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

NCT ID: NCT02964741

Last Updated: 2022-08-26

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: NA
• Total Enrollment: 44 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-02-22
• Study Completion Date: 2021-08-01

Brief Summary

This study investigates whether non-invasive brain stimulation, given for 20 minutes/once per day for ten days (M-F) can reduce migraine pain. Thirty patients will receive this treatment, while thirty will receive a "sham" procedure. Up to thirty healthy volunteers will be asked to undergo baseline assessments only (imaging, but no brain stimulation). Healthy volunteer data may be used from a prior study (NINDS-K23062946 project [IRBMED #HUM00027383; Dr. Alexandre DaSilva, Principal Investigator]).

Detailed Description

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-discriminative 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.

Conditions

Migraine

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Migraine Patients Active Group

Episodic migraine 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).

*Active Comparator

Group Type: ACTIVE_COMPARATOR

Active Comparator

Intervention Type: DEVICE

non-invasive brain stimulation (active protocol)

Migraine Patients Sham Group

Episodic migraine 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).

*Sham Comparator

Group Type: SHAM_COMPARATOR

Sham Comparator

Intervention Type: DEVICE

non-invasive brain stimulation (sham protocol)

Healthy Control Group

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 (NINDS-K23062946 project [IRBMED #HUM00027383; 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.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Active Comparator

non-invasive brain stimulation (active protocol)

Intervention Type: DEVICE

Sham Comparator

non-invasive brain stimulation (sham protocol)

Intervention Type: DEVICE

Other Intervention Names

HD-tDCS (active protocol); HD-tDCS (sham protocol)

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute of Neurological Disorders and Stroke (NINDS)

NIH

Sponsor Role: collaborator

University of Michigan

OTHER

Sponsor Role: lead

Responsible Party

Alexandre DaSilva, DDS, DMedSc

Assistant Professor of Biologic and Materials Science, School of Dentistry and Research Assistant Professor, Center for Human Growth & Development

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Alexandre F DaSilva, DDS, DMedSc

Role: PRINCIPAL_INVESTIGATOR

University of Michigan

Locations

University of Michigan School of Dentistry

Ann Arbor, Michigan, United States

Countries

United States

References

Lim M, Kim DJ, Nascimento TD, DaSilva AF. High-definition tDCS over primary motor cortex modulates brain signal variability and functional connectivity in episodic migraine. Clin Neurophysiol. 2024 May;161:101-111. doi: 10.1016/j.clinph.2024.02.012. Epub 2024 Feb 15.

Reference Type: DERIVED

PMID: 38460220 (View on PubMed)

DaSilva AF, Kim DJ, Lim M, Nascimento TD, Scott PJH, Smith YR, Koeppe RA, Zubieta JK, Kaciroti N. Effect of High-Definition Transcranial Direct Current Stimulation on Headache Severity and Central micro-Opioid Receptor Availability in Episodic Migraine. J Pain Res. 2023 Jul 21;16:2509-2523. doi: 10.2147/JPR.S407738. eCollection 2023.

Reference Type: DERIVED

PMID: 37497372 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

R01NS094413

Identifier Type: NIH

Identifier Source: secondary_id

View Link

HUM00107286

Identifier Type: -

Identifier Source: org_study_id