinical trial. Manuscripts that include these secondary data sets will clearly indicate the use of this data and clarify that the data was collected separate from the clinical trial data.

Official Title
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Investigation and Modulation of the Mu-opioid Mechanisms in TMD (in Vivo)

Conditions
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Temporomandibular Disorder

Intervention / Treatment
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* Device: HD-tDCS*
* Device: Sham HD-tDCS*


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provide signed and dated informed consent form; Male or female, aged 18 to 65 (inclusive); tDCS naïve; and Willing to comply with all study procedures and be available for the duration of the study. In addition, TMD subjects must qualify as: • Diagnosed with chronic TMD as defined by the Diagnostic Criteria (DC) for TMD and the American Academy of Orofacial Pain (DC/TMD): Chronic TMD pain and dysfunction for at least one year from the clinical exam session (DC/TMD: Masticatory myofacial pain with/without referral) not adequately controlled by previous therapies (eg, NSAIDs, muscle relaxants) TMJ open-surgery naïve; TMD maximum pain score pain of greater than or equal to 3 (moderate to severe) on a 0-10 VAS, despite existing treatment, for 3 days in the 7 days preceding study consent, based on report at the screening session; If taking pain medications, the dose regimen must be stable for at least 4 weeks prior to screening; and Willing to halt the introduction of new medications for chronic TMD symptoms during the study. Emphasis is therefore placed on generalizability and chronicity of symptoms. OR To qualify as a Healthy Volunteer, subjects must be: Without self-reported history of systemic disorders or other chronic pain disorders, including migraine. Exclusion Criteria: Existence of chronic pain disorder(s) other than TMD History of a traumatic brain injury History or current evidence of a psychotic disorder (e.g. schizophrenia) or substance abuse (self-reported) Bipolar or severe major depression, as evidenced by a Beck Depression Inventory score of ≥ 30 Ongoing, unresolved disability litigation (self-reported) History of neurological disorder (e.g. epilepsy, stroke, neuropathy, neuropathic pain; self-reported) Opioid pain medications taken within the past 3 months Past allergic response to opioids or chemically related drugs (e.g., carfentanil) Excluded by MRI Center or PET Center safety screening checklist (as administered by study staff) Drug test positive for opioid or recreational drug (e.g., cannabis) at the time of the PET scan visits Pregnant or lactating (negative urine pregnancy test must be available before any PET procedures are initiated) Treatment with an investigational drug, device or other intervention within 30 days of study enrollment Anything that would place the individual at increased risk or preclude the individual's full compliance with or completion of the study (e.g., medical condition, laboratory finding, physical exam finding, logistical complication).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: TMD Patients Active Group: Active Comparator<br>30 TMD patients will be randomized (Taves method) to receive high-definition transcranial direct current stimulation (HD-tDCS*) as 20 minute sessions, once daily for 10 days (M-F for 2 weeks). | Device: HD-tDCS*<br>* Non-invasive brain stimulation (active protocol)<br>* Other names: HD-tDCS (active protocol);|
| Sham Comparator: TMD Patients Sham Group: Sham Comparator<br>30 TMD patients will be randomized (Taves method) to receive high-definition transcranial direct current stimulation (HD-tDCS*) as 30-second administrations at the beginning and end of each 20 minute session, once daily for 10 days (M-F for 2 weeks). | Device: Sham HD-tDCS*<br>* Non-invasive brain stimulation (sham protocol)<br>* Other names: HD-tDCS (sham protocol);|
| No Intervention: Healthy Control Group<br>20 Healthy Volunteers will be asked to undergo baseline assessments only (including imaging, but no brain stimulation). Healthy volunteer data (n </= 10) may be used from a prior study (NIDCR-R56-DE022637 project [IRBMED #HUM00080911; Dr. Alexandre DaSilva, Principal Investigator]). Consent to use data for a future study was obtained in the informed consent document at the time of participation. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Clinical Visual Analog Scale Pain Score From Baseline (Screening Day) to 4 Weeks After Completion of HD-tDCS Sessions (Follow Up #2). | Change in clinical Visual Analog Scale pain score from baseline (Screening Day) to 4 weeks after completion of HD-tDCS sessions (Follow Up #2). Pain is measured on a scale of 1-10, with 10 being the worst. | Screening (Baseline), 4 Weeks after completion of HD-tDCS sessions | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Clinical Visual Analog Scale Pain Score During Sustained Masseteric Pain Stress Challenge From Baseline PET (#1) Session to Follow-up PET (#2) Session, 1 Week After Completion of HD-tDCS Sessions. | Change in clinical Visual Analog Scale pain score during sustained masseteric pain stress challenge from baseline PET (#1) session to follow-up PET (#2) session, 1 week after completion of HD-tDCS sessions. | Baseline, 1 Week after completion of HD-tDCS sessions | 
| Changes in GeoPain Measures (PAINS - Summation of Area and Intensity) From Baseline Daily Over the Treatment Period and Through Follow-up (4 Weeks After Completion of HD-tDCS Sessions). | Short- and long-term changes in GeoPain measures (percentage of pain area extension in the head region, average of pain intensity in the affected region, and their summation, meaning percentage of combined pain area and intensity in the affected region) from baseline daily over the treatment period and through follow-up at 4 weeks after completion of HD-tDCS sessions). | Baseline to 4 weeks after completion of HD-tDCS sessions | 
| Difference in µOR BPND Levels of Thalamus From Baseline PET (#1) Session to Follow-up PET (#2) Session, 1 Week After Completion of HD-tDCS Sessions. | The difference in µOR BPND levels (a measure of receptor availability) between Baseline PET #1 and PET (#2) in TMD patients (active vs sham treatment groups). The values indicate changes in the availability of mu-opioid receptors (µOR), referred to as the non-displaceable binding potential (BPND), which reflects the density or concentration of available µORs in a particular region of interest in the brain, specifically the left thalamus. These changes are assessed by conducting baseline positron emission tomography (PET) scans prior to treatment and follow-up PET scans one week after the completion of HD-tDCS sessions. During each PET scan, µOR measurements are taken during an early resting phase. A positive value indicates increased µOR availability following treatment, while a negative value indicates decreased availability after treatment. | Baseline to 1 Week after completion of HD-tDCS sessions. | 
| Change in Clinical Visual Analog Scale Pain Score at Rest From Baseline PET (#1) Session to Follow-up PET (#2) Session, 1 Week After Completion of HD-tDCS Sessions. | Change in clinical Visual Analog Scale pain score at rest from baseline PET (#1) session to follow-up PET (#2) session, 1 week after completion of HD-tDCS sessions. | Baseline, 1 Week after completion of HD-tDCS sessions. | 
| Difference in µOR BPND Levels at Rest During PET (#1) in Chronic TMD Patients as Compared to Healthy Subjects. | The difference in µOR BPND levels (a measure of receptor availability) at rest (5-40 mins after radiotracer injection) during baseline PET in TMD patients as compared to healthy subjects. The values for each group the availability of mu-opioid receptors (µOR), referred to as the non-displaceable binding potential (BPND), which reflects the density or concentration of available µORs in a particular region of interest in the brain, specifically the left thalamus. It was assessed by conducting baseline positron emission tomography (PET) scans. The outcome measure 6 was taken during an early-resting (outcome 6) | During PET #1, at rest (5-40 mins after radiotracer injection) | 
| Difference in µOR BPND Levels During Experimental Sustained Masseteric Pain Stress Challenge During PET (#1) in Chronic TMD Patients as Compared to Healthy Subjects | Difference in µOR BPND levels (a measure of receptor availability) at experimental sustained masseteric pain stress challenge (45-90 mins after radiotracer injection) during baseline PET in TMD patients as compared to healthy subjects. The values for each group the availability of mu-opioid receptors (µOR), referred to as the non-displaceable binding potential (BPND), which reflects the density or concentration of available µORs in a particular region of interest in the brain, specifically the left thalamus. It was assessed by conducting baseline positron emission tomography (PET) scans. The outcome measure 7 was taken during a late pain stimulus (hypertonic saline infusion) phase. | PET (#1) during experimental sustained masseteric pain stress challenge (45-90 mins after radiotracer injection) |