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

Primary Purpose

Temporomandibular Disorder

Status
Terminated
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
HD-tDCS*
Sham HD-tDCS*
Sponsored by
University of Michigan
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Temporomandibular Disorder

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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).

Sites / Locations

  • University of Michigan School of Dentistry

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Sham Comparator

No Intervention

Arm Label

TMD Patients Active Group: Active Comparator

TMD Patients Sham Group: Sham Comparator

Healthy Control Group

Arm Description

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).

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).

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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).
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.
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.
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)
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.

Full Information

First Posted
October 26, 2018
Last Updated
May 19, 2023
Sponsor
University of Michigan
Collaborators
National Institute of Dental and Craniofacial Research (NIDCR)
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1. Study Identification

Unique Protocol Identification Number
NCT03724032
Brief Title
Investigation and Modulation of the Mu-opioid Mechanisms in TMD (in Vivo)
Official Title
Investigation and Modulation of the Mu-opioid Mechanisms in TMD (in Vivo)
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Terminated
Why Stopped
Low enrollment
Study Start Date
December 13, 2018 (Actual)
Primary Completion Date
January 17, 2022 (Actual)
Study Completion Date
January 17, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Michigan
Collaborators
National Institute of Dental and Craniofacial Research (NIDCR)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
Yes
Device Product Not Approved or Cleared by U.S. FDA
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Temporomandibular Disorder

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
15 (Actual)

8. Arms, Groups, and Interventions

Arm Title
TMD Patients Active Group: Active Comparator
Arm Type
Active Comparator
Arm Description
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).
Arm Title
TMD Patients Sham Group: Sham Comparator
Arm Type
Sham Comparator
Arm Description
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).
Arm Title
Healthy Control Group
Arm Type
No Intervention
Arm Description
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.
Intervention Type
Device
Intervention Name(s)
HD-tDCS*
Other Intervention Name(s)
HD-tDCS (active protocol)
Intervention Description
Non-invasive brain stimulation (active protocol)
Intervention Type
Device
Intervention Name(s)
Sham HD-tDCS*
Other Intervention Name(s)
HD-tDCS (sham protocol)
Intervention Description
Non-invasive brain stimulation (sham protocol)
Primary Outcome Measure Information:
Title
Change in Clinical Visual Analog Scale Pain Score From Baseline (Screening Day) to 4 Weeks After Completion of HD-tDCS Sessions (Follow Up #2).
Description
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.
Time Frame
Screening (Baseline), 4 Weeks after completion of HD-tDCS sessions
Secondary Outcome Measure Information:
Title
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.
Description
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.
Time Frame
Baseline, 1 Week after completion of HD-tDCS sessions
Title
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).
Description
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).
Time Frame
Baseline to 4 weeks after completion of HD-tDCS sessions
Title
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.
Description
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.
Time Frame
Baseline to 1 Week after completion of HD-tDCS sessions.
Title
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.
Description
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.
Time Frame
Baseline, 1 Week after completion of HD-tDCS sessions.
Title
Difference in µOR BPND Levels at Rest During PET (#1) in Chronic TMD Patients as Compared to Healthy Subjects.
Description
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)
Time Frame
During PET #1, at rest (5-40 mins after radiotracer injection)
Title
Difference in µOR BPND Levels During Experimental Sustained Masseteric Pain Stress Challenge During PET (#1) in Chronic TMD Patients as Compared to Healthy Subjects
Description
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.
Time Frame
PET (#1) during experimental sustained masseteric pain stress challenge (45-90 mins after radiotracer injection)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alexandre F DaSilva, DDS, DMedSc
Organizational Affiliation
University of Michigan
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Michigan School of Dentistry
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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

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