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

Using Repetitive Transcranial Magnetic Stimulation (rTMS) to Explore Neural Mechanisms of Stress-Induced Opioid Use

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.

Study Overview

• Status: Withdrawn
• Conditions: Stress; Opioid-use Disorder
• Intervention / Treatment: Drug: Placebo oral tablet; Device: sham rTMS; Device: active rTMS; Drug: Yohimbine + Hydrocortisone

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.

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Tabitha Moses; Phone Number: 313-577-8257; Email: druglabdetroit@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 60 years (Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / 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)	Device: sham rTMS; sham rTMS (inactive coil); Drug: Yohimbine + Hydrocortisone; Yohimbine 54mg + Hydrocortisone 20mg
Active Comparator: stressor, active rTMS; stressor (yohimbine 54mg + hydrocortisone 20mg), active rTMS (10 Hz dlPFC in group 1; 1 Hz mPFC in group 2)	Device: active rTMS; active rTMS (10 Hz dlPFC stimulation in group 1; 1 Hz mPFC stimulation in group 2); Drug: Yohimbine + Hydrocortisone; Yohimbine 54mg + Hydrocortisone 20mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Addiction Stroop task	reaction time (msec) measure of cognitive interference	change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Digit Span Task	number of digits recalled, measure of verbal working memory	change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Wisconsin Card Sorting Task	number of correct items, measures ability to shift set and assesses cognitive flexibility	change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Monetary Incentive Delay task	number of rewards received, measure of motivation	change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Delay Discounting task	rate of monetary discounting	change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Drug/Money Choice Task	number of hypothetical choices between a constant amount of preferred opioid (relative to money)	change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Blood pressure	Systolic/diastolic BP (mm Hg)	change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Heart rate	Heart rate (beats/min)	change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Saliva cortisol level	Saliva cortisol level (µg/dL)	change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Saliva alpha-amylase level	Saliva alpha-amylase level (U/mL)	change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Serum prolactin level	Serum prolactin level (pg/dL)	change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Serum BDNF level	Serum brain derived neurotrophic factor level (pg/dL)	change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Positive and Negative Affect Schedule (PANAS) positive affect	10-item sub scale score of positive affect	change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Positive and Negative Affect Schedule (PANAS) negative affect	10-item sub scale score of negative affect	change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
State Trait Anxiety Inventory	state anxiety scores	change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Desire for Drug Questionnaire	opioid craving score	change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Opiate-32 Questionnaire, Agonist score	total opioid agonist score (16 items)	change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Opiate-32 Questionnaire, Withdrawal score	total opioid withdrawal symptom score (16 items)	change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Resting-state EEG activation	relative (gamma band ÷ slow band) ratio in electroencephalogram (EEG) power during resting state	change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)

Collaborators and Investigators

• Sponsor: Wayne State University

Study record dates

Study Major Dates

• Study Start (Actual): April 10, 2023
• Primary Completion (Actual): April 10, 2023
• Study Completion (Actual): April 10, 2023

Study Registration Dates

• First Submitted: November 24, 2019
• First Submitted That Met QC Criteria: November 27, 2019
• First Posted (Actual): November 29, 2019

Study Record Updates

• Last Update Posted (Actual): April 13, 2023
• Last Update Submitted That Met QC Criteria: April 10, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Narcotic-Related Disorders; Opioid-Related Disorders; Physiological Effects of Drugs; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Urological Agents; Anti-Inflammatory Agents; Adrenergic alpha-Antagonists; Mydriatics; Adrenergic alpha-2 Receptor Antagonists; Hydrocortisone; Yohimbine
• Other Study ID Numbers: OTC-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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.
• IPD Sharing Time Frame: Available after the study is completed
• IPD Sharing Access Criteria: Qualified investigators may apply in writing.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• 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