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
Phase: NA
Conditions: Opiate Dependence, Chronic Pain
Sponsor: Medical University of South Carolina

 
 
 
1 of  19 
ArTMS_CUD_IRB_v1.7_09/16/19 
 
 
 
 
PI Name: Gregory Sahlem 
Co-I Names:  Aimee L. McRae-Clark, Paul J Nietert, Mark S. George. 
 
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  
 
Once protocol is complete, save it as a Word document.  Go back to the IRB application and upload the protocol.  
 
TABLE OF CONTENTS –  
Page 1-2 Specific AIMS 
Page 2-3 Background and Significance 
Page 3 Preliminary Studies 
Page 4-7 Research Design and Methods 
Page 7-11 Protection of Human Subjects 
Page 11-13 References and Literature citations 
 
A. SPECIFIC AIMS___________________________________________________________________________ 
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 (1). Uncontrolled pain (2-4) and opiate craving (5, 6) 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 (7, 8), decrease the amount of self-administered morphine following 
open gastric bypass surgery (9), and decrease the affective and sensory components of pain following 
laparoscopic gastric-bypass surgery (10). 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% (11). 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 (12, 13). In substance use disordered populations, the use of 
rTMS has garnered significant attention as an innovative tool to decrease craving [see reviews: (14-17)]. 
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 (18), nicotine (19) and cocaine 
(20) 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% (19). 
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 
Medical University of South Carolina 
Protocol 

 
 
 
2 of  19 
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. 
The goal of this proposal is to investigate whether multiple sessions of rTMS applied to the DLPFC 
result in decreased craving (Aim 1) and pain (Aim 2) in treatment-seeking opiate users with or without 
chronic pain, who are currently hospitalized for opiate detoxification. Additionally, we will follow 
participants for four weeks to determine if treated participants have a higher rate of abstinence than 
un-treated participants (Exploratory Aim). These aims will be addressed through a double-blind, 
randomized, sham-controlled study. 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). 
 
Aim 1: Determine if a course of excitatory rTMS applied to the DLPFC results in reduced cue-induced 
craving. We hypothesize that patients receiving active rTMS will have a greater reduction in cue induced 
craving (post-treatment vs. pre-treatment) as compared to those receiving sham rTMS. Cue craving will be 
assessed using a standardized measure (21) during a validated opiate cue paradigm (22). 
 
Aim 2: Determine if a course of excitatory rTMS applied to the DLPFC results in decreased pain. We 
hypothesize that patients receiving active rTMS will have a greater reduction in pain (post-treatment vs. pre-
treatment) as compared to those receiving sham rTMS. Pain will be assessed using clinically relevant 
subjective measures (23, 24). We will also assess pain using a validated quantitative sensory testing 
paradigm. 
Exploratory Aim: Determine if participants receiving active rTMS have a higher rate of abstinence 
following treatment as compared to participants receiving sham rTMS. We hypothesize that participants 
receiving active rTMS will be more likely to be abstinent over the final two-weeks of the study period than those 
receiving sham rTMS. We will define abstinence as no self-reported opiate use over the final two weeks of the 
study, and a negative urine drug screen for opiates on the final post treatment assessment visit. 
B. BACKGROUND AND SIGNIFICANCE_________________________________________________________ 
Prescription opiate use disorder (OUD) is a common problem in the United States with high morbidity 
and mortality. Approximately 1.9 million Americans suffer from prescription OUD (25), and 22,000 of those 1.9 
million die each year due to accidental overdose (26). Economic costs are estimated at $55 billion per year 
(health care, criminal justice system, and workplace costs) (27). There have been advances in the treatment of 
OUD with the introduction of buprenorphine as a replacement therapy; however, relapse rates remain high (1). 
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 (2-4). As is the case with other substance use disorders, opiate craving is 
commonly described by abstinent patients whether or not they are stabilized on buprenorphine (5, 6). 
Subsequently a treatment that reduces pain and craving could improve the clinical course of opiate addiction.    
    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 (28). Single sessions of 
rTMS induce temporary changes; however, 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 (29). rTMS applied over the 
DLPFC likely exerts its anti-depressant effect by acting to re-regulate these dysfunctional cortical-limbic circuits 
(30). Single sessions of rTMS have little effect on depression; however, multiple sessions of rTMS have been 
demonstrated to be an effective (31, 32) and durable (33, 34) 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 (35-
37). 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.  

 
 
 
3 of  19 
    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 (38), this imbalance may play a key role in 
the inability of those with substance use disorders to modulate drug craving and use (38-44). 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:(14-17)]. 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 network 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 (45), providing further evidence of this relationship.  
    Of note, two recent clinical trials demonstrated that multiple sessions of rTMS may have a more durable 
effect on craving and reduce drug use (19, 20) 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% (19). 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% (20).  
    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 (7, 8), decrease the amount of self-administered morphine 
following open gastric bypass surgery (9), and decrease the affective and sensory components of pain 
following laparoscopic gastric-bypass surgery (10). 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% (11). 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% (12), 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 (46). Additionally, pre-treatment with naloxone (an opioid antagonist) blocks this effect, 
suggesting that rTMS exerts its action through the opioid system (46, 47).  
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 opiate system. We have successfully applied rTMS to an OUD 
population with promising early results. The next step in the development of this novel treatment for OUD is to 
determine the effects of a course of treatment in a treatment seeking OUD population with chronic pain.  
 
C. PRELIMINARY STUDIES___________________________________________________________________ 
 
Of direct relevance to the proposed project, the investigative team has 
demonstrated 1) The ability to conduct a trial using an accelerated rTMS 
treatment paradigm in acutely ill inpatients and; 2) the ability to apply rTMS to 
an OUD population, while determining its effect on craving and pain. 
1) Recently the investigative team completed a trial in acutely suicidal, 
depressed inpatients. In that trial we demonstrated the feasibility of delivering 
an accellerated course of rTMS (the equivalent of 18 sessions over three 
days), to acutely ill inpatients (35). 16 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 acutely ill inpatients into an rTMS 
based trial and the feasability of this treatment paradigm.  
 
Baseline
Post-Rx Opiate Cue
Pre rTMS
Post rTMS with Cue
15 Mins Post rTMS
30 Mins Post rTMS
-1.50
-0.75
0.00
0.75
1.50
Craving Normalized to Baseline
Craving ± SEM
Active rTMS
Sham rTMS
Preliminary Data Related to Aim 1

 
 
 
4 of  19 
2) The investigative team recently completed a single-blind, sham controlled 
crossover study demonstrating that a single session of active 10Hz DLPFC TMS 
acutely decreases self-reported opiate craving and thermal pain sensitivity 
among opiate use disordered individuals (48). In addition to demonstrating that a 
single session of rTMS may have an effect on both pain and craving 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).  
 
 
 
 
 
 
D. RESEARCH DESIGN AND METHODS (including data analysis) 
C: Approach: General Overview (Figure 1):  Our primary aims 
are to determine if 18 sessions of 10 Hz DLPFC rTMS decreases 
cue induced opiate craving (Aim 1) and decreases pain (Aim 2) 
in individuals with OUD with, or without chronic pain. Participants 
will be recruited from an inpatient unit for opiate detoxification. 
The majority of this study will take place over a 5-day period 
during which both primary aims will be accomplished. In an 
exploratory fashion we will also collect data at one, four, and 12 
weeks following discharge to determine the interventions effect 
on substance use and pain. Acute Phase: We will screen, 
consent, enroll, and assess participants during an enrollment 
session which will occur following either a buprenorphine or 
methadone induction. The morning following induction, prior to 
their daily dose of buprenorphine or morphine, each participant 
will be randomized, and undergo both a opiate drug cue-craving 
paradigm, an inhibitory control/delay discounting paradigm,  and 
a quantitative sensory testing paradigm (as outlined below). 
Participants will then receive a total of six sessions of rTMS on 
three consecutive days during the acute phase of the study (18 
total treatments). On the day of discharge, prior to a final dose of 
buprenorphine or methadone, and several hours prior to actual 
discharge, the prescription opiate cue-craving, inhibitory 
control/delay discounting paradigm, and quantitative sensory 
testing paradigms will be repeated. Daily craving will be 
assessed during visual cue presentations, and daily pain will be 
assessed using validated questionnaires. Continuation Phase: 
Participants will either return in person, or receive a phone call at 
one and four weeks for follow-up for the collection of clinical 
substance use and pain outcomes. Additionally, the South 
Carolina Reporting and Identification Prescriptions Tracking 
System (SCRIPTS), will be accessed once, three months 
following the hospital discharge. 
Quantitative Sensory Testing (QST): Repeated QST sessions 
will be conducted at the same time of day (during the morning, 
prior to receiving buprenorphine/methadone). Participants will not 
be permitted to take any prn analgesic medication for at least five 
hours prior to the QST sessions prior to assessment. Testing 
paradigm: Three types of pain will be assessed (mechanical 
pain; diffuse noxious inhibitory control; and thermal pain). First, 
each participants mechanical pain threshold will be estimated 
Sensory Threshold
Pain Threshold
Pain Tolerance
-6
-4
-2
0
2
4
Degrees C°
Change in Thresholds ± SEM
Active rTMS
Sham rTMS
p<.05
Preliminary Data Related to Aim 2
Day 2, AM  
Prior to daily Bup 
1 week 
 follow-up 
Figure 1 
N= 40 Opiate Use Disordered 
Inpatients with / without  
Chronic Pain 
 6 sessions  
Active rTMS 
N=20 
N=20 
Day 2, PM after 
Bup=8mg 
 6 sessions  
Active rTMS 
Day 3 
Bup=4mg 
Cue-Craving and Sensory Assessments  
1: Enrollment 
2: Randomization based on: 
 Pain, Depression, Planned MAT   
Day 1, PM after 
Bup induction 
dose=8mg 
 6 sessions  
Sham rTMS 
 6 sessions  
Sham rTMS 
1: Clinical Substance Use Outcomes 
2: Clinical Pain Outcomes 
1 month 
 follow-up 
1: Clinical Substance Use Outcomes 
2: Clinical Pain Outcomes 
Day 5, PM  
After daily Bup 
Bup=4mg 
Discharge
 6 sessions  
Active rTMS 
 6 sessions  
Sham rTMS 
Day 4 
Bup=4mg 
Day 5, AM  
Prior to daily Bup 
Bup=4mg 
Bup=Buprenorphine; MAT=Medication Assisted Treatment; 
rTMS=Repetitive Transcranial Magnetic Stimulation 
Cue-Craving, and Sensory Assessments  
Craving and Sensory Assessments  

 
 
 
5 of  19 
using a digital pressure algometer. In this procedure (similar to (49)), 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). 
 
Prescription Opiate Cue Paradigm: Cue craving will be assessed using a standard craving questionnaire 
(21), before and after a validated cue paradigm (22). The drug cue paradigm consists of: a) an imagery 
induction script, b) in vivo cues (e.g., bottle of OxyContin pills, glass of water, pill crusher), and c) a video. This 
drug cue paradigm was successfully applied in our previous trial using rTMS in prescription opiate users. 
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). This system is FDA cleared for the 
treatment of depression, and only differs from the standard clinical system in its ability to be sham-controlled. 
We will use a standard resting motor threshold (rMT) determination to determine the TMS dose (50). 
Treatment will be delivered at 120% rMT. Each active rTMS treatment will consist of a total of 3000 pulses of 
10Hz stimulation (5s-on,10s-off). Treatments will be delivered at the EEG coordinate for F3 (approximating the 
left DLPFC), and will be found using the Beam-F3 method (51). This is a treatment paradigm that has been 
used extensively in other trials (9, 12, 35, 52). 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 active rTMS. This type of sham has been 
demonstrated to be indistinguishable from active rTMS, has been well tolerated (31, 35) and successfully used 
in other clinical trials (53, 54). During each session of rTMS we will present a series of prescription opiate 
related images, including those utilized in previous studies (55, 56). The application of drug cues during rTMS 
appears to enhance its efficacy (19). We chose an alternate cue paradigm during treatment (as opposed to the 
one used to assess cue induced craving) to avoid habituation to the drug cue. The P.I. will perform all resting 
motor threshold assessments, and closely supervise a specially trained research specialist, who will deliver 
rTMS treatments.  
Recruitment, Participant Population, and Integration of Study Procedures to Standard Care: 
    Recruitment: Participants will be recruited from patients who have been admitted to the Charleston Center 
of South Carolina for detoxification. The Charleston Center is a community based drug and alcohol treatment 
facility that serves all of Charleston County. Over the past 12 months, approximately 400 patients were 
admitted for acute detoxification of opiates. The inpatient treatment team will refer interested participants, who 
will undergo a brief screen with research staff, and if meeting very general inclusion/exclusion criteria will meet 
with a qualified member of the research staff (most often the PI), for consent and enrollment. 
    Integration of Study Procedures Into Inpatient Care: During inpatient care, standard treatment includes a 
combination of pharmacotherapy, psychotherapy, and social work interventions. Pharmacotherapy consists of 
detoxification from opiates (using a standardized protocol), and the use of medications to treat co-occurring 
conditions. During detoxification patients are assessed twice daily using the Clinical Opiate Withdrawal Scale 
(COWS) (57), and then undergo either a standardized buprenorphine taper (8mg x 2 days, 4mg x 3 days), or a 
standardized methadone taper (30, 25, 20, 15, 10, 5). Induction using either medication occurs at approximately 
10am on the first morning of admission. On each of the following four days, medication is given at 
approximately 10am, and patients are discharged on the final day of their taper following their final dose of 

 
 
 
6 of  19 
medication. Currently there are no regular group therapy sessions, and regular meetings with individual 
therapists, social workers, and prescribers are less than 60 minutes in duration each. 
The study has been designed specifically to not interfere with any aspect of the normal unit operations. 
One of the qualified study members will meet with interested patients once they are stable on 
buprenorphine/methadone, and no longer in acute withdrawal, subsequently the study will not interfere with the 
initiation of buprenorphine/methadone. Patients who would like to participate in the study, will be consented, 
enrolled, and will complete baseline assessments prior to starting treatment. The opiate cue craving paradigm, 
inhibitory control/delayed discounting paradigm, and the quantitative sensory testing will be completed on the 
morning after being induced on buprenorphine/methadone (before any rTMS), and the morning of the last dose 
of buprenorphine/methadone on the discharge day (after all rTMS has been delivered). Subsequently 
assessments will occur at the same time of day, and prior to patients taking buprenorphine/methadone, without 
disrupting the normal dispensing of medications (which is approximately 10am). Six 15 minute treatments will 
be delivered each of the next three days with approximately 30 minutes in between each treatment. Given that 
all standard treatment meetings (see above) occur in windows of less than 60 minutes, and rTMS will be 
delivered on the same floor as detoxification, study treatment will not interfere with any of the standard of care 
interventions participants receive. 
The study procedures will also not interfere with any of the standard of care pharmacotherapy 
commonly delivered during detoxification. There is no known added risk of rTMS during a 
buprenorphine/methadone taper (in our pilot trial several of our participants were stabilized on buprenorphine). 
The commonly used non-opiate medications including acetaminophen, hydroxyzine, and cyclobenzaprine, will 
be allowed during this study (but be held for at least 5 hours prior to each pain assessment). Patients being 
treated for OUD commonly have co-morbid symptoms of depression and anxiety (58). Subsequently, the 
initiation of antidepressant medications is common in the acute treatment setting, and will be allowed during 
this trial (and are commonly used safely with concurrent rTMS).  
        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 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.  
3: Participants must be admitted to the inpatient unit for opiate detoxification.  
4: Participants must consent to random assignment. 
 
    Exclusion Criteria:  
1: Participants who are pregnant will be excluded.  
2: Participants with a history of/or current psychotic disorder will be excluded.  
3: Participants with a history of dementia or other cognitive impairment will be excluded.  
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) will be excluded.  
6: Those with unstable general medical conditions will be excluded.  
7: Those who are currently using naltrexone, or tramadol, will be excluded.  
8: Those with alcohol or benzodiazepine use disorders will be excluded due to increased risk of seizure.  

 
 
 
7 of  19 
 
 
Schedule of Visits and Assessments:  
 
Assessment 
Domain 
Baseline 
Post 
1 and 4 week 
F/U 
3-Month 
SCRIPTS 
Review 
Screening and Enrollment Eligibility: 
 
Mini International Neuropsychiatric Interview 
for the DSM-5 (MINI)(59): Structured interview 
to determine Axis I psychiatric conditions based 
on DSM-5 criteria. 
Psychiatric History 
X 
 
 
 
Patient Health Questionnaire Nine 
(PHQ9)(60): Self-Report measure of depressive 
symptoms. 
Depressive 
Symptoms 
X 
 
X 
 
Time Line Follow Back (TLFB)(61) and 
Clinical Opioid Withdrawal Scale 
(COWS)(57): The TLFB is a validated measure 
quantifying drug use; average daily morphine 
equivalents will be calculated. The COWS is a 
validated measure quantifying withdrawal 
severity. 
Opiate Use and 
Withdrawal 
X 
 
 
 
Subjective Opioid Withdrawal Scale (SOWS) 
(68): The SOWS is a validated self-administered 
measure of opioid withdrawal. 
Opiate Withdrawal 
X 
X 
 
 
The Barratt Impulsiveness Scale (BIS11) (69): 
The BIS is a validated questionnaire designed to 
assess the personality/behavioral construct of 
impulsivity. 
Impulsivity 
X 
 
 
 
The Pittsburgh Sleep Quality Index (PSQI) 
(70): Validated instrument used to measure the 
quality and patterns of sleep in adults. 
Sleep 
X 
 
X 
 
Work Productivity and Activity Impairment 
Questionnaire (71): The Work Productivity and 
Activity Impairment (WPAI) questionnaire is a 
well validated instrument to measure 
impairments in work and activities. 
Functional 
Impairment 
X 
 
X 
 
The Rand 36 Item Short Form Health Survey 
(73): Validated self-report to assess quality of 
life. 
Quality of Life 
X 
 
X 
 
Aim 1: Cue induced Craving: Primary outcome: Change score in peak to final craving during cue 
paradigm. 
 
Prescription Opiate Craving Scale (21): Three 
item opiate craving scale. The three-item scale 
will also be administered at 1 and 4 week follow-
Provoked Opiate 
Craving  
X 
X 
 
 

 
 
 
8 of  19 
ups, but there will be no cue provocation. 
Aim 2: Pain Outcomes: Primary outcome: Change score in thermal pain threshold and pain tolerance. 
 
Mechanical, Thermal, and DNIC Pain 
Assessment: See description above. 
Quantitative 
Sensory 
Assessment 
X 
X 
 
 
Brief Pain Inventory (23) and McGill Pain 
Questionnaire (24): Self report measures 
assessing severity, functional impairment, and 
affective components of pain. 
Administered daily during the acute phase of the 
study and at both follow-up visits. 
Subjective Pain 
X 
X 
X 
 
Exploratory Aims: Substance Use: Primary outcome: Abstinence over the final two weeks of the 
study, as defined by no self-reported use and a negative final urine drug screen. Executive function/inhibitory 
control: Will be measured using two validated computer tasks. 
 
Urine Drug Screen 
Objective 
Substance Use 
X 
 
X 
 
Time Line Follow Back (61): See above. 
Subjective 
Substance Use 
X 
 
X 
 
South Carolina Prescription Monitoring 
Program: 
Online database of all controlled substance 
prescriptions filled in the state of South Carolina. 
Filled Prescription 
Opiates 
 
 
 
X 
The “GoGo/NoGo” task: Participants are 
instructed to press a button in response to 
common (gray colored circles: 75% of trials) and 
rare (yellow colored circles: 12.5% of trials) Go 
stimuli and inhibit responding to rare NoGo 
stimuli (blue colored circles: 12.5% of trials). The 
task provides errors of omission and reaction 
times during Go trials, controls for novelty 
detection during processing of rare Go trials 
(yellow circles) and errors of commission on 
NoGo trials (blue circles). 
Inhibitory Control 
 
 
 
 
Delayed Discounting Task: Participants will 
decide between a series of theoretical monetary 
rewards (exe: smaller rewards now, or larger 
rewards later) in a brief computerized task.  
Delayed 
Discounting 
X 
X 
 
 
 
DATA MANAGEMENT AND STATISTICAL ANALYSIS: Data will be managed using REDCap. DATA 
MANAGEMENT AND STATISTICAL ANALYSIS: Data will be managed using REDCap. Randomization: 
Participants will be randomized to active or sham rTMS. Urn randomization will be used to ensure balance on 
three pre-specified covariates: depression status (HRSD at baseline ≥16 indicating moderate or greater 
depression), self-reported pain over the past three months, and planned use of replacement therapy following 
discharge. Statistical Analysis: Changes in study outcomes will be estimated and analyzed using several 
approaches. When parametric modeling assumptions can be made, changes over time will be compared 
between treatment groups (active rTMS vs. sham rTMS) using general linear mixed models (GLMMs). The 

 
 
 
9 of  19 
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). In an attempt to determine whether rTMS impacts craving and pain by reducing 
depressive symptoms, we will also examine models that do and do not control for changes in depression 
scores. Although we will likely not be powered to detect between-group differences in binary outcomes (i.e. 
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 to estimate treatment efficacy 
and its precision. Primary 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) are associated with a better 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. Sample Size Justification: A total of n=40 participants (n=20 
per arm) will be recruited. We anticipate that <20% of study participants will withdraw from the study or be lost 
to follow-up, meaning that ≥ n=32 participants are expected to complete the study. This sample size ensures 
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 will likely extend 
only 0.3 standard deviation units. As an exploratory and developmental R21 project, we recognize that our final 
sample size may not result in a fully powered study design. Nevertheless, our sample size will provide >80% 
power to detect large effect sizes (equivalent to a Cohen’s d of 1.0), assuming 2-sided hypothesis testing and 
an alpha level of 0.05. Our preliminary work and work of others suggests that differences of this magnitude 
may be present within our proposed sample. For example, for Aim 1, recent investigations have found large 
effect sizes, with (20) reporting a d=0.84, and (18) reporting a d=0.98. For Aim 2, our recent single session 
study reported a d=0.65. 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 
R01 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 disorder, will be assessed on a case-by-case basis and appropriate referral will be made. 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. Strategies to Ensure a Robust and Unbiased Approach: The proposed 
study will achieve robust and unbiased results via several design features including: explicit inclusion/exclusion 
criteria; randomization of treatment condition; the use of a validated sham control; use of validated laboratory 
and interview/self-report measures and methods; explicit hypotheses and corresponding planned statistical 
analyses; power estimates; planned handling of retention/attrition and missing data; and careful consideration 
of potential confounds. All experimental details are reported in a detailed manner to support replication. 
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. Should there be a potential 
gender difference found, we will use that data to power a larger trial 
 
 
 
 
 
 
 

 
 
 
10 of  19 
 
E. PROTECTION OF HUMAN SUBJECTS________________________________________________________ 
 
1.  RISKS TO THE SUBJECTS 
 
Targeted/Planned Enrollment Table 
Total Planned Enrollment 40 
 
 
TARGETED/PLANNED ENROLLMENT: Number of Subjects 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
   1 
    1 
      2 
Not Hispanic or Latino 
   19 
    19 
      38 
Ethnic Category: Total of All Subjects* 
40 
Racial Categories 
 
American Indian/Alaska Native 
0 
0 
0 
Asian 
1 
1 
2 
Native Hawaiian or Other Pacific Islander 
1 
1 
2 
Black or African American 
4 
4 
8 
White 
14 
14 
28 
Racial Categories: Total of All Subjects* 
20 
20 
40 
 
The most recent information reported by the South Carolina Department of Alcohol and Other Drug 
Abuse Services reports 49.6% of those admitted to an inpatient unit for opiate detoxification are women, and 
50.4% are men. Additionally, 91% are Caucasian, 7.2% are African American, and 1.7% are of another race. 
We expect our recruited population to have a similar demographic make-up, with the exception of being more 
ethnically diverse (Charleston is more diverse than other SC counties). 
We will attempt to recruit all potential participants from the community. We will not exclude anyone 
based on age, gender, ethnicity, or race.  
 
Review of Adverse Events: Adverse events (AEs) will be assessed daily by study personnel. The type of AE, 
severity of AE, and the relationship to the application of rTMS will be recorded. AEs will be coded using 
Medical Dictionary for Regulatory Activities (MedDRA) rules. 
Compensation and Retention: Participants will receive $160 for completion of the acute treatment phase of 
the study, and $120 for in-person completion of both the one and four-week follow-up visits. If participants elect 
to complete the follow-up visits by phone, they will be compensated $60 per phone call. The total possible 
compensation will be $400. Compensation will be given in the form of Greenphire MasterCard debit cards. 
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. Forty 
opiate use disordered patients will be recruited from a pool of patients admitted to an inpatient unit for 
detoxification. Inclusion/exclusion criteria that apply to all participants are listed below: 
 
General Inclusion / Exclusion 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.  

 
 
 
11 of  19 
2: 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.  
3: Participants must be admitted to the inpatient unit for opiate detoxification.  
4: Participants must consent to random assignment. 
 
    Exclusion Criteria:  
1: Participants who are pregnant will be excluded.  
2: Participants with a history of/or current psychotic disorder will be excluded.  
3: Participants with a history of dementia or other cognitive impairment will be excluded.  
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) will be excluded. 
6: Those with unstable general medical conditions will be excluded.  
7: Those who are currently using naltrexone, or tramadol, will be excluded.  
8: Those with alcohol or benzodiazepine use disorders will be excluded 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. All data will be directly input into REDCap which is a secure, password 
protected web-based data collection system. The only written research material will be the informed consent 
and HIPAA documents. These paper records will be stored in an office in the Roper Medical Office Building 
(RMOB) 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 (35), pain (12), and 
addictions (48, 52). 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 opiate users. 
    The common clinical dose of rTMS in depression is 36 treatments with 3000 pulses per treatment, for a total 
of 108,000 pulses (33). We will deliver a total of 18 treatments over 3 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 (35-37, 62), and addictions 
(63, 64) 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(65), there has only been one documented seizure with 
the type of rTMS we will deliver. The risk of seizure has been estimated to be less than 0.1% which is lower 

 
 
 
12 of  19 
than the risk of seizure associated with pharmacologic antidepressants(66). 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 
caused by rTMS, over the counter analgesics are sufficient to alleviate the headaches, and will be available to 
patients on the inpatient unit. 
 
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. 
    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 admissions process. 
     Potential risks of cue Induced craving paradigm: Drug cues are known to increase craving, and 
subsequently the use of an opiate cue paradigm will likely increase craving for opiates. The craving induced 
will be transient (22), with craving approaching baseline within 90 minutes. Additionally, it is unlikely our 
delivered craving paradigm will induce craving that is more intense than the individual cues that participants 
will encounter once they leave the hospital. Given that all of our drug cues will be given while patients are 
admitted to the inpatient unit, it is highly unlikely that the increased opiate craving produced by the opiate cue 
paradigm will result in any substance use. Our final cue-craving paradigm will be delivered on the day of 
discharge, however it will be done several hours prior to discharge, and we will closely monitor the craving 
response patients exhibit. Study staff will stay with each participant until their craving has returned to baseline 
levels. In the unlikely event that the individual has prolonged cue-induced craving, the P.I. will provide an 
appropriate referral. 
2. ADEQUACY OF PROTECTION AGAINSTS RISKS  
a. Recruitment and Informed Consent 
    Patients will be referred to the study by the inpatient medical team. Medical records will not be reviewed to 
identify potential study participants. Qualified, IRB approved study staff 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 MUSC 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.  

 
 
 
13 of  19 
    To ensure confidentiality, all subject data will be directly input into REDCap which is a secure, password 
protected, web-based data collection system. All paper records (which will likely only be the consent and 
HIPAA document) will be kept in a locked cabinet in an office that will be locked at times when not in use. The 
research staff understands the importance of maintaining confidentiality, and this method of maintaining 
confidentiality has been effectively used by our research group in the past. All electronic databases are stored 
on HIPAA-compliant servers with restricted access. All co-investigators and study personnel have completed 
(or will complete upon hiring) training in Good Research Practices as mandated by the MUSC IRB. 
    Participants will be taught about potential side effects of rTMS, and will be closely followed by both inpatient 
psychiatrists, and members of the research team. Pregnancy tests will be performed as part of normal 
admission procedures. Adverse events will be monitored throughout the study as described in the research 
strategy section.  
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. 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 pain and 
craving. 
 
4. IMPORTANCE OF THE KNOWLEDGE TO BE GAINED 
    This study may provide important information that can improve treatment for future patients with opiate 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 
    This section is based on the recommendations in NIDA’s “Guidelines for Developing a Data and Safety 
Monitoring Plan” (www.drugabuse.gov/funding/dsmbsop.html). A detailed DSMP will be developed and 
approved by NIH program staff prior to study initiation.  
 
a.  Summary of the Protocol.   
    This application proposes to investigate the effects of rTMS on craving and pain on opiate use disordered 
patients with chronic pain. The primary outcomes of interest are craving (Aim 1) and pain (Aim 2). 
Inclusion/exclusion criteria are outlined above.  Power calculations and sample sizes are in the Data Analysis 
Plan section.  
 
b. Trial Management.   
    The study will be managed from the Addictions Sciences Division within the Department of Psychiatry and 
Behavioral Sciences at the Medical University of South Carolina.  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 NIH 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 

 
 
 
14 of  19 
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.  
 
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 
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) 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. Communication with the IRB is through email, memos, 
official IRB forms, and online reporting.  
    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.  
    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.Sahlem.  
 
An interim analysis is not planned at this time. 

 
 
 
15 of  19 
 
i. DSM Plan Administration. 
    Dr.Sahlem will be responsible for monitoring the study, and will participate in weekly study meetings. A DSM 
report will be filed with the IRB on a yearly basis, unless greater than expected problems occur. 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. CLINICALTRIALS.GOV REQUIREMENTS 
    In accordance with Public Law 110-85, this project will be registered at the ClinicalTrials.gov Protocol 
Registration System Information Website prior to study initiation. 
 
F. REFERENCES/LITERATURE CITATIONS______________________________________________________ 
1. 
Fiellin DA, Schottenfeld RS, Cutter CJ, Moore BA, Barry DT, O'Connor PG. Primary care-based buprenorphine 
taper vs maintenance therapy for prescription opioid dependence: a randomized clinical trial. JAMA internal medicine. 
2014;174(12):1947-54. doi: 10.1001/jamainternmed.2014.5302. PubMed PMID: 25330017. 
2. 
Hartwell KJ, Back SE, McRae-Clark AL, Shaftman SR, Brady KT. Motives for using: a comparison of prescription 
opioid, marijuana and cocaine dependent individuals. Addictive behaviors. 2012;37(4):373-8. doi: 
10.1016/j.addbeh.2011.11.014. PubMed PMID: 22284583; PMCID: 3288828. 
3. 
Barth KS, Maria MM, Lawson K, Shaftman S, Brady KT, Back SE. Pain and motives for use among non-treatment 
seeking individuals with prescription opioid dependence. The American journal on addictions / American Academy of 
Psychiatrists in Alcoholism and Addictions. 2013;22(5):486-91. doi: 10.1111/j.1521-0391.2013.12038.x. PubMed PMID: 
23952895; PMCID: 3748383. 
4. 
McCauley JL, Mercer MA, Barth KS, Brady KT, Back SE. Pain management perceptions among prescription 
opioid dependent individuals. Drug and alcohol dependence. 2014;142:354-8. doi: 10.1016/j.drugalcdep.2014.06.024. 
PubMed PMID: 25034899; PMCID: 4127153. 
5. 
Northrup TF, Stotts AL, Green C, Potter JS, Marino EN, Walker R, Weiss RD, Trivedi M. Opioid withdrawal, 
craving, and use during and after outpatient buprenorphine stabilization and taper: a discrete survival and growth mixture 
model. Addictive behaviors. 2015;41:20-8. doi: 10.1016/j.addbeh.2014.09.021. PubMed PMID: 25282598; PMCID: 
4252696. 
6. 
Tsui JI, Anderson BJ, Strong DR, Stein MD. Craving predicts opioid use in opioid-dependent patients initiating 
buprenorphine treatment: a longitudinal study. The American journal of drug and alcohol abuse. 2014;40(2):163-9. doi: 
10.3109/00952990.2013.848875. PubMed PMID: 24521036. 
7. 
Borckardt JJ, Smith AR, Reeves ST, Weinstein M, Kozel FA, Nahas Z, Shelley N, Branham RK, Thomas KJ, 
George MS. Fifteen minutes of left prefrontal repetitive transcranial magnetic stimulation acutely increases thermal pain 
thresholds in healthy adults. Pain research & management : the journal of the Canadian Pain Society = journal de la 
societe canadienne pour le traitement de la douleur. 2007;12(4):287-90. PubMed PMID: 18080048; PMCID: 2670740. 
8. 
Mylius V, Borckardt JJ, Lefaucheur JP. Noninvasive cortical modulation of experimental pain. Pain. 
2012;153(7):1350-63. doi: 10.1016/j.pain.2012.04.009. PubMed PMID: 22633979. 
9. 
Borckardt JJ, Reeves ST, Weinstein M, Smith AR, Shelley N, Kozel FA, Nahas Z, Byrne KT, Morgan K, George 
MS. Significant analgesic effects of one session of postoperative left prefrontal cortex repetitive transcranial magnetic 
stimulation: a replication study. Brain stimulation. 2008;1(2):122-7. doi: 10.1016/j.brs.2008.04.002. PubMed PMID: 
19759838; PMCID: 2744083. 
10. 
Borckardt JJ, Reeves ST, Kotlowski P, Abernathy JH, Field LC, Dong L, Frohman H, Moore H, Ryan K, Madan A, 
George MS. Fast left prefrontal rTMS reduces post-gastric bypass surgery pain: findings from a large-scale, double-blind, 
sham-controlled clinical trial. Brain stimulation. 2014;7(1):42-8. PubMed PMID: 24527503. 

 
 
 
16 of  19 
11. 
Borckardt JJ, Nahas ZH, Teal J, Lisanby SH, McDonald WM, Avery D, Durkalski V, Pavlicova M, Long JM, 
Sackeim HA, George MS. The painfulness of active, but not sham, transcranial magnetic stimulation decreases rapidly 
over time: results from the double-blind phase of the OPT-TMS Trial. Brain stimulation. 2013;6(6):925-8. doi: 
10.1016/j.brs.2013.04.009. PubMed PMID: 23769413; PMCID: 3819406. 
12. 
Short EB, Borckardt JJ, Anderson BS, Frohman H, Beam W, Reeves ST, George MS. Ten sessions of adjunctive 
left prefrontal rTMS significantly reduces fibromyalgia pain: a randomized, controlled pilot study. Pain. 2011;152(11):2477-
84. doi: 10.1016/j.pain.2011.05.033. PubMed PMID: 21764215; PMCID: 3199360. 
13. 
Umezaki Y, Badran BW, Gonzales TS, George MS. Daily left prefrontal repetitive transcranial magnetic 
stimulation for medication-resistant burning mouth syndrome. International journal of oral and maxillofacial surgery. 2015. 
doi: 10.1016/j.ijom.2015.04.008. PubMed PMID: 25979192. 
14. 
Bellamoli E, Manganotti P, Schwartz RP, Rimondo C, Gomma M, Serpelloni G. rTMS in the treatment of drug 
addiction: an update about human studies. Behavioural neurology. 2014;2014:815215. doi: 10.1155/2014/815215. 
PubMed PMID: 24803733; PMCID: 4006612. 
15. 
Gorelick DA, Zangen A, George MS. Transcranial magnetic stimulation in the treatment of substance addiction. 
Annals of the New York Academy of Sciences. 2014;1327:79-93. doi: 10.1111/nyas.12479. PubMed PMID: 25069523; 
PMCID: 4206564. 
16. 
Wing VC, Barr MS, Wass CE, Lipsman N, Lozano AM, Daskalakis ZJ, George TP. Brain stimulation methods to 
treat tobacco addiction. Brain stimulation. 2013;6(3):221-30. doi: 10.1016/j.brs.2012.06.008. PubMed PMID: 22809824. 
17. 
Barr MS, Farzan F, Wing VC, George TP, Fitzgerald PB, Daskalakis ZJ. Repetitive transcranial magnetic 
stimulation and drug addiction. International review of psychiatry. 2011;23(5):454-66. doi: 
10.3109/09540261.2011.618827. PubMed PMID: 22200135. 
18. 
Mishra BR, Nizamie SH, Das B, Praharaj SK. Efficacy of repetitive transcranial magnetic stimulation in alcohol 
dependence: a sham-controlled study. Addiction. 2010;105(1):49-55. doi: 10.1111/j.1360-0443.2009.02777.x. PubMed 
PMID: 20078462. 
19. 
Dinur-Klein L, Dannon P, Hadar A, Rosenberg O, Roth Y, Kotler M, Zangen A. Smoking cessation induced by 
deep repetitive transcranial magnetic stimulation of the prefrontal and insular cortices: a prospective, randomized 
controlled trial. Biological psychiatry. 2014;76(9):742-9. doi: 10.1016/j.biopsych.2014.05.020. PubMed PMID: 25038985. 
20. 
Terraneoa AL, Lorenzo;  Saladinie, Marina;  Ermanie,Mario; Boncib, Antonello; Gallimbertia, Luigi. Transcranial 
magnetic stimulation of dorsolateral prefrontal cortex reduces cocaine use: A pilot study. European 
Neuropsychopharmacology. 2015. doi: 10.1016/j.euroneuro.2015.11.011. 
21. 
McHugh RK, Fitzmaurice GM, Carroll KM, Griffin ML, Hill KP, Wasan AD, Weiss RD. Assessing craving and its 
relationship to subsequent prescription opioid use among treatment-seeking prescription opioid dependent patients. Drug 
and alcohol dependence. 2014;145:121-6. doi: 10.1016/j.drugalcdep.2014.10.002. PubMed PMID: 25454409; PMCID: 
4254575. 
22. 
Back SE, Gros DF, McCauley JL, Flanagan JC, Cox E, Barth KS, Brady KT. Laboratory-induced cue reactivity 
among individuals with prescription opioid dependence. Addictive behaviors. 2014;39(8):1217-23. doi: 
10.1016/j.addbeh.2014.04.007. PubMed PMID: 24813546; PMCID: 4059191. 
23. 
Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Annals of the Academy of 
Medicine, Singapore. 1994;23(2):129-38. PubMed PMID: 8080219. 
24. 
Melzack R. The short-form McGill Pain Questionnaire. Pain. 1987;30(2):191-7. PubMed PMID: 3670870. 
25. 
SAMHSA. Behavioral health trends in the United States: Results from the 2014 National Survey on Drug Use and 
Health. Substance Abuse and Mental Health Services Administration, 2015 [Internet]. 2017. 
26. 
Health TfA. The Facts Hurt: A State-By-State Injury Prevention Policy Report. http://www.healthyamericans.org/: 
2015 June2015. Report No. 
27. 
Birnbaum HG, White AG, Schiller M, Waldman T, Cleveland JM, Roland CL. Societal costs of prescription opioid 
abuse, dependence, and misuse in the United States. Pain medicine. 2011;12(4):657-67. doi: 10.1111/j.1526-
4637.2011.01075.x. PubMed PMID: 21392250. 
28. 
Pascual-Leone A, Tormos JM, Keenan J, Tarazona F, Canete C, Catala MD. Study and modulation of human 
cortical excitability with transcranial magnetic stimulation. Journal of clinical neurophysiology : official publication of the 
American Electroencephalographic Society. 1998;15(4):333-43. PubMed PMID: 9736467. 
29. 
Mayberg HS. Limbic-cortical dysregulation: a proposed model of depression. The Journal of neuropsychiatry and 
clinical neurosciences. 1997;9(3):471-81. doi: 10.1176/jnp.9.3.471. PubMed PMID: 9276848. 
30. 
Li X, Nahas Z, Kozel FA, Anderson B, Bohning DE, George MS. Acute left prefrontal transcranial magnetic 
stimulation in depressed patients is associated with immediately increased activity in prefrontal cortical as well as 
subcortical regions. Biological psychiatry. 2004;55(9):882-90. doi: 10.1016/j.biopsych.2004.01.017. PubMed PMID: 
15110731. 
31. 
George MS, Lisanby SH, Avery D, McDonald WM, Durkalski V, Pavlicova M, Anderson B, Nahas Z, Bulow P, 
Zarkowski P, Holtzheimer PE, 3rd, Schwartz T, Sackeim HA. Daily left prefrontal transcranial magnetic stimulation therapy 

 
 
 
17 of  19 
for major depressive disorder: a sham-controlled randomized trial. Archives of general psychiatry. 2010;67(5):507-16. doi: 
10.1001/archgenpsychiatry.2010.46. PubMed PMID: 20439832. 
32. 
McDonald WM, Durkalski V, Ball ER, Holtzheimer PE, Pavlicova M, Lisanby SH, Avery D, Anderson BS, Nahas Z, 
Zarkowski P, Sackeim HA, George MS. Improving the antidepressant efficacy of transcranial magnetic stimulation: 
maximizing the number of stimulations and treatment location in treatment-resistant depression. Depression and anxiety. 
2011;28(11):973-80. doi: 10.1002/da.20885. PubMed PMID: 21898711. 
33. 
Dunner DL, Aaronson ST, Sackeim HA, Janicak PG, Carpenter LL, Boyadjis T, Brock DG, Bonneh-Barkay D, 
Cook IA, Lanocha K, Solvason HB, Demitrack MA. A Multisite, Naturalistic, Observational Study of Transcranial Magnetic 
Stimulation for Patients With Pharmacoresistant Major Depressive Disorder. The Journal of clinical psychiatry. 2014. doi: 
10.4088/JCP.13m08977. 
34. 
Levkovitz Y, Isserles M, Padberg F, Lisanby SH, Bystritsky A, Xia G, Tendler A, Daskalakis ZJ, Winston JL, 
Dannon P, Hafez HM, Reti IM, Morales OG, Schlaepfer TE, Hollander E, Berman JA, Husain MM, Sofer U, Stein A, Adler 
S, Deutsch L, Deutsch F, Roth Y, George MS, Zangen A. Efficacy and safety of deep transcranial magnetic stimulation for 
major depression: a prospective multicenter randomized controlled trial. World psychiatry : official journal of the World 
Psychiatric Association. 2015;14(1):64-73. doi: 10.1002/wps.20199. PubMed PMID: 25655160. 
35. 
George MS, Raman R, Benedek DM, Pelic CG, Grammer GG, Stokes KT, Schmidt M, Spiegel C, Dealmeida N, 
Beaver KL, Borckardt JJ, Sun X, Jain S, Stein MB. A two-site pilot randomized 3 day trial of high dose left prefrontal 
repetitive transcranial magnetic stimulation (rTMS) for suicidal inpatients. Brain stimulation. 2014;7(3):421-31. doi: 
10.1016/j.brs.2014.03.006. PubMed PMID: 24731434. 
36. 
Holtzheimer PE, 3rd, McDonald WM, Mufti M, Kelley ME, Quinn S, Corso G, Epstein CM. Accelerated repetitive 
transcranial magnetic stimulation for treatment-resistant depression. Depression and anxiety. 2010;27(10):960-3. doi: 
10.1002/da.20731. PubMed PMID: 20734360; PMCID: PMC3020591. 
37. 
Baeken C, Vanderhasselt MA, Remue J, Herremans S, Vanderbruggen N, Zeeuws D, Santermans L, De Raedt 
R. Intensive HF-rTMS treatment in refractory medication-resistant unipolar depressed patients. Journal of affective 
disorders. 2013;151(2):625-31. doi: 10.1016/j.jad.2013.07.008. PubMed PMID: 23896317. 
38. 
Kober H, Mende-Siedlecki P, Kross EF, Weber J, Mischel W, Hart CL, Ochsner KN. Prefrontal-striatal pathway 
underlies cognitive regulation of craving. Proceedings of the National Academy of Sciences of the United States of 
America. 2010;107(33):14811-6. doi: 10.1073/pnas.1007779107. PubMed PMID: 20679212; PMCID: 2930456. 
39. 
Hanlon CA, Dowdle LT, Austelle CW, DeVries W, Mithoefer O, Badran BW, George MS. What goes up, can come 
down: Novel brain stimulation paradigms may attenuate craving and craving-related neural circuitry in substance 
dependent individuals. Brain research. 2015. doi: 10.1016/j.brainres.2015.02.053. PubMed PMID: 25770818. 
40. 
Sutherland MT, McHugh MJ, Pariyadath V, Stein EA. Resting state functional connectivity in addiction: Lessons 
learned and a road ahead. NeuroImage. 2012;62(4):2281-95. doi: 10.1016/j.neuroimage.2012.01.117. PubMed PMID: 
22326834; PMCID: 3401637. 
41. 
Volkow ND, Fowler JS, Wang GJ, Telang F, Logan J, Jayne M, Ma Y, Pradhan K, Wong C, Swanson JM. 
Cognitive control of drug craving inhibits brain reward regions in cocaine abusers. NeuroImage. 2010;49(3):2536-43. doi: 
10.1016/j.neuroimage.2009.10.088. PubMed PMID: 19913102; PMCID: 2818484. 
42. 
Charboneau EJ, Dietrich MS, Park S, Cao A, Watkins TJ, Blackford JU, Benningfield MM, Martin PR, Buchowski 
MS, Cowan RL. Cannabis cue-induced brain activation correlates with drug craving in limbic and visual salience regions: 
preliminary results. Psychiatry research. 2013;214(2):122-31. doi: 10.1016/j.pscychresns.2013.06.005. PubMed PMID: 
24035535; PMCID: 3904759. 
43. 
Cousijn J, Goudriaan AE, Ridderinkhof KR, van den Brink W, Veltman DJ, Wiers RW. Neural responses 
associated with cue-reactivity in frequent cannabis users. Addiction biology. 2013;18(3):570-80. doi: 10.1111/j.1369-
1600.2011.00417.x. PubMed PMID: 22264344. 
44. 
Goldman M, Szucs-Reed RP, Jagannathan K, Ehrman RN, Wang Z, Li Y, Suh JJ, Kampman K, O'Brien CP, 
Childress AR, Franklin TR. Reward-related brain response and craving correlates of marijuana cue exposure: a 
preliminary study in treatment-seeking marijuana-dependent subjects. Journal of addiction medicine. 2013;7(1):8-16. doi: 
10.1097/ADM.0b013e318273863a. PubMed PMID: 23188041; PMCID: 3567235. 
45. 
Li X, Malcolm RJ, Huebner K, Hanlon CA, Taylor JJ, Brady KT, George MS, See RE. Low frequency repetitive 
transcranial magnetic stimulation of the left dorsolateral prefrontal cortex transiently increases cue-induced craving for 
methamphetamine: a preliminary study. Drug and alcohol dependence. 2013;133(2):641-6. doi: 
10.1016/j.drugalcdep.2013.08.012. PubMed PMID: 24028801; PMCID: 4196687. 
46. 
Taylor JJ, Borckardt JJ, Canterberry M, Li X, Hanlon CA, Brown TR, George MS. Naloxone-reversible modulation 
of pain circuitry by left prefrontal rTMS. Neuropsychopharmacology : official publication of the American College of 
Neuropsychopharmacology. 2013;38(7):1189-97. doi: 10.1038/npp.2013.13. PubMed PMID: 23314221; PMCID: 3656361. 
47. 
Taylor JJ, Borckardt JJ, George MS. Endogenous opioids mediate left dorsolateral prefrontal cortex rTMS-
induced analgesia. Pain. 2012;153(6):1219-25. doi: 10.1016/j.pain.2012.02.030. PubMed PMID: 22444187; PMCID: 
3530383. 

 
 
 
18 of  19 
48. 
Breedlove JL, A; Back, SE; Borckardt, JJ; Taylor,  JJ; Badran, BW; Sahlem, GL; Rostami, R; Brady, KT; George, 
MS; and Hanlon, CA., editor. 10 Hz rTMS May Reduce Pain and Craving in Prescription Opiate Dependent Individuals: a 
pilot study. Annual Meeting of the Society of Biological Psychiatry; May 14th-16th, 2015; Toronto, On. 
49. 
Staahl C, Reddy H, Andersen SD, Arendt-Nielsen L, Drewes AM. Multi-modal and tissue-differentiated 
experimental pain assessment: reproducibility of a new concept for assessment of analgesics. Basic Clin Pharmacol 
Toxicol. 2006;98(2):201-11. Epub 2006/02/01. doi: 10.1111/j.1742-7843.2006.pto_211.x. PubMed PMID: 16445596. 
50. 
Borckardt JJ, Nahas Z, Koola J, George MS. Estimating resting motor thresholds in transcranial magnetic 
stimulation research and practice: a computer simulation evaluation of best methods. The journal of ECT. 2006;22(3):169-
75. doi: 10.1097/01.yct.0000235923.52741.72. PubMed PMID: 16957531. 
51. 
Beam W, Borckardt JJ, Reeves ST, George MS. An efficient and accurate new method for locating the F3 
position for prefrontal TMS applications. Brain stimulation. 2009;2(1):50-4. doi: 10.1016/j.brs.2008.09.006. PubMed PMID: 
20539835; PMCID: 2882797. 
52. 
Li X, Hartwell KJ, Owens M, Lematty T, Borckardt JJ, Hanlon CA, Brady KT, George MS. Repetitive transcranial 
magnetic stimulation of the dorsolateral prefrontal cortex reduces nicotine cue craving. Biological psychiatry. 
2013;73(8):714-20. doi: 10.1016/j.biopsych.2013.01.003. PubMed PMID: 23485014; PMCID: 3615051. 
53. 
Borckardt JJ, Walker J, Branham RK, Rydin-Gray S, Hunter C, Beeson H, Reeves ST, Madan A, Sackeim H, 
George MS. Development and evaluation of a portable sham transcranial magnetic stimulation system. Brain stimulation. 
2008;1(1):52-9. doi: 10.1016/j.brs.2007.09.003. PubMed PMID: 19424444; PMCID: 2677803. 
54. 
Arana AB, Borckardt JJ, Ricci R, Anderson B, Li X, Linder KJ, Long J, Sackeim HA, George MS. Focal electrical 
stimulation as a sham control for repetitive transcranial magnetic stimulation: Does it truly mimic the cutaneous sensation 
and pain of active prefrontal repetitive transcranial magnetic stimulation? Brain stimulation. 2008;1(1):44-51. doi: 
10.1016/j.brs.2007.08.006. PubMed PMID: 19424459; PMCID: 2678025. 
55. 
Garland EL, Froeliger B, Howard MO. Allostatic dysregulation of natural reward processing in prescription opioid 
misuse: autonomic and attentional evidence. Biological psychology. 2015;105:124-9. doi: 
10.1016/j.biopsycho.2015.01.005. PubMed PMID: 25603284; PMCID: PMC4336801. 
56. 
Garland EL, Howard MO. Opioid attentional bias and cue-elicited craving predict future risk of prescription opioid 
misuse among chronic pain patients. Drug and alcohol dependence. 2014;144:283-7. doi: 
10.1016/j.drugalcdep.2014.09.014. PubMed PMID: 25282309; PMCID: PMC4252536. 
57. 
Tompkins DA, Bigelow GE, Harrison JA, Johnson RE, Fudala PJ, Strain EC. Concurrent validation of the Clinical 
Opiate Withdrawal Scale (COWS) and single-item indices against the Clinical Institute Narcotic Assessment (CINA) opioid 
withdrawal instrument. Drug and alcohol dependence. 2009;105(1-2):154-9. doi: 10.1016/j.drugalcdep.2009.07.001. 
PubMed PMID: 19647958; PMCID: 2774236. 
58. 
Gros DF, Milanak ME, Brady KT, Back SE. Frequency and severity of comorbid mood and anxiety disorders in 
prescription opioid dependence. The American journal on addictions / American Academy of Psychiatrists in Alcoholism 
and Addictions. 2013;22(3):261-5. doi: 10.1111/j.1521-0391.2012.12008.x. PubMed PMID: 23617869. 
59. 
Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC. The 
Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic 
psychiatric interview for DSM-IV and ICD-10. The Journal of clinical psychiatry. 1998;59 Suppl 20:22-33;quiz 4-57. 
PubMed PMID: 9881538. 
60. 
Kroenke K, Spitzer, RL, Williams,  JB. The PHQ-9: Validity of a Brief Depression Severity Measure. J GEN 
INTERN MED. 2001;16:606±13. 
61. 
Sobell LC aSM. Timeline Follow-Back.  Measuring Alcohol Consumption1992. p. 41-72. 
62. 
McGirr A, Van den Eynde F, Tovar-Perdomo S, Fleck MP, Berlim MT. Effectiveness and acceptability of 
accelerated repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant major depressive disorder: an open 
label trial. Journal of affective disorders. 2015;173:216-20. doi: 10.1016/j.jad.2014.10.068. PubMed PMID: 25462419. 
63. 
Herremans SC, De Raedt R, Van Schuerbeek P, Marinazzo D, Matthys F, De Mey J, Baeken C. Accelerated HF-
rTMS Protocol has a Rate-Dependent Effect on dACC Activation in Alcohol-Dependent Patients: An Open-Label 
Feasibility Study. Alcoholism, clinical and experimental research. 2016;40(1):196-205. doi: 10.1111/acer.12937. PubMed 
PMID: 26727534. 
64. 
Herremans SC, Van Schuerbeek P, De Raedt R, Matthys F, Buyl R, De Mey J, Baeken C. The Impact of 
Accelerated Right Prefrontal High-Frequency Repetitive Transcranial Magnetic Stimulation (rTMS) on Cue-Reactivity: An 
fMRI Study on Craving in Recently Detoxified Alcohol-Dependent Patients. PloS one. 2015;10(8):e0136182. doi: 
10.1371/journal.pone.0136182. PubMed PMID: 26295336; PMCID: PMC4546410. 
65. 
Wassermann EM. Risk and safety of repetitive transcranial magnetic stimulation: report and 
suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial 
Magnetic Stimulation, June 5-7, 1996. Electroencephalography and clinical neurophysiology. 1998;108(1):1-16. 
Epub 1998/02/25. PubMed PMID: 9474057. 

 
 
 
19 of  19 
66. 
Janicak P, Dokucu ME. Transcranial magnetic stimulation for the treatment of major depression. Neuropsychiatric 
disease and treatment. 2015:1549. doi: 10.2147/ndt.s67477. 
65. Heckathorn, D.D. (1997). Respondent-driven sampling: A new approach to the study of hidden populations. Social 
Problems, 44(2), 174-199.  
66. Lejuez CW, Read JP, Kahler CW, Richards JB, Ramsey SE, Stuart GL, Strong DR, Brown RA. Evaluation of a 
behavioral measure of risk taking: the Balloon Analogue Risk Task (BART). Journal of experimental psychology Applied. 
2002;8(2):75-84. PubMed PMID: 12075692. 
67. Johnson, M. W., Bickel, W. K., Baker, F., Moore, B. A., Badger, G. J., & Budney, A. J. (2010). Delay Discounting in 
Current and Former Marijuana-Dependent Individuals. Experimental and Clinical Psychopharmacology, 18(1), 99–107. 
http://doi.org/10.1037/a0018333 
68. Handelsman L, Cochrane KJ, Aronson MJ, Ness R, Rubinstein KJ, Kanof PD. Two New Rating Scales for Opiate 
Withdrawal. 1987. American Journal of Alcohol Abuse 13, 293-308. 
69. Patton JH, Stanford MS, and Barratt ES (1995). Factor structure of the Barratt Impulsiveness Scale. Journal of Clinical 
Psychology, 51, 768-774.   PubMed ID 8778124 
70.  Buysse DJ, Reynolds CF, 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new 
instrument for psychiatric practice and research. Psychiatry Res. 1989;28(2):193–213.  
71. Reilly MC, Zbrozek AS, Dukes E: The validity and reproducibility of a work productivity and activity impairment 
measure.  PharmacoEconomics 1993; 4(5):353-365. 
72. McLellan AT, Luborsky L, Woody GE, O’Brien CP (1980). An improved diagnostic evaluation instrument for substance 
abuse patients. The Addiction Severity Index. Journal of Nervous and Mental Disorders, 168 (1):26-33. 
73. Ware, J.E., Jr., and Sherbourne, C. D. “The MOS 36-Item Short-Form Health Survey (SF-36): I. Conceptual 
Framework and item Selection,” Medical Care, 30:473-483, 1992.