Investigation and Modulation of the Mu-Opioid Mechanisms in Migraine (in Vivo)

Migraine is a debilitating chronic condition that affects most of the patient's existence,
from childhood to late adulthood. During frequent headache attacks, its sufferers show marked
increased sensitivity to noxious (hyperalgesia) and even non-noxious stimuli, a phenomenon
called cutaneous allodynia that affects 63% of the patients. Although MRI-based techniques
have provided insights into some brain mechanisms of migraine, many questions regarding its
molecular impact in the brain are still unanswered. The overall goal of this project is to
provide a detailed understanding of the µ-opioid receptor mediated transmission in the brain
of migraine patients, one of the most important central pain regulatory systems in humans,
with the long-term objective of developing more focused neuromechanism-driven methods for
migraine research and therapy.

Preliminary studies from an earlier project (NINDS-NIHK23 NS0629946) using positron emission
tomography (PET) with [11C] carfentanil, a selective radiotracer for μ-opioid receptor (μOR),
have indicated that there is a decrease in µOR availability (non-displaceable binding
potential; BPND) in the brain of migraine patients during the headache attacks and allodynia,
including areas like thalamus and periaqueductal gray matter (PAG). µOR BPND is an objective
measurement, in vivo, of endogenous μ-opioid availability, and its acute reduction reflects
the activation of this neurotransmitter system. This is arguably one of the neuromechanisms
most centrally involved in pain regulation, affecting multiple elements of the pain
experience. Moreover, MRI-based reports have found that those findings co-localize with
neuroplastic changes in migraine patients. Conventional therapies are unable to selectively
target those dysfunctional brain regions, and there is a paucity of data on how to reverse
embedded neuroplastic molecular mechanisms when available medications and surgical therapies
fail. 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
refractory central. The rationale for MCS stimulation is based in part on the thalamic
dysfunction noticed in chronic pain and migraine, and also on studies demonstrating that MCS
significantly changes thalamic activity. Evidently, the invasive nature of such a procedure
limits its indication to highly severe chronic pain disorders. New non-invasive brain
neuromodulatory methods for M1, such as transcranial direct current stimulation (tDCS), can
now safely modulate and activate the µOR system, providing relatively lasting pain relief in
chronic pain patients and migraine. However, the electric fields generated by its most
conventional analgesic montage are widely spread across the brain, lacking specificity on the
pain-related structures directly targeted. Recently, a novel high-definition tDCS (HD-tDCS)
montage created by our group was able to reduce exclusively "contralateral"
sensory-discrimative clinical pain measures (pain intensity/area) in chronic patients by
targeting more precisely the putative M1 region. It is hoped that this montage will provide
durable relief of pain for this episodic migraine population.

This is a phase 2, single center, two-arm, double-masked, randomized investigation and
modulation of the µ-opioid mechanisms in migraine (in vivo). We will enroll 60 patients with
episodic migraine (30 for the active M1 HD-tDCS group and 30 for a sham group). Each
participant will undergo a sequence of events and evaluations that will include baseline
assessments, 10 days of HD-tDCS, pre- and post-PET and MRI scans, and questionnaires to
evaluate pain and quality of life.

Inclusion Criteria:

- Episodic migraine (ICHD-3-beta) for at least 6 months, with at least one attack per
month and less than 15 attacks per month

- No intake of opiate medication for the past six months

- No overuse of analgesic medication, defined as regular intake on ≥15 days per month
for more than 3 months

- Willing to limit the introduction of new treatments for headache management

Exclusion Criteria:

- Presence of any other systemic or chronic pain disorder

- History or current evidence of a psychotic disorder (e.g. schizophrenia) or substance
abuse; bipolar or severe major depression, as evidenced by Beck Depression score of ≥
30

- History of neurological disorder (e.g. epilepsy, stroke, neuropathy, neuropathic pain)

- Prior use of tDCS

- Current use of opioid pain medications