Vanderbilt Integrated Community TMS for Opioid Recovery

Opioid Use Disorder is a Public Health Crisis with a High Risk of Relapse Worldwide, opioid use disorder (OUD) affects \>16 million people annually, and \>300 people/day die from overdose. Buprenorphine is an effective medication for OUD that reduces use, relapse, and mortality. However, within 6 months of starting buprenorphine, only 50% continue treatment and 91% will relapse. The 3-month period following buprenorphine initiation is highest risk for treatment discontinuation and relapse. Those who discontinue treatment have high risk of relapse and overdose. Thus, personalized interventions in the period following buprenorphine initiation may improve retention and reduce relapse. The strongest predictor of relapse is craving, defined as a "strong desire for drugs,". Following buprenorphine initiation, craving remains the top predictor of relapse. Relapse occurs when the urge to use (i.e., craving) is outweighed by the ability to resist that urge (i.e. inhibitory control). Higher inhibitory control is associated with less craving and less relapse. After an acute period of abstinence, individuals with OUD continue to struggle with craving, poor inhibitory control, depression, pain, and sleep disturbance, even with buprenorphine treatment. Both patients (The Voice of the Patient: A Series of Reports From the US Food and Drug Administration's (FDA's) Patient-Focused Drug Development Initiative: Opioid Use Disorder 2018) and experts have called for novel, symptom-specific interventions that enable personalized treatment of these refractory symptoms of OUD. Craving and inhibitory control can be readily measured and quantified using broadly available behavioral tasks (e.g., cue reactivity, go/no-go) and are targets for intervention.

Substance Use Disorder Symptoms are Linked to Brain Circuit Dysfunction The brain correlates of craving and inhibitory control are well-established in frontal-striatal circuitry, and it is well-known that individuals with substance use disorders have dysfunction in these circuits. Craving and impaired inhibitory control have been linked to decreased functional connectivity between the dorsolateral prefrontal cortex (DLPFC) and dorsal striatum. Therefore, modulating connectivity in this circuit may serve as effective interventions to treat substance use disorders.

iTBS is an FDA-Approved Treatment for Depression with Promising Applications for OUD. Repetitive transcranial magnetic stimulation (rTMS) is a form of non-invasive brain stimulation that uses electromagnetic fields to temporarily change neuronal patterns of connectivity in brain networks. When international safety guidelines are followed, rTMS is a safe and well-tolerated intervention in individuals with and without psychiatric illness. rTMS is also a versatile research tool whose stimulation parameters can be changed. Depending on the parameters, rTMS can increase or decrease brain activity. Specifically, intermittent theta burst stimulation (iTBS) tends to increase brain activity, while continuous theta burst stimulation (cTBS) tends to decrease brain activity.

rTMS is FDA-approved for the treatment of major depressive disorder, obsessive-compulsive disorder, and smoking cessation. rTMS has also shown promising results in research studies as a potential treatment for substance use disorders. Multiple systematic reviews have observed that rTMS reduces substance use and craving across substance use disorders, including OUD.

In studies of rTMS for OUD, the majority of trials have applied high frequency (10-20 Hz) rTMS or iTBS to the L DLPFC and observed significant reductions in craving and opioid use. It is hypothesized that applying high frequency (10-20 Hz) rTMS or iTBS to the L DLPFC will increase DLPFC activation and increase connectivity between the DLPFC and dorsal striatum, thereby improving inhibitory control and reducing craving and opioid use. In preliminary data for this proposal, a single session of iTBS applied to the L DLPFC in individuals with OUD receiving medication for OUD significantly reduced craving (n=30, p\<.03).

Therefore, in this protocol, this intervention will be scaled-up to deliver a total of 16 sessions of iTBS to the L DLPFC to rescue impaired L DLPFC activity in OUD to reduce opioid craving and opioid use. This will test this intervention in a population of individuals with OUD who are currently taking buprenorphine, the most commonly used medication for OUD. iTBS applied to the L DLPFC is an FDA-approved treatment for depression. When international safety guidelines are followed, rTMS is a safe and well-tolerated intervention for people with and without substance use disorders.

In most clinical and research protocols, iTBS is applied in daily sessions for 4-6 weeks. In one of the FDA-approved protocols for depression, iTBS is applied 10-times per day for 5 consecutive days, totaling 50 sessions. In this study, 16 sessions of iTBS (2 per day x 8 weeks) will be applied to individuals with OUD using the same FDA-approved parameters approved for depression. It is believed that weekly sessions will enhance feasibility of this intervention for an OUD population, as previous studies have shown that individuals with SUDs have difficulty attending daily TMS sessions.

The central hypothesis is this: Opioid craving and use can be reduced with iTBS when applied to individuals with OUD. This study seeks to provide evidence that L DLFPC-targeted iTBS leads to reduced craving and opioid use in individuals with OUD. If successful, this will have identified a safe, effective, and broadly applicable adjunctive treatment to reduce craving and relapse for people with OUD - a devastating disease with deadly consequences and partially-effective treatments.

This is a randomized, sham-controlled trial testing the effect of an FDA-approved protocol (L DLPFC-targeted iTBS) on craving and opioid use in individuals with OUD who are taking buprenorphine. This is a multisite study where VUMC is both the Coordinating Site and a recruiting site. This study will enroll up to 60 individuals with OUD at VUMC to obtain a completion sample of n=50. Across all sites, there will be a completion sample of n=100.

The principal aim of this investigation is:

Aim 1: Determine the effects of active L DLPFC-targeted iTBS compared to sham on craving and opioid use in people with OUD (n=100).

As an exploratory analysis, it will also determine if L DLPFC functional connectivity change is associated with change in craving (n=50).

Individuals who between the ages of 18-65 and who have been diagnosed with OUD and in stable psychiatric outpatient treatment with buprenorphine will be enrolled in the present study. An international TMS consensus group determined that there were no additional risks of major adverse events, including seizures, in individuals with psychiatric disorders. Neither opioid use nor buprenorphine are associated with increased seizure risk or alterations in seizure threshold.

Indeed, in the meta-analysis of the safety of rTMS for substance use disorders, the prevalence of rTMS-induced seizure was approximately 1/1000, which was not significantly different from the seizure risk in the general population. There have been no rTMS-induced seizures in anyone with OUD.

rTMS is FDA-approved for treatment depression in adolescents down to age 15. However, there is a lack of data on the use of rTMS for substance use disorders in adolescents. For this reason children and teens under the age of 18 will be excluded. The same rationale applies to the exclusion based on race, gender, or ethnic background. If, as the study progresses, it is found that a representative population is not being entered into the study with respect to gender and race, recruitment methods will be reviewed.

Up to 60 individuals with OUD will be enrolled taking buprenorphine in a randomized, sham-controlled trial of L DLFPC-targeted iTBS. Prospective participants who meet inclusion and exclusion criteria will be entered into the study.

Participants will undergo an initial phone screening session. Following the phone screening, this study consists of 12 study visits. At the first visit (Consent), participants will complete informed consent. After completing consent, participants will undergo additional screening procedures to ensure safety to under rTMS and MRI (if participants elects to complete the Optional MRIs) and will complete questionnaires about substance use and psychiatric symptoms.

Enrolled participants will then undergo 8 weekly sessions of L DLPFC-targeted iTBS. Prior to the first TMS visit, individuals will be randomized to receive active or sham iTBS. For the sham condition, the iTBS coil will be flipped 180 degrees so that the sham iTBS looks and sounds like active iTBS but delivers no actual significant stimulation to the participant. At each TMS visit, participants will complete questionnaires about their substance use and psychiatric symptoms and provide a sample for urine toxicology.

After the 8-week TMS intervention, participants will return for visits at weeks 10, 12, and 20. At each follow-up visit, participants will complete questionnaires about their substance use and psychiatric symptoms and provide a sample for urine toxicology.

If a participant elects to undergo the Optional MRI visits, they will undergo 2 MRI scans 1) before the first TMS visit; and 2) after the week 8 TMS visit. The MRI scan includes structural and resting-state functional magnetic resonance imaging (rsfMRI). During both MRI scans, participants will also perform a cognitive task.

The primary endpoint will be to use a paired t-test comparing changes in craving and opioid use between active and sham iTBS.

After the week 20 visit, participants who were randomized to receive sham stimulation will be offered the opportunity to receive active FDA-approved L DLPFC-targeted iTBS for 8 weeks.

The PI is a board-certified psychiatrist and internationally recognized expert in the use of rTMS for substance use disorders. She has served as PI on multiple clinical trials of rTMS for substance use disorders, including at VUMC, where she is Director of Neuromodulation Research. All rTMS has been well-tolerated, and there have been no severe adverse events related to rTMS, including no seizures, hospitalizations, or medical treatments. The personal experience is consistent with the vast literature on the safety of rTMS in substance use disorders.

rTMS has been studied in thousands of people with substance use disorders (n = 2,865 participants), including OUD, with no evidence of increased risk of psychiatric or medical adverse events. rTMS has been studied extensively in substance use disorder populations with no evidence of increased medical or psychiatric risk. The Safety of TMS Consensus Group recommended, "available data indicate no additional risks of major AEs \[adverse events\] in specific patient populations \[including OUD\] so this is not a concern that needs to be taken into account".

In a meta-analysis examining the prevalence of seizure with rTMS for substance use disorders, the prevalence of rTMS-induced seizure was approximately 1/1000, which was not significantly different from the seizure risk in the general population. Moreover, there were no seizures observed in OUD, providing reassuring evidence that there is no increased risk of rTMS-induced seizure in an OUD population.

All rTMS will be administered according to an FDA-approved protocol for depression that applies iTBS to the L DLPFC. rTMS is already FDA-approved for treatment of substance use disorder (nicotine). Compared to nicotine use, opioid use does not represent an increased risk for any rTMS-induced side effect, including seizure. Importantly, opioid use or treatment for OUD is NOT a contraindication to FDA-approved iTBS for depression, meaning that individuals with OUD and depression receive FDA-approved iTBS to the L DLPFC for depression in t

• Determining if left DLPFC functional connectivity change is associated with change in craving on the OCS (n=50) through resting state MRI imaging. [Срок оценки: From the start of the study (screening visit) to the 20 week follow-up visit.]