An Exploratory Investigation Utilizing Repetitive Transcranial Magnetic Stimulation (rTMS) as a Tool to Decrease Pain and Improve Functioning in Veterans With Opioid Use Disorder
Phase: NA
Conditions: Opioid Use Disorder
Sponsor: VA Office of Research and Development

9.2.21 
 
An Exploratory Investigation Utilizing Repetitive Transcranial Magnetic Stimulation (rTMS) as a Tool to Decrease 
Pain and Improve Functioning in Veterans with Opioid Use Disorder 
 
BACKGROUND AND SIGNIFICANCE 
Opioid use disorder (OUD) is common among Veterans, with high morbidity and mortality. Despite the 
availability of opioid replacement therapies, many individuals continue to abuse opioids and relapse rates remain 
high (Fiellin et al., 2014). In 2015, it was reported that approximately 60% of Veterans returning from the Middle 
East and more than 50% of older Veterans in the VA health care system have chronic pain (Clancy, 2015). 
Veterans are nearly twice as likely to die from accidental opioid overdose than the general population (Bohnert 
et al., 2011). Further, post-traumatic stress disorder, a common comorbidity in the Veteran population, has been 
shown to negatively impact early engagement and retention of individuals in OUD treatment (Jaremko et al., 
2015). OUD is associated with elevated rates of posttraumatic stress disorder (PTSD), with lifetime PTSD 
prevalence up to 50% among individuals with OUD compared to 7% in the general population (Kessler et al., 
2005). Importantly, people with OUD have a 42% increase in odds of PTSD, as well as more severe PTSD 
impairment and symptoms, compared to both non-users and individuals with other substance use disorders 
(Meier et al., 2014). Recent data suggests that there is a high prevalence of untreated pain in OUD, and that in 
most cases pain was the initial reason for use (Hartwell et al., 2012; Barth et al., 2013; McCauley et al., 2014). 
The significant comorbidity of OUD, PTSD, and chronic pain has been explained both through overlapping 
neurobiology and conceptual models. Specifically, for individuals with PTSD, stress enhances the rewarding 
properties of opioids and exacerbates the adverse effects of opioid withdrawal (Logrip et al., 2012). Erratic 
patterns of repeated withdrawal episodes in OUD exacerbate acute stress symptoms and increase vulnerability 
for development of PTSD. Further, stress dysregulation generated by PTSD impairs recovery from OUD by 
lowering the threshold for stress-induced relapse, and nociceptive alterations have also been reported (Scioli- 
Salter et al., 2015). As is the case with other substance use disorders, opioid craving is commonly described by 
abstinent patients whether or not they are stabilized on buprenorphine (Northrup et al., 2015; Tsui et al., 2014). 
Subsequently, a treatment that reduces pain and craving, while also improving early engagement and retention 
in treatment, would improve recovery from opioid addiction, and could have particular salience for the Veteran 
population. 
Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that is 
able to alter cortical excitability and is FDA-approved to treat Major Depressive Disorder. Magnetic fields 
pass unimpeded through the scalp, skull and meninges, and can directly excite cortical areas. High frequency 
rTMS (greater than 5 pulses per second) increases cortical excitability (Pascual-Leone et al., 1998). Single 
sessions of rTMS induce temporary changes, while multiple sessions can induce more long-term changes. 
The dorsolateral pre-frontal cortex (DLPFC) is a key node in the executive control network. Current and historical 
evidence suggests that in major depressive disorder there is an imbalance of so called cognitive control (exerted 
by the executive control network) over deeper limbic regions (Mayberg, 1997). rTMS applied over the DLPFC 
likely exerts its anti-depressant effect by acting to re-regulate these dysfunctional cortical-limbic circuits (Li et al., 
2004). Single sessions of rTMS have little effect on depression; however, multiple sessions of rTMS have been 
demonstrated to be an effective (George et al., 2010; McDonald et al., 2011) and durable (Dunner et al., 2014; 
Levkovitz et al., 2015) antidepressant treatment. Further, although single daily-sessions given over a period of 
four to six weeks are often utilized, studies support the efficacy of accelerated treatment courses where multiple 
sessions are given each day over a shorter period of time (George et al., 2014; Holtzheimer et al., 2010; Baeken 
et al., 2013). The advantages of accelerated treatment paradigms include more rapid delivery of treatment (with 
more rapid improvement) and fewer needed visits, thus likely enhancing compliance and reducing attrition. 
 
Accelerated rTMS: Lessening treatment burden toward enhancing adherence. In addition to establishing the 
dose-response curve for transdiagnostic psychosocial impairment as opposed to disorder-specific symptoms, we 
also propose to innovate by utilizing a high-dose accelerated protocol. A therapeutic course of rTMS for depression 
typically consists of approximately 30-40 minutes of high-frequency (i.e., 10 Hz) treatment on each weekday, for 4 
to 6 weeks. This schedule can be burdensome and reduce adherence. More recently, a number of groups have 
examined the safety, feasibility, acceptability, and effectiveness of accelerated rTMS delivery (Holtzheimer et al., 
2010; McGirr, et al., 2015; Tovar-Perdomo et al., 2017) during which sessions are repeated on the same day to 
reduce total days of treatment, typically spaced by at least 30 minutes. Safety has also been assessed with both 
structural and metabolic imaging as well as neurocognitive testing, which has shown no adverse effects on neural 
integrity and modest gains in cognition (Holtzheimer et al., 2010; McGirr, et al., 2015; Tovar-Perdomo et al., 2017). 
Furthermore, acceptability results have suggested that accelerated protocols could increase adherence and 

9.2.21 
decrease interruptions to daily obligations (Holtzheimer et al., 2010; McGirr, et al., 2015; Tovar-Perdomo et al., 
2017).  
Specific to a transdiagnostic sample of Veterans with affective/anxiety disorders, Co-investigator Mark George, 
M.D. (31) and colleagues demonstrated that delivering three high-dose sessions per day (i.e., 10 Hz; 6,000 pulses 
for 30 minutes; 18,000 pulses/day total) on each of consecutive three days was safe, feasible, and suggestive of 
rapid antidepressant effects. Also, these patients received in three days, nearly the equivalent dose of a 
conventional 4- to 6-week course.  
In a recent further innovation, intermittent theta burst (iTBS) rTMS has been shown to be as efficacious as 10 Hz 
rTMS in remediating depression (Garrett-Mayer, 2006).  Notably, a single session of excitatory iTBS rTMS entails 
600 pulses in merely 3 minutes.  More specifically, pulses are delivered in triplets at 50 Hz for 2 s (i.e., 5 Hz triplets) 
and repeated every 10 s for a total of 190 s (600 pulses). While the use of iTBS in accelerated protocols is only 
now emerging for the remediation of neuropsychiatric dysfunction, accumulating safety and efficacy results are 
promising, even among the most impaired and vulnerable patients (Lasonos et al., 2011). From a practical 
standpoint, theta burst sessions are typically spaced by 20-60 minutes apart with no requirements on the 
intervening time period. As such, veterans could potentially undergo multiple 3-minute sessions in a single day with 
more limited interference to daily demands than more conventional 10 Hz protocols.  
In substance use disorders, there is mounting evidence that there is an imbalance of neural activity 
between the executive control network and the reward network. As the executive control network is 
thought to have a modulatory effect on the reward network (Kober et al., 2010), this imbalance may play 
a key role in the inability of those with substance use disorders to modulate drug craving and use (Kober 
et al., 2010; Hanlon et al., 2015; Sutherland et al., 2012; Volkow et al., 2010; Charboneau et al., 2013; 
Cousijn et al., 2013). If in fact an imbalance of these two networks results in craving, then it would follow that 
either the application of excitatory rTMS to the executive control network or inhibitory rTMS to the reward network 
would result in decreased craving. More than 20 studies have confirmed this relationship [see reviews: Bellamoli 
et al., 2014; Gorelick et al., 2014; Wing et al., 2013; Barr et al., 2011]. The majority of these studies applied single 
sessions of excitatory stimulation to the DLPFC with the idea that this type of stimulation can result in enhanced 
executive control modulation of the reward network and less reactivity to drug cues. Of note, another study 
demonstrated that inhibitory rTMS applied to the DLPFC resulted in increased craving (Li et al., 2013), providing 
further evidence of this relationship. 
Two recent clinical trials demonstrated that multiple sessions of rTMS may have a more durable effect on craving 
and reduced drug use (Dinur-Klein et al., 2014; Terraneo et al., 2015) than a single session treatment. The 
largest trial (n=130 smokers) demonstrated that 13 sessions of excitatory DLPFC stimulation resulted in six- 
month tobacco abstinence rates of 33% (Dinur-Klein et al., 2014). The second clinical trial demonstrated that 8 
sessions of DLPFC rTMS decreased cocaine cue-induced craving and resulted in one-month abstinence rates 
of 69% (Terraneo et al., 2015). 
In chronic pain patients, there is also promising data suggesting that treatment with excitatory rTMS 
applied to the DLPFC can have an anti-pain effect. Even a single session of excitatory DLFPC rTMS can 
decrease the perception of laboratory induced pain (Borckardt et al., 2007; Mylius et al., 2012), decrease the 
amount of self-administered morphine following open gastric bypass surgery (Borckardt et al., 2008), and 
decrease the affective and sensory components of pain following laparoscopic gastric-bypass surgery (Borckardt 
et al., 2014). 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% (Borckardt et al., 2013). In addition to the literature in 
laboratory induced pain, there is also preliminary data in the treatment of chronic pain. In a study of fibromyalgia 
patients, 10 sessions of excitatory DLPFC rTMS reduced average daily pain by 30% (Short et al., 2011), a 
comparable magnitude to the effect of duloxetine and pregabalin (FDA-approved medications for pain). In a 
similar fashion to the anti-depressant and anti-craving mechanisms of action, the analgesic effect of excitatory 
DLPFC rTMS also appears to be associated with executive control modulation of limbic sub-cortical pain 
structures (Taylor et al., 2013). Additionally, pre-treatment with naloxone (an opioid antagonist) blocks this effect, 
suggesting that rTMS exerts its action through the opioid system (Taylor et al., 2012). 
In sum, studies across substance use disorders (including OUD) suggest that dysfunction of the executive control 
network and reward network are associated with drug cue-reactivity. Excitatory rTMS applied to the DLPFC (a 
key node in the executive control network) reduces craving, and has translated to two recent positive clinical 
trials. It has also been demonstrated that excitatory rTMS applied to the DLPFC has an anti-pain effect that is 
mediated through the opioid system. We have successfully applied rTMS to an OUD population with promising 

9.2.21 
early results. The next step in the development of this novel treatment for OUD is to determine the feasibility 
and acceptability of a course of treatment in a treatment seeking, Veteran OUD population with chronic 
pain. rTMS is becoming increasingly available at many other VAMC’s; subsequently positive results in this line 
of research could be easily adopted across the country and potentially improve Veteran outcomes. 
PRELIMINARY DATA 
Expertise of Research Team: The current application involves a strong, multidisciplinary team of investigators 
with expertise in addictions (McRae-Clark, Sahlem, Hartwell, Hanlon, and Brady), pain (Borckardt), and brain 
stimulation (George, McRae-Clark, Sahlem, Hanlon, Borckardt) research as well as statistics (Baker). The team 
is uniquely poised to complete the proposed project having the needed expertise, equipment, and access to the 
clinical population in question as well as a history of successful collaborations. 
Preliminary Studies: Of direct relevance to the proposed project, the investigative team has demonstrated 1) 
significant experience with TMS research; 2) the ability to conduct a trial using an accelerated rTMS treatment 
paradigm and; 3) the ability to apply rTMS to an OUD population, while determining its effect on craving and 
pain. The team will be led by Dr. Aimee McRae-Clark, an established addictions researcher. Although the 
majority of her research to date has focused on treatment development for cannabis and cocaine use disorders, 
given the critical public health consequences of the opioid epidemic she has turned her focus to opioid addiction. 
As such, the SPiRE mechanism seems ideal as it supports senior 
investigators in their exploration of new research areas in which 
they have not been previously funded. 
1) Members of the investigative team have conducted multiple 
trials of rTMS, including pivotal trials for FDA-approval of TMS 
for depression (George et al., 1997) and in substance using 
individuals (Hanlon et al, 2015; Hanlon et al., 2017; Sahlem et 
al., 2017). 
2) The investigative team completed a trial in acutely suicidal, 
depressed Veterans. In that trial we demonstrated the feasibility 
of delivering an accelerated course of rTMS (the equivalent of 
18 sessions over three days), to acutely ill inpatients (George 
et al., 2014). Sixteen of 18 participants in the active group and 
20 of 21 in the sham group completed the three day course. 
These findings demonstrate our team’s ability to recruit 
Veterans into an accelerated rTMS based trial and the feasibility 
of this treatment paradigm. 
Figure 1. Change in craving ± SEM 

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3) The investigative team also completed a single-blind, sham 
controlled crossover study demonstrating that a single session of 
active 10Hz DLPFC TMS acutely decreases self-reported opioid 
craving and thermal pain sensitivity among opioid use disordered 
individuals both on and off buprenorphine (Breedlove et al., 
2015). In addition to demonstrating that a single session of rTMS 
may have an effect on both craving (Figure 1) and pain (Figure 
2) in this group, this small trial demonstrated that our group is 
able to feasibly deliver rTMS to this population, with a retention 
rate of 81% (13/16). 
Innovation: This pilot trial is innovative in several respects. 1: 
This trial will be the first randomized-controlled trial applying 
multiple sessions of rTMS to a cohort of OUD patients. This is 
important as it is well established that multiple sessions of rTMS 
have a larger and more durable effect than single sessions of 
Figure 2. Change in pain thresholds ± SEM 
rTMS. Furthermore, it is well known that in order to derive a meaningful clinical effect, the application of multiple 
sessions of rTMS are needed. 2: This will be the first trial testing an accelerated rTMS treatment paradigm using 
established rTMS doses in an addictions population. This is important as there is a clear dose response effect 
in rTMS, where larger doses of rTMS result in a larger clinical effect (George et al., 2010; McDonald et al., 2011). 
It is additionally important as OUD and other substance use disordered populations may be difficult to treat using 
the standard treatment paradigm of one session per day over several weeks. 3: This trial will be the first to use 
rTMS as an adjunct to standard of care opioid treatment. OUD patients, including Veterans, are difficult to engage 
in outpatient care. Subsequently, a treatment that encourages retention and integration early in the recovery 
process could have a significant impact on patient outcomes. 
RESEARCH DESIGN AND METHODS 
Approach Overview (Figure 3): Participants will be recruited from the Ralph H. Johnson VAMC,local VA clinics, 
and Charleston Center. We will collect data at one week, four weeks, and three months following rTMS completion. 
Acute Phase: We will screen, consent, enroll, and assess participants during an enrollment session. Following 
enrollment, each participant will complete baseline measurements of opioid use, opioid craving, pain, and 
functioning (as outlined below). Following the enrollment session, each participant will be randomized and begin 
the acute treatment phase of the trial. Participants will receive a total of six sessions of rTMS on three days 
during the acute phase of the study over a period of up to three weeks. A period of up to one-week in between 
treatment days will be allowed to maximize feasibility of intervention deliverability in this population while 
minimizing risk of a treatment gap that is too long to allow for a summation of effect. On the third treatment day, 
pain assessments will be repeated. Craving and pain will be assessed using validated questionnaires. 
Continuation Phase: Participants will return at one week, four weeks, and three months for follow-up visits to 
preliminarily assess the intervention’s impact on opioid use, pain, and functional outcomes. 
Recruitment: Participants will be recruited from the Ralph H. Johnson VA Medical Center, other local VA clinics, 
,Charleston Center, and through community and online advertising. Co-I Dr. Hartwell is Medical Director of the 
STAR program and will assist in participant referrals. CPRS chart review will also be utilized. 
Approximately four Veterans per month are initiated on buprenorphine medication assisted treatment (MAT), the 
majority (77%) of which endorse chronic pain. As such, we do not anticipate any issue meeting recruitment goals 
for this pilot project; however, feasibility of recruitment will be assessed as an aim in this project. 
Integration of Study Procedures into Standard Care: Outpatient care for includes a combination of 
pharmacotherapy, psychotherapy, and social work interventions. Pharmacotherapy consists of medication 
assisted therapy, typically buprenorphine/naloxone. The study procedures will not interfere with this standard 
MAT treatment or other interventions. Patients being treated for OUD commonly have co-morbid symptoms of 
depression and anxiety (Gros et al., 2013); as such, antidepressant treatment will be allowed to enhance 
generalizability. 

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Inclusion Criteria: 1: Be able to provide informed consent 
and function at an intellectual level sufficient to allow 
accurate completion of assessments. 2: Meet moderate to 
severe DSM-5 criteria for OUD. Individuals may also meet 
criteria for other substance use disorders (with the 
exception of alcohol or benzodiazepines), but must identify 
opioids as their primary substance of abuse. 3: Report 
chronic pain for at least the past three months and have a 
Brief Pain Inventory Score ≥ 3. 4: Participants must be 
receiving Medication Assisted Treatment (MAT). 
Exclusion Criteria: 1: Pregnancy. 2: History of/or current 
psychotic disorder. 3: History of dementia or other 
cognitive impairment. 4: Active suicidal ideation, or a 
suicide 
attempt 
within 
the 
past 
90 
days. 
5: 
Contraindications to receiving rTMS (including a history of 
seizures, or any implanted metal above the neck). 6: 
Unstable general medical conditions. 7: Current use of 
tramadol. 8: Active moderate or severe alcohol or 
benzodiazepine use disorder due to increased risk of 
seizure. 
Screening and Eligibility Assessment: Individuals will 
be screened by the research study intake coordinator. An 
initial 
pre-screen 
focused 
on 
inclusion/exclusion 
psychiatric diagnoses, medical status, current medication 
regimen, and ability and willingness to commit to 
completion of study procedures will be used to initially 
determine potential study eligibility. Interested individuals 
will be given a full description of the study procedures and 
asked to read and sign an IRB-approved informed consent 
form before participating in a detailed, comprehensive 
screening and assessment phase. To ensure subjects are 
not experiencing any acute effects of alcohol, individuals 
whose breath or saliva alcohol concentration reading 
exceeds the instruments margin of error (0.002%) will not 
be allowed to participate until their BAC is not detectable. 
Diagnostic/Descriptive 
Assessment: 
The 
M.I.N.I. 
International Neuropsychiatric Interview 7.0 for DSM 5 will 
be used to assess psychiatric and substance use 
diagnoses, including assessment of opiate use. A medical 
history will be collected to ensure that the individual is 
eligible to participate, and the VA medical record may be 
reviewed to verify medications. In the event that an 
individual is found to be ineligible, he or she will be given 
an appropriate referral for further medical or other 
necessary care. If the individual is eligible, he or she will 
fill out questionnaires and provide a urine sample to verify 
self-report of substance use. If female, the urine will first 
be tested for pregnancy. If the pregnancy test is negative 
or the individual is male, the urine will be tested for drugs 
of abuse. A randomization/initial rTMS visit will be 
scheduled. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
rTMS=Repetitive Transcranial Magnetic 
Opioid use and craving outcomes 
Pain outcomes 
Functional outcomes 
Visit 1 
1 week 
follow-up 
1 month 
follow-up 
Opioid use and craving outcomes 
Pain outcomes 
Functional outcomes 
Figure 3 
N=10 
N=10 
6 Sessions 
Active rTMS 
6 Sessions 
Active rTMS 
Opioid use and craving outcomes 
Pain outcomes 
Functional outcomes 
N=20 Opioid Use Disordered 
Veterans with Chronic Pain 
1: Screening and enrollment 
2: Baseline assessments 
6 Sessions 
Sham rTMS 
6 Sessions 
Sham rTMS 
Visit 3 
6 Sessions 
Active rTMS 
6 Sessions 
Sham rTMS 
Visit 2 
3 month 
follow-up 

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Treatment Assignment: Eligible individuals will be randomized to receive active rTMS or sham treatment. 
Participants will be randomized using a stratified permuted random block design with block sizes of 2 and 4; this 
will be utilized to maintain treatment assignment balance throughout the treatment enrollment period based on 
concomitant pain medication use (yes/no). 
rTMS Treatments: rTMS will be delivered via a MagPro double blinded rTMS Research System (MagVenture, 
Denmark) with a Cool-B65 Butterfly Coil (a combined active and sham coil). We will use a standard resting motor 
threshold (rMT) determination to determine the TMS dose (Borckardt et al., 2006). Treatment will be delivered 
at 120% rMT. Each active rTMS treatment will consist of a total of 600 pulses of 50 Hz triplets for 2s, and repeated 
every 10s for a total of 190s of stimulation. Treatments will be delivered at the EEG coordinate for F3 
(approximating the left DLPFC), and will be found using the Beam-F3 method (Beam et al., 2009). This is a 
treatment paradigm that has been used extensively in other trials (Borckardt et al., 2008; Short et al., 2011; 
George et al., 2014; Li et al., 2013). Sham sessions will be delivered using an electronic sham system consisting 
of a coil that mimics the appearance and sound of TMS, combined with a TENS device which produces a small 
electric shock mimicking the feeling of real rTMS. This type of sham has been demonstrated to be 
indistinguishable from real rTMS, has been well tolerated (George et al., 2010; George et al., 2014) and 
successfully used in other clinical trials (Borckardt et al., 2008; Arana et al., 2008). During each session of rTMS 
we will present a series of opioid related images, including those utilized in previous studies (Garland et al., 2015; 
Garland & Howard, 2014). The application of drug cues during rTMS appears to enhance its efficacy (Dinur-Klein 
et al., 2014).Opiate craving and stress will be assessed before and after each TMS treatment. 
 
Quantitative Sensory Testing (QST): Three types of pain will be assessed (mechanical pain; diffuse noxious 
inhibitory control; and thermal pain). First, each participant’s mechanical pain threshold will be estimated using a 
digital pressure algometer. In this procedure (similar to (1)), the middle of the non-dominant supinator muscle will 
be located and marked (approximately 15% from elbow to wrist), and then pressure from the algometer will be 
increased at a rate of 10g/second until the participant perceives a shift in sensation from pressure to pain (the 
pain threshold). This procedure will be repeated three more times (for a total of four trials), with 30-seconds 
separating trials. Next diffuse noxious inhibitory control (DNIC) will be measured using the same protocol as 
above, but during mechanical pain assessments, participants will have their dominant hand submerged up to the 
wrist in a circulating ice water bath maintained at 4.5 degrees C (40 degrees Fahrenheit). After a 2-minute rest 
interval, thermal pain will be measured using the cold pressor test. During the cold pressor test, each participant 
will again submerge their dominant hand up to the wrist in a circulating ice water bath maintained at 4.5 degrees 
C (40 degrees Fahrenheit). On this trial however, they will leave their hand in until: first they perceive the 
sensation has shifted from cold to pain (pain threshold), and second when they perceive the inability to tolerate 
the pain (pain tolerance), at which point they will remove their hand. The maximum allowed duration for the cold 
pressor test will be 300 seconds (5-mins). QST will be done on treatment Days 1 and 3 and at the one-week 
follow-up.,  
 
Compensation and Retention: Participants will receive $40 for the screening visit, $40 for completion of 
each rTMS day, and $40 for each follow-up visit. Compensation will be given in the form electronic funds 
transfer. 
Table 1. Assessment Instruments and Schedule 
 
Instrument 
Purpose/Domain 
Screening 
TMS 
Sessions 
1-3 
1 wk, 4 wk, 
follow- up 
Informed Consent 
Obtain informed consent 
X 
Demographics 
Characterize sample 
X 
M.I.N.I. International Neuropsychiatric Interview 
Assess DSM-5 psychiatric disorders 
X 
Timeline Follow-Back: TLFB 
Assess opioid and other substance 
use 
X 
X 
X 
Urine Drug Screen: UDS 
Assess illicit drug use 
X 
X 
X 
Alcohol Breathalyzer 
Assess alcohol use 
X 
X 
X 

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Community Reintegration for Servicemembers 
Assess community reintegration 
X 
X 
Community Participation Index 
Assess community functioning 
X 
X 
ShortForm36 Health Survey: SF36 
Assess quality of life 
X 
X 
Patient Health Questionnaire nine (PHQ9) 
Assess depression 
X 
X 
Trait form of the State-Trait-Anxiety Inventory 
Assess anxiety symptoms 
X 
X 
Pittsburgh Sleep Quality Index: PSQI 
Assess sleep functioning 
X 
 
X 
Daily Pain Diaries (Numeric Rating Scales; NRS) 
Assess pain level 
X 
X 
X 
Brief Pain Inventory: BPI 
Assess pain severity and functional 
impairment 
X 
X 
X 
McGill Pain Inventory 
Assess pain severity 
X 
X 
X 
Patient Health Questionnaire: PHQ-15 
Assess health status 
X 
X 
Treatment Services Review: TSR 
Monitor services utilization 
X 
 
X 
Best Guess Questionnaire 
Assess rTMS blind integrity 
Adverse events 
Assess tolerability of rTMS 
     x 
 
Data Management: Data will be managed using REDCap as specified in the DMAP. 
Statistical Analysis: Study feasibility will be primarily measured by a) the total number of rTMS sessions 
completed (out of 18 total sessions) b) the proportion of participants completing all of the rTMS session and c) 
the proportion of participants completing all of the rTMS sessions as well as the follow-up visits. Study tolerability 
will be measured as the total number of treatment emergent adverse events. Group differences (active rTMS 
vs. sham rTMS) in the feasibility and tolerability measures will be estimated using generalized linear models with 
appropriate distributions (Negative binomial for session and AE count and logit for study treatment completion). 
In addition to study feasibility, efficacy measures (opioid use amounts, pain, and sleep quality) will be estimated 
for the entire cohort as well as estimates of between group differences. Changes in study efficacy outcomes 
from baseline to follow-up visits will be estimated and analyzed using appropriate statistical approaches. When 
parametric modeling assumptions can be made, changes over time and associated variability will be estimated 
between treatment groups using general linear mixed models (GLMMs). The GLMMs will allow us to estimate 
group-specific changes over time and overall effect sizes, along with the variation in those measures, while 
controlling for relevant baseline covariates (e.g. baseline craving, morphine equivalents, withdrawal). Although we 
will likely not be powered to detect between-group differences in binary outcomes (i.e. any drug use), such effects 
will be explored using generalized mixed models, and for time-to-event data (e.g. days to first opioid use), survival 
analysis models will be constructed. When parametric modeling assumptions do not appear to be valid, alternative 
(e.g. non-parametric) approaches will be used. Efficacy outcomes will also be analyzed for evidence of differential 
treatment effects in subgroups determined by gender, race, and ethnicity. Post-hoc exploratory analyses using 
GLMMs within the active rTMS group will address whether specific characteristics (e.g. demographics, baseline 
craving, morphine equivalents, withdrawal, PTSD) are associated with a differential treatment effect. The subgroup-
specific treatment effects and corresponding confidence intervals will be constructed and will be interpreted in terms 
of their clinical, rather than statistical, significance, and effect size of treatment to inform future trials will be 
estimated. Missing Data and Attrition: Missing data in longitudinal studies can be a problematic feature but can 
be mitigated through study design considerations. We will make every effort to prevent attrition, e.g., 
telephone/text/e-mail reminders prior to visits, and reinforcing attendance at each visit. However, these methods do 
not ensure that all data will be collected, and appropriate analysis methods will be employed to accommodate 
missing data. Maximum likelihood estimation yields valid inferences assuming ignorable attrition (i.e., attrition is 
accounted for by covariates or the dependent variable measured prior to dropout). In addition, in keeping with the 
ITT, we will make every effort to continue assessments for the entire course of randomized treatment, even among 
those who stop participating in the study assigned intervention or fail to complete the full rTMS time course. 
Sample Size Justification: A total of n=20 participants (n=10 per arm) will be enrolled. We anticipate that <20% 
of study participants will withdraw from the study or be lost to follow-up, meaning that ≥ n=16 participants are 
expected to complete the study. This sample size should allow us to assess feasibility and tolerability of the 
intervention, and ensure that group-specific changes will be able to be estimated in a precise fashion, with 95% 
confidence intervals extending ~0.5 standard deviation units. Similarly, the overall effect size confidence interval 

9.2.21 
will likely extend only 0.3 standard deviation units. As an exploratory and developmental project, we recognize 
that our final sample size will not result in a fully powered study design. Model based means and variability 
estimates will be derived from unadjusted and adjusted analyses and will be vital for designing a larger, more 
definitive trial in the context of a subsequent MERIT submission. Relapse, Drop-Out and Clinical 
Deterioration: Every effort will be made to re-engage participants who miss appointments. Clinical deterioration, 
such as exacerbation of psychiatric or substance use disorders, will be assessed on a case-by-case basis and 
appropriate care will be arranged. In the case of suicidal ideation, standard STAR program operating procedures 
will be followed which entails contact of on-call STAR clinicians. Participants will be considered drop outs if they 
do not come back for follow-up visits after three attempts to contact. With the exception of participants who 
formally withdraw from the study, we will attempt to assess early terminators at the time of discontinuation and 
at the post-treatment time points. These participants will be considered in the intent-to-treat efficacy analyses. 
Design Considerations: Choice of treating participants likely undergoing buprenorphine treatment and using 
an accelerated (multiple sessions per day) treatment paradigm: The standard rTMS treatment paradigm in 
depression is to treat outpatients using one session of rTMS each day, five times per week, for four to six weeks. 
We considered using this treatment paradigm; however, we chose to use an accelerated paradigm (multiple 
sessions per day), for the following reasons: 1: If treating outpatients with once daily sessions, there would likely 
be a great deal of variability in the number of attended sessions per week (OUD patients frequently miss 
appointments) and a large attrition rate (the opioid relapse rate is high amongst outpatients). 2: Patients are often 
seen frequently early in treatment (leaving an opportunity for an acute intervention that could easily be applied 
in other facilities). 3: Our preliminary evidence suggests that rTMS is tolerated while participants are on 
buprenorphine. Choice of including participants with co-morbid depressive symptoms: Because rTMS is known 
to have an anti-depressant effect we considered excluding patients with concurrent depressive symptoms to 
avoid the potential confound of improved depression driving anti-pain and anti-craving effects. We chose to 
include these patients as there is a high rate of comorbid depression in this population (Gros et al., 2013), and 
excluding these patients would reduce the generalizability of our findings. We will control for depression 
statistically by including depression as a covariate in analyses. Consideration of gender as a biological variable: 
Though this trial is not powered to detect gender differences, we will perform our analysis using gender as a 
potential covariate. 
Operational Plan and Research Timetable: Funding for two years is requested. The first three months will be 
used for submitting regulatory documents, staff training and preparing for study initiation. Eighteen months will 
be needed for patient recruitment and data collection. The final three months will be used for data analysis, 
dissemination, and MERIT grant submission. At a recruitment rate of approximately 1-2 participants per month, 
we should have no difficulty in completing the study in the proposed timeframe. 
 
 
PROTECTION OF HUMAN SUBJECTS 
1. RISKS TO THE SUBJECTS 
a. Human Subjects Involvement and Characteristics 
Admission into the study is open to men and women and to all racial and ethnic groups, age 18-65. Twenty 
opioid use disordered patients will be recruited from a pool of patients receiving treatment at the Substance 
Treatment and Recovery (STAR) program at the Ralph H. Johnson VA Medical Center, Charleston area VA 
clinics, and Charleston Center. Inclusion/exclusion criteria that apply to all participants are listed below: 
 
General Inclusion / Exclusion Criteria Inclusion Criteria 
Inclusion Criteria: 
1: Participants must be able to provide informed consent and function at an intellectual level sufficient to allow 
accurate completion of all assessment instruments. 
2: Participants must meet moderate to severe DSM-5 criteria for OUD. While individuals may also meet criteria 
for use disorders of other substances (with the exception of alcohol or benzodiazepines), they must identify 
opioids as their primary substance of abuse. 
3: Participants must report chronic pain for at least the past three months and have a Brief Pain Inventory 
score≥ 3. 
4: Participants must be receiving Medication Assisted Treatment (MAT). 

9.2.21 
 
Exclusion Criteria: 
1: Participants who are pregnant. 
2: Participants with a history of/or current psychotic disorder. 
3: Participants with a history of dementia or other cognitive impairment. 
4: Participants with active suicidal ideation, or a suicide attempt within the past 90 days will be excluded. 
5: Participants with contraindications to receiving rTMS (including a history of seizures, or any implanted metal 
above the neck). 
6: Those with unstable general medical conditions. 
7: Those who are currently using tramadol. 
8: Those with active moderate or severe alcohol or benzodiazepine use disorder due to increased risk of 
seizure. 
 
b. Sources of Materials 
Research material obtained from individual participants includes questionnaires and interviews with study 
personnel and urine samples. Data will be collected with paper and pencil and then entered into the VA 
REDCap database, which is a secure, password protected web-based data collection system. Coded data will 
be stored separately from the informed consent and HIPAA documents. Paper records will be stored in an 
office in the Ralph H. Johnson VAMC that is locked when not in use. Urine samples will never be marked with 
any identifying information. They will be discarded once read. 
 
c. Potential Risks and Risk Mitigation Strategies: 
Potential risks of rTMS: The use of high frequency rTMS has been FDA approved for the treatment of major 
depressive disorder since 2008. Our stimulation parameters (3000 pulses, 10Hz, 5-Seconds on 10-Seconds 
off) are nearly identical to the FDA approved protocol (3000 pulses, 10Hz, 4-Seconds On, 8-Seconds off), and 
have been used safely in many investigations including those in depression, pain, and addictions. We chose to 
use the slightly longer train duration of 5-seconds rather than 4-seconds due to its safety and efficacy in many 
trials including our preliminary single session trial with opioid users. 
The common clinical dose of rTMS in depression is 36 treatments with 3000 pulses per treatment, for a total of 
108,000 pulses. We will deliver a total of 18 treatments over 5 days with 3,000 pulses per treatment, for a total 
of 54,000 pulses. We subsequently will be giving a substantially lower total dose to each participant than is 
commonly given to patients being treated for depression. Accelerated treatment paradigms (including those 
with 6 treatments delivered daily) have been safely delivered in both depression and addictions populations 
without any clear adverse effect. 
Risk of Seizure: The most serious risk associated with the use of rTMS is seizure. Since the adoption and 
widespread use of standard safety guidelines in 1997, there has only been one documented seizure. The risk 
of seizure has been estimated to be less than 0.1% which is lower than the risk of seizure associated with 
pharmacologic antidepressants. The risk of seizure is related to the various stimulation parameters   
(intensity,frequency, train duration), location of application, pre-existing risk of seizure, and 
substance/medication factors. In the very rare event a seizure is caused, removing the coil is typically sufficient 
to stop the seizure, and there is no increased risk of subsequent seizure. In order to mitigate the risk of seizure 
we will carefully individualize the intensity of stimulus (by performing a resting motor threshold determination), 
treat using standard treatment protocols (used safely in other studies), and exclude potential participants at 
higher risk of seizure (those with a past history of seizures, those in withdrawal from alcohol or 
benzodiazepines, etc). 
Risk of Site discomfort and headache: Two relatively common risks associated with the use of rTMS include 
the risk of mild transient site discomfort during treatment (most patients), and the risk of headache 
(Approximately 5%) following treatment. Both of these potential side effects are typically mild. In terms of 
mitigating site discomfort, we will slowly ramp up stimulation intensity during the first three sessions. In our 
experience both clinically and experimentally this is a successful strategy. Additionally, due to the anti-pain 
effect of rTMS, participants rapidly adjust to stimulation. In the unusual circumstance that a headache is 

9.2.21 
caused by rTMS, over the counter analgesics are sufficient to alleviate the headaches, and will be available to 
patients on the inpatient unit. 
Potential hearing loss: The discharge of the rTMS coil generates a high-energy click that may cause cochlear 
damage. Humans exposed to rTMS have shown temporary increases in auditory threshold (especially at high 
frequencies) lasting at least 5 minutes and less than 4 hours. Foam earplugs can protect against these 
changes and will be worn during rTMS sessions. 
Safety in the case of pregnancy: This protocol will exclude pregnant women. Pregnancy status will be 
confirmed as part of the standard screening process. 
Pain task: The pain task may cause discomfort but will not cause injury. The task will be stopped when it 
becomes painful to the participant. 
2. ADEQUACY OF PROTECTION AGAINSTS RISKS 
a. Recruitment and Informed Consent 
E-consent and the first diagnostic interview, will be an option if the participant is not able to come into the 
laboratory for consenting (Due to COVID-19, or any other in person limiting factor). The e-consent will be 
emailed through REDCap and approved research personnel will go through the e-consent with the participant 
over the phone or over video conferencing. The participant will receive a copy of the signed e-consent by email 
from the research personnel. 
Participants will be recruited to the study from the STAR program. The study PI , Co-I, or other qualified, IRB-
approved personnel will obtain informed consent. The informed consent form includes a detailed description of 
the study procedures, along with statements regarding participants’ rights to withdraw from the procedure at 
any time without consequences. The informed consent form will be explained to participants in easy-to-
understand language, and participants will be instructed to read the form carefully prior to signing it. Consent 
will be documented by the signature of the participant on the informed consent agreement, accompanied by 
the signature of the individual obtaining the consent. 
 
b. Protections Against Risks 
All study participants will be closely monitored for psychiatric and medical stability. If hospitalization is indicated 
during one of the follow-up visits, the patient will be hospitalized at the Ralph H. Johnson VAMC or an 
appropriate referral will be made. All participants will be fully informed that they may withdraw from the 
experiment at any time without penalty. 
To ensure confidentiality, all subject data will be coded and stored in the VA REDCap system which is a secure, 
password protected, web-based data collection system. We will take careful precautions to maintain 
confidentiality for all subjects, using procedures we have used in other studies. Data will be compiled using 
codes in lieu of personal identifiers. Access to study data will be limited to research personnel. The application 
will provide: 1) an intuitive interface for data entry (with data validation); 2) audit trails for tracking data 
manipulation and export procedures; 3) automated export procedures for seamless data downloads to common 
statistical packages (SPSS, SAS, Stata, R); 4) procedures for importing data from external sources; and 5) 
advanced features, such as branching logic and calculated fields. Finally, it should be highlighted that only 
coded data will be entered into the electronic database. Thus, no protected health information (PHI) will be 
entered into the database. All paper records will be kept in a locked cabinet in Charleston VAMC research 
space (where Dr. McRae-Clark’s VA office is located). A file of names, contact addresses, telephone numbers, 
and other research identification numbers will be stored separately on paper and on computer, for purposes of 
audit by VA R&D and MUSC IRB. 
All investigators and project personnel will also complete a certified program of instruction in the protection of 
human subjects in research, such as the VA website tutorial, NIH website tutorial, or the University of Miami 
CITI course. These courses in the responsible conduct of research and the protection of human research 
participants will be completed in compliance with institutional, PHS, and NIH regulations. 
Participants will be taught about potential side effects of rTMS, and will be closely followed by members of the 
research team. Pregnancy tests will be performed as part of normal screening procedures. Adverse events will 
be monitored throughout the study as described in the research strategy section. 
MUSC IRB and VA R&D will review and approve the funded protocol, review patient consent forms, ensure 
protection of patient privacy and safety, and monitor the study on an on- going basis. Adverse events will be 
reported to MUSC IRB and VA R&D as they occur. Annual reports to MUSC IRB and VA R&D will indicate 

9.2.21 
enrollment rates, adverse events, new findings that may influence continuation of the study, and reports of the 
DSMB. 
 
3. POTENTIAL  BENEFITS  OF  THE  PROPOSED   RESEARCH   TO   THE   SUBJECT AND  OTHERS As 
rTMS is an FDA approved treatment for depression, and preliminary evidence suggests that it also has anti-pain 
and anti-craving effects. Research participants receiving active treatment may have improvement in craving, 
pain, and symptoms of depression. After the study data has been unblinded, we will offer open label treatment 
to those participants randomized to sham treatment. In addition to the potential direct benefits of participation in 
this study, participants will help investigators understand the utility of rTMS as a potential 
treatment for OUD. 
 
4. IMPORTANCE OF THE KNOWLEDGE TO BE GAINED 
This study may provide important information that can improve treatment for future patients with opioid and 
other substance use disorders. The moderate risks of the investigation are considered reasonable in relation to 
the expected knowledge to be gained. 
 
5. DATA AND SAFETY MONITORING PLAN 
a. Summary of the Protocol. 
This application proposes to investigate feasibility and acceptability of rTMS in opioid use disordered Veterans 
with chronic pain. Inclusion/exclusion criteria are outlined above. 
 
b. Trial Management. 
The study will be managed from Ralph H. Johnson VA Medical Center. The target population is described 
above in the inclusion/exclusion criteria. 
 
c. Data Management and Analysis. 
Data will be entered by research assistants directly into a computer using standard database software using 
REDCap. The data analysis plan is outlined in the Data Analysis Plan section. 
 
d. Quality Assurance. 
Quarterly data audits will be conducted. Confidentiality protections are outlined above. 
 
e. Regulatory Issues. 
Potential conflicts of interest will be reported using the VA rules for disclosure. Adverse Events (AEs)/Serious 
Adverse Events (SAEs) occurring during the course of the project will be collected, documented, and reported 
in accordance with protocol and IRB reporting requirements. All research staff involved with adverse event 
reporting will receive general and protocol specific AE/SAE training including identification, assessment and 
evaluation, and documentation and reporting. A research specialist will identify any potential adverse events 
during the course of the study from participant self-report and administration of the visit assessments and 
procedures. The research assistant will provide information to a study physician, who will be responsible for 
AE/SAE assessment and evaluation including a determination of seriousness and study relatedness. Any 
significant actions taken by the local IRB and protocol changes will be relayed to VA RR&D. 
 
f. Definition of AE and SAE. 
An Adverse Event (AE) is defined as any untoward medical occurrence in a study subject administered a 
pharmaceutical product that does not necessarily have a causal relationship with this treatment (ICH GCP). Any 
unwanted change, physically, psychologically or behaviorally, that occurs in a study participant during the 

9.2.21 
course of the trial is an adverse event. A Serious Adverse Event (SAE) is defined as an adverse event that has 
one of the following outcomes: 
• 
Results in death, 
• 
Is life-threatening, 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization, 
• 
Results in persistent or significant disability/incapacity, 
• 
Is a congenital anomaly/birth defect OR 
• 
Requires intervention to prevent one of the above outcomes. 
 
g. Documentation and Reporting. 
AEs/SAEs are documented and reported as per protocol and IRB requirements. Research staff will identify 
adverse events and obtain all available information to assess severity, seriousness, study relatedness, 
expectedness, outcome and the need for change or discontinuation in the study intervention. Adverse events 
are generally documented on AE Logs and AE Case Report Forms (CRFs). Additional relevant AE information 
if available should be documented in a progress note in the research record as appropriate to allow monitoring 
and evaluating of the AE. If the AE meets the definition for serious, appropriate SAE protocol specific reporting 
forms are completed and disseminated to the appropriate persons and within the designated timeframes as 
indicated above. For each AE/SAE recorded, the research staff will follow the AE/SAE until resolution, 
stabilization or until the participant is no longer in the study as stated in the protocol. When a reportable SAE is 
identified, the research staff will notify the MUSC Institutional Review Board (IRB) and VA R&D within 24 hours 
and complete the AE report form in conjunction with the PI. The MUSC IRB meets monthly and is located at 
165 Cannon Street, Rm. 501, Charleston, SC 29425. The MUSC IRB has a MOU to provide HHRP oversight 
for clinical research conducted at the Ralph H. Johnson VA Medical Center. Communication with the IRB is 
through email, memos, official IRB forms, and online reporting. A report will also be sent to the VA RR&D 
program officer assigned to the project. 
If complete information is not available when the initial 24-hour SAE report is disseminated, follow-up 
information will be gathered to enable a complete assessment and outcome of the event. This information may 
include hospital discharge records, autopsy reports, clinic records, etc. The research staff will attach copies of 
source documents to the SAE report for review by the PI and for forwarding to the NIH program officer as 
appropriate within 2 weeks of the initial SAE report. In addition, the PI will provide a signed, dated SAE 
summary report, which will be sent to the VA RR&D Project Officer within two weeks of the initial SAE report. 
We will report adverse events to the Medical University of South Carolina (MUSC) Institutional Review Board 
(IRB) online as soon as possible, but no later than 10 working days after the investigator first learns of the 
event. The MUSC IRB AE reporting requirements are as follows: All deaths that occur during the study or 30 
days post termination from the study are required to be reported as adverse events even if they are expected 
or unrelated. Other adverse events are reportable to the MUSC IRB if the AE is unexpected AND related or 
possibly related AND serious or more prevalent than expected. All three criteria must be met for an AE to be 
reported to the MUSC IRB. The IRB definition of unexpected is that the AE is not identified in nature, severity 
or frequency in the current protocol, informed consent, investigator brochure or with other current risk 
information. The definition of related is that there is a reasonable possibility that the adverse event may have 
been caused by the drug, device or intervention. Reportable AEs are reviewed by the IRB Chair and reported 
to the IRB Board at the next meeting. 
h. Trial Safety. 
The potential risks and benefits and methods to minimize these risks are outlined above. The research staff will 
report any unexpected AEs or any scores of “severe” on the side-effect symptom rating form or any FDA- 
defined serious AEs to the PI within 24 hrs so that the PI can decide on the appropriate action. All unexpected 
AEs will be monitored while they are active to determine if treatment is needed. Study procedures will follow 
the FDA’s Good Clinical Practice Guidelines (www.fda.gov/oc/gcp). Any outside requests for information or any 
breaches in confidentiality will be reported to Dr. McRae-Clark. 
 
An interim analysis is not planned at this time. 
 

9.2.21 
i. DSM Plan Administration. 
Dr. McRae-Clark will be responsible for monitoring the study, and will participate in weekly study meetings. A 
DSM report will be filed with the IRB and VA R&D on a yearly basis, unless greater than expected 
problemsoccur. The report will include participant characteristics, retention and disposition of study 
participants, quality assurance issues and reports of AEs, significant/unexpected AEs and serious AEs. We will 
report outcomes at the end of the trial. 
 
j. DSM Board 
A Data Safety and Monitoring Board will be formed to monitor both the rate and severity of adverse   events. 
This panel will include 3 clinicians with expertise in substance use disorders and a statistician. 
k. Risk Benefit Ratio. 
The assessments and questionnaires are non-invasive and have inherently minimal risks. Potential risks of 
concern are loss of confidentiality and adverse events to rTMS. As discussed above, our research team will 
attempt to minimize these risks. Knowledge gained by the proposed study would help fill an important void in 
development of a potential treatment for opiate use disorder. 
6. STATEMENT OF DISCLOSURE 
No financial or contractual relationship exists between any organization involved in the proposed study that 
could constitute a real or apparent conflict of interest for either the PIs, Co-Is, or collaborators devoting > 5% or 
more effort to the project. 
7. ACKNOWLEDGEMENT OF VA POLICY TO INCLUDE WOMEN AND MINORITIES 
The PI acknowledges receipt of VHA Handbook 1200.9 which delineates VA policy regarding the requirement 
for the inclusion of women and minorities in any DVA-sponsored research. The PI has carefully reviewed this 
policy and, hereby, provides assurance that if the proposed research outlined in the Letter of Intent is approved 
and funded, every effort will be made to include women and minorities in the study.