Effects of Pharmacological Stress and rTMS on Executive Function in Opioid Use Disorder

Effects of Pharmacological Stress and Repetitive Transcranial Magnetic Stimulation Interventions on Executive Function in Opioid Use Disorder

This preliminary study is designed to evaluate mechanisms by which excitatory dorsolateral prefrontal cortex (dlPFC) repetitive transcranial magnetic stimulation (rTMS) (vs. sham) and pharmacological stress (vs. placebo) alter behavior in non-treatment seeking individuals with opioid use disorder (OUD). Specific Aims are to (1) Evaluate how stress impacts domains of behavior including (1a) executive function and (1b) opioid-seeking behavior; and (2) Determine whether rTMS stimulation attenuates (2a) executive dysfunction, (2b) stress-reactivity, and (2c) opioid-seeking in individuals with OUD not receiving treatment.

Study Overview

• Status: Not yet recruiting
• Conditions: Opioid Use Disorder
• Intervention / Treatment: Drug: Placebo; Device: Sham rTMS; Device: Active rTMS; Drug: Yohimbine + Hydrocortisone

Detailed Description

This study will use a double-blind, 10Hz left dlPFC rTMS (vs. sham) and pharmacological stressor ([yohimbine + hydrocortisone] vs. placebo) within-subject, randomized crossover design. Each participant will complete 4 sessions (stressor vs. placebo, crossed with rTMS vs. sham), each separated by at least 1 week. Participants will complete these 4 (2x2 within subject) test conditions in randomized order: sham rTMS/placebo stress, sham rTMS/active stress, active rTMS/ placebo stress, and active rTMS/active stress.

The PI will perform randomization using a Latin Square and will assign participants to conditions and prepare medication (stressor or placebo) for each participant's sessions. The PI will keep others blinded and will not be involved in study assessments.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Tolan Park Medical Building

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; and
• 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: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: placebo stressor, sham rTMS; Placebo stressor (lactose) + sham (inactive) rTMS over the left dlPFC	Drug: Placebo; lactose (inside capsule); Device: Sham rTMS; inactive stimulation over the left dlPFC
Experimental: placebo stressor, active rTMS; Placebo stressor (lactose) + active 10Hz rTMS over the left dlPFC	Drug: Placebo; lactose (inside capsule); Device: Active rTMS; 10Hz rTMS over the left dlPFC
Experimental: active stressor, sham rTMS; Stressor (yohimbine 54mg + hydrocortisone 20mg) + sham (inactive) rTMS over the left dlPFC	Device: Sham rTMS; inactive stimulation over the left dlPFC; Drug: Yohimbine + Hydrocortisone; Yohimbine (54mg bulk powder inside capsule) administered in combination with Hydrocortisone (20mg tablet inside capsule)
Experimental: active stressor, active rTMS; Stressor (yohimbine 54mg + hydrocortisone 20mg) + active 10Hz rTMS over the left dlPFC	Device: Active rTMS; 10Hz rTMS over the left dlPFC; Drug: Yohimbine + Hydrocortisone; Yohimbine (54mg bulk powder inside capsule) administered in combination with Hydrocortisone (20mg tablet inside capsule)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Color-Word Stroop Task	measures cognitive control in response to opioid-related words.	change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Digit Span Task	measures verbal working memory. Participants are asked to repeat strings of numbers of increasing length, both forward and backward.	change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Wisconsin Card Sorting Task	measures ability to shift set and assesses cognitive flexibility.	change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Emotion Regulation Task	subjects rate the unpleasantness and arousal of different emotional pictures	change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Positive and Negative Affect Schedule	subjects rate their positive and negative affect	change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
State-Trait Anxiety Inventory	subjects rate their level state anxiety	change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Monetary Incentive Delay Task	Participants respond to a visual target that follows 2 different cues: incentive or non-incentive. No reward or punishment occurs on non-incentive trials. On incentive trials, participants must respond within a fixed amount of time. In the reward condition, responses within that time result in receiving the incentive , else nothing. In the punishment condition, the participant will lose money if they do not respond within the time limit	change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Delay Discounting Task	Participants perform a brief (<1min) hypothetical version of the traditional monetary task with a 5-trial adjusting delay previously validated to rapidly assess discount rate	change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Drug/Money Choice Task	participants choose hypothetically between a constant amount of their preferred opioid ($10 unit dose) or money ($2)	change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Systolic blood pressure	millimeters mercury (mmHg)	change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Diastolic blood pressure	millimeters mercury (mmHg)	change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Heart rate	beats per minute	change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Saliva cortisol level	measure of the activity of the HPA axis	change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Saliva alpha-amylase level	indirect measure of adrenergic stimulation	change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Serum prolactin level	indirect measure of dopamine stimulation	change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Serum brain derived neurotrophic factor (BDNF) level	indirect measure of brain derived neurotrophic factor activation	change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Relative electroencephalogram (EEG) gamma power	Prefrontal gamma (25-100 Hz) EEG power, relative to slow-wave EEG power, is a stress biomarker	change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Opioid craving	Desire for Drug Questionnaire total score; higher scores indicate greater craving	change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Opioid agonist symptoms	Opiate-32 questionnaire agonist symptom total score; higher scores indicate greater opioid symptom severity	change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Opioid withdrawal symptoms	Opiate-32 questionnaire withdrawal symptom total score; higher scores indicate greater withdrawal severity	change from pre- to 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 (Estimated): October 1, 2024
• Primary Completion (Estimated): October 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: January 9, 2020
• First Submitted That Met QC Criteria: January 13, 2020
• First Posted (Actual): January 18, 2020

Study Record Updates

• Last Update Posted (Actual): March 12, 2024
• Last Update Submitted That Met QC Criteria: March 7, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Narcotic-Related Disorders; Substance-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: DL-STR-OUD

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: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes