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

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.

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).