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

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]).

Study Overview

• Status: Terminated
• Conditions: Migraine
• Intervention / Treatment: Device: Active Comparator; Device: Sham Comparator

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.

• Study Type: Interventional
• Enrollment (Actual): 44
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-5720
      • University of Michigan School of Dentistry

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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	Device: Active Comparator; non-invasive brain stimulation (active protocol); Other Names: HD-tDCS (active protocol)
Sham Comparator: 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	Device: Sham Comparator; non-invasive brain stimulation (sham protocol); Other Names: HD-tDCS (sham protocol)
No Intervention: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Days With Moderate-to-severe Headache	Moderate to severe headache is defined by the pain over 3 in an Numeric Rating Scale (NRS) ranging from 0 to 10 between end of treatment and one month follow-up.	End of treatment - over 1 month follow-up
Responder Rate	Number of participants who showed a 50% reduction of days with moderate-to-severe headache compared to baseline.	End of treatment - over 1 month follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Pain Intensity Level Measured by the Visual Analog Scale in Migraineurs (Active or Sham)	Visual Analog Scale measures pain on a 0 to 10 scale, where 0 is "no pain" and 10 is "worst possible pain"	Approximately 45 days (Screening Visit [Original Baseline] to Follow Up #2 [28-days post-HD-tDCS treatment])
Moderate to Severe Headache	Percentage of participants having moderate-to-severe headache between end of treatment and one month follow-up. Defined as a response greater than 3 on the (0-10) NRS scale	End of treatment - over 1 month follow-up
Use of Rescue Medication	Percentage of participants who used rescue medication between end of treatment and one month follow-up	End of treatment - over 1 month follow-up
Change in Mu-opioid Receptor Non-displaceable Binding Potential (BPND) in the Brains of Migraineurs During Sustained Thermal Pain Threshold Stress Challenge Subsequent to Treatment by HD-tDCS (Active or Sham).	Mu-opioid receptor BPND at PET #2 will be subtracted from mu-opioid receptor BPND at PET #1. PET #1 occurs during the week before HD-tDCS treatment begins. PET #2 occurs during the week after the final HD-tDCS treatment is completed.	Time between PET #1 and PET #2 is typically 21 days (minimum 17 days; maximum 42 days).
Change in Mu-opioid Receptor Non-displaceable Binding Potential (BPND) in the Brains of Migraineurs at Rest Subsequent to Treatment by HD-tDCS (Active or Sham).	Mu-opioid receptor BPND at PET #2 will be subtracted from mu-opioid receptor BPND at PET #1. PET #1 occurs during the week before HD-tDCS treatment begins. PET #2 occurs during the week after the final HD-tDCS treatment is completed.	Time between PET #1 and PET #2 is typically 21 days (minimum 17 days; maximum 42 days).

Collaborators and Investigators

• Sponsor: University of Michigan
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS)

Study record dates

Study Major Dates

• Study Start (Actual): February 22, 2017
• Primary Completion (Actual): June 1, 2021
• Study Completion (Actual): August 1, 2021

Study Registration Dates

• First Submitted: October 7, 2016
• First Submitted That Met QC Criteria: November 10, 2016
• First Posted (Estimate): November 16, 2016

Study Record Updates

• Last Update Posted (Actual): August 26, 2022
• Last Update Submitted That Met QC Criteria: July 27, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: Headache; Opioid; Episodic Migraine
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Headache Disorders, Primary; Headache Disorders; Migraine Disorders
• Other Study ID Numbers: HUM00107286; R01NS094413 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes