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Using rTMS to Explore Neural Mechanisms of Stress-Induced Opioid Use (OTC-1)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04181515
Recruitment Status : Not yet recruiting
First Posted : November 29, 2019
Last Update Posted : May 13, 2020
Sponsor:
Information provided by (Responsible Party):
Mark Greenwald, PhD, Wayne State University

Brief Summary:
This study will use a stress (vs. placebo) exposure model, paired with single-session sham vs. active rTMS at two distinct cortical locations (dlPFC vs. mPFC in parallel groups) to assess whether rTMS neuromodulation at these alternative loci differentially influence stress-reactivity and opioid reinforcement in non-treatment seeking participants with OUD. Stress-reactivity will be measured using cognitive, affective, behavioral and biological phenotypes.

Condition or disease Intervention/treatment Phase
Stress Opioid-use Disorder Drug: Placebo oral tablet Drug: Yohimbine + Hydrocortisone Device: sham rTMS Device: active rTMS Phase 2

Detailed Description:

The Competing Neurobehavioral Decisions Systems (CNDS) model of addiction suggests that persons with SUDs have hyperactive limbic reward circuitry and hypoactive executive control circuitry. CNDS theory supports targeting the dorsolateral prefrontal cortex (dlPFC, part of executive control circuit) and other cortical targets with repetitive transcranial magnetic stimulation (rTMS). One candidate-the medial prefrontal cortex (mPFC)-is part of limbic reward circuitry and accessible using rTMS. We validated a rigorous pharmacological stress-induction method (yohimbine + hydrocortisone) that emulates endogenous stress-reactivity and have established linkages between stress-exposure, executive dysfunction, and drug seeking. Our lab is developing rTMS as a potential "anti-stress" neuromodulation approach in people with opioid use disorder (OUD).

This study will use a stress (vs. placebo) exposure model, paired with single-session sham vs. active rTMS at two distinct cortical locations (dlPFC vs. mPFC in parallel groups) to assess whether rTMS neuromodulation at these alternative cortical loci differentially influence stress-reactivity and opioid reinforcement in non-treatment seeking participants with OUD. Stress-reactivity will be measured using cognitive, affective, behavioral and biological phenotypes.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 32 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: mixed design, with 4 (2x2) within-subject conditions (placebo vs. stressor X sham vs. rTMS), each occurring in two parallel groups (10 Hz dorsolateral prefrontal cortex vs. sham rTMS in group 1, and 1 Hz medial prefrontal cortex vs. sham rTMS in group 2)
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description: placebo for stressor, and sham figure of 8 coil for rTMS
Primary Purpose: Basic Science
Official Title: Using Repetitive Transcranial Magnetic Stimulation (rTMS) to Explore Neural Mechanisms of Stress-Induced Opioid Use
Estimated Study Start Date : July 2020
Estimated Primary Completion Date : June 2023
Estimated Study Completion Date : June 2025

Arm Intervention/treatment
Placebo Comparator: placebo stressor, sham rTMS
placebo stressor (lactose), sham rTMS (inactive coil)
Drug: Placebo oral tablet
placebo stressor

Device: sham rTMS
sham rTMS (inactive coil)

Active Comparator: placebo stressor, active rTMS
placebo stressor (lactose), active rTMS (10 Hz dlPFC in group 1; 1 Hz mPFC in group 2)
Drug: Placebo oral tablet
placebo stressor

Device: active rTMS
active rTMS (10 Hz dlPFC stimulation in group 1; 1 Hz mPFC stimulation in group 2)

Active Comparator: stressor, sham rTMS
stressor (yohimbine 54mg + hydrocortisone 20mg), sham rTMS (inactive coil)
Drug: Yohimbine + Hydrocortisone
Yohimbine 54mg + Hydrocortisone 20mg

Device: sham rTMS
sham rTMS (inactive coil)

Active Comparator: stressor, active rTMS
stressor (yohimbine 54mg + hydrocortisone 20mg), active rTMS (10 Hz dlPFC in group 1; 1 Hz mPFC in group 2)
Drug: Yohimbine + Hydrocortisone
Yohimbine 54mg + Hydrocortisone 20mg

Device: active rTMS
active rTMS (10 Hz dlPFC stimulation in group 1; 1 Hz mPFC stimulation in group 2)




Primary Outcome Measures :
  1. Addiction Stroop task [ Time Frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) ]
    reaction time (msec) measure of cognitive interference

  2. Digit Span Task [ Time Frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) ]
    number of digits recalled, measure of verbal working memory

  3. Wisconsin Card Sorting Task [ Time Frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) ]
    number of correct items, measures ability to shift set and assesses cognitive flexibility

  4. Monetary Incentive Delay task [ Time Frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) ]
    number of rewards received, measure of motivation

  5. Delay Discounting task [ Time Frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) ]
    rate of monetary discounting

  6. Drug/Money Choice Task [ Time Frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) ]
    number of hypothetical choices between a constant amount of preferred opioid (relative to money)

  7. Blood pressure [ Time Frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) ]
    Systolic/diastolic BP (mm Hg)

  8. Heart rate [ Time Frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) ]
    Heart rate (beats/min)

  9. Saliva cortisol level [ Time Frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) ]
    Saliva cortisol level (µg/dL)

  10. Saliva alpha-amylase level [ Time Frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) ]
    Saliva alpha-amylase level (U/mL)

  11. Serum prolactin level [ Time Frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) ]
    Serum prolactin level (pg/dL)

  12. Serum BDNF level [ Time Frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) ]
    Serum brain derived neurotrophic factor level (pg/dL)

  13. Positive and Negative Affect Schedule (PANAS) positive affect [ Time Frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) ]
    10-item sub scale score of positive affect

  14. Positive and Negative Affect Schedule (PANAS) negative affect [ Time Frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) ]
    10-item sub scale score of negative affect

  15. State Trait Anxiety Inventory [ Time Frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) ]
    state anxiety scores

  16. Desire for Drug Questionnaire [ Time Frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) ]
    opioid craving score

  17. Opiate-32 Questionnaire, Agonist score [ Time Frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) ]
    total opioid agonist score (16 items)

  18. Opiate-32 Questionnaire, Withdrawal score [ Time Frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) ]
    total opioid withdrawal symptom score (16 items)

  19. Resting-state EEG activation [ Time Frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total) ]
    relative (gamma band ÷ slow band) ratio in electroencephalogram (EEG) power during resting state



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   21 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Meet DSM-5 criteria for OUD
  • Age 21-60 yr
  • Right handed
  • Males and non-pregnant/non-lactating females
  • Cognitively intact (total IQ score >80 on Shipley Institute of Living Scale
  • Screening cardiovascular indices within ranges for safe use of the pharmacological stressor: resting HR 50-90 bpm, systolic BP 90-140 mmHg, and diastolic BP 50-90 mmHg
  • Use alcohol and/or marijuana <3 times/week; each "time" should consist of <1 marijuana "joint" equivalent and <3 alcoholic drinks.

Exclusion Criteria:

  • Under influence of any substance during session
  • Past 7-day use of illicit drugs other than opioids (except marijuana, which is legal in Michigan)
  • Urinalysis positive for cocaine metabolites, benzodiazepines, barbiturates, amphetamines or pregnancy
  • Medical conditions prohibiting use of rTMS (e.g. seizure history; based on rTMS screening questionnaire)
  • Lifetime diagnosis of: psychotic disorder, bipolar disorder, generalized anxiety disorder, or obsessive compulsive disorder; major depression in the past 5 years; or potentially antisocial personality disorder (if the clinical psychologist judges such behaviors to be potentially disruptive or unsafe in our lab)
  • Past-year SUD other than OUD
  • Acute/unstable illness: conditions making it unsafe for participation (e.g. neurological, cardiovascular, pulmonary, or systemic diseases)
  • Lactose intolerance (placebo dose)
  • Any prohibited medications: medications that lower seizure threshold, psychiatric medications, prescription pain medications, or blood pressure medications
  • Chronic head or neck pain
  • Past-month participation in a research study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04181515


Contacts
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Contact: Tabitha Moses 313-577-8257 druglabdetroit@gmail.com
Contact: Alina Woodford 313-993-3960 awoodford@med.wayne.edu

Sponsors and Collaborators
Wayne State University
Investigators
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Principal Investigator: Mark Greenwald, PhD Wayne State University
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Responsible Party: Mark Greenwald, PhD, Professor, Wayne State University
ClinicalTrials.gov Identifier: NCT04181515    
Other Study ID Numbers: OTC-1
First Posted: November 29, 2019    Key Record Dates
Last Update Posted: May 13, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: After the study is completed, qualified investigators may apply in writing to receive the study protocol. At this time, it has not been determined whether data will be shared and the conditions for access.
Supporting Materials: Study Protocol
Time Frame: Available after the study is completed
Access Criteria: Qualified investigators may apply in writing.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Hydrocortisone
Yohimbine
Anti-Inflammatory Agents
Mydriatics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Adrenergic alpha-2 Receptor Antagonists
Adrenergic alpha-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Urological Agents