Clinical trial NCT03605342
Conditions: Post-Traumatic Stress Disorders Opiate Use Disorder
Keywords: PTSD Opiate Use Disorder
Sponsor: VA Office of Research and Development
Start date: 2018-10-01; Completion date: 2023-04-14
Enrollment: 38 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this study is to test a standard psychotherapy for PTSD in Veterans who also suffer from Opiate Use Disorder (OUD). Specifically, this study will test whether Cognitive Processing Therapy (CPT)-C is more effective in treating PTSD, compared to a control group (Individual Drug Counseling (IDC); which approximates treatment as usual), among Veterans with PTSD and comorbid OUD who are maintained on buprenorphine.

The study has three phases. In Phase I: induction to buprenorphine/naloxone (BUP/NLX) maintenance. Phase II: treatment. During this phase participants will be randomly assigned to CPT-C or IDC for 12 weeks. They will be seen weekly for psychotherapy and also regularly (weekly, then biweekly, then monthly) for buprenorphine management, symptom evaluation, and medication refill. After completing treatment participants will be referred to a buprenorphine clinic for ongoing care. Phase III: follow-up.

Approximately 160 male and female Veterans (18-65 years old) with PTSD and comorbid opiate use disorder (OUD) will be enrolled in this study. Recruitment will be through VA clinics, word-of-mouth, referrals from area programs and by advertisement. Veterans who are interested will complete a brief pre-screening and detailed in-person screening. After completing the screening process, all eligible participants will be started on buprenorphine maintenance and once withdrawal symptoms are stabilized, participants will be randomly assigned to 1 of 2 conditions (CPT-C or IDC) for 12 weeks. Veterans who are already on BUP/NLX will be allowed to participate and will start at Phase II of the study, after completing the screening.

Detailed description:
The purpose of this study is to test whether Cognitive Processing Therapy (CPT-C) is more effective than Individual Drug Counseling (IDC), which is standard counseling, for the treatment of PTSD among Veterans with PTSD and comorbid opioid use disorder who are also maintained on buprenorphine. The investigators propose to conduct a randomized, controlled trial and Veterans (n=160) diagnosed with PTSD and comorbid OUD will be randomized to one of 2 groups: (a) buprenorphine and CPT-C or (b) buprenorphine and IDC (treatment as usual).

Primary Aim 1:.To test whether CPT-C is more effective than IDC in treating symptoms of PTSD among Veterans with OUD maintained on buprenorphine. PTSD symptoms will be measured using the PTSD Checklist - Military version (PCL-5) and confirmed by the Clinician Administered PTSD Scale using the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria (CAPS-5).

Secondary Aim 1: To test whether CPT-C is more effective than IDC in reducing opioid use among Veterans with PTSD and comorbid OUD maintained on buprenorphine. Opioid use will be measured using the Timeline Follow-back (TLFB) and confirmed by urine toxicology results.

Exploratory Aims: To examine if treatment groups differ in 1) retention, measured by days in treatment, 2) psychosocial functioning, measured by the Veterans RAND 12-Item Short Form Health Survey (VR-12), 3) sleep as measured by the Insomnia Severity Index (ISI), since sleep disturbance is a hallmark of PTSD and during early abstinence from opioids, and 4) Because of the high comorbidity between PTSD and chronic pain the investigators will explore this relationship and will measure pain intensity (measured by the Numeric Rating Scale (NRS), and functional impairment using the Patient-Reported Outcomes Measurement Information System (PROMIS-29) longitudinally over the course of treatment. Follow up will be conducted 1 and 3 months after completion of the study to evaluate durability of effect on PTSD symptoms (measured as changes in PTSD symptoms), opioid use and treatment utilization.

This study will be a randomized, open-label clinical trial. The study has three phases. In Phase I: induction to buprenorphine/naloxone (BUP/NLX) maintenance. Phase II: treatment. During this phase participants will be randomly assigned to CPT-C or IDC for 12 weeks. They will be seen weekly for psychotherapy and also regularly (weekly, then biweekly, then monthly) for buprenorphine management, symptom evaluation, and medication refill. After completing treatment participants will be referred to a buprenorphine clinic for ongoing care. Phase III: follow-up.

Approximately 160 male and female Veterans (18-65 years old) with PTSD and comorbid opiate use disorder (OUD) will be enrolled in this study. Recruitment will be through VA clinics, word-of-mouth, referrals from area programs and by advertisement. Veterans who are interested will complete a brief pre-screening and detailed in-person screening (including: consent, lab work, interview with clinician including the Structured Clinical Interview for DSM-5 (SCID-5) and Clinician Administered PTSD Scale for DSM-5 (CAPS-5), medical and psychiatric history). After completing the screening process, all eligible participants will be started on buprenorphine maintenance and once withdrawal symptoms are stabilized, participants will be randomly assigned to 1 of 2 conditions (CPT-C or IDC) for 12 weeks. Veterans who are already on BUP/NLX will be allowed to participate and will start at Phase II of the study, after completing the screening. The investigators will use mixed effects models to assess changes in PTSD symptoms and opiate use over time. Treatments will be used as between-subject factors and time (in weeks) will be used as a within-subject factor. The primary outcome variables will be PTSD symptoms as measured by the PCL-5 and CAPS scales. The secondary outcome variables will be frequency of opiate use generated from the TLFB and confirmed with urine toxicology results at each medication visit (weeks 1-4, 6,8, 12) and follow-up.

Potential benefits of participation in this study may include a reduction in PTSD symptoms. However, there is no guarantee or promise that participants will receive any benefit from participation in this study.

Since 11 September 2001, more than 1.5 million Service Members have deployed more than 2 million times in support of combat operations in Afghanistan and Iraq. One of the signature injuries from these operations is PTSD. Various reports of the post-deployment health-related needs estimated that 20% of Veterans returning from deployment will have symptoms of PTSD or related behavioral health conditions. In addition, the prescription opioid epidemic has seriously affected Veterans, and Veterans with PTSD are more likely to abuse opioids and to have high-risk behaviors. Nevertheless, treating comorbid PTSD and OUD has not been systematically tested. This study proposes to test an evidence based psychotherapy for PTSD vs. individual drug counseling in Veterans given opioid maintenance treatment who have both PTSD and OUD.

Arms: arm 1: Buprenorphine induction and stabilization for all participants (x1 week). Participants will be started at a dose of 2mg/0.5 mg BUP/NLX and this dose will be increased as needed for stabilization of opioid withdrawal symptoms up to 24 mg per day, then CPT-C for 12 weeks. arm 2: Buprenorphine induction and stabilization for all participants (x1 week). Participants will be started at a dose of 2mg/0.5 mg BUP/NLX and this dose will be increased as needed for stabilization of opioid withdrawal symptoms up to 24 mg per day, then IDC for 12 weeks
Interventions: intervention 1: Buprenorphine intervention 2: Cognitive Processing Therapy (CPT) intervention 3: Individual Drug Counseling (IDC)
Intervention descriptions: intervention 1: Participants will be started at a dose of 2mg/0.5 mg BUP/NLX and this dose will be increased as needed for stabilization of opioid withdrawal symptoms up to 24 mg per day, which is standard practice. intervention 2: CPT-C is a manualized, 12-session 1:1 cognitive therapy that has been designed for patients with PTSD. In this study the sessions will be conducted weekly. CPT-C uses Socratic questioning targeting distorted cognitions such as self-blame, hindsight bias, and other guilt cognitions. CPT-C is focused on the cognitive components of the therapy without exposure. intervention 3: IDC will serve as the control group. The current standard of treatment for Veterans entering buprenorphine maintenance is to do drug counseling. Standard counseling is the primary means to achieve goals. IDC uses a semi-structured, time-limited addictions-counseling model in a 1:1 setting. The IDC manual provides an organized, concise version of what is currently practiced by most addiction counselors.

Protocol documents:
Prot_SAP_000.pdf: 
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1.  PRINCIPAL INVESTIGATOR:   Ismene Petrakis, MD 
 
Authorized Prescribers: Ismene Petrakis, MD, Gihyun Yoon, MD  
 
2.  PROJECT TITLE: Optimal Treatment of Veterans with PTSD and Comorbid Opiate Use Disorder (OUD) 
 
3. PURPOSE: 
Posttraumatic stress disorder (PTSD) is a serious psychiatric disorder affecting Veterans, particularly 
those from the recent conflicts.[1]  PTSD is complicated by high rates of comorbidity with other disorders, 
notably substance use disorders.[2] Given the clinical need for the treatment of PTSD, the Veterans 
Administration (VA) and the Department of Defense (DoD) have invested in making access to evidenced based 
treatments a priority. This includes Cognitive Processing Therapy (CPT) which is an integration of 
psychoeducation, cognitive therapy and imaginal exposure therapy. CPT  was rolled out nationally in a large 
dissemination project by the VA and the DoD as one of the gold standard treatments for PTSD. [Recently, the 
VA/DoD Practice Guidelines for The Management of Posttraumatic Stress Disorder and Acute Stress Disorder 
(2017)[4] have been released and recommend behavioral interventions, specifically trauma focused manual-
driven therapy, as first line of treatment.[5] However, the effectiveness of the treatments remain to be 
demonstrated in Veterans with comorbidities. This gap is particularly significant for those Veterans with 
opioid use disorder (OUD), which occurs at a particularly high rate among Veterans with PTSD.] 
Recently a national opioid epidemic has emerged as a major public health problem in the United 
States. This epidemic has had a significant effect on Veterans, particularly those from the recent conflicts[6], 
prompting a high level of public awareness. Prescription opioid use dramatically increased, in part because of 
the increasing emphasis on adequate management of pain, with changes in prescribing patterns of physicians 
and easier availability of opioids on the internet.[7] The rates of prescribed opioids increased several fold over 
10 years (2001-2009) among military personnel, a factor which was found to undermine military readiness.[8]  
Veterans with mental health disorders, notably PTSD, are more likely to experience chronic pain, to be 
prescribed opioids, more likely to participate in high risk behaviors and more likely to have adverse outcomes 
[9] including more susceptibility to developing substance use disorders.[10]  As awareness of the prescription 
opioid epidemic increased among health professionals, availability of prescription opioids decreased and in its 
wake there has been an alarming increase in heroin use. The rates of reported heroin use has doubled between 
2006-2012[11] and there is a fourfold increase in heroin overdose deaths between 2000 and 2014.[12] 
Buprenorphine is a partial µ-opioid agonist, that has been shown to be effective as a first line treatment 
for OUD.[13] Office based opioid substitution therapy is a standard of care within the VA and its utilization 
since FY15 is part of the mental health performance measures [14]. Unfortunately, the efficacy of treatments for 
comorbid conditions among those maintained on buprenorphine has not been examined.  To date no studies 
have demonstrated that evidence-based therapies for PTSD also work in those with comorbid OUD. 
Therefore, this proposed application will specifically address this gap in the treatment of co-morbid PTSD 
and OUD. 
The purpose of this study is to test whether CPT is more effective than Individual Drug Counseling 
(IDC), which is standard counseling, for the treatment of PTSD among Veterans and civilians with PTSD and 
comorbid opioid use disorder who are also maintained on buprenorphine. We propose to conduct a 
randomized, controlled trial among Veterans and civilians (n=160) diagnosed with PTSD and comorbid OUD 
will be randomized to one of 2 groups: (a) buprenorphine and CPT  or (b) buprenorphine and IDC (treatment 
as usual).  
 
Specific Aims:  
Primary Aim 1:.To test whether CPT is more effective than IDC in treating symptoms of PTSD among 
Veterans and civilians with OUD maintained on buprenorphine. PTSD symptoms will be measured using the 
PTSD Checklist – Military version (PCL-5), and confirmed by the Clinician Administered PTSD Scale using 
the DSM-5 criteria (CAPS-5).  
 
Secondary Aim 1: To test whether CPT- is more effective than IDC in reducing opioid use among Veterans 
and civilians with PTSD and comorbid OUD maintained on buprenorphine. Opioid use will be measured using 
the Timeline Follow-back (TLFB) and confirmed by urine toxicology results. 


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Exploratory Aims: To examine if treatment groups differ in 1) retention, measured by days in treatment, 2) 
psychosocial functioning, measured by the participants RAND 12-Item Short Form Health Survey (VR-12), 3) 
sleep as measured by the Insomnia Severity Index (ISI), since sleep disturbance is a hallmark of PTSD and 
during early abstinence from opioids, and 4) Because of the high comorbidity between PTSD and chronic pain 
we will explore this relationship and will measure pain intensity (measured by the Numeric Rating Scale 
(NRS), and functional impairment using the PROMIS-29 (Patient-Reported Outcomes Measurement 
Information System)  longitudinally over the course of treatment.  Follow up will be conducted 1 and 3 months 
after completion of the study to evaluate durability of effect on PTSD symptoms (measured as changes in 
PTSD symptoms), opioid use and treatment utilization.  
 
4-5. BACKGROUND AND SIGNIFICANCE: 
This proposal was originally developed in collaboration with the Consortium to Alleviate PTSD (CAP) (Dr. Alan 
Peterson Director and Dr. Terrence Keane co-Director), underwent scientific review and was proposed for 
funding. However, CAP was unable to fund it as buprenorphine treatment is of limited importance for active-
duty personnel. The CAP leadership group encouraged our group to send this application to the VA as it has 
great clinical relevance for the VA and for Veterans, although CAP is no longer involved in this proposal. 
Please see the attached letter of support.  
 
A. Posttraumatic stress disorder (PTSD)  
i) PTSD is a serious psychiatric disorder that can occur after the experience of a traumatic event. 
Symptoms include intrusive memories associated with the traumatic event, avoidance of stimuli related to the 
event, negative changes in mood and cognition and changes in arousal and reactivity. Population surveys have 
estimated that the prevalence of PTSD is between 4.8% (National Epidemiologic Survey on Alcohol and 
Related Conditions [NESARC]) and 7.8% of the general population (Epidemiologic Catchment Area 
[ECA]).[15]  PTSD is an important issue for military personnel and Veterans, particularly those from the recent 
conflicts, as rates among military personnel are much higher than those in the general population. Among male 
and female soldiers age 18 or older returning from Iraq and Afghanistan, rates range from 9% shortly after 
returning from deployment to 31% a year later.[16] A review of several studies that evaluated rates of PTSD in 
those who served in the recent conflicts found prevalence rates of adult men and women previously deployed 
ranging from 5% to 20% for those who do not seek treatment, and around 50% for those who seek 
treatment.[17]  Among those returning from the recent conflicts, those at highest risk included youngest 
Veterans, under 25 years of age.[18]  Vietnam Veterans also report high lifetime rates of PTSD ranging from 
10% to 31%.[19] It should be noted that PTSD is the third most prevalent psychiatric diagnosis among Veterans 
using VA services,[20] and Veterans from recent conflicts have enrolled in VA care at historically high rates, 
making this of high clinical importance to the VA nationally.[18] 
PTSD is complicated by high rates of comorbidity with other disorders, and it has been hypothesized 
that comorbidity is the norm rather than the exception.  Substance use disorders are among the most common 
to co-occur.[2] Administrative date from VA nationally, indicates that there are approximately 640,000 
Veterans who have the diagnosis of PTSD; of those 70,000 Veterans (19% of those with PTSD diagnosis) have a 
substance use disorder (another almost 70,000 have alcohol use disorder without another substance use 
disorder) (personal communication, B Rosenheck). These data most likely represent lower-than-actual 
prevalence rates, as administrative data have been shown to underreport diagnoses in certain disorders by up 
to a factor of 5 (personal communication, B Rosenheck). The rates of substance use disorders may be higher 
among Veterans from the recent conflicts.  When surveying Veterans on their “psychosocial concerns”, 
substance abuse is reported by 25% of Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF) 
Veterans.[21]  Rates of comorbidity among the recent returnees are higher in more vulnerable populations: 
among those who suffered from combat injuries [22] and among homeless Veterans.[23] In examining opioid 
use disorders (OUD) specifically, there is evidence of high comorbidity. Having a diagnosis of PTSD is 
associated with high rates of opioid prescription use and high-risk opioid use.[18] Among those with opioid 
dependence, PTSD prevalence has been as high as 33%.[24]  Comorbidity has been shown to lead to worse 
outcomes than when either disorder occurs alone. For example, those with comorbid conditions have more 
health and social issues, have greater symptom severity, and higher utilization of services (including inpatient) 
than those without comorbidity.[25] Prescription opioid use is associated with PTSD symptoms severity[26] 
and the diagnosis of PTSD is associated with higher doses of opioid treatment among Veterans treated with 
opioid substitution.[27]  


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There are very few studies and even fewer evidence-based guidelines for treatment of comorbid PTSD 
and opioid use disorders.[28]  Several treatments are available for these disorders when they occur without 
comorbidity, but there is evidence that the presence of comorbidity may alter the efficacy of the treatment.[29] 
Therefore testing evidence based treatments in real world clinical patients is of great importance.  Further, 
treatment is still compartmentalized into specialty PTSD clinics and specialty substance abuse clinics and 
clinical staff often require sobriety for some predetermined length of time before entry into specialty PTSD 
clinics. This suggests that those Veterans treated primarily in substance abuse clinics may not have access to 
evidence based treatments for PTSD and therefore do not get adequate treatment for PTSD. 
PTSD is an important clinical issue and health care priority for the VA as Veterans from recent 
conflicts have enrolled in VA care at historically high rates. The high rates of comorbid disorders such as 
OUDs must be accounted for in designing clinical care for Veterans with PTSD. 
 
ii) Cognitive Processing Therapy as Treatment for PTSD 
 
Cognitive Processing Therapy (CPT)[3] was developed for the treatment of PTSD among rape victims.  It is 
based on an information processing theory of PTSD and is an integration of psychoeducation, cognitive therapy 
and imaginal exposure therapy. [CPT addresses the influence of traumatic events on an individual’s thoughts, 
and how that affects cognitive, emotional, and behavioral responses (e.g., Resick & Schnicke, 1992[3]). CPT has 
been found to improve PTSD symptoms as well as associated symptoms (depression, anxiety, guilt, shame), 
day-to-day functioning.[30]  and is effective in both individual and group therapy formats[31];  improvements 
in PTSD symptoms appear to be sustained over time.[32] CPT has been successfully used among military 
Veterans,[33] [34, 35]and was rolled out nationally in a large dissemination project by the U.S. Department of 
Veterans Affairs and the U.S. Department of Defense as one of the gold standard treatments for PTSD. A meta-
analysis of treatments for PTSD found the largest effect size for cognitive behavioral treatments (1.63), larger 
than for somatic therapies and for the pharmacotherapies.[36]   The VA/DoD Practice Guidelines for The 
Management of Posttraumatic Stress Disorder and Acute Stress Disorder (2017) recommend behavioral 
interventions, specifically trauma focused manual-driven therapy such as CPT, as first line of treatment 
before other therapies including medication]. 
 
 
 
CPT has also been tested in individuals with comorbid conditions, notably alcohol use disorders.[CPT is a 
particularly good choice for patients with co-morbidity because there is flexibility within the therapy during 
which thoughts related to drug use are addressed. It has been hypothesized that the cognitive restructuring 
associated with CPT can promote recovery from substance use.][38] Kaysen and her colleagues [39] compared 
CPT outcomes among those with and without alcohol use disorders. Results suggested that CPT was safe and 
effective in this comorbid group because there were no differences in completion rates and both groups showed 
an improvement in PTSD symptoms. In this study, current alcohol use disorder was defined as having the 
disorder in the last 12 months. Our group piloted CPT in a small study that integrated CPT for treating PTSD 
symptoms with coping skills training for the treatment of alcohol dependence. This was piloted in currently 
drinking, alcohol dependent Veterans with PTSD and efficacy was tested using standardized scales evaluating 
symptoms for PTSD (Clinician Administered PTSD Symptom Scale-CAPS) and alcohol consumption (Timeline 
Follow-back Method - TLFB), as well as mood ratings and quality of life data (see pilot data). Findings from our 
preliminary studies (please see preliminary studies section) has shown that CPT is effective in reducing 
symptoms of PTSD (significant decrease in CAPS from 60.5, sd=9.6 at baseline to 20.3, sd=19.9 at post 
treatment; p=0.03). We also reported on its effective use when the comorbid condition of alcohol dependence 
was treated with disulfiram.  There CPT was effective in treating symptoms of PTSD. Recently, we also have 
incorporated this therapy in an ongoing study of PTSD with comorbid alcohol dependence using CPT combined 
with pharmacotherapy (zonisamide vs. placebo) (clinical trials website) (see pilot data). 
CPT is one of the mainstays of treatment for PTSD, with a large effect size. While this therapy has been used 
safely in dually diagnosed individuals who have PTSD and comorbid alcohol dependence, Our pilot data also 
suggests it is also safe and effective in those with comorbid opioid use disorder (OUD), supporting the 
rationale for a larger clinical trial. 
 
B. Opioid use disorder (OUD) epidemic 
The abuse of prescription opioids, including oxycodone, hydrocodone, hydromorphone, 
morphine, codeine, propoxyphene, and methadone, has emerged as a major public health problem particularly 
in the United States (US), which represents about 5% of the world’s population but consumes 80% of the global 
opioid supply.[40]  Prescriptions for opioid medications have increased dramatically over a 10 year period with 


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174 million prescriptions dispensed from retail pharmacies nationally in 2000, increasing to 257 million 
prescriptions by 2009. [41] Abuse or non-medical use of prescription opioids is defined as use without a 
prescription and/or in a manner other than intended or prescribed, and more than 12 million people reported 
using prescription opioids non-medically in 2010.[42] Unlike other drugs of abuse, prescription opioid 
medications are primarily obtained from physicians, friends or family members and/or the Internet, rather 
than through drug dealers.  
Use of prescription opioids is associated with significant morbidity and mortality.[43] Deaths from 
prescription opioids have dramatically increased over the past 10 years and are now the second leading cause of 
accidental death in the US[44]. According to data from the Centers for Disease Control and Prevention (CDC), 
deaths due to prescription opioids went from 1.3 per 100,000 in 1999 to 5.0 per 100,000 in 2008, resulting in 
14,800 prescription painkiller deaths in 2008.[6] As expected, exposure to opioids, including days of supply 
and higher doses of opioids, has been found to increase the risk of abuse and dependence.[45]  A task force on 
prescription opioid non-medical use and abuse was convened by the College for Problems of Drug Dependence 
(2003).  Their report confirms an increase in the incidence of prescription OUD, including survey data and 
from data collected regarding treatment admissions for drug abuse, based on the Treatment Episode Data Set 
(TEDS).[46]  Many states showed an increase in incidence of 20% or more[46] over a 10 year period.  
Opioid prescription drug use has been shown to be a “gateway” to use of other drugs of 
abuse such as heroin.[47] As awareness of the prescription opioid epidemic increased, availability of 
prescription opioid medications has decreased and in its wake there has been an alarming increase in heroin 
use, with devastating morbidity and mortality. The rate of reported heroin use has doubled between 2006-
2012[11] and there is a fourfold increase in heroin overdose deaths between 2000 and 2014.[12] [Further, the 
spike in overdose deaths is also due to a is a proliferation of other deadly drugs such as fentanyl.[48] This has 
led to a national crisis and as reported in the media, (e.g. The New York Times) and the current 
administration recently declared the opioid epidemic an National Emergency.] 
The recent opioid epidemic has had a significant effect on Veterans mirroring the national trends [49]  
This may be in part due to iatrogenic factors. For example, pain conditions, are common among young 
Veterans, with report of almost 50% of patients in outpatient VA settings reporting pain primarily due to 
musculoskeletal injuries.[50]  The prevalence of these injuries may be in part due to medical advances, since 
more military personnel are surviving war related complex injuries, including blast injuries and this results in 
an increase in the number of Veterans suffering from chronic pain.  Treating chronic pain is challenging, as 
highly addictive prescription opioids have been the mainstay of treatment.[10] The rates of prescribed opioids 
increased dramatically over a 10-year period (2001-2009) among military personnel, a factor which was found 
to undermine military readiness.[8]  This issue is particularly challenging in Veterans with trauma[51] and 
those diagnosed with PTSD, as they are more susceptible to developing substance use disorders.[8]  Veterans 
with mental health disorders, notably PTSD, are more likely to be prescribed opioids, more likely to participate 
in high risk behaviors and more likely to have adverse outcomes.[9]   
 After the implementation of the Opioid Safety Initiative by the VA in 2013, specifically to alert 
prescribers to the risk of prescription opioid use particularly in combination with sedative hypnotics, the 
number of Veterans prescribed opioids has dropped significantly. However, it is estimated that over 50% of 
Veterans continue to use them: risk factors for continuing use include diagnosis of PTSD.[52, 53]  Because this 
is an evolving issue, good statistics are not available about how many result to heroin use.  
The high prevalence of OUD and its frequent comorbidity with PTSD indicates that that treatment of 
OUD among Veterans is a high priority for the VA, particularly for those individuals with comorbid PTSD.  
By extension, it also is critical to empirically determine whether a standard PTSD treatment such as CPT will 
be efficacious in OUD patients. 
Chronic Pain is an important clinical issue and frequently co-occurs with PTSD, with high comorbid 
prevalence in both directions.[54] This relationship may have several etiologies: (1) those that have 
experienced psychological trauma may also have had physical injuries and (2) there is a well-established link 
between psychological distress, mental health disorders in general and chronic pain. The link between PTSD 
and chronic pain is particularly relevant for military Veterans. Research suggests that psychological distress 
and pain perception are closely related, both cognitively and mechanistically.[55, 56]  Reports have yielded 
high rates of comorbidity between traumatic events such as combat and motor vehicle accidents with amplified 
pain perceptions related to chronic headache, back pain, and fibromyalgia.[55] This link may explain in part 
the increased vulnerability of those with PTSD to develop OUD.[28] For example, among Veterans from recent 
conflicts, the diagnosis of PTSD is associated with high-risk opioid use.[9] 


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PTSD and chronic pain are frequently comorbid, and given the high comorbidity and the link between 
psychological distress and pain tolerance, the measurement of pain tolerance as related to possible 
improvement in symptoms of PTSD would be of clinical interest/importance. In addition, any potential 
relationship between PTSD symptoms and chronic pain and its functional impairment would be relevant to 
explore.  
Buprenorphine, a derivative of the opiate alkaloid thebaine, is a partial µ-opioid agonist and a weak k-
opioid antagonist.[57]  In clinically used doses, buprenorphine effects are similar to low doses of the full µ-
opioid agonist like morphine or methadone.  However, the effects of buprenorphine plateau, and it acts like an 
opioid antagonist of higher dose effects.  This “ceiling” effect of buprenorphine blocks the effects of higher 
opioids and decreases the risk of overdose even at high intravenous doses and limits the abuse liability of 
buprenorphine itself.[57]  In addition, its slow dissociation from the opioid receptors allows flexible dosing 
ranging from several times a day to three times per week.  It should be noted that agonist properties of 
buprenorphine result in full analgesic efficacy as shown in multiple clinical trials (reviewed in Raffa et al, 
2014).[58]   
Buprenorphine, formulated as a sublingual tablet or film, is available alone or in a combination tablet 
containing buprenorphine and naloxone (BUP/NLX) in a ratio of 4:1.  Since naloxone is poorly absorbed 
when taken orally or sublingually, naloxone effects are negligible when the medication is taken as directed.   
However, injection of this combination in dependent individuals would precipitate opioid withdrawal 
symptoms due to naloxone effects, and thereby deters the diversion of this product to injection drug use.  A 
large number of studies have demonstrated the efficacy of buprenorphine as an agonist treatment in opioid 
dependent individuals and those who are addicted to prescription opioids.[59, 60]  Office based opioid 
substitution therapy is standard of care within the VA.[14]  In recognition of the importance of using opioid 
substitution therapy in Veterans with OUD, the Fiscal Year (FY) 15 VA performance measures include 
utilization of opioid substitution therapy (percent of patients with OUD receiving opioid substitution therapy) 
as a measure within the population coverage composite. As more Veterans are prescribed buprenorphine in 
the VA nationally, the efficacy of treatments in this population will be of increasing clinical importance.  
 
C. Significance 
Conducting studies in populations with “multi-morbidities” is increasingly recognized as an important area 
of study within the field of medicine in general and psychiatry in particular. This concept challenges the single 
disease framework used throughout medicine in education, reimbursement, and research [61]. The co-
occurrence of comorbid conditions is not simply additive, as the presence of one disorder can complicate the 
other. Rather, the influence of each disorder is bi-directional creating a loop that leads to worsening of 
symptoms in both conditions over time. For example, symptoms of PTSD can lead to ongoing opioid use and 
relapse, while opioid withdrawal symptoms can precipitate and mimic symptoms of PTSD; more severe 
symptoms of PTSD are associated with higher risk for opioid dependence. (reviewed in Fareed et al)[28] 
Although there is recognition that individuals with comorbidity have special treatment needs, several 
aspects of treatment remain controversial. For example, are trauma- focused treatments effective for 
individuals in early recovery? Does[62]  treatment of PTSD lead to improvements in substance use outcomes?  
Is substance abuse treatment alone adequate in early recovery and does it lead to improvement in PTSD 
symptoms? 
The growing literature on treatments of comorbidity suggests  that trauma-focused interventions can be 
safely administered in individuals with comorbidity and, in general, are associated with better PTSD outcomes 
than the comparison conditions.[63] Improvement in symptoms of PTSD is associated with improvement in 
substance use outcomes, while the opposite relationship is not always true [64], From laboratory studies, it has 
been shown that substance use can be cued by strong emotions and trauma cues are more potent than other 
stressors in inducing craving in the laboratory[65]-suggesting that inadequate treatment of PTSD can lead to 
relapse. Our own pilot data shows that among those with OUD, trauma-focused interventions lead to better 
substance abuse outcomes that substance abuse treatment alone.] 
Despite this growing literature, there is a gap in the published research regarding opioid use disorder and 
comorbid PTSD.[28] There is some evidence that treatment with buprenorphine among those with PTSD leads 
to an overall improvement in treatment outcomes[28] and an observational study suggests buprenorphine 
treatment is associated with improvement in PTSD symptoms compared to a control group prescribed high 
dose opioid therapy.[66] Despite these advances, there are no studies evaluating the combination of opioid 
substitution therapy with a PTSD evidence-based treatment. This has been identified as an important area of 
study[28] that the proposed research is intended to address. 


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Studying an evidence based psychotherapy for co-occurring PTSD among those with comorbid OUD has 
substantial significance and great clinical relevance. To apply an intervention to a new vulnerable clinical 
population has a potential to change clinical practice. Most importantly, this study has the potential to fill 
knowledge gaps and challenge the VA to improve healthcare delivery based on scientific evidence. 
We would like to underscore that while we hypothesize that CPT will be safe and effective for Veterans with 
PTSD and OUD, we believe that we cannot assume this to be true.  There is a body of literature that suggests 
that treatments developed for a single condition, such as PTSD, are not equally effective when used in 
individuals with comorbidity. For example, medications to treat PTSD including the FDA-approved 
antidepressant, sertraline and the alpha adrenergic medication prazosin [which are recommended by the 
VA/DoD practice guidelines [67] for sleep disturbances associated with PTSD] are not equally effective when 
used among individuals with comorbid alcohol use disorders.[68-71] Without well-designed clinical trials 
conducted in comorbid groups, assumptions about efficacy would have been mistaken. Particularly with 
behavioral therapies, there is controversy regarding the use of evidence-based psychotherapy in individuals 
with comorbid substance use disorders for fear of precipitating relapse.[62]  Studies among those with opioid 
use disorders maintained on buprenorphine are therefore important. Clinical trials are needed to show 
efficacy and safety. 
 
1. Potential benefits of research to subjects and others: Potential benefits of participation in this 
study may include a reduction in PTSD symptoms.  However, there is no guarantee or promise that 
participants will receive any benefit from participation in this study. 
2. Importance of knowledge to be gained: Since 11 September 2001, more than 1.5 million Service 
Members have deployed more than 2 million times in support of combat operations in Afghanistan and 
Iraq. One of the signature injuries from these operations is PTSD.  Various reports of the post-deployment 
health-related needs estimated that 20% of Veterans returning from deployment will have symptoms of 
PTSD or related behavioral health conditions. In addition, the prescription opioid epidemic has seriously 
affected Veterans, and Veterans with PTSD are more likely to abuse opioids and to have high-risk 
behaviors. Nevertheless, treating comorbid PTSD and OUD has not been systematically tested. This study 
proposes to test an evidence based psychotherapy for PTSD vs. individual drug counseling in Veterans with 
PTSD OUD, working towards characterizing effective, evidence-based interventions for this at-risk group. 
The plans for monitoring risk as described above warrant the conduct of this study for the knowledge that 
may reasonably be expected to result. 
 
D. Preliminary studies  
(1) Clinical Trials in Veterans with PTSD and Comorbid Alcohol Dependence:  Our group has 
conducted several clinical trials in Veterans with PTSD and comorbid alcohol dependence. These studies are 
randomized, multi-site, outpatient clinical trials evaluating (a) medications to treat alcoholism in a comorbid 
group of patients [72]; (b) a comparison of 2 different antidepressants in patients with PTSD and comorbid 
alcohol dependence [69] and (c) a recently completed study of prazosin for dually diagnosed Veterans with 
PTSD [71].  
 
(2) Use of CPT for Veterans with PTSD and comorbid alcohol dependence: 
(a) Pilot study of CPT in Veterans with PTSD and comorbid alcohol dependence.[73] 
 
CPT is a mainstay of treatment for PTSD, but Veterans with comorbid alcohol dependence are excluded 
from participation. Our group piloted CPT treatment, incorporating sessions addressing alcohol consumption 
as a symptom of PTSD (eg. challenging beliefs, patterns of problematic thinking worksheets to be completed on 
alcohol use) and role of drinking throughout treatment. CPT was tested in a pilot study of (n=5) male Veterans 
diagnosed with PTSD and comorbid alcohol dependence. CPT was administered by a trained psychologist for 
12 weeks and PTSD symptoms were assessed using the CAPS (Clinician Administered PTSD Scale) every 2 
weeks while daily drinking data was assessed using the TLFB (Timeline Follow-back Method).   
Results: Therapy participation was excellent, with an average of 9.4 (out of 12) sessions attended.  PTSD 
symptoms (see Figure 1) significantly decreased with treatment. Alcohol use (see Figure 2 and Figure 3) 
measured as total number of standard drinks and percent of heavy drinking days also decreased during 
treatment.   


BUP CPT  
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v. 4/12/2022 
Figure 1: Total CAPS scores over time across 
participants
0
10
20
30
40
50
60
70
80
Baseline
wk2
wk4
wk6
wk8
wk10
wk12
 
Figure 2: Total number of standard drinks before and 
after treatment
784.22
204
0
100
200
300
400
500
600
700
800
900
Baseline
End of tx
 
Figure 3: Percent heavy drinking days before and 
after treatment
48.89
20.6
0
10
20
30
40
50
60
Baseline
End of tx
  
 (b.) Report on the Use of Cognitive Processing Therapy, Enhanced to Address Alcohol Use. [74] 
 
This case report described the 12-week course of CPT treatment which also addressed heavy alcohol use in 
a Veteran with PTSD and comorbid alcohol dependence. During the therapy sessions, he became more aware of 
the negative consequences of his heavy alcohol use. In week 9 of the therapy, the patient requested and began 
disulfiram therapy to help him abstain from alcohol use. His alcohol use dramatically decreased, and his 
symptoms of PTSD continued to abate with the therapy. This study supports an integrated treatment model for 
PTSD and heavy alcohol use and suggests the combination of CPT and pharmacotherapy can be used 
effectively. 
(c.) Zonisamide in Addition to Cognitive Processing Therapy (CPT) for Veterans with PTSD and Comorbid 
Alcohol Dependence (pilot study) 
 
In this pilot study, the anticonvulsant zonisamide was tested as an augmentation of CPT therapy, in 
Veterans with PTSD and comorbid alcohol dependence. Veterans with current PTSD and current alcohol 
dependence were recruited. All participants (n=24) received CPT; participants were also randomized to receive 
zonisamide or placebo (3:1 ratio). Overall, CPT was very well tolerated among these dually diagnosed subjects 
and subjects showed a decrease in symptoms of PTSD from baseline to end of treatment (see figure below). 
Zonisamide treatment was associated with reduced number of drinking days compared to placebo (see below), 
increased rates of abstinence (78% vs 50%) and a greater reduction in craving. 
 
 These studies demonstrate our group’s extensive 
experience in: a) the methodology proposed, b) our 
ability to recruit, and c) safely and effectively 
conducting studies in Veterans with PTSD and 
comorbid substance use disorders. Further, it 
demonstrates our experience in conducting studies 
using standardized psychotherapy, notably CPT in 
individuals with comorbid disorders and in 
conjunction with pharmacotherapy. Finally, these 
studies highlight the importance and feasibility of 
conducting clinical trials in “real world” patients, as 
treatment efficacy may vary based on comorbid 
conditions.  
 
(3) Experience with Buprenorphine:  
(a) Setting up a Buprenorphine Clinic: One year Later: The Principal Investigator (PI) developed and set 
up the buprenorphine clinic as a Mental Illness Research, Education, and Clinical Center (MIRECC) clinical 
project in 2004; [the clinic is now well developed and has 166 Veterans. VA Connecticut, at Newington, also 
has a robust clinical program, with another 115 Veterans.  MD investigators involved in this project (Petrakis, 
Arias, and Yoon) and other study physicians (Dr. Belinda LeBlanc) have the ability (DEA X-license) to 
prescribe buprenorphine, as well as extensive experience with this patient population.] The PI has authored 
several articles considering clinical issues that have arisen since the inception of the clinic.  
(b) Buprenorphine/Naloxone treatment for prescription opiate dependence (not currently recruiting): A 
study was initiated to evaluate whether low vs. high dose of buprenorphine was more effective in treating 
Veterans with prescription opioid dependence entering buprenorphine treatment. Following seven days of 
buprenorphine induction, n=10 Veterans with OUD were randomized in an open label fashion to low dose (LD) 


BUP CPT  
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(<8mg) vs high dose (HD) (>16 mg) of buprenorphine. There was a higher dropout rate in the LD group (3/5, 
60%) vs the HD group (1/4, 25%) (one participant was never randomized). Three of the drop-outs (2 in the LD 
group and 1 in the HD group) were lost to follow up, and one dropped out because the low dose was not 
effective. It is important to note that 4 out of 10 participants (40%) also had a diagnosis of PTSD in this sample. 
Results suggest patients prefer higher doses of buprenorphine. 
 
Investigators in this study have had extensive clinical experience with buprenorphine 
(Petrakis, Arias, Yoon) and Dr. Sofuolgu have had research experience in conducting clinical 
trials in individuals maintained on buprenorphine. 
(4) Use of CPT for Veterans with PTSD and comorbid Opioid Use Disorder (OUD): 
 
This retrospective chart review evaluated the feasibility and outcome of Veterans admitted to the 
examined all Buprenorphine Clinic at VA CT in West Haven to evaluate feasibility and outcomes for those with 
comorbid PTSD. In this study, all new buprenorphine clinic admissions between January 2016-December 2016 
were identified via the electronic consult (n=103) Of those, 4 were not examined (n= 2 had a restricted record, 
n=2 were deceased).  The remaining 99 records were evaluated for rates of comorbid PTSD, rates of referral to 
trauma focused treatment and retention in buprenorphine clinic after 3 months. PTSD diagnosis was evaluated 
using the problem list in the electronic medical record or service connection status. 
Results: Of the 99 records examined, 46 (46.5%) had the diagnosis of PTSD. Most of the Veterans were male 
(94.9%), with an average age of 45.3 years and majority were Caucasian (78.8%); approximately half (52.5% 
were single/never married. Of those with PTSD, 10 (21.5%) were referred to trauma focused treatment: of those 
4 were referred to CPT, 1 was referred to Prolonged Exposure (PE), and the rest received unspecified trauma-
focused therapy. Of those who received trauma-focused treatment, 4/5 (80%) completed 12 sessions. Retention 
at 3 months was significantly different between groups: of those referred to trauma focused therapy 10/10 
(100%) were retained in treatment compared to 11/36 (30.5%) (p<.05) of those without referral to trauma 
focused therapy (See Fig 1). As a comparator, among those without PTSD (n=53) 28 were retained in treatment 
(52.8%). While PCL scores are not available in all cases, the n=5 who participated in the EBP had PCL scores 
documented in the record. The average PCL score= 61.4 (range 53-68) at the beginning of therapy was 
significantly reduced to PCL= 29.2 (range 10-48) (p<.05) at the end of the 12-session intervention. (See 
Fig 2)] 
These studies demonstrate our group’s 
extensive experience in the methodology proposed and our ability to recruit and safely and 
effectively conduct pharmacologic studies in Veterans with PTSD and comorbid substance use 
disorders. Further, it demonstrates our experience in conducting studies using standardized 
psychotherapy, notably CPT in individuals with comorbid disorders and in conjunction with 
pharmacotherapy. 
 
6. RESEARCH PLAN 
Research design and methods 
 
Overview: We propose to conduct a randomized, controlled trial with 160 (assuming a 30% drop out rate, for 
120 participants) Veterans and civilians diagnosed with PTSD and comorbid OUD. This study will use open 


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randomization to 2 groups: (a) buprenorphine + CPT  vs. (b) buprenorphine + IDC. All subjects will be 
maintained on buprenorphine and the standard clinical treatment. Participants will be recruited primarily 
through the clinical facilities at the VA and from other collaborators. 
 
The Bedford VAMC has been added as an additional enrollment site for this study.  The principal investigator 
for the Bedford site is Megan Kelly, PhD and the study will be overseen by the Bedford VA IRB has gained local 
IRB approval.  
 
Experimental subjects:  Veterans and civilians (n=160) aged 18- 65 years old, with a current diagnosis of 
PTSD and opioid use disorder (OUD) will be enrolled at 2 sites (VA Connecticut Healthcare System, Bedford 
VAMC) for a study with 12-weeks of active treatment.  Participants will be recruited from four main sources: 1) 
from the PTSD clinic patients at the local VAs , 2) from the group of Veterans entering treatment for opioid use 
disorders at the local VA Substance Abuse Treatment Programs and 3) advertisement (flyers, posters, 
Craigslist) 4. Community clinics.  Under a HIPAA waiver, IRB-approved letters of invitation can be mailed to 
prospective participants with a past diagnosis of OUD or PTSD who otherwise might meet eligibility criteria.  
Outreach will also be conducted at local Veteran Centers, where staff from both VAs consult.  The PTSD staff 
has also been involved in outreach to the community for returning OIF/OEF Veterans.  Each participant will be 
carefully screened and assessed using the following inclusion and exclusion criteria: 
Inclusion Criteria: 
1) Male and female Veterans and civilians between the ages of 18-70 years old.  
2) Current diagnosis of PTSD as determined by an independent evaluator assessment using CAPS-5.   
3) Opioid Use Disorder diagnosed by Mini International Neuropsychiatric Interview for DSM-5 (MINI).  To 
meet entry criteria for buprenorphine treatment, will also have documented prior treatment for opioid use 
disorder, history of opioid withdrawal or signs of opiate withdrawal as evidenced by a Clinical Opiate 
Withdrawal Scale (COWS) score of 7 or greater, and a positive urine toxicology for opioids.  
4) For women, negative pregnancy test and use of acceptable method of contraception. 
Please note, because of the high incidence of depression that co-occurs with PTSD, those individuals with 
comorbid depressive disorders will be allowed into the study. This is in keeping with the purpose of this study 
to evaluate the effectiveness of a CPT in a “real world” clinical population. It also is anticipated that a 
significant proportion of Veterans and civilians will likely be treated with concurrent antidepressant 
pharmacotherapy [and/or with other medications (eg. prazosin).]However, again this enhances the “real 
world” application of treatments within the VA system, and secondly it is common to allow antidepressant 
medication in psychotherapy trials and still be able to show benefit with CPT.[37] For those who are already 
prescribed antidepressant medication, they will be continued on their current pharmacologic treatment Please 
note that since not all subjects will be on psychotropic medications, randomization will be stratified by 
presence of concurrent medications-a strategy we have used successfully in other comorbidity studies with 
PTSD[71]  
Exclusion Criteria: 
1) Females who are pregnant or lactating. 
2) Veterans and civilians with a current unstable medical condition such as neurological, cardiovascular, 
endocrine, renal, liver, or thyroid pathology (e.g. abnormal BUN and creatinine, and unmanaged hypertension 
with BP > 200/120) which in the opinion of the physician would preclude the patient from fully cooperating or 
be of potential harm during the course of the study. 
3) Veterans and civilians who meet current criteria for the following diagnoses (schizophrenia and 
schizophrenia spectrum and psychotic disorders) as determined by the MINI. 
4) Veterans and civilians who have significant current suicidal or homicidal risks necessitating a higher level of 
care. 
5) Those with known allergy or intolerance to buprenorphine. 
 
Methods:  
Overview: This study is a 14-week, RCT with open-label randomization to 2 groups (described in detail below): 
(a) buprenorphine (BUP) + CPT  vs. (b) BUP + IDC. This study will be conducted in 3 Phases: Phase I: 


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buprenorphine induction and stablization for all participants (x1 week). Participants will be started at a dose of 
2mg/0.5 mg BUP/NLX and this dose will be increased as needed for stabilization of opioid withdrawal 
symptoms up to 32 mg per day, which is standard practice. Phase II: randomization to CPT vs. IDC (x12 
weeks). CPT will be provided by one of our licensed therapists trained and who has been trained and certified 
in the standard VA rollout. The therapists will have weekly case consultation from a qualified CPT consultant. 
IDC will be provided by research staff under the supervision of Dr. Martino.   All of the sessions will be 
recorded for supervision purposes and for the independent fidelity raters to assess 20% of the sessions for 
adherence and competence.* [Phase III: Subjects wil be referred to one of the buprenorphine clinics (West 
Haven or Newington) and will be referred for ongoing treatment for PTSD if they choose, including the option 
for CPT for those who did not receive this during the study.]  
Participants will be seen on a daily basis (excluding weekends) for the initial 5-7 day induction. Once 
subjects are on maintenance dose of BUP/NLX (goal is within 5 days), they will be seen weekly by study RN for 
the first 4 weeks, biweekly for a month then monthly for symptom evaluation, and medication refill.   
[At study end, participants will be referred to a buprenorphine clinic.  Buprenorphine treatment is the 
standard treatment for OUD, and subjects who discontinue are at high risk for relapse. ] 
* Due to COVID-19 precautions it may not be possible to record CPT/IDC sessions especially those 
conducted via telephone or telemedicine. 
Main Outcome Measures:  Symptoms of PTSD using the CAPS-5 and PCL-5. Frequency of opioid use using 
the TLFB and confirmed by urine toxicology. Other outcomes will include treatment retention measured by 
days in treatment and functioning using the VR-12.  Functional impairment related to pain will be measured 
during the trial. Follow-up will be conducted at 1 and 3 months after end of the study to evaluate the durability 
of treatment effects on drug use and psychosocial outcomes.  
To fully assess and appreciate complex symptomatology in this patient population, assessments were 
selected to have both relevance to our study of PTSD and comorbid OUD.  Assessments will be done by an 
Independent Evaluator (IE) blind to treatment group.  
Screening: After signing informed consent*, participants will undergo screening. Screening will be done by 
members of the research team (i.e., research assistant, nurse, clinician) and will take about 3-4 hours. In order 
to qualify for participation, individuals will complete the following: (1) Subjects will be personally interviewed 
with the CAPS-5 (diagnosis of PTSD) and MINI.  The MINI is a widely used structured psychiatric diagnostic 
instrument. (2) Frequency of opioid use will be assessed using the TLFB method[75] and confirmed with urine 
toxicology results.  (3) PTSD symptoms will be assessed using the CAPS-5 and PCL-5.  
Non-veterans who do not already have a medical record at the VA will have a medical record created for them, 
following VA guidelines, in order to order study relevant laboratory assessments, medications, and to document 
consent and study procedures.  Non-veterans will be provided with a copy of the VHA Notice of Privacy Practices 
and asked to sign the corresponding acknowledgement form. 
 
*In order to reduce face-to-face interactions during COVID-19 potential participants will be 
given the option to complete a portion of the screening procedures remotely using a VA 
approved video platform (or by telephone when video is not feasible).   If the psychological 
screening is conducted remotely, the participant will be mailed/emailed a blank consent form 
and an informed consent process with study staff will then take place either over the phone or 
via VA-approved video platform.  We will go over the consent form in detail with the 
participants. We will obtain their verbal consent, which we will record in CPRS.  Consents that 
are mailed will be sent using US Mail (USPS/UPS/FedEx).  Consents that are e-mailed will be 
encrypted using a VA approved encryption platform (e.g. Azure Rights Management, My 
HealtheVet).     
A fully signed consent and HIPAA will then be obtained prior to randomization should they still 
be interested and eligible to continue in the study.  We will accept the following forms of signed 
consent and HIPAA: a) signed in person; b) signed at home and mailed back to the research 
team using a pre-addressed envelope; c) signed at home and the patient will take a photo of the 
consent and HIPAA pages and email the images to a member of the research team (or use My 
HealtheVet); or d) signed at home during a video visit where we will ask the patient to hold 


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v. 4/12/2022 
each consent and HIPAA page up to the camera and we will take a screenshot of the pages 
(ensuring the patient’s face is not in view) and print and file the screenshots in the patient’s 
research record.    
 
Standard Treatment for all Participants:  
Buprenorphine: Buprenorphine will be prescribed for all subjects. Buprenorphine is available alone or in 
combination tablet containing buprenorphine and naloxone in a ratio of 4:1 or in an injectable form. In this 
study, a combination tablet is preferred, since it is less likely to be diverted than the buprenorphine only 
formulation, however if an injectable formulation of buprenorphine is prescribed, the participant can continue 
on that medication. Consistent with the clinical guidelines, before BUP/NLX is administered, participants will 
be instructed not to use any prescription opioids for 24 hours and be prepared to stay in the clinic for at least 2 
hours following the first dose of BUP/NLX. [During induction into buprenorphine, all participants will be 
started at a dose of 2mg, and this dose will be increased as needed (up to 32mg per day) for stabilization of 
opioid withdrawal symptoms within about a 5-7-day period, which is standard practice. Participants will be 
seen on a daily basis (excluding weekends) for the initial 5-7-day induction. Once subjects are on maintenance 
dose of BUP/NLX, they will be seen weekly by study RN for the first 4 weeks, biweekly for a month then 
monthly for Medical Management, symptom evaluation, and medication refill. *+  At the end of the active 
study, participants will be referred to a buprenorphine clinic.]  
* Due to COVID-19 we are reducing the frequency of in-person visits.  During this time, patients will be seen 
in the research clinic by the study RN on a monthly basis.  All other regularly scheduled visits will still occur 
(as outlined in Table 1) but they will be telemedicine visits using VA approved platforms (e.g. VA Video 
Connect or VVC) or telephone if a video platform is not feasible.  In order to maintain continuity of care, 
patients may opt to have their BUP/NLX prescribed by their regular provider (instead of the study 
physicians) and dispensed via the VA Pharmacy rather than the VA Research Pharmacy.  This decision will 
be communicated with the patient’s provider by the research team. 
+ Subjects will be allowed to receive their medications according to their clinic dosing schedule (weekly, 
monthly, daily) and can change based on the clinical judgement of the provider. 
Any participants already taking Buprenorphine will skip the induction phase and continue with their 
prescribed dose dispensed through the research pharmacy while enrolled in this study.  For participants 
receiving daily Buprenorphine through the Methadone clinic, they will continue to receive their medication 
from there.  Any participants who cannot tolerate BUP/NLX and are on standalone Buprenorphine will 
continue to receive their medication directly from their VA provider. 
 
Buprenorphine is a Schedule III drug that, in community settings, is often prescribed for up to a one 
month’s supply at a time. Patients are generally seen on a weekly or monthly basis like those treated with other 
psychiatric medications. Buprenorphine will be delivered by the research pharmacy on the day of the 
participant’s weekly, biweekly, or monthly appointment, and will be returned to the research pharmacy should 
the subject fail to present for the appointment.  Buprenorphine treatment is generally well tolerated. Its side 
effects, such as abdominal pain, constipation, nausea, vomiting, headache and sweating, are similar to other 
opioids. Increases in liver enzymes and hepatitis are rarely reported.  Participants will be educated to keep 
their medication in a safe place to prevent unintentional exposure to others, especially children. 
Medical Management:  Medical Management (MM) will be provided for all patients in the study.  It is a 
behavioral intervention designed for patients with substance dependence, and is particularly well suited to a 
medication clinical trial [76].  The objective of MM is to focus on medication compliance and symptom 
reduction.  In this study MM will be provided by a trained registered nurse and will be conducted at each visit. 
The initial visit will be 40-60 minutes and the focus will be on educating the patient on medication regiment 
and compliance; other health issue such as negative consequences of drug use, may also be discussed.  
Consecutive sessions will be 15-20 minutes and will be focused on monitoring of compliance with the 
medication and psychoeducation. This intervention was chosen because of MM’s focus on medical issues which 


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makes it highly compatible with a pharmacologic intervention. Our group has extensive experience with MM in 
a comorbid group of patients. 
Medication Compliance: We employ a number of strategies to ensure maximum compliance with the 
medication regimen. All medications will be dispensed in clearly labeled prescription vials. Before each visit 
each patient will receive a reminder phone call about his/her appointment and is also reminded to return the 
bottle with the study medication regardless of whether any medication is left over.  At the beginning of each 
study visit the left-over medication will be counted, and the patient will be prompted to report any doubling of 
dose or missing days of study medication.  If the visit is completed via video, the patient will be asked to count 
the medication “in front” of the research staff member.  If the visit is completed by telephone (without a video 
option), the patient will be asked to count the remaining study medication and report this to the staff member 
conducting the visit; accountability will be conducted during the monthly in-person visits.  Since BUP/NLX is a 
controlled substance, study staff will instruct the participant on how to properly dispose of any leftover 
medication, in a manner that is compliant with VA policy (e.g. take back envelopes, flushing down the 
sink/toilet, or by placing in CS waste disposal bins while being observed by VA staff).   The session will also 
provide an opportunity for subjects to review critical issues and problem areas, the subjects' involvement in any 
ancillary treatments, and other clinically significant events. Other formal treatment concurrent with their study 
treatment (including self-help meetings) will be monitored.   
All medications (buprenorphine) will be prescribed by the study physicians or individuals’ current 
physician. Participants will be seen weekly by research staff for the first four weeks then biweekly for 1 month, 
and then monthly. There will be close monitoring for psychiatric symptoms in the study, as well as safety 
monitoring through Adverse Events (AE) reporting (see Human Subjects section), we believe this will provide a 
reasonable level of protection for a control group for this trial. 
Experimental Treatments: Subjects will be randomized to (1) CPT or (2) IDC.  
Cognitive Processing Therapy (CPT): CPT is a manualized, 12-session 1:1 cognitive therapy that has been 
designed for patients with PTSD [76].  In this study the sessions will be conducted weekly.  The stated goal of 
CPT is “to assist the client in refraining from assimilating (distorting the event to fit prior beliefs) and in 
accommodating schemas to the new information without over-accommodating".[77]  CPT uses Socratic 
questioning targeting distorted cognitions such as self-blame, hindsight bias, and other guilt cognitions.  CPT is 
focused on the cognitive components of the therapy without exposure.  Therapy will be provided by 
psychologists who either have been or will be trained in conventional CPT through the VA rollout initiative. 
[Dr. Meshberg-Cohen will be responsible for coordinating therapy and therapists will have weekly case 
consultation/supervision from a qualified CPT consultant (Dr. Greer Richardson, who is a national CPT trainer 
and supervisor).] 
Individual Drug Counseling (IDC): IDC will serve as the control group.  The current standard of 
treatment for individuals entering buprenorphine maintenance is to do drug counseling.  In most VA settings, 
including VA Connecticut Healthcare System, psychiatric symptoms (such as PTSD) are evaluated but 
psychiatric treatment is often deferred until the individual demonstrates a commitment to treatment and 
demonstrates abstinence. Standard counseling is the primary means to achieve these goals. IDC uses a semi-
structured, time-limited addictions-counseling model in a 1:1 setting. The main focus is on helping individuals 
achieve and maintain abstinence by encouraging behavioral changes, such as avoiding triggers, structuring 
one's life, and engaging in healthy behaviors (e.g., exercise). The IDC manual provides an organized, concise 
version of what is currently practiced by most addiction counselors. In operationalizing this approach, the 
developers drew from their own clinical experience and that of expert drug counselors in the field The 
approach is consistent with the 12-step approach that regards recovery as a gradual process, and participation 
in self-help groups such as Alcoholics Anonymous or Narcotics Anonymous is strongly encouraged. IDC will be 
conducted by study personnel and supervised by Dr. Martino on a weekly basis.[78]  
Initial certification for CPT and IDC will be defined as at least adequate or average adherence and competence 
ratings on the respective CPT and IDC consistent techniques on six consecutive practice sessions. After 
certification, the therapists will begin seeing participants in the trial.  The CPT and IDC supervisors will rate 
one audio recorded session each week, rotating among study therapists, and discuss feedback in weekly 
supervision. If this ongoing review determines that a therapist drifts below the initial certification level, then 
the therapist will be provided additional supervision and training to assure adequate delivery of their assigned 
treatment.  
Fidelity to ratings: 


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To assure the study therapies are delivered in a manner consistent with manual guidelines, all CPT and 
IDC sessions will be audio recorded* and selected sessions (3 randomly selected sessions from each 
participant) will be evaluated by raters, who are blind to type of treatment received, using the Yale Adherence 
and Competence Scale (YACS) rating system developed for assessing therapist adherence and competence in 
previous trials.[79-81]  The YACS consists of a series of Likert-type items utilizing key unique components of 
specific therapies (e.g., Cognitive Behavioral Therapy, Motivational Interviewing, CPT, Twelve Step 
Facilitation, contingency management, clinical management) as well as a series of scales utilizing common 
factors in general drug counseling (e.g., assessment of substance use and functioning, facilitative 
conditions).  For each item, raters are asked to rate the degree to which the therapist used that particular 
intervention in the session (adherence), as well as how skillfully the therapist implemented the intervention 
(skillfulness).   The YACS measure used in our proposed study will focus on items specific to CPT and IDC, 
allowing for a test of discrimination between the delivery of the two distinct treatments. The YACS has very 
good psychometric properties, with coefficient alpha for the treatment scales in the .80-.95 range, indicating a 
high degree of internal consistency, and ICC’s (intraclass correlation coefficients) for the adherence and 
competence scales ranging from .75 to .90.  Dr. Martino has extensive experience training YACS raters to 
perform very reliable session process ratings.  
* Due to COVID-19 precautions it may not be possible to record CPT/IDC sessions especially those 
conducted via telephone or telemedicine. 
Study Assessments:   
Table 1: Summary of Study Assessments  
 
 
 
  Assessments        
Baseline 
1 
2* 3* 
4 
5 
6* 7 
8 9 
10 11 
12 
Follow Up 
1 and 3 
months* 
CAPS 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
PCL-5 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
MINI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
TLFB 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
DRRI-2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
COWS  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Pressure/Pulse** 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Toxicology** 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
Pregnancy test (females) 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
PHQ-9 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
ISI 
X 
 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
VR-12 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
C-SSRS 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
AE (SAFTEE) 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
NRS for pain intensity 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
PROMIS–29  
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
LEC-5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CTQ 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cannabis Use History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Synthetic Cannabinoids Use 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Study visits occur weekly for 4 weeks, then biweekly, then monthly.  Study assessments collected 
weekly are self-assessments and can be distributed and collected by the therapist conducting the therapy.  
* In order to reduce the number of in-person visits weeks 2, 3, 6, and the two follow-ups (months 1 and 3) will 
be conducted via telephone or telemedicine.  


BUP CPT  
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v. 4/12/2022 
** Due to COVID-19, blood pressure/pulse and urine toxicology will not be collected unless the visit is done in 
person. 
 
COVID-19 Safety Precautions: 
1. 
Adhere to local VA policies or mandates (ie., wearing cloth face coverings, COVID-19 screening at 
the main entrance, temperature checks, etc). 
2. 
A study staff member will call participants the day before their scheduled visit and ask the COVID-
19 screening questions; anyone who screens positive for COVID-19 (exposure or symptoms) will be 
rescheduled. 
3. 
Staff members will sanitize high-touch surfaces before and after each in-person visit with approved 
disinfectant. 
4. 
Staff members will wear protective facial masks, participate in frequent handwashing, and/or use 
alcohol-based hand sanitizer, and practice social distancing. 
5. 
Only one participant will be scheduled for an in person visit at a time and visits will take place in a 
large enough space so that study staff and the participant can practice social distancing. 
6. 
Contact information will be updated at each visit in the event that contact tracing needs to occur. 
7. 
We will minimize the frequency and duration of study visits in the following ways: 
a. Attempt to schedule study visits on the same day as another clinic visit the patient has 
scheduled. 
b. As much as possible, self-assessment forms should be completed via telephone or telemedicine 
and can be given directly or mailed to the participant in advance of any appointment.  If the 
patient desires to complete in-person visit forms on site, staff will honor that request while 
maintaining social distancing. 
c. Study therapy sessions (CPT or IDC) will be allowed to be conducted as telemedicine visits using 
VA approved platforms (e.g. VA Video Connect or VVC).  If a video option is not possible, 
therapy can be conducted over the phone or in person (patient’s choice).   
d. Scheduled in-person visits at weeks 2, 3, 6, and the two follow-up visits (months 1 and 3) will 
now be conducted by telephone or telemedicine. 
 
(a) Clinician Administered PTSD Scale (CAPS-5) will be used to diagnose PTSD and to obtain data [(pre 
and post treatment, follow-up)] on the frequency and severity of PTSD symptoms. The CAPS-5 is a structured 
diagnostic interview for DSM-5 diagnosis and the gold standard for assessing PTSD. It has excellent 
psychometric properties and diagnostic efficiency.[82] The CAPS for DSM-5[83] uses only a single 5-point 
ordinal rating scale to measure symptom severity. CAPS-5 scores range from 0 to 80 with higher scores 
indicating greater PTSD symptom severity. The CAPS-5 was revised with an eye towards maintaining 
backwards compatibility with the DSM-IV version of the instrument.  
(b) PCL-5 will be used to collect information on PTSD symptoms. The PTSD Checklist for DSM-5 [83] is 
similar in form to the PTSD Checklist (PCL) based on the DSM-IV.[84] The PCL-IV has excellent psychometric 
characteristics.  The PCL-5 is a 20-item self-report measure, selected for its dimensional sensitivity, with 
higher scores reflecting greater PTSD severity. Scoring is based on how much the patient has been bothered by 
the symptoms on a scale from “0 = not at all” to “4 = extremely.”  PCL scores will be collected based upon 
symptoms experienced in the past month at baseline, but since the last visit, during the weekly assessments.  
(c) The MINI International Neuropsychiatric Interview for DSM-5 (MINI) will be used for 
diagnosing other possible psychiatric disorders. The MINI is a widely used structured diagnostic instrument 
designed for evaluating major AXIS I disorders and is a standard assessment in OUD clinical trials.  Our group 
has extensive experience using the MINI with high degree of inter-rater agreement.  Note: Sections B, L, M, 
and MB will be omitted as these are assessed by other measures (section B: Suicidality assessed by the C-SSRS) 
or do not impact study inclusion/exclusion (sections L, M, and MB which assess eating disorders).      
(d) Calendar-based interviews using the Timeline Follow-Back (TLFB) method [75] will document the 
frequency of opioid use for the month prior to and during the 12 weeks of treatment.  The TLFB will also be 
used to document the frequency of use of other substances (i.e.; alcohol). 


BUP CPT  
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v. 4/12/2022 
(e) The Deployment Risk and Resiliency Inventory-2 (DRRI-2) will be used to determine war zone 
exposure. The DRRI-2[86] is a suite of 17 individual scales that assess key deployment-related risk and 
resilience factors with demonstrated implications for Veterans’ long-term health.  The following subscales will 
be used to assess deployment factors: Combat Experiences, Aftermath of Battle, and Unit Social Support. We 
will use the post-deployment stressors and social support scales to evaluate post-deployment factors (for 
service members and Veterans).   
(f) Basic demographic characteristics will be collected using the Demographics and Military Service 
Characteristics Form. The Demographics and Military Service Characteristics Form measures standard 
demographics (race, gender, age) and military service information (e.g., rank).   
(g) Clinical Opiate Withdrawal Scale (COWS) will be used to determine if an individual has opioid 
withdrawal symptoms prior to treatment with buprenorphine.[87] 
(h) The Patient Health Questionnaire-9 (PHQ-9) will be used to measure depressive symptoms; [ these 
will be collected weekly.]  The PHQ-9 is a widely used and well-validated instrument for measuring the severity 
of depressive symptoms.[88]  It consists of 9 items that assess both affective and somatic symptoms related to 
depression and depressive disorders; these 9 items correspond to the diagnostic criteria for DSM Major 
Depressive Disorder (MDD). Respondents rate the frequency with which they have been bothered by 
depressive symptoms within the past two weeks on a scale ranging from 0 (“not at all”) to 3 (“nearly every 
day”). Scores on all items are summed to obtain a total severity score.  Scores reflect no significant depressive 
symptoms (0-4), mild depressive symptoms (5-9), moderate depressive symptoms (10-14), moderately severe 
depressive symptoms (15-19), and severe depressive symptoms (>19).  Respondents also indicate the degree to 
which their depressive symptoms have made it difficult for them to do their work, take care of things at home, 
or get along with other people, from “not difficult at all” to “extremely difficult.” The PHQ-9 has high internal 
consistency (e.g., alpha ranging from .83 to .92), and correlates strongly with other measures of 
depression.[88]   
(i) Sleep will be measured by the Insomnia Severity Index (ISI)[89] which is a 7-item self-report measure 
that assesses perceived severity of insomnia. Each item uses a 4-point Likert type scale from 0 (not at all 
satisfied) to 4 (very much satisfied). The items sum to produce a total score (range 0 – 28). The ISI has an 
internal consistency alpha coefficient of 0.74, and has shown convergent validity with other measures such as 
the Pittsburgh Sleep Quality Index (r = 0.67), the Dysfunctional Beliefs and Attitudes about Sleep (r = 0.55), 
and sleep diaries (r ranges from 0.32-0.91)[90]. 
 (j) Columbia-Suicide Severity Rating Scale (C-SSRS): The C-SSRS has both lifetime/recent and since 
last visit versions.  The “Lifetime/Recent” version gathers information on lifetime history of suicidality and 
recent suicidal ideation/self-injurious behavior.  The “Since Last Visit” version of the C-SSRS asks about any 
suicidal thoughts or behaviors the subject has exhibited since the last time administered the C-SSRS[91] 
 (k) Adverse Events (AE) will be assessed by the RN at each weekly assessment using Food and Drug 
Administration (FDA) standards for AE reporting.  Serious Adverse Events (SAE) and Unanticipated Problems 
Involving Risk to Subjects or Others (UPIRSO) will be reported to the local IRB as well as to the DSMB and 
other authorities according to their standard reporting requirements.  
(l) Pain will be measured during the clinical trial using recommendations from the consensus group that has 
published a large number of papers with recommendations for pain clinical trials called the Initiative of 
Methods, Measurement and Pain Assessment in Clinical Trials (IMMPACT)[92].  IMMPACT recommends an 
assessment of several key domains including pain intensity and functional interference. For pain intensity, a 
simple 11-point Numeric Rating Scale (NRS) has been recommended by IMMPACT and remains the gold 
standard in clinical trials.  It is the VA’s “5th vital sign” so participants will be familiar with it.  Functional 
impairment due to pain will be measured using the PROMIS–29 scale.[93] 
(m) Additional baseline characteristics will be assessed using the Life Events Checklist for DSM-5 (LEC-5), 
Child Trauma Questionnaire (CTQ), Cannabis Use History Questionnaire, and the Synthetic Cannabinoids Use 
History Questionnaire.  
Confirmation of self-reported drug use: Urine toxicology screening will be done at every in-person MM 
visit and urine will be tested using Abbott Diagnostics CI8200 screen done at the VA Facility. The standard 
urine toxicology includes testing for amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine and 
oxycodone. Methadone and buprenorphine are ordered separately, but all will be including in the weekly 


BUP CPT  
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v. 4/12/2022 
screening. Fentanyl is a separate test and will be ordered if a participant has a history of use/abuse. Testing 
for each of these substances uses immunoassays; if there is a question about accuracy, testing is confirmed 
using gas chromatography/mass spectroscopy. Urine drug testing is a routine part of buprenorphine 
maintenance treatment.  
 
Subject Payment.  All participants will be compensated for their participation.  Participants will be paid $30 
for the initial screening/baseline assessment.  They will be compensated $30 for each medication visit (x7), and 
$45 for follow up visits.  There will be no payment for therapy sessions. Individuals can receive up to a total of 
$330 if attending all scheduled treatment and visits.  Payment will be made through electronic funds transfer 
(EFT).  Participants will need to provide us with your banking information by completing a special payment 
form.  Alternatively, if participants do not have a bank account, a check will be mailed to them instead.  This 
check(s) will be mailed to the address they provide us with.  Patients may choose to receive gift certificates 
issued to them for use at the VCS canteen (retail store) or VCS cafeteria here at the VACHS in lieu of EFT/check 
payment.  If a patient chooses to receive payment by gift certificate they will be paid for the 
telemedicine/telehealth visits they participated in at their next in-person visit (e.g. if they complete weeks 2 
and 3 by telephone they will receive gift certificates for weeks 2, 3, and 4 at the week 4 visit).     Study payments 
are subject to withholding for outstanding federal debts (i.e., defaulted student loans, interstate child support, 
back taxes etc) without notification. 
 
Power analysis: The sample size calculation for our primary hypothesis (change in PTSD symptoms) was 
based on findings from one of the largest and most comprehensive meta-analysis reports on PTSD treatment to 
date.[36] The report evaluated N=112 studies and reported on 137 comparisons, using validated PTSD 
symptom measures. The meta-analysis reported that the effect sizes for psychotherapy when contrasted with a 
control group were consistently large and averaged g=1.14. Three studies administered CPT specifically and the 
overall effect size for those was large and averaged g=1.69. For this study we conservatively are basing our 
calculations on a moderate effect size by Cohen’s definition.[95] For the First and Second Primary aim we 
estimate that with 60 subjects randomized to each group we have 80% power to detect a medium effect size 
(f=0.25) at two-sided alpha level of 0.05, and assuming 25% dropout we will recruit a total of N=160.] 
 
Data Analysis:  
Study data will be collected and managed using REDCap electronic data capture tools hosted at VA CT 
Healthcare System. REDCap (Research Electronic Data Capture) is a secure, web-based application designed to 
support data capture for research studies, providing 1) an intuitive interface for validated data entry; 2) audit 
trails for tracking data manipulation and export procedures; 3) automated export procedures for seamless data 
downloads to common statistical packages; and 4) procedures for importing data from external sources. 
 
Descriptive statistics and graphs will be used to summarize the data on all randomized subjects. All continuous 
variables will be examined for adherence to the normal distribution using normal probability plots and 
Shapiro-Wilk tests. Transformations will be applied if needed. If normality is not satisfied and transformations 
do not help with achieving normality alternative analytic strategies will be considered such as generalized 
estimating equations (GEE) or nonparametric methods for repeated measures analysis.  Baseline demographic 
and clinical characteristics for the two randomized groups (e.g., age, gender, severity of PTSD, and opiate use) 
will be compared using chi-square tests for categorical variables and t-tests or nonparametric tests for 
continuous variables. If there are baseline differences between study treatment groups, these variables will be 
used as covariates in the mixed-effects models analyses described below.  Drop outs and completers will also be 
compared on baseline characteristics using the same approach. Between group differences in treatment 
retention, medication compliance and frequency of the occurrence of side effect symptoms across the 
treatment period will also be assessed. Residual plots and other diagnostics will be used to assess model 
assumptions. 
 
The primary analyses will be intent-to-treat but sensitivity analyses on completers and non-completers will also 
be performed. All statistical testing will be at a two-tailed alpha level of 0.05. Adjustments for multiple 
comparisons will be conducted among measures in specific domains. In the case of PTSD symptoms (use of 2 
measures, PCL-5 and CAPS-5) and opiate use (use of TLFB and urine toxicology) the level of significance will 
be adjusted to 0.025. 


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v. 4/12/2022 
Primary and Secondary Hypotheses: 
For the primary and secondary hypotheses, we will use mixed effects models to assess changes in PTSD 
symptoms and opiate use over time. Treatments will be used as between-subject factors and time (in weeks) 
will be used as a within-subject factor. The primary outcome variables will be PTSD symptoms as measured by 
generated from the PCL-5 and CAPS scales.  The secondary outcome variables will be frequency of opiate use 
generated from the TLFB and confirmed with urine toxicology results each medication visit (weeks 1-4, 6,8, 
12) and follow-up. The use of the mixed-effects models approach for the analysis of our longitudinal data has 
several specific advantages. Unlike traditional repeated measures analyses, mixed effects models allow for 
different numbers of observations per subject, use all available data on each subject and are unaffected by 
randomly missing data. They also provide flexibility in modeling the correlation structure of the data.[96] 
Primary Aim 1. We hypothesize that CPT will significantly reduce PTSD symptoms compared 
IDC in Veterans and civilians with PTSD and comorbid OUD maintained on buprenorphine.  
This hypothesis will be tested by the interaction of treatment (CPT vs. IDC), and time in the mixed model 
specified above. Significantly greater decrease in PTSD symptoms in the CPT group will be considered 
supportive of the hypothesis.  
Secondary Aim 1. We hypothesize that CPT will significantly reduce opioid use compared to 
IDC in Veterans and civilians with PTSD and comorbid OUD maintained on buprenorphine.  
This hypothesis will be tested by the same approach as described in primary aim 1 but with frequency of opioid 
use as the dependent measure. 
Exploratory Hypothesis: 
We hypothesize that CPT will significantly improve retention (days in treatment) compared 
to IDC in Veterans and civilians with PTSD and comorbid OUD maintained on buprenorphine.  
This hypothesis will be tested using ANOVA or nonparametric equivalent comparing the two treatment groups 
(CPT vs. IDC).  
We hypothesize that CPT will significantly improve psychosocial functioning (measured by 
the VR-12 survey) compared to standard counseling in Veterans and civilians with PTSD and 
comorbid OUD maintained on buprenorphine.  This hypothesis will be tested by the interaction of 
treatment (CPT vs. IDC) and time. 
We hypothesize that CPT will significantly improve sleep (measured by the ISI) compared to 
standard counseling in Veterans and civilians with PTSD and comorbid OUD maintained on 
buprenorphine.  This hypothesis will be tested by the interaction of treatment (CPT vs. IDC) and time. 
We hypothesize that CPT will significantly reduce pain intensity (measured by the NRS) and 
improve functional impairment due to pain (measured by the PROMIS-29) when compared to 
standard counseling during 12 weeks of treatment in Veterans and civilians with PTSD and 
comorbid OUD maintained on buprenorphine.  These hypotheses will be tested by the interaction of 
treatment (CPT vs. IDC), and time (four time points during treatment) in the mixed model. We propose to 
follow up Veterans and civilians 1 and 3 months after completion of the study to evaluate 
changes in PTSD symptoms, opioid use and treatment utilization.  This analysis is exploratory and 
will assess change over time in symptoms and treatment using mixed-effects models with two factors (study 
treatments [CPT vs. IDC], and time (end of treatment, 1 month, and 3 months follow up).   
Potential Risks and Adequacy of Protection from Risks 
Potential Risks:  There are potential risks, discomforts and inconveniences associated with 
participation in this study. These may be due to buprenorphine maintenance, Cognitive Processing 
Therapy (CPT), standard (drug) counseling, and nonspecific risks such as loss of confidentiality. 
a) All subjects will be treated with buprenorphine maintenance. Buprenorphine is a partial µ-opioid agonist 
and a weak k-opioid antagonist available alone or in combination tablet containing buprenorphine and 
naloxone in a ratio of 4:1. In this study, a combination tablet will be used, since it is less likely to be diverted 
than the buprenorphine only formulation.  The doses of buprenorphine/naloxone used here are within the 
recommended guidelines of the manufacturer. Consistent with the clinical guidelines, before BUP/NLX is 
administered, participants will be instructed not to use any prescription opioids for 24 hours and be prepared 
to stay in the clinic for at least 2 hours following the first dose of BUP/NLX. [During induction into 
buprenorphine, all participants will be started at a dose of 2mg, and this dose will be increased up to 32 mg per 


BUP CPT  
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v. 4/12/2022 
day as needed for stabilization of opioid withdrawal symptoms, within a 5-7-day period, which is standard 
practice. At the end of the active study, participants will be referred to a buprenorphine clinic.].  
Common side effects of buprenorphine/naloxone, which are similar to other opioids, include: abdominal pain, 
constipation, nausea, vomiting, headache, sweating, sedation, and allergic reaction.  Uncommon but more 
serious adverse effects of BUP/NLX include liver enzyme and/or hepatic abnormalities, orthostatic 
hypotension, and respiratory depression.  There is also a risk of unintentional exposure, especially with 
children, so for that reason participants will be educated to keep their medication in a safe place to prevent 
unintentional exposure to others.  Buprenorphine is a Schedule III drug and is generally well tolerated, 
although it does cause a physiologic addiction and may lead to withdrawal effects if discontinued abruptly.  
Buprenorphine/Naloxone detoxification: detoxification from BUP/NLX can produce signs and symptoms of 
opiate withdrawal including: nasal congestion, abdominal symptoms, anxiety, myalgia, insomnia, sweating, 
and diarrhea. 
b) Subjects who are randomized to Cognitive Processing Therapy (CPT) will receive 12 weeks of therapy by a 
licensed provider. CPT may produce some discomfort and/or emotional upset including an initial increase of 
PTSD symptoms due to the discussion of traumatic events.  This is likely to happen during the early sessions of 
therapy as the participant begins to describe his/her experiences, thoughts, images and feelings to the therapist 
as well as during the evaluations.  However, these experiences are believed to be an important part of the 
treatment and recovery process.  Dealing effectively with emotional upset means experiencing the negative 
emotion in order to learn to handle it in future instances.  Concerns have been expressed about the safety of 
CPT, particularly the concern that some individuals may find the treatment overwhelming and cause an 
increase in symptoms or further deterioration in functioning.  These concerns are based primarily on 
unsystematic clinical impression and research does not support such concerns.  
c) Subjects who are randomized to Individual Drug Counseling (IDC) will receive 12 weeks of therapy by a 
licensed provider. IDC uses a semi-structured, time-limited addictions-counseling model. The main focus is on 
helping individuals achieve and maintain abstinence by encouraging behavioral changes, such as avoiding 
triggers, structuring one's life, and engaging in healthy behaviors (e.g., exercise).  The current standard of 
treatment for individuals entering buprenorphine maintenance is to do drug counseling.  In most VA settings, 
including VA Connecticut Healthcare System, psychiatric symptoms (such as PTSD) are evaluated but 
psychiatric treatment is often deferred until the individual demonstrates a commitment to treatment and 
demonstrates abstinence. Standard counseling is the primary means to achieve these goals. PTSD symptoms 
are not addressed and this may lead to worsening of PTSD symptoms. In cases where worsening of PTSD 
symptoms necessitates a change in case, the same strategies (outlined later in this document) will be used 
across treatment conditions.  
d) Nonspecific Risks: Other risks from the counseling, rating scales and urine collections are not beyond usual 
clinical procedures in a substance abuse treatment program.  Confidentiality of study results are specifically 
protected by Federal laws, and all records will be identified by code number only, with the master file kept 
under lock by the Principal Investigator or Data Manager.  With the handling of medical and research records, 
there is always the possibility of a breach of confidentiality.     
• 
Sources of Materials: Sources of research material include interview assessments conducted by 
trained Independent Evaluators, self-reported questionnaires, medical record review, urine samples, 
activity patterns, sleep patterns, etc. that will be obtained specifically for research purposes.   
• 
Therapeutic risk: All subjects will be inducted into buprenorphine maintenance, the risks of which 
are described above.  
• 
Research risk: The research risks include the risks of the interventions into which subjects will be 
randomized, and include CPT and standard counseling, all of which are described above. In addition, 
there are risks associated with gathering of assessments, and a potential breach of confidentiality. These 
have also been described above. 
Adequacy of Protection from Risk 
• 
Recruitment and Informed Consent:  Potential participants may be identified through referrals 
from various health care providers at hospital clinics. Providers may forward contact information of 
interested individuals directly to the study team. Or, potential participants may self-refer in response to 


BUP CPT  
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v. 4/12/2022 
the recruitment flyer approved by the IRB. Flyers will be distributed to various health care providers 
and will be posted in locations in the hospital and surrounding community frequented by Service 
Members. Interested persons may call or walk in to the research offices. Research staff will field 
incoming phone calls and walk-ins.  
We will also conduct chart reviews for patients enrolled in VA clinics (e.g., Mental Health Clinic; Buprenorphine 
Clinic) in order to screen for potential participants.  When we identify a patient who may meet the study criteria 
we will reach out to their provider and we will ask the provider to give the patient our contact information, if they 
may be interested in the study.   Patients who are interested in the study will be able to walk in to our research 
office or call us on the phone for more information and to complete the screening procedures (outlined earlier in 
the protocol as well as below).   
Research staff will discuss the study treatment and eligibility requirements with the interested person. 
If the person believes they may qualify for the study, an appointment will be made for consent and 
screening. During this appointment, potential participants will have the study explained to them in a 
safe and private location. The potential participant will be given a copy of the informed consent 
document to read. After the subject, has read the informed consent they will be given the opportunity to 
take the consent home to discuss the research with family and friends. The research team will be 
available to answer any questions about the research. Once the potential participant has reached a 
decision, the advising staff member will go over the risks and benefits of the study and ensure the 
subject understands the research. The advising staff member will have the individual sign the consent 
form. A copy of the signed informed consent will be given to the subject. The advising staff member will 
document the informed consent process in the medical record of the participant.  
Following the baseline assessment, participants who meet the inclusion criteria for the study will be 
randomized into the study. For individuals not meeting study inclusion criteria, the study staff will 
provide options for follow-up outside of the study. 
• 
Protection Against Risk:  
• 
General procedures to protect against risks: Before initiating any research activity, each subject 
must give informed consent that will detail the risks of study participation. Eligibility will be 
determined by the medical and psychiatric history, drug use history, and the laboratory studies 
done prior to beginning this research protocol. Subjects will be provided a number to call to reach 
an on-call psychiatrist (24 hours/day) should unpleasant effects occur after subjects have left the 
testing facility.  
• 
Protection against adverse events from buprenorphine maintenance: Subjects will be monitored 
carefully for the development of adverse side effects (including symptoms of withdrawal) during the 
study. Subjects will be withdrawn if they show severe psychological or symptomatic deterioration or 
if clinically necessary for ethical or safety purposes. Any psychiatric hospitalization will be reported 
to the Principal Investigator for review regarding the appropriateness for continuation in the study. 
Similarly, medical complications will be reviewed in the manner described above. Subjects who may 
no longer participate for these reasons, or who choose to terminate from the study, will be offered 
treatment at the VA according to the individual’s needs.  If a subject shows clinical deterioration the 
PI will determine: 1) whether the subject can remain in the study, or; 2) whether a higher level of 
care (e.g. referral back to treating psychiatrist or referral to emergency or inpatient care) is needed. 
• 
[Protection against adverse events from Cognitive Processing Therapy (CPT) Individual Drug 
Counseling (IDC) and Medication Management (MM):] The therapists and research team will 
closely monitor for any increase in distress during all treatment sessions. Any indication that the 
participant is considering suicide will be handled using standard clinical procedures, and referral 
for additional assessment or treatment for distress will be done in accordance with the local site 
policies and procedures. If a participant becomes upset in-between sessions, he or she will be 
encouraged to contact their regular clinician.  If a participant needs or desires immediate attention 
and their therapist is not available, arrangements will be made for an appointment with an 
experienced mental health provider.  The informed consent document provides direction to contact 
the study staff during duty hours and/or the Emergency Room at any time for worsening of 
symptoms. 


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v. 4/12/2022 
• 
Loss of confidentiality: Data collected will be coded using an assigned number. All data will be 
secured in locked cabinets in locked offices.  Every member of the Research Team will be trained 
and monitored about how to handle and protect both medical and research records.  
 
Database Server.  All data will be stored on VA servers behind VA firewalls. All de-identified 
data will be scanned and saved on VA servers. SPSS software will be used for data 
maintained and analysis.   
 
Security.  Access to the research data will be restricted to research personnel affiliated with 
the study.  
 
Audio recording security: Audio recordings will be stored as computer files on a secure server and 
only include subject IDs to label the interview. To assure the confidentiality and protection of study 
participants, we will (a) give participants the right to refuse digital recording, to stop the recording at 
any time, or to request that we erase all recordings involving them, (b) have all recordings take place 
in privacy, (c) only permit access to the recordings by research staff for supervision purposes and by 
raters who will be specially trained to rate the recordings using the YACS, and (d) erase the 
recordings one year upon study completion. 
 
Data Safety and Monitoring Plan (DSMP). The risk associated with participating in this study is 
moderate, because the treatments administered may be associated with mild to moderate side effects. Serious 
side effects associated with this treatment are not expected. This project will be monitored by a Data and Safety 
Monitoring Board (DSMB), because the study involves randomized treatment of Veterans and civilians with 
PTSD and OUD. This board is composed of persons not otherwise affiliated with the clinical study who are 
experienced in various aspects of the conduct of clinical trials for the treatment of addictive disorders. We 
propose three investigators located here in Connecticut who are not directly involved in this study – Declan 
Berry, Ph.D., Sherry McKee, Ph.D., and David Fiellin, M.D. as the members of the DSMB.  
 
We will report recruitment, follow-up, and adverse events to this panel on a quarterly fashion.  Prior to study 
initiation, critical parameters for collection of side effects and for study discontinuation will be recommended 
to the DSMB who may use these or other measures to monitor safety of the ongoing trial. The DSMB will be 
available to convene outside of scheduled meetings, if necessary, due to concerns regarding a particular subject 
or due to any troublesome developments in subjects' experiences during the study. The DSMB will make 
appropriate recommendations for changes in the study protocol, if needed.   
 


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7. REFERENCES 
 
1. 
Cifu, D.X., et al., Traumatic brain injury, posttraumatic stress disorder, and pain diagnoses in 
OIF/OEF/OND Veterans. J Rehabil Res Dev, 2013. 50(9): p. 1169-76. 
2. 
Pugh, M.J., et al., Complex comorbidity clusters in OEF/OIF veterans: the polytrauma clinical triad 
and beyond. Med Care, 2014. 52(2): p. 172-81. 
3. 
Resick, P.A. and M.K. Schnicke, Cognitive processing therapy for sexual assault victims. Journal of 
Consulting & Clinical Psychology, 1992. 60(5): p. 748-56. 
4. 
The Management of Posttraumatic Stress Disorder Work Group, VA/DoD Clinical Practice Guidelines 
for Management of Posttraumatic Stress Disorder and Acute Stress Disorder, W.D. The Office of 
Quality Safety and Value VA and U.S.A.M.C. Office of Evidence Based Practice, Editors. 2017: 
Washington DC. p. 1-200. 
5. 
Institute of Medicine, Treatment for Posttraumatic Stress Disorder in Military and Veteran 
Populations: Final Assessment. 2014, Washington, DC: The National Academies Press. 
6. 
Centers for Disease Control and Prevention, CDC grand rounds: prescription drug overdoses - a US 
epidemic. 2012, MMWR Morb Mortal Weekly Report. p. 10-13. 
7. 
Compton, W.M. and N.D. Volkow, Major increases in opioid analgesic abuse in the United States: 
concerns and strategies. Drug Alcohol Depend, 2006. 81(2): p. 103-7. 
8. 
Institute of Medicine, Substance Use Disorders in the U.S. Armed Forces. 2013, Washington, D.C.: The 
National Academies Press. 
9. 
Seal, K.H., et al., Association of mental health disorders with prescription opioids and high-risk opioid 
use in US veterans of Iraq and Afghanistan. JAMA, 2012. 307(9): p. 940-7. 
10. 
Gibson, C.A., Review of posttraumatic stress disorder and chronic pain: the path to integrated care. J 
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Stecker, T., et al., Co-occurring medical, psychiatric, and alcohol-related disorders among veterans 
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Goldstein, G., et al., Comorbidity between psychiatric and general medical disorders in homeless 
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Macey, T.A., et al., Patterns and correlates of prescription opioid use in OEF/OIF veterans with 
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Raffa, R.B., et al., The clinical analgesic efficacy of buprenorphine. J Clin Pharm Ther, 2014. 
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Weiss, R.D., et al., A multi-site, two-phase, Prescription Opioid Addiction Treatment Study (POATS): 
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Petrakis, I.L., et al., Noradrenergic vs Serotonergic Antidepressant with or without Naltrexone for 
Veterans with PTSD and Comorbid Alcohol Dependence. Neuropsychopharmacology, 2012. 37(4): p. 
996-1004. 
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ICF_001.pdf: 
VA RESEARCH CONSENT FORM
Subject Name:______________________________ 
                             First Name   MI    Last Name                                  
Title of Study:    Optimal Treatment of Veterans with PTSD and Comorbid Opiate Use Disorder
 
 
Principal Investigator:    Ismene Petrakis, MD
 
         VA Connecticut Healthcare System/689 
(v.04.12.2022)
SECTION I:  THE PURPOSE OF THE STUDY AND HOW LONG IT WILL LAST.
You are invited to participate in a research study designed to evaluate the use of a standard psychotherapy 
for post-traumatic stress disorder (PTSD) in Veterans and civilians who also suffer from an opiate use 
disorder (OUD).  You have been invited to participate because you have been diagnosed with PTSD and 
OUD. Your participation will last for approximately 30 hours spread over 14 weeks with additional 
follow-up visits scheduled approximately 1 and 3 months after study completion. 
In order to decide whether or not you wish to be a part of this research study, you should know enough 
about its risks and benefits to make an informed judgment.  This consent form gives you detailed 
information about the research study which a member of the research team will discuss with you.  This 
discussion will go over all aspects of this research; its purpose, the procedures that will be performed, any 
risks of the procedures, and possible benefits.  Once you understand the study, you will be asked if you 
wish to participate, if so, you will be asked to sign this form.
SECTION II:  DESCRIPTION OF THE STUDY INCLUDING PROCEDURES TO BE USED.
This study will evaluate two types of counseling, Cognitive Processing Therapy (CPT) and Individual 
Drug Counseling (IDC), among participants diagnosed with both PTSD and an opiate use disorder (OUD) 
who are on buprenorphine maintenance.  Several studies have shown that CPT is effective in reducing 
PTSD symptoms and is a standard therapy that is used among individuals with PTSD. IDC is the standard 
treatment for individuals who are participating in buprenorphine maintenance.   Buprenorphine 
maintenance with buprenorphine/naloxone (BUP/NLX) is a standard line of treatment for individuals with 
an opiate use disorder. In order to participate in this study you must be willing to take BUP/NLX or 
already be participating in a buprenorphine maintenance program with BUP/NLX or BUP.  We anticipate 
that approximately 160 people will be enrolled in this study.
Screening: If you agree to participate in this study you will be asked to provide a thorough medical and 
psychiatric history and participate in a detailed psychiatric interview.  You will also have urine tests done 
at in-person visits, which will become part of your medical record. This screening appointment will take 
approximately four hours  The screening visit may also be done over several shorter visits, instead of all 
at once. The purpose of this visit is to make sure it is safe for you to participate in this study.
You will have the option to complete part of this screening visit remotely using a VA approved video 
platform.  If you choose this option a member of the research team will contact you to set up an 
appointment to go over this consent with you.  If you would still like to participate in the study after 
reviewing the consent, we will obtain verbal consent to continue and this will be documented in your 
medical record.  You will need to sign written consent at your first in-person study visit, prior to starting 
any study treatment/therapy. 
                                         VACHS FORM 
March 2015
VA   Department of Veterans Affairs
 
VA Connecticut Healthcare System Human Studies
Subcommittee
Effective Date:
April 21, 2022


VA RESEARCH CONSENT FORM
(Continuation Page 2 of 8 )
version.04/12/2022
Treatment Assignment: 
Buprenorphine/Naloxone (BUP/NLX)
Everyone who participates in this study will be taking the medication buprenorphine.  If you have already 
started buprenorphine/naloxone (BUP/NLX) treatment with a healthcare provider, you will continue to 
take the medication, as prescribed.
If you are taking standalone Buprenorphine, including injectable buprenorphine, you will continue to take 
the medication, as prescribed.
Medication Dosing: If you are not already taking BUP/NLX, you will meet with a study nurse to start the 
medication.  You will be asked to stop taking any opiates for 24 hours before you are scheduled to start 
taking BUP/NLX and you may be asked to stay in the clinic for up to 2 hours after your first dose of 
BUP/NLX.  A nurse will go over what medications/drugs you need to stop taking.  Examples of opiates 
include (this is not a complete list): hydromorphone (Dilaudid), demerol, oxycodone (OxyContin, 
Percocet), hydrocodone (Vicodin, Lorcet, Lortab), fentanyl, methadone, heroin, morphine, and codeine.
 
During induction into buprenorphine, you  will be started at a dose of 2mg, and this dose will be increased 
as needed until your withdrawal symptoms have been stabilized, up to 32mg per day.  This will take 
approximately 7 days.  You will be seen on a daily basis (excluding weekends) for the initial 5-7 days.   
Once you reach the maintenance dose you will remain on that dose for the rest of the study.  Your 
symptoms will be monitored on a regular basis (see “Study Schedule” below) and your dose will be 
modified if needed. At the end of the 12-weeks of treatment you  will be referred to a buprenorphine 
clinic.
The BUP/NLX will be prescribed to you by either your current provider or a study provider.  The research 
team will work with you and your provider to decide which option is best for you prior to starting the 
study.  The amount of medication dispensed to you at one time (daily, weekly, or monthly supply) will be 
determined by your provider and may change during the study at the discretion of your provider.   
Medication will be dispensed by either the VA Pharmacy or the VA Research Pharmacy. 
Medication Storage: You will be given a pill bottle at each visit that indicates how you should take your 
study medication.  We will review with you how you should take your study medication each visit. You 
should keep all medication containers out of the reach of children.  
Counseling:  You will have a 50% chance of being assigned to CPT, and a 50% chance of being assigned 
to IDC. The study uses a procedure like flipping a coin, so that you will have a 1 in 2 chance of receiving 
CPT or IDC. You will participate in either CPT or IDC for the entire study (the type of counseling you are 
receiving will not change during the 12 weeks of treatment).  After the study is completed, you will be 
given a referral to continue treatment for PTSD (if you choose) and if you were not assigned to receive 
CPT in this study, you will be given a referral to a provider that can provide you with CPT therapy.
Study Schedule:  Your participation will last for approximately 30 hours spread over 14 weeks with 
additional follow-up visits scheduled approximately 1 and 3 months after study completion.  Visits will be 
broken into four different parts: (1) induction to BUP/NLX; (2) counseling visits; (3) medication visits; 
and (4) follow-up.
                          
    
     VACHS FORM March 2015
VA   Department of Veterans Affairs
 
VA Connecticut Healthcare System Human Studies
Subcommittee
Effective Date:
April 21, 2022


VA RESEARCH CONSENT FORM
(Continuation Page 3 of 8 )
version.04/12/2022
Once you have completed the BUP/NLX induction, the counseling and medication visits will begin.  
Counseling visits will occur once a week for weeks 1-12.  Medication visits will occur on weeks 1-4, 6, 8, 
12.  On weeks where you have both a counseling visit and medication visit (weeks 1-4, 6, 8, and 12), we 
will try and schedule your appointments on the same day.  However, this will depend on your schedule 
and may not always be possible.  This means you may have to come in for study related visits 
approximately 1-2 times a week. 
Induction:  If you are not already taking BUP/NLX, you will be started on it.  This will take place over 
approximately 7 days and is described earlier under “Medication Dosing”.  If you are already taking BUP/
NLX, you will skip the induction phase of the study.
Counseling visits:  You will be asked to attend 12  therapy sessions of CPT or IDC (described below).  
These sessions will occur once a week for 12 weeks, and they will be approximately 60-90 minutes long.  
At each session you will talk one on one with a therapist and also be asked to fill out surveys asking you 
about your feelings, PTSD symptoms and drug use.  These sessions will be audio (voice) recorded.  In 
order to maintain social distancing we will ask you to complete the counseling visits using a VA approved 
video platform (eg. VA Video Connect or VVC).  If this is not possible you can complete the counseling 
session by telephone or in person. 
Cognitive Processing Therapy (CPT): CPT is a 12-session therapy that has been found to be 
effective for PTSD. CPT aims to give you new ways of handling distressing thoughts and feelings 
and to gain an understanding of traumatic experiences.  Throughout the course of CPT, you will be 
asked to discuss various aspects of the traumatic event, including its details and consequences.  
CPT has four main parts: 1) learning about PTSD symptoms, 2) becoming aware of thoughts and 
feelings, 3) learning skills to help you have more adaptive beliefs about your trauma(s), and 4) 
understanding how your trauma(s) may have impacted your beliefs about yourself, others, and the 
world.  You will be asked to complete daily practice assignments.  
Individual Drug Counseling (IDC): IDC is the standard treatment used with individuals who are 
receiving buprenorphine maintenance.  The main focus of this counseling is to help individuals 
achieve and maintain abstinence by encouraging behavioral changes (avoiding triggers, adding 
structure, engaging in healthy behaviors such as exercising).   
Medication visits:  Medication visits are conducted by a Registered Nurse (RN) and/or research staff  
member during weeks 1-4, 6, 8, and 12.  These appointments will be approximately 60 minutes each and 
are for medical management, symptom evaluation, and medication refill (if study physician is providing).  
You will be asked to come into the research clinic for an in-person visit during weeks 1, 4, 8, and 12; this 
may be conducted by telephone (including video call).  The other visits (weeks 2, 3, and 6) will be 
conducted by telemedicine using a VA approved video platform (e.g. VA Video Connect or VVC) or by 
telephone. 
 
At each in-person visit you will be asked to provide a sample of urine for drug screening and to take a 
breathalyzer test (which involves blowing into a tube to estimate your blood alcohol level).  Females will 
have a urine pregnancy test done on weeks 4,  8, and 12.  During each visit (in-person or 
telemedicine/telephone), you will also be asked to complete several questionnaires asking about your 
mood, drug and alcohol use, and PTSD symptoms.  You will receive a reminder call before each visit and 
you will be asked to bring in the bottle with the study medication, regardless of whether any medication is 
left over.  
                          
    
     VACHS FORM March 2015
VA   Department of Veterans Affairs
 
VA Connecticut Healthcare System Human Studies
Subcommittee
Effective Date:
April 21, 2022


VA RESEARCH CONSENT FORM
(Continuation Page 4 of 8 )
version.04/12/2022
Follow-up: Follow-up sessions will be scheduled with a research staff  member following the completion 
of the study, and will take place at approximately 1 and 3 months after your last visit.  You will meet with 
the study staff and be asked to complete several questionnaires asking about your mood, drug and alcohol 
use, and PTSD symptoms.  These visits will be approximately 60-90 minutes each and will be conducted 
by telemedicine or telephone.
For all in-person visits you will be required to follow current COVID-19 local guidelines.  This may 
include wearing a cloth face covering during your visits, participating in a temperature check, and passing 
a screening before entering the hospital.  If you have a scheduled appointment and have a fever (99.9 F or 
higher) or any symptoms of COVID-19 you will need to contact us to reschedule your appointment.
SECTION III:  DESCRIPTION OF ANY PROCEDURES THAT MAY RESULT IN 
DISCOMFORT OR INCONVENIENCE.                                                                                                 
At any point in the study, you will be discharged if study personnel are concerned that continued study 
participation may cause you physical or psychological harm. If you are discharged from  the study, you 
will be referred back to your regular clinician. The procedures that may result in discomfort or 
inconveniences include: attending appointments, completing evaluations/surveys, and attending 
psychotherapy (CPT or IDC).
Attending Appointments: Attending appointments weekly for evaluations may be inconvenient for you.
Evaluations/ Surveys: Talking about your trauma and drug use history can be stressful and can 
sometimes increase anxiety, craving, or PTSD symptoms. 
CPT:  Previous research shows that PTSD symptoms increase somewhat during the early part of CPT 
before they decrease.  This is expected because you are thinking more about your traumatic experience(s). 
It is also possible that CPT will not help you.
IDC:  PTSD symptoms are not typically addressed during IDC.  If you are assigned to this type of 
therapy, it is possible that your PTSD symptoms may increase.
SECTION IV:  EXPECTED RISKS OF STUDY:
The risks in this study include: side effects from BUP/NLX, BUP/NLX detoxification, increased PTSD 
symptoms/anxiety/craving, loss of confidentiality, causes for early discharge, and unanticipated risks.  
These risks are described below: 
Buprenorphine/naloxone (BUP/NLX): Side effects associated with BUP/NLX include: abdominal pain, 
constipation, nausea, vomiting, headache sweating, sedation, and allergic reaction. BUP/NLX can also 
cause physical addiction or dependence.  Uncommon but more serious adverse side effects of BUP/NLX 
include liver abnormalities,  feeling dizzy when you suddenly get up, and a possibility that your breathing 
could significantly slow down. You are asked not to use alcohol throughout the study because it may 
interact with buprenorphine/naloxone and increase the risk of side effects and serious life-threatening 
breathing problems.  Use of benzodiazepines, sedatives, or tranquilizers also increases these risks.
  
Buprenorphine/naloxone Detoxification: Detoxification from BUP/NLX can produce signs and 
symptoms of opiate withdrawal, including nasal congestion, abdominal symptoms, anxiety, muscle pain, 
insomnia, sweating, and diarrhea.  You should take BUP/NLX as prescribed and should not suddenly stop 
taking the medication.
                          
    
     VACHS FORM March 2015
VA   Department of Veterans Affairs
 
VA Connecticut Healthcare System Human Studies
Subcommittee
Effective Date:
April 21, 2022


VA RESEARCH CONSENT FORM
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Increased PTSD Symptoms, anxiety, and craving:  You will be asked to talk about your PTSD 
symptoms, anxiety and craving at most appointments.  This may cause all of these symptoms to become 
worse.  If you are uncomfortable at any point, you should let a member of the research team know.  If 
your symptoms bother you after you go home, you should contact the numbers listed on the last page of 
this consent document.  A study doctor will be contacted to evaluate you by phone or in person, if 
necessary, to see if any further treatment is needed.  
If the research staff is concerned about your safety during the study, you may be evaluated by a study 
clinician and if necessary referred for further evaluation and/or treatment.  If it is determined that you are 
a danger to yourself or others, or are so ill you can’t take care of your basic needs at home, you may be 
held in the hospital against your will.  
Loss of Confidentiality: Participation in research may involve a loss of confidentiality.  Your research 
records will be kept as confidential as possible.  Only a code number will identify your research records.  
The code number will not be based on any information that could be used to identify you (for example, 
social security number, initials, birth date, etc.)  The master list linking names to code numbers will be 
kept separately from the research data.  All urine drug screens will become a part of your medical record.  
All research information will be secured in locked files.  Your identity will not be revealed in any reports 
or publications resulting from this study.  Only authorized persons will have access to the information 
gathered in this study.  Authorized persons may include regulatory agencies such as the Food and Drug 
Administration, (FDA), the Government Accountability Office (GAO), the Office for Human Research 
Protections (OHRP), Office of Research Oversight (ORO),  and VA Connecticut Healthcare System 
Research Office.  
The Department of Veterans Affairs (VA) requires some information to be recorded in the VA electronic 
medical record for Veteran and non-Veteran research subjects.  Therefore, if you participate in this study, 
a medical record will be created if you do not already have one.  Notes from your visits, procedures, and 
laboratory tests will be included in this record.  In addition to the research team, and the VA staff who 
provide clinical services, other researchers may be granted approval to access this information in the 
future.  Federal laws and regulation that protect privacy of medical records will apply to your VA record.  
Causes for Early Discharge:  At any point in the study, you will be discharged: 1) If your behavior is too 
disruptive 2) If you experience serious side effects due to the study medication, 3) If you regularly miss 
medications, 4) if urine toxicology screens show frequent use of benzodiazepines or barbiturates, 5) If the 
investigator has evidence that your health or well-being may be threatened by continuation in the study, 6) 
(Females only) Should a pregnancy test become positive, you will be withdrawn from the study and 
referred to an appropriate treatment program.  
Unanticipated risks: If at any time during the study you observe any unusual or uncomfortable feelings, 
you should contact the research staff by coming in to the research office or calling (203) 932-5711 ext. 
3121 during weekdays from 8:00 a.m. to 4:00 p.m. After hours, you may call the Psychiatric Emergency 
Room at the VA Connecticut Healthcare System (West Haven, CT) at (203) 932-5711, extension 4472 
and ask for the substance abuse research psychiatrist on call. If you become suicidal, hospitalization is 
possible.
Females Only: Since this research may have bad or unforeseen effects on a fetus and should not be done 
during pregnancy, it is necessary that a pregnancy test be done first. You will have pregnancy test during 
                          
    
     VACHS FORM March 2015
VA   Department of Veterans Affairs
 
VA Connecticut Healthcare System Human Studies
Subcommittee
Effective Date:
April 21, 2022


VA RESEARCH CONSENT FORM
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version.04/12/2022
the screening and at weeks 4, 8, and 12. To your knowledge, you are not pregnant at the present time.  
You also agree to avoid becoming pregnant (to use contraceptives, to take precautions against becoming 
pregnant, etc.) during this study.  You will be given counseling about acceptable forms of contraception 
that include barrier (diaphragm and condom) methods and birth control pills. You will also be counseled 
about the implications of opiate use while pregnant.  You will be discharged from the study if you become 
pregnant at any time during the course of the study.
SECTION V:  EXPECTED BENEFITS OF STUDY.
Potential benefits may include a reduction in PTSD symptoms.  However, there is no guarantee or 
promise that you will receive any benefit from participation in this study.  Your participation may help to 
develop more effective treatment approaches for indivuduals with PTSD and Opiate Use Disorder that 
may help others.
SECTION VI:  ALTERNATIVE THERAPY OR DIAGNOSTIC TEST.
The alternatives to being in this research study are to not be in this research study and, if you are not 
already in substance abuse or PTSD treatment, to enter treatment at a general facility.  If you do not wish 
to be in this study, your condition will be treated according to standard medical practice, and we will 
provide you with referral information for PTSD or substance abuse treatment, if you wish. If your drug or 
psychiatric symptoms require further care, you may be referred for either inpatient or outpatient services 
under the guidance and recommendation of the study psychiatrist. A decision not to be in the study or to 
withdraw from the study will not affect your future interactions with the VA Connecticut Healthcare 
System, West Haven and/or Newington.  
SECTION VII:  USE OF RESEARCH RESULTS.
You will be informed of any important discoveries made during this study, which may affect you, your 
condition, or your willingness to participate in this study. If the research staff is concerned about your 
safety during the study, you may be evaluated by a study clinician and if necessary referred for further 
evaluation and/or treatment.  If determined that you are a danger to yourself or others you may be held in 
hospital against your will.  If results of this study are reported in medical journals or at meetings, you will 
not be identified by name, by recognizable photograph, or by any other means without your specific 
consent. Your medical records will be maintained according to VA requirements. The Food and Drug 
Administration or designated individuals from the National Institute of Health may inspect the records. 
SECTION VIII:  SPECIAL CIRCUMSTANCES.
Participants can receive up to $330 for participating in the study.  Payment is outlined below:
Visit
Payment Amount
Screening
$30
Medication- week 1
$30
Medication- week 2
$30
Medication- week 3
$30
Medication- week 4
$30
Medication- week 6
$30
Medication- week 8
$30
Medication- week 12
$30
1 month follow-up
$45
3 month follow-up
$45
Counseling visits (weeks 1-12)
No payment
Total Payment
$330
                          
    
     VACHS FORM March 2015
VA   Department of Veterans Affairs
 
VA Connecticut Healthcare System Human Studies
Subcommittee
Effective Date:
April 21, 2022


VA RESEARCH CONSENT FORM
(Continuation Page 7 of 8 )
version.04/12/2022
Payment for your participation (for your visit(s)) will be made through electronic funds transfer (EFT).  
You will need to provide us with your banking information by completing a special payment form.  If 
your banking information changes while you are still participating in the study, you will need to fill out 
the form again.  It is your responsibility to notify us if your banking information changes. Alternatively, if 
you do not have a bank account, a check will be mailed to you instead.  This check(s) will be mailed to 
the address you provide us with.  You may choose to receive gift certificates issued to you  for use at the 
VCS canteen (retail store) or VCS cafeteria here at the VACHS, instead of EFT or check payment.  If you 
choose to receive payment by gift certificate you will be paid for the telemedicine/telehealth visits you 
participated in at your next in-person visit (e.g. if you complete weeks 2 and 3 by telephone you will 
receive gift certificates for weeks 2, 3, and 4 at your week 4 visit).  Please note, study payments are 
subject to withholding for outstanding federal debts (i.e., defaulted student loans, interstate child support, 
back taxes etc.) without notification.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law.  This Web site will not include information that can identify you.  At most, the Web site will include 
a summary of the results.  You can search this Web site at any time.
There will be no charge for care received as part of your participation in this study.  However, some 
Veterans are required to pay a co-payment for medical and other services provided by the VA Connecticut 
Healthcare System that are not part of the study.  These co-pay requirements will continue to apply to 
medical care and services provided by VA that are not part of this study.  This may include co-pays for 
Buprenorphine/Naloxone and/or CPT, if you choose to receive these treatments after your study 
participation has ended.
If you are injured as a direct result of your participation in this research study, VA will provide necessary 
medical treatment at no cost to you. Except in very limited circumstances, this medical treatment will be 
provided in a VA Medical facility.  There are no plans to provide compensation for disability or other 
losses occurring over the long term or if an injury becomes apparent after your participation in the study 
has ended.  However, by agreeing to participate in this research study, you are not waiving or giving up 
any legal rights to seek compensation.  If you have any questions about your rights as a participant, you 
may contact the Chairman of the Human Studies Subcommittee at 203-932-5711, extension 3350.  If you 
have any complaints, concerns or pertinent questions regarding the conduct of this study, or if you have 
any questions about compensation for injury, you may contact the Human Studies Coordinator in the 
Research Office at 203-937-3830.
                          
    
     VACHS FORM March 2015
VA   Department of Veterans Affairs
 
VA Connecticut Healthcare System Human Studies
Subcommittee
Effective Date:
April 21, 2022


VA RESEARCH CONSENT FORM
(Continuation Page 8 of 8   )
version. 04/12/2022
RESEARCH SUBJECTS' RIGHTS 
       I have read or have had read to me all of the above and I voluntarily consent to participate in this 
study.  The study has been explained to me and my questions have been answered.  I have been told of the 
risks or discomforts and possible benefits of the study.  I have been told of other choices of treatment 
available to me.
    
       I understand that I do not have to take part in this study, and my refusal to participate will involve no 
penalty or loss of rights to which I am entitled. I may withdraw from this study at any time without 
penalty or loss of VA or other benefits to which I am entitled.  I will receive a signed copy of this consent 
form.
     
     The results of this study may be published, but my records will not be revealed unless required by law.
 
     In case there are medical problems, a research related injury or complaints, concerns, or pertinent 
questions about the research.  I have been told I can call Dr. Petrakis at (203) 932-5711 ext. 2244 during 
the day and  the on-call physician at (203) 932-5711, ext. 4471 after hours.
            
 
             
 
             
 
             
 
 
___________
Signature of Subject
Date
            
 
             
 
             
 
             
 
 
            
 
             
 
             
 
             
 
 
            
 
             
 
 
Signature of Person Obtaining Consent 
Name of Person Obtaining Consent (Print)
    Date
            
 
             
 
             
 
             
 
 
            
 
             
 
 
Signature of Principal Investigator
            Date
                                         
                                                        VACHS FORM March 2015
VA   Department of Veterans Affairs
 
VA Connecticut Healthcare System Human Studies
Subcommittee
Effective Date:
April 21, 2022