Repetitive Transcranial Magnetic Stimulation for Opiate Use Disorder

Study Overview
=================
Brief Summary
-----------------
This double-blind, randomized, controlled trials will investigate the effect of accelerated, repeated transcranial magnetic stimulation on opiate craving and perceived pain .

Detailed Description
-----------------
Prescription opiate use disorder (OUD) is common in the United States, with high morbidity and mortality. Despite the availability of opiate replacement therapies, many individuals continue to abuse opiates and relapse rates remain high. Uncontrolled pain and opiate craving are both commonly reported by OUD individuals attempting abstinence, and likely contribute to relapse. As such, development of novel treatment strategies targeting pain and craving would have important clinical implications. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique which is currently FDA-approved as a treatment for major depressive disorder. TMS is actively being pursued as a treatment for chronic pain disorders as well as for substance use disorders. In chronic pain patients, there is promising data suggesting that treatment with excitatory rTMS to the dorsolateral pre-frontal cortex (DLPFC) can have an anti-pain effect. A single session of excitatory DLPFC rTMS can decrease the perception of laboratory induced pain, decrease the amount of self administered morphine following open gastric bypass surgery and decrease the affective and sensory components of pain following laparoscopic gastric-bypass surgery. While the effects of a single session last for only approximately 1 hour, repeated sessions appear to have an additive and more durable effect, and following 15 sessions, the subjective experience of provoked pain has been shown to decrease by as much as 37%. In addition to the literature in laboratory induced pain, there is also preliminary data suggesting that rTMS may be an effective treatment for chronic pain disorders. In substance use disordered populations, the use of rTMS has garnered significant attention as an innovative tool to decrease craving [see reviews:. Several single session rTMS studies have demonstrated that applying excitatory rTMS to the DLPFC can decrease cue-induced craving in nicotine, cocaine, and alcohol use disordered populations. As expected, single session studies have only found small temporary reductions in craving; however, these promising data have led to preliminary clinical trials using multiple sessions of rTMS in alcohol, nicotine and cocaine use disorders. The largest such clinical trial (n=130 smokers) demonstrated that 13 sessions of DLPFC rTMS resulted in six month tobacco abstinence rates of 33% . To date there has been limited work examining the effect of rTMS on craving or pain in individuals with OUD. Drawing from the published literature suggesting that excitatory rTMS applied to the DLPFC can reduce both pain and craving, our group completed a preliminary sham-controlled crossover study in prescription OUD patients with chronic pain. Our data suggest that a single session of excitatory DLPFC rTMS acutely decreased opiate cue induced craving and thermal pain sensitivity in this group. The promising results from our single session trial parallel the single session results found in nicotine and cocaine use disordered populations which subsequently translated into positive multiple session clinical trials. As such, it follows that a trial utilizing multiple sessions of rTMS in OUD patients may yield positive results. 40 participants (20/group) admitted to an inpatient community treatment facility for opiate detoxification will be given 18 sessions of either active or sham rTMS applied to the DLPFC, in an accelerated fashion over three days (6-sessions each day).

Official Title
-----------------
A Double-Blind, Randomized, Controlled Trial, Utilizing Accelerated Repetitive Transcranial Magnetic Stimulation (rTMS) as a Tool to Decrease Pain and Craving in Hospitalized Patients With Opiate Use Disorder

Conditions
-----------------
Opiate Dependence, Chronic Pain

Intervention / Treatment
-----------------
* Device: Repetitive Transcranial Magnetic Stimulation
* Device: Sham rTMS


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participants must be able to provide informed consent and function at an intellectual level sufficient to allow accurate completion of all assessment instruments. Participants must meet DSM-5 criteria for moderate or severe OUD. While individuals may also meet criteria for use disorders of other substances (with the exception of alcohol or benzodiazepines), they must identify prescription opiates as their primary substance of abuse. Participants must be admitted to the inpatient unit for opiate detoxification. Participants must consent to random assignment. Exclusion Criteria: Participants who are pregnant will be excluded. Participants with a history of/or current psychotic disorder will be excluded. Participants with a history of dementia or other cognitive impairment will be excluded. Participants with active suicidal ideation, or a suicide attempt within the past 90 days will be excluded. Participants with contraindications to receiving rTMS (including a history of seizures, or any implanted metal above the neck) will be excluded. Those with unstable general medical conditions will be excluded. Those who are currently using naltrexone, or tramadol, will be excluded. Those with alcohol or benzodiazepine use disorders will be excluded due to increased risk of seizure.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 40 individuals (20 per group) will be randomly assigned to either active or sham rTMS.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active rTMS<br>Participants will receive 18 sessions of active repetitive Transcranial Magnetic Stimulation over a period of three days. TMS consists of 3000 pulses of 10Hz stimulation applied to the left DLPFC using the beam F3 method | Device: Repetitive Transcranial Magnetic Stimulation<br>* Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique which is currently FDA-approved as a treatment for major depressive disorder<br>* Other names: Active rTMS;|
| Placebo Comparator: Sham rTMS<br>Participants will receive 18 sessions of sham rTMS over a period of three days. | Device: Sham rTMS<br>* Participants will undergo procedures that mimic rTMS, but that are inactive.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite Opioid Craving (Want, Resist, Crave) | Change in cue-induced craving ratings on 10 point Likert Scales. 0=Not at all; 10=Extremely How much do you WANT TO USE _(opiate of choice)_ right now? HOW HARD would it be for you TO RESIST USING_(opiate of choice)_ right now if it was offered to you? How much do you currently crave opiates? (scores on each of those questions are summed to be between 0 and 30 with 30 being the highest (and indicating the most craving). | Baseline and three days: Pre-assessment (day 1-prior to the first delivered rTMS treatment) compared to post assessment (AM of day4 the morning following the final of three days of rTMS) |