Conditions: Drug Dependence
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 117
Healthy volunteers: no

Brief summary:
Overall, this proposal seeks to improve treatment strategies for the significant public health problem of prescription opioid dependence by determining whether gabapentin, a non-narcotic pharmaceutical agent with minimal abuse potential and preliminary efficacy, will be effective in ameliorating withdrawal symptoms, craving and illicit drug use in prescription opioid dependent participants undergoing a 10-day detoxification from buprenorphine. In addition, the acceptability and feasibility of transitioning to depot naltrexone therapy will also be determined. If successful, this study would provide data to support further development of gabapentin as a pharmacological tool for improved outcomes during opioid detoxification as well as an integrated outpatient approach for treating prescription opioid dependence.

Detailed description:
Opioid dependence is a serious public health problem, particularly with the dramatic rise in prescription opioid abuse, but long-term opioid agonist maintenance with methadone or buprenorphine (BUP) may not be optimal for many prescription opioid abusers. Yet current opioid detoxification strategies are limited by high relapse rates and/or lack of efficacy in relieving subjective symptoms. In addition, antagonist maintenance with naltrexone (NTX), which may be an optimal longer-term strategy for this population, requires prior opioid detoxification and has been associated with relatively poor outcomes in heroin abusers. This application takes a novel, broad approach to address the problem of prescription opioid dependence by determining the 1) utility of adjunct gabapentin (GBP) during outpatient BUP detoxification to improve initial outcomes and 2) feasibility of transitioning prescription opioid -dependent patients to depot NTX following detoxification, which may improve longer-term outcomes. GBP, an N-type calcium channel blocker with low abuse potential, potentiates opioid analgesia, decreases both postoperative morphine consumption and movement-related pain, and reverses tolerance to the antinociceptive effects of morphine. GBP is also well tolerated and effective in reducing craving and illicit opioid use in pilot detoxification trials. The efficacy and tolerability of adjunct GBP during BUP-assisted detoxification and the feasibility of subsequent transition to depot NTX therapy in prescription opioid -dependent participants will be assessed. This 12-week, randomized, placebo-controlled clinical trial will determine the potential utility of adjunct GBP in 150 prescription opioid -dependent individuals undergoing outpatient BUP detoxification and whether transition to short-term depot NTX therapy is feasible. Our three specific aims are to determine (1) the efficacy and tolerability of GBP to reduce craving and illicit use of opioids in prescription opioid-dependent individuals undergoing outpatient BUP detoxification; (2) acceptability and feasibility of transition to, and short-term maintenance on, depot NTX following detoxification; and (3) prognosticators of completion of the BUP taper, successful induction onto depot NTX, symptomatology, and longer-term outcomes. Currently, the only Food and Drug Administration (FDA)-approved medications for the treatment of opioid withdrawal are the opioid agonists methadone and BUP, both of which have abuse liability, and NTX, which can produce low levels of withdrawal-like symptoms, especially early in treatment. Findings, if positive, will support further development of GBP as an adjunct medication as well as provide an integrated, seamless approach to outpatient prescription opioid-dependence treatment. Ultimately, this work could impact the addiction field by providing both procedural and pharmacological tools for treating prescription opioid dependence that significantly improve outpatient detoxification outcomes and markedly enhance access and transition to NTX therapy. This would shift clinical practice, establishing an effective adjunct regimen for BUP detoxification and an integrated approach for transition to NTX therapy. GBP may also be clinically useful for other situations where opioid withdrawal is a concern.

Arms:
arm 1: Gabapentin started on day 3 of week 1, increased up to a maximum dose of 800 mg BID by day 3 of week 2 and maintained for 2 weeks followed by 5-day taper.

Buprenorphine (BUP) stabilization up to 12 mg (day 2 of week 1) then a 10-day BUP taper by the end of week 3.

During week 4, detoxed subjects get 0.1 mg of clonidine followed by oral naltrexone (NTX) at 6.25 mg and another 6.25 mg (day 1), 25 mg (day 2) and 50 mg (day 3) then depot NTX injection (later on day 3 or day 4). arm 2: Participants in this arm begin receiving placebo (microcrystalline cellulose) in twice daily capsules on day 3 of week 1 and continue to do so through the beginning of week 5.

Buprenorphine (BUP) stabilization up to 12 mg (day 2 of week 1) then a 10-day BUP taper by the end of week 3.

During week 4, detoxed subjects get 0.1 mg of clonidine followed by oral naltrexone (NTX) at 6.25 mg and another 6.25 mg (day 1), 25 mg (day 2) and 50 mg (day 3) then depot NTX injection (later on day 3 or day 4).

Interventions: intervention 1: Gabapentin intervention 2: Buprenorphine intervention 3: Clonidine intervention 4: Naltrexone (oral) intervention 5: Naltrexone (depot) intervention 6: Placebo
Intervention descriptions: intervention 1: N-type calcium channel blocker being examined for its potential efficacy to alleviate opioid withdrawal during buprenorphine-assisted detoxification and transition to depot naltrexone. intervention 2: All participants are stabilized on buprenorphine and then undergo a 10 day taper off buprenorphine. intervention 3: All participants who successfully taper off buprenorphine receive Clonidine (0.1 mg) prior to induction onto oral naltrexone. intervention 4: All participants receive increasing doses of oral naltrexone over a 3 day period (day 1: 6.25 and 6.25 mg; day 2: 25 mg; day 3: 50 mg) intervention 5: All participants who tolerate oral naltrexone at 50 mg will receive the naltrexone injection on either the same day as the 50 mg dose or the day after. intervention 6: Microcrystalline cellulose

Protocol document:
ICF_002.pdf: 
Study Title: Improving Treatment Outcomes for Prescription Opioid Dependence 
PIs (researchers): Alison Oliveto, PhD and Michael Mancino, MD 
Institution: University of Arkansas for Medical Sciences 
Sponsor: National Institute on Drug Abuse 
 
 
Version 20                      
 
7/24/2020 
Page 1 
 
 
 
 
 
Informed Consent  
 
 
Study Title: Improving Treatment Outcomes for Prescription Opioid 
Dependence 
 
NCT Number: NCT02543944 
 
Version 20 
 
July 24, 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Study Title: Improving Treatment Outcomes for Prescription Opioid Dependence 
PIs (researchers): Alison Oliveto, PhD and Michael Mancino, MD 
Institution: University of Arkansas for Medical Sciences 
Sponsor: National Institute on Drug Abuse 
 
 
Version 20                      
 
7/24/2020 
Page 2 
 
 
 
 
 University of Arkansas for Medical Sciences Informed Consent Form 
 
Why am I being asked to be in this research study? 
▪ 
We are asking people like you who have a problem stopping pain med use to help us. Up to 200 people 
aged 18-64 years old will be part of this study.  
▪ 
We want to learn more about how to help people who have uncomfortable, flu-like symptoms (called 
“opioid withdrawal”) when they try to stop using pain meds, and how to help them not go back to 
using. 
▪ 
This study will help us learn more about whether certain drugs will decrease these uncomfortable 
symptoms that occur once a pain med is stopped.  
▪ 
During the study, you will be given by mouth buprenorphine, approved by the FDA for opioid 
dependence, and naltrexone, approved by the FDA for opioid dependence in people who no longer 
physically need opioids.  
 
▪ 
You may also get gabapentin, a drug that is approved by the FDA for nerve pain and may help 
decrease opioid withdrawal symptoms, or a placebo (inactive drug). You will not know whether you 
are getting gabapentin or the placebo. All drugs on the list are approved by the FDA, but gabapentin 
is not a treatment for opioid withdrawal.  
What if I don’t understand something? 
▪ 
This form may have words you don’t understand. The research staff will read it with you, if you like. 
▪ 
You may ask as many questions as you like before you decide whether you want to be in this study.   
▪ 
You are free to ask questions at any time before, during, or after you are in the study. 
How long will this study take and where will it take place?  
▪ We are asking you to be in a research study. 
▪ You do not have to be in the study. 
▪ If you say yes, you can quit the study at any time. 
▪ Please take as much time as you need to make your choice. 
▪ You can still get your medical care from UAMS even if you are not in the study. 
▪ During the study, we will tell you if we learn any new information that might affect 
whether you wish to stay in the study.  


Study Title: Improving Treatment Outcomes for Prescription Opioid Dependence 
PIs (researchers): Alison Oliveto, PhD and Michael Mancino, MD 
Institution: University of Arkansas for Medical Sciences 
Sponsor: National Institute on Drug Abuse 
 
 
Version 20                      
 
7/24/2020 
Page 3 
 
 
 
 
▪ 
The study will last about 12 weeks in total and will include: 
✓ Taking buprenorphine to help ease withdrawal symptoms 
✓ Getting either gabapentin or placebo (inactive pill) 
✓ While getting either gabapentin or placebo, you will be gradually taken off buprenorphine and 
start taking naltrexone 
✓ You will be gradually taken off gabapentin (or placebo) while taking naltrexone 
The study will take place at the Psychiatric Research Institute (PRI) at UAMS. The screening part, 
outpatient clinic visits, and follow up interview will take place on the 4th floor of PRI.   
 
What if I say yes, I want to be in this study?  
If you have already been screened, you don’t need to read this part. If not, we will make sure you don’t have 
any major medical problems so you can safely be in the study.  
▪ 
The screening will include 
✓ a medical history 
✓ physical exam 
✓ mental health exam 
✓ routine blood tests 
✓ heart test (electrocardiogram) 
✓ urine (pee) tests (1 test will tell us what drugs you may have used) 
▪ 
Women will also have a pregnancy test. 
▪ 
We will not charge you for the screening.  
▪ 
You and your doctor can ask for screening results.  
▪ 
The screening usually is done in a week, but could take longer if you 
✓ miss visits 
✓ have to get a doctor’s record 
✓ have to get treated first for a minor health issue  
✓ have certain drugs in your system that need to be cleared 
▪ 
If you are healthy and do have a problem using prescription pain meds, you can be in the study. 
What will I have to do if I am in the study? 
▪ 
You will be asked to stop your use of pain pills the day before you start in the study. 
 
 
 
 
▪ 
You may receive the following medications while in the study: 


Study Title: Improving Treatment Outcomes for Prescription Opioid Dependence 
PIs (researchers): Alison Oliveto, PhD and Michael Mancino, MD 
Institution: University of Arkansas for Medical Sciences 
Sponsor: National Institute on Drug Abuse 
 
 
Version 20                      
 
7/24/2020 
Page 4 
 
 
 
 
 
Name of medication 
What the FDA has approved the medication to do 
Buprenorphine 
Decrease opioid withdrawal symptoms 
Naltrexone  
Prevent relapse to opioid use 
Vivitrol (Naltrexone injection) 
Prevent relapse to opioid use 
Gabapentin 
Decrease nerve pain 
Placebo 
N/A – no active medication 
Clonidine 
Lower high blood pressure 
 
▪ 
During clinic visits the following will usually occur:  
 
✓ Complete assessments of mood, behavior, symptoms, decision making, drug craving and 
drug use  
✓ Measure how long you can hold your breath and how much you can handle stress at 
intake and a few other times during the study 
✓ Give a supervised urine (pee) sample to test for drug use and breath sample to test for 
alcohol three times per week 
✓ Have sensors attached to your body and finger in order to measure heart rate 
variability, a way to see how balanced your autonomic nervous system is in terms of 
stress/relaxation. 
✓ Give a blood sample to test for medication blood levels, how well your liver is working, 
and possibly levels of substances indicate inflammation in the body (week 4) 
✓ Have vital signs (blood pressure and pulse) done weekly and orthostatic vital signs (get 
blood pressure and pulse while lying down, sitting and standing) done before and after 
clonidine/naltrexone administration on days 1-4 of week 4 
✓ At least once per week you will meet privately, either in person or via telephone or 
video conference, with a counselor who will give aspects of behavioral naltrexone 
therapy, cognitive behavioral therapy and case management, discuss long-term 
treatment goals and give treatment referrals, if desired. 
 
Buprenorphine and Detox Phase (weeks 0-3) 
 
▪ 
The intake procedures may last up to 4 hours. During the first 3 weeks of the study, you will 
typically attend clinic three to six days per week (thrice weekly or Monday through Saturday) 
to receive a dose of buprenorphine.  
▪ 
You will be asked to take part in some computer tasks. If you qualify for these, we will do 
these things: 
 


Study Title: Improving Treatment Outcomes for Prescription Opioid Dependence 
PIs (researchers): Alison Oliveto, PhD and Michael Mancino, MD 
Institution: University of Arkansas for Medical Sciences 
Sponsor: National Institute on Drug Abuse 
 
 
Version 20                      
 
7/24/2020 
Page 5 
 
 
 
 
✓ Give you some computer games. In one game, you decide between making easy or 
difficult button presses for points.  
✓ In the other game, you will be asked to move a mouse cursor around the shape of a 
star shown onscreen.  
✓ If you make a mistake, the computer game will make a loud noise. Both of these tasks 
take about 20 minutes to play. 
✓ Taking part in these activities gives you the chance to earn some extra money. You 
may earn $20 plus an extra $5 per task based on how well you do.  
 
▪ 
On Wednesday during week 1, you will also start getting gabapentin or placebo (inactive 
substance) when you receive your buprenorphine as well as a take-home dose of gabapentin 
or placebo to take that evening.  
 
▪ 
If attending clinic on Saturdays, you may be given a double-dose of buprenorphine and your 
doses of gabapentin or placebo to take Saturday evening and on Sunday. Alternatively, you 
may be given additional take-home doses of gabapentin as well as take-home doses of 
buprenorphine to take on holidays or if participating under truncated study visits due to the 
COVID-19 virus. Which drug you get (gabapentin or placebo) will be by random assignment 
(the luck of the draw) and you have a 50% chance of getting gabapentin. Neither you nor the 
staff will know which one you are receiving. However, we can find out in the event of an 
emergency. 
 
▪ 
The buprenorphine will be given by mouth in a tablet form to hold under the tongue until 
dissolved along with capsules to swallow that contains your dose of gabapentin or placebo.  
 
▪ 
Each visit will take typically about 30-120 minutes.  
 
▪ 
During weeks 2-3, you will undergo detoxification from buprenorphine. At this time, your dose 
of buprenorphine will be gradually lessened over this period of time, while your dose of 
gabapentin or placebo remains the same. This will tell us if gabapentin helps reduce 
withdrawal symptoms.  
 
▪ 
If you miss a scheduled assessment, you may need to complete it at the next possible 
appointment. At any point during week 1 of the study, if you miss medications on any two 
days you will be immediately discharged. In weeks 2-4, you will be immediately discharged if 
you miss medications three times in a row or miss attending clinic visits. If attending clinic 
Monday through Saturday and you miss a Saturday dosing, this counts as two missed days.  
 
▪ 
During week 4, if you do not take home your weekly medication blister packs, you will be 
discharged.  
 
▪ 
You may be discharged from the study if you submit breath samples positive for alcohol.  
 
▪ 
In addition, the investigators can stop your participation at any time. If you are discharged 
from the study, you will be offered detoxification from buprenorphine and given a referral to 


Study Title: Improving Treatment Outcomes for Prescription Opioid Dependence 
PIs (researchers): Alison Oliveto, PhD and Michael Mancino, MD 
Institution: University of Arkansas for Medical Sciences 
Sponsor: National Institute on Drug Abuse 
 
 
Version 20                      
 
7/24/2020 
Page 6 
 
 
 
 
an appropriate treatment provider, such as an outpatient methadone or buprenorphine 
program, a residential therapeutic community, or an inpatient treatment program.  
 
Transition to Injection (shot) Naltrexone (week 4) 
 
▪ 
On days 1 (Monday or Tuesday) through 4 (Thursday) of week 4, you will need to give a 
supervised urine sample to help the research staff members decide whether you have 
relapsed to opioid use. If the urine sample is negative for opioids or relapse has not happened, 
research staff will take your blood pressure and pulse while you are lying down, sitting and 
standing before and after a low dose of clonidine as well as after a low dose of naltrexone 
given by mouth. Your blood pressure and pulse may be repeated if the readings indicate 
possible low blood pressure.  
 
▪ 
Your clinic visit will last for about 2-3 hours each day.  
 
▪ 
After taking clonidine, if your blood pressure is outside of study safety limits and/or you are 
experiencing side effects, your blood pressure will be taken again in 30 minutes. If it is still 
outside study safety limits, naltrexone will not be given and you may be asked to return the 
next day to try again.  
 
▪ 
On days 3 and 4 you will receive increasing doses of naltrexone given by mouth. On day 5 you 
will receive the injection (shot) of naltrexone.  
 
▪ 
You normally will have up to Wednesday during week 4 to start the transition to naltrexone. If 
you do not submit a urine negative for opioids and/or relapse has happened, you will be 
offered buprenorphine. 
 
▪ 
If you miss clinic or leave clinic prior to completing the drug administration and monitoring 
procedures, you will not be able to transition to injection naltrexone.  
 
▪ 
If you have not relapsed to opioid use and did not transition to injection naltrexone you will be 
offered treatment referrals or continued weekly study participation without naltrexone 
therapy.  
 
Naltrexone Maintenance (weeks 5-12)  
 
▪ 
During weeks 5-12 you will attend clinic once a week.  
 
▪ 
A second naltrexone shot will be given during your week 8, if you are eligible and choose to 
receive it. Your last visit will be during week 12, at which final assessments will be done. 
 
▪ 
At study discharge, we will help you with a referral to an appropriate treatment program, if 
you wish it. 
 
Follow-up Visit (week 16) 


Study Title: Improving Treatment Outcomes for Prescription Opioid Dependence 
PIs (researchers): Alison Oliveto, PhD and Michael Mancino, MD 
Institution: University of Arkansas for Medical Sciences 
Sponsor: National Institute on Drug Abuse 
 
 
Version 20                      
 
7/24/2020 
Page 7 
 
 
 
 
 
▪ 
We will ask for information on two stable contacts in order to keep in contact with you, 
schedule your follow up visit and provide appointment reminders.  
 
▪ 
At the follow up visit, you will be asked to submit a supervised urine sample to test for drugs 
of abuse as well as complete several study assessments as before. 
Who will see the information about me that is collected? 
▪ 
The study team will know your name and have access to your information.  
▪ 
We will do our best to make sure no one outside the study knows you are part of the study. 
✓ All research data will be labeled with a code that is linked to your name on a master list 
that is kept in a locked file cabinet in a secured room.  
✓ When we share the results of the study in presentation, posters and articles, we will not 
include your name or any other details that might identify you.  
▪ 
We have a Certificate of Confidentiality from the Department of Health and Human Services. This 
means researchers cannot be made to release information, even by a court order or subpoena. 
This is not a guarantee. Your information might be released if:  
✓ You have a disease others could catch from you (such as TB or HIV)  
✓ Researchers report current abuse (such as child or adult abuse) you may be involved in 
✓ Researchers think you are in danger of hurting yourself or others 
✓ A federal agency or UAMS office asks for information 
✓ The Certificate of Confidentiality does not mean the Department of Health and Human 
Services recommends this study.  
▪ 
Researchers may also give medical information without your permission in the event of an 
emergency. 
▪ 
Your personal information that can identify you may be removed from identifiable data or 
specimens for future research without additional consent. 
▪ 
There are also people who make sure the study is run the right way. These people may see 
information from the study about you. They are: 
✓ OHRP (Office for Human Research Protections), a federal agency 
✓ UAMS Institutional Review Board and/or other UAMS institutional oversight offices 
✓ FDA (Food and Drug Administration) 
 Where and how long will my information and samples be kept?  
▪ 
We will code your information and study samples and keep the code in a locked file.  
▪ 
Research records will be kept for up to 5 years after the study results are published. 


Study Title: Improving Treatment Outcomes for Prescription Opioid Dependence 
PIs (researchers): Alison Oliveto, PhD and Michael Mancino, MD 
Institution: University of Arkansas for Medical Sciences 
Sponsor: National Institute on Drug Abuse 
 
 
Version 20                      
 
7/24/2020 
Page 8 
 
 
 
 
▪ 
Only research staff members will have access to the code for your information. 
▪ 
We will not put information about you from the study in your UAMS medical record.  
What if I say no, I do not want to be in this study? 
▪ 
Nothing bad will happen.   
▪ 
You can still get medical care at UAMS.  
What happens if I say yes, but change my mind later? 
▪ 
Being in the study is completely up to you. You may leave the study at any time.  
▪ 
If you decide to not be in the study (now or later), nothing bad will happen. 
▪ 
You can still get health care at UAMS. 
▪ 
We will refer you to a drug treatment program, if you want.  
▪ 
If you change your mind after starting the study, your lab samples and study records will stay in the 
study files 
If you decide to stop being in the study, call the research staff at 501-526-7969. 
Can I be taken out of the study even if I want to continue? 
Yes, the study doctor (or head researcher) can take you out of the study if: 
▪ 
You do not follow study instructions. 
▪ 
It is not in your best interest to continue. 
▪ 
The study is stopped for any reason. 
▪ 
If you have to quarantine due to COVID-19. 
▪ 
You do not behave properly on the unit. 
▪ 
For any reason that may not be known at this time. 
If I stop being in the study, what will happen to any information or samples collected from me in the 
study? 
We will not be able to take your information or samples out of the study after it has started.  
Will my personal information or samples from the study be used for anything else, including future 
research? 
No. Your personal information and samples will be used only in this study. 
Will it cost me anything to be in the study? 
The study will not cost you anything.  


Study Title: Improving Treatment Outcomes for Prescription Opioid Dependence 
PIs (researchers): Alison Oliveto, PhD and Michael Mancino, MD 
Institution: University of Arkansas for Medical Sciences 
Sponsor: National Institute on Drug Abuse 
 
 
Version 20                      
 
7/24/2020 
Page 9 
 
 
 
 
Will I be paid?  
▪ 
Yes. We will give you money to thank you for your time.  
 
▪ 
Every day that you come in, you will get draws from the fishbowl. The number of draws per 
day depends on which week of participation you are in. You can also earn bonus draws if you 
have perfect attendance for a given week. The tables below show the possible amounts of 
money earned during the study. 
 
Number of Each Ticket and Value in the Fishbowl: 
 
Prize 
 
Number of Tickets 
“Good Job!” 
250 
 $1 
229 
$5 
10 
$25 
10 
$100 
1 
 
Number of Possible Draws and Money Paid: 
 
Draws 
 
Bonus Draws 
per Week for 
Attendance  
Maximum 
Total 
Possible 
Draws per 
week 
Money paid for attendance and 
returning blister packs 
Week 0 (Screening 
& Intake) 
0 
0 
   0 
$10 for physical, $25 for intake 
Week 1 (M-F or 
THRICE WEEKLY) 
1 
1 
6 
0 
Week 2 (M-F or 
THRICE WEEKLY) 
2 
2 
12 
$5 weekly for returning blister 
packs 
Week 3 (M-F or 
THRICE WEEKLY) 
4 
4 
24 
$5 weekly for returning blister 
packs 
Week 4 (M or T-F 
Naltrexone 
Transition) 
5 
5 
30 
$20 daily for attendance, $5 
weekly for returning blister packs 
Weeks 5-12 (1 Visit 
per Week, 
Naltrexone 
5 
0 
0 
$50 once weekly for attendance, 
$5 weekly in weeks 5-6 for 
returning blister packs 


Study Title: Improving Treatment Outcomes for Prescription Opioid Dependence 
PIs (researchers): Alison Oliveto, PhD and Michael Mancino, MD 
Institution: University of Arkansas for Medical Sciences 
Sponsor: National Institute on Drug Abuse 
 
 
Version 20                      
 
7/24/2020 
Page 10 
 
 
 
 
* On average, your earnings (fishbowl plus fixed monetary payment) will be up to $35 upon completion 
of intake, $90 during weeks 1-3, $150 during week 4 and $480 during weeks 5-12, for a possible total of 
$755. This amount is randomly determined (luck of the draw), and cannot be guaranteed due to the 
random nature of the fishbowl pulls. 
▪ 
If you do not come to all visits or drop out before the end of the study, you will get a check for the 
amount you had earned. If you do not come to the follow up visit, the check will be mailed to you 
at the address you give us. 
▪ 
If you receive more than $600 in one year (January-December) from UAMS, UAMS may report the 
amount earned to the Internal Revenue Service (IRS) and send you a tax form, if required by law 
▪ 
If you are attending clinic during weeks 1 – 3 on the truncated schedule (thrice weekly) due to the 
COVID-19 virus, you will receive the same total number of fishbowl pulls as above, redistributed 
according to your days of clinic attendance. 
Will being in this study help me in any way?  
▪ 
This study may or may not help you. 
▪ 
It might help you quit pain meds and/or stay sober. 
▪ 
Even if the study does not help you, what is learned from the study might help others who want 
treatment for a pain med problem. 
 
What are the risks of being in this study? 
 
It is important that you stop using pain pills or heroin at least 24-48 hours before starting 
buprenorphine.  
 
The main risks include the following: 
▪ 
Taking buprenorphine can cause: 
✓ Feeling drowsy 
✓ Feeling weak, tired 
✓ Nausea, vomiting 
✓ Dry mouth 
✓ Dreaming 
✓ Dizziness 
✓ Anxiety 
✓ Flushing (hot, red skin) 
✓ Sweating 
✓ Depression 
✓ Chills 
✓ Low blood pressure 
✓ Slurred speech 
✓ Very small pupils 
✓ Tingling skin 
✓ Ears ringing 
✓ Problems breathing 
✓ Fast heartbeat 
Maintenance)  
Week 16 (1 time 
follow-up visit) 
0 
0 
0 
$50 for attendance 
Total $ 
 
 
 
$610 (not including fishbowl 
draws)* 


Study Title: Improving Treatment Outcomes for Prescription Opioid Dependence 
PIs (researchers): Alison Oliveto, PhD and Michael Mancino, MD 
Institution: University of Arkansas for Medical Sciences 
Sponsor: National Institute on Drug Abuse 
 
 
Version 20                      
 
7/24/2020 
Page 11 
 
 
 
 
✓ Bloodshot eyes 
✓ Confusion 
✓ Constipation 
✓ Vision problems 
✓ Bad itching 
✓ Feeling “high” 
✓ Problems urinating 
✓ Difficulty know what is 
and isn’t real 
 
▪ 
Detox from buprenorphine can cause: 
✓ Anxiety 
✓ Yawning 
✓ Backache 
✓ Nausea 
✓ Restlessness 
✓ Feeling tense 
✓ Diarrhea 
✓ Watery eyes 
✓ Feeling jittery 
✓ Hot and cold sweats 
✓ Runny nose 
✓ Depression 
✓ Hot flashes 
✓ Chills / chill bumps 
✓ Feeling sleepy 
✓ Muscle cramps 
✓ Sneezing 
✓ Noise sensitivity 
✓ Flushing 
✓ Stomach cramps 
✓ Clammy / damp skin 
✓ Joint pain 
 
 
        These symptoms can be unpleasant, are not dangerous and only last for a while. 
 
▪ 
Taking gabapentin can cause: 
✓ Sleepiness 
✓ Problems moving 
✓ Nausea/vomiting 
✓ dizziness 
✓ Serious breathing difficulties*
 
*  While taking gabapentin, serious breathing difficulties can occur if you use certain medicines that 
decrease central nervous system activity (for example: opioid pain medicines, antihistamines, or 
medicines that help with anxiety or depression), have a medical condition that lowers the lungs’ 
ability to work, and/or are 65 or older. 
▪ 
Taking buprenorphine combined with gabapentin can cause: 
✓ Sleepiness 
✓ Nausea/vomiting 
✓ Sleep disturbances 
✓ Loss of motor skills 
✓ Lightheadedness 
 
✓ Serious breathing 
difficulties* 
▪ 
Taking clonidine can cause: 
✓ Dry mouth 
✓ Dizziness 
✓ Sleepiness 
✓ Drowsiness 
✓ Tiredness 
✓ Headache 
✓ Changes in heart rate 
and blood pressure 
 
▪ 
Taking naltrexone and/or clonidine and/or gabapentin can cause:
 
✓ tearfulness 
✓ Restlessness 
✓ Difficulty sleeping 
✓ Mild nausea 
✓ Bone, joint or muscle 
pain 
✓ Anxiety 
✓ Stomach cramps 
✓ Runny nose 
✓ Nervousness 
✓ Abdominal pain 
✓ Low energy 
✓ Diarrhea 
✓ Constipation 
✓ Increased thirst 
✓ Increased energy 


Study Title: Improving Treatment Outcomes for Prescription Opioid Dependence 
PIs (researchers): Alison Oliveto, PhD and Michael Mancino, MD 
Institution: University of Arkansas for Medical Sciences 
Sponsor: National Institute on Drug Abuse 
 
 
Version 20                      
 
7/24/2020 
Page 12 
 
 
 
 
✓ Feeling down 
✓ Irritability 
✓ Dizziness 
✓ Skin rash 
✓ Chills 
✓ Delayed ejaculation 
✓ Decreased sexual 
potency 
 
 
 
You may not benefit from opioid containing medicines, such as certain cough and cold meds, 
antidiarrheal meds, and opioid pain relievers.  
 
▪ 
Other side effects can include a type of pneumonia with symptoms such as coughing, difficulty 
breathing and night sweats, accidental symptoms of opioid withdrawal, and possibly liver 
damage. 
 
▪ 
In addition, symptoms such as vomiting and diarrhea can lead to dehydration and/or low blood 
pressure if you do not keep well hydrated. It is very important that you drink lots of water 
before and after your clinic visits during week 4; a beverage containing electrolytes will also be 
given to you during your week 4 clinic visits to help you stay hydrated.  
 
▪ 
If you need opioid pain relievers, the amount of drugs required may be more than normal, and 
might cause breathing problems. Trying to cancel out the effects of naltrexone by taking large 
amounts of opioids is very dangerous and may lead to a fatal overdose.  
 
▪ 
Also, the risk of overdose on opioids goes up as naltrexone’s effects wear off. So, it is very 
important that you avoid using opioids during the first two weeks after the effects of 
naltrexone have worn off, because using opioids during this time could result in overdose and 
even death.  
 
▪ 
The injection(s) may result in irritation, itching, soreness, swelling and/or bruising where the 
injection was given. 
▪ 
Other risks or inconveniences 
✓ You may feel pain and get a bruise from blood draws. You may feel faint.  
✓ Someone could find out that you were in the study and learn something about you that you did 
not want others to know. We will do our best to protect your privacy. 
✓ The questions could make you sad or upset.  
✓ This study may involve risks that are not currently known. 
 
▪ 
WOMEN PLEASE NOTE: This research may have bad effects on an unborn fetus. 
✓ Do not be in the study if you are pregnant. 
✓ We must do a test to make sure you are not pregnant before letting you in the study. 
✓ If you agree to be in the study, you agree to not get pregnant and to use birth control during the 
study.  


Study Title: Improving Treatment Outcomes for Prescription Opioid Dependence 
PIs (researchers): Alison Oliveto, PhD and Michael Mancino, MD 
Institution: University of Arkansas for Medical Sciences 
Sponsor: National Institute on Drug Abuse 
 
 
Version 20                      
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Page 13 
What if I get sick or hurt while I’m in this study? 
▪ 
If you are hurt by being in the study, you may be treated. You or your insurance will pay for treatment 
in most cases. It may include 
✓ first aid  
✓ emergency treatment  
✓ follow-up care  
▪ 
If you get hurt when you are here for the study we will help you get the care you need. 
✓ If you are thinking about hurting yourself or have another serious health problem, the study 
doctor will be told right away.  
✓ If you are at risk of hurting yourself or someone else, an ambulance and campus police will be 
called. You may be taken to the ER. You may be put in the hospital against your will.  
▪ 
If you get hurt or sick when you are not here, call your doctor or 911 in an emergency.  
▪ 
If you are quarantined due to COVID-19, you must tell staff immediately. You may be discharged from 
the study. If so, the researchers will refer you to treatment and make arrangements for you to finish 
the buprenorphine taper, if you have not completed the detox. 
▪ 
If being sick has to do with being in the study 
✓ tell the emergency medical staff or your doctor about the study 
✓ give the name of the study and copy of this form if you have it 
✓ page one of the study doctors (501-688-6101) as soon as you can  
What if new information comes up about the study? 
▪ 
We will call you or send you a letter.  
▪ 
We will tell you about anything that might change your mind about being in the study.  
Where can I find more information about this clinical trial? 
▪ 
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. 
Who do I call if I have questions about the study? 
▪ 
Dr. Oliveto at 501-526-8441. After hours, page one of the study doctors at 501-688-6101.  
▪ 
UAMS Institutional Review Board (IRB) representative at 501-686-5667, if you  
✓ have questions about your rights as a study subject  
✓ have questions concerning a research-related injury 
✓ can’t reach the study team 
✓ need to speak to someone not directly involved with this study 


Study Title: Improving Treatment Outcomes for Prescription Opioid Dependence 
PIs (researchers): Alison Oliveto, PhD and Michael Mancino, MD 
Institution: University of Arkansas for Medical Sciences 
Sponsor: National Institute on Drug Abuse 
 
 
Version 20                      
 7/24/2020 
Page 14 
▪ 
The IRB makes sure people in research studies are protected from harm by the study. For more 
information go to https://irb.uams.edu/about_us/ 
What should I do if I want to be in the study? 
Sign this form. We will give you a copy of the form to keep. 
 
By signing the document I am saying: 
▪ 
I understand that joining this study is voluntary. 
▪ 
I agree to be in the study. 
▪ 
Someone talked with me about the information in this document and answered all my questions.  
▪ 
I have been asked if I wish to talk directly to the head researcher or study doctor.  
I know that: 
▪ 
I can stop answering questions at any time and nothing will happen to me. 
▪ 
I can call the office that supervises research (UAMS IRB) at 501-686-5667 if I have any questions about 
the study or about my rights. 
▪ 
My decision will not change my medical care at UAMS. 
▪ 
I do not give up any of my rights by signing this form. 
▪ 
The purpose and voluntary nature of this study, as well as the potential benefits and risks that are 
involved have been explained to me. I have been able to ask questions and express concerns, which 
have been satisfactorily responded to by the study team. I understand that I have waived no rights by 
signing this consent form. 
▪ 
I have been told that I will be given a signed copy of this consent form. 
I agree to be part of this study: 
 
__________________________  
 
 
_______________________________ 
Your name (please print) 
 
 
 
Your signature 
 
____________________________ 
Date 
 
____________________________ 
 
 
_________________________________ 
Name of person obtaining consent (please print) 
Signature of person obtaining consent 
 
____________________________ 
Date 

Prot_000.pdf: 
Improving treatment outcomes for prescription opioid dependence                                         PI: Alison Oliveto, Ph.D. 
 
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Protocol  
 
 
Study Title: Improving Treatment Outcomes for Prescription Opioid Dependence 
 
NCT Number: NCT02543944 
 
Version 26 
 
July 24, 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1. Principal Investigators: Alison Oliveto, Ph.D. (contact PI) and Michael Mancino, M.D. (Co-PI) 
 
2. Title and Abstract: Improving treatment outcomes for prescription opioid dependence  
 
Opioid dependence is a serious public health problem, particularly with the dramatic rise in prescription 
opioid abuse, but long-term opioid agonist maintenance with methadone or buprenorphine (BUP) may not 
be optimal for many prescription opioid abusers. Yet current opioid detoxification strategies are limited by 
high relapse rates and/or lack of efficacy in relieving subjective symptoms. In addition, antagonist 
maintenance with naltrexone (NTX), which may be an optimal longer-term strategy for this population, 
requires prior opioid detoxification and has been associated with relatively poor outcomes in heroin abusers.  
This application takes a novel, broad approach to address the problem of prescription opioid dependence 
by determining the 1) utility of adjunct gabapentin (GBP) during outpatient BUP detoxification to improve 
initial outcomes and 2) feasibility of transitioning prescription opioid -dependent patients to depot NTX 
following detoxification, which may improve longer-term outcomes. GBP, an N-type calcium channel blocker 
with low abuse potential, potentiates opioid analgesia, decreases both postoperative morphine consumption 
and movement-related pain, and reverses tolerance to the antinociceptive effects of morphine. GBP is also 
well tolerated and effective in reducing craving and illicit opioid use in pilot detoxification trials. We propose 
to assess the efficacy and tolerability of adjunct GBP during BUP-assisted detoxification and the feasibility 
of subsequent transition to depot NTX therapy in prescription opioid -dependent participants. This 12-week, 
randomized, placebo-controlled clinical trial will determine the potential utility of adjunct GBP in 150 
prescription opioid -dependent individuals undergoing outpatient BUP detoxification and whether transition 
to short-term depot NTX therapy is feasible. Our three specific aims are to determine (1) the efficacy and 
tolerability of GBP to reduce craving and illicit use of opioids in prescription opioid -dependent individuals 
undergoing outpatient BUP detoxification; (2) acceptability and feasibility of transition to, and short-term 
maintenance on, depot NTX following detoxification; and (3) prognosticators of completion of the BUP taper, 
successful induction onto depot NTX, symptomatology, and longer-term outcomes. Currently, the only FDA-
approved medications for the treatment of opioid withdrawal are the opioid agonists methadone and BUP, 
both of which have abuse liability, and NTX, which can produce low levels of withdrawal-like symptoms, 
especially early in treatment. Our findings, if positive, will support further development of GBP as an adjunct 
medication as well as provide an integrated, seamless approach to outpatient prescription opioid -
dependence treatment. Ultimately, this work could impact the addiction field by providing both procedural 
and pharmacological tools for treating prescription opioid dependence that significantly improve outpatient 
detoxification outcomes and markedly enhance access and transition to NTX therapy. This would shift 
clinical practice, establishing an effective adjunct regimen for BUP detoxification and an integrated 
approach f or transition to NTX therapy. GBP may also be clinically useful for other situations where opioid 
withdrawal is a concern. 
 
3. Purpose: 
 
The specific aims are the following:  
Specific Aim 1. Determine the tolerability and efficacy of GBP (1600 mg/day) to reduce 
withdrawal symptoms, craving, and illicit use of opioids in prescription opioid -dependent 
individuals undergoing BUP detox. Our hypothesis is that GBP will be well tolerated and reduce, relative 
to placebo, illicit use of opioids during and immediately following the BUP detox. Gabapentin may also 
reduce secondary outcomes of withdrawal symptoms and craving relative to placebo during and/or 
immediately following the BUP detox. 
Specific Aim 2. Determine the acceptability and feasibility of transitioning patients completing 
detox to depot NTX. Our hypothesis is that the majority of those abstinent immediately post-detox will be 
successfully transitioned to depot NTX.   


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Specific Aim 3. Determine prognosticators of completion of the BUP taper, successful induction 
onto depot NTX, symptomatology, and longer-term outcomes at the 16-week follow-up. Mediators 
(e.g., changes in ratings over time) associated with outcomes will also be explored. 
 
4. Background: 
 
 
Opioid dependence continues to be a serious public health problem, particularly with the dramatic 
rise in abuse of prescription opioids [1]. Prescription pain relievers were second to marijuana in terms of 
prevalence of dependence or abuse in 2009 [1]. Moreover, the number of emergency department visits in 
2009 involving narcotic pain relievers was 137% higher than the 2004 level of 144,644 visits [2]. 
Prescription-opioid abuse is associated with serious negative consequences that include physiological 
dependence, high-risk behaviors [3, 4], overdose [5, 6], and death [7-9]. Particularly concerning, the rate of 
current nonmedical use of prescription opioids increased 17% from 2002 to 2009 among young adults aged 
18–25 [1]. This project seeks to address the problem of opioid dependence by improving upon detoxification 
strategies for opioid dependence. 
The three existing FDA-approved treatments for opioid dependence were developed in trials with heroin 
users and include agonist maintenance with methadone or buprenorphine (BUP), methadone- or BUP-
assisted detox, and maintenance on the opioid antagonist naltrexone (NTX) in post-opioid dependent 
patients. Each of the three approaches has significant drawbacks for prescription opioid abusers. 
Opioid Agonist Maintenance. A major factor involved in relapse among chronic opioid abusers is the 
experience of a particular set of “flu-like” symptoms indicative of opioid withdrawal upon stopping opioids or 
taking an opioid antagonist (e.g., naloxone). Longer-term maintenance with the opioid agonist methadone or 
BUP has shown efficacy for treating prescription opioid dependence [10], with prescription opioid users 
generally showing better outcomes than heroin users [11, 12]. However, given that prescription opioid 
abusers tend to be younger, have shorter treatment histories and have less severe dependence than heroin 
users [13, 14], longer-term maintenance may not always be appropriate or feasible. Prescription opioid 
abusers may also find opioid agonist treatments unacceptable due to the related stigma [14, 15]. The use of 
longer-term opioid agonist treatment is especially undesirable in the growing population of adolescents and 
young adults using prescription opioids [16]. Opioid agonist treatment is also considered suboptimal in 
certain other populations, including criminal justice and professionals [17, 18]. In addition, opioid agonist 
maintenance treatments may not be accessible in rural regions, which is ironically where prescription opioid 
use is highly prevalent [19, 20]. In addition to all those disadvantages, the most commonly cited concern of 
opioid maintained patients regarding coming off opioid agonist treatment is withdrawal symptoms [21]. 
Thus, alternate treatment options need to be uncovered to enhance accessibility, acceptability, and 
treatment outcomes. 
Detoxification. Traditional opioid detox methods, including methadone taper and supportive treatment of 
symptoms with the alpha2-adrenergic receptor agonists, are limited by high relapse rates and lack of 
efficacy in relieving subjective symptoms [22-28]. Although BUP appears similar to methadone in relieving 
withdrawal symptoms and may resolve withdrawal symptoms faster than methadone, symptoms are still 
moderate [29] and highly variable among patients [30]. BUP detox is also complicated by the emergence of 
withdrawal symptoms post-taper [31, 32]. To our knowledge, only three studies have specifically recruited 
prescription opioid users to determine outcomes with BUP detox [10, 33, 34]. In a multi-site trial of BUP-
naloxone (NX) treatment for prescription opioid dependence, patients who failed a 2-week BUP taper 
reduced opioid use during extended BUP-NX, but still had high rates of relapse following a 4-week BUP 
taper similar to those without extended BUP-NX treatment [10]. A feasibility study showed that 14 
prescription opioid users undergoing a brief BUP taper had high rates of opioid abstinence during, but not 
following, the taper, with a subset having high rates of abstinence during the taper and subsequent oral 
NTX therapy [33]. A small randomized, double-blind trial that included a strong behavioral intervention 
showed that a 4-, relative to 2- or 1-, week BUP taper resulted in greater opioid abstinence during the taper 
and subsequent oral NTX therapy in prescription opioid abusers, although response was not complete [34]. 
These findings highlight the need to identify subpopulations of prescription opioid users most likely to 


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respond to detox versus opioid agonist maintenance [33]. Thus, improving treatments for opioid withdrawal 
and identifying those most likely to benefit from this strategy are of great importance for optimizing opioid 
detox strategies in prescription opioid-dependent patients. 
NTX Maintenance. Given the more positive prognosis for prescription opioid users relative to heroin 
users [11, 13], NTX may be a good long-term approach to maintaining abstinence from opioids. NTX is 
used to prevent reinstatement of drug use and dependence by blocking the effects of opioid agonists. 
Evidence suggests that NTX therapy does not worsen depression [35, 36] and may help reduce craving for 
opioids [37] among medication-compliant patients. However, NTX is limited by the need for patients to 
undergo detox from opioids and remain abstinent prior to NTX therapy, which reduces acceptability of NTX 
and success rates [38]. Oral NTX therapy also has been associated with high rates of dropout, medication 
noncompliance, and relapse associated with noncompliance [39-41] as well as risk of overdose [42]. 
Although new, sustained-release formulations of NTX have helped to mitigate issues of medication 
noncompliance, illicit opioid use, retention [38, 43, 44] and overdose [45-47], and the strategic use of 
contingency management procedures has enhanced outcomes [48, 49], treatment improvements are still 
necessary to help reduce symptoms, which would bolster outcomes and success rates. For instance, 
patients have reported experiencing opioid withdrawal-like symptoms of mild to moderate severity during 
the first few weeks after beginning NTX therapy [50].  
Relative Lack of Treatment Research Specific to the Prescription Opioid User Population. Importantly, 
the vast majority of NTX studies have recruited almost exclusively heroin users [40, 50-52]. Given that 
acceptability of receiving a second NTX implant has been associated with pretreatment employment length, 
less drug use, less criminality, and concern about family problems [53], prescription opioid users may be 
better candidates for this treatment option. However, to our knowledge, two studies have examined BUP 
detox and transition to oral NTX in prescription opioid users [33, 34]. One uncontrolled study examined the 
feasibility of a brief BUP detox and transition to oral NTX [33]. Of the 14 who entered the taper phase, all 14 
transitioned to oral NTX, but only 5 (36%) individuals seemed to benefit with minimal, if any, opioid use 
during NTX maintenance. Moreover, only 36% of participants had opioid-negative urines the day following 
the taper [33]. In another randomized, double blind trial combined with a strong behavioral intervention, 
greater opioid abstinence occurred during the BUP taper and subsequent NTX therapy among those 
undergoing a longer versus shorter BUP taper [34]. These findings highlight the need to examine various 
strategies for optimal transition to, and maintenance on, NTX therapy, particularly sustained-release 
formulations, in this population to optimize treatment outcomes. 
The mechanisms of opioid withdrawal are not well understood, but there is evidence to suggest that the 
expression of opioid withdrawal is mediated, in part, by mu opioid and other neurotransmitter systems 
acting through the locus coeruleus, which is the largest noradrenergic nucleus in the brain [54-57] (for 
exception, see [58]). The locus coeruleus also receives a major excitatory amino acid input from the nucleus 
paragigantocellularis [59, 60], and excitatory amino acids play a role in opiate dependence and withdrawal 
[59, 61, 62]. One site where excitatory amino acid neurotransmission occurs is the N-methyl-D-aspartic acid 
(NMDA) receptor, part of a receptor/ion channel complex with multiple regulatory sites, including sites on 
cationic channels permeable to potassium, sodium, and calcium [63]. Activation of the NMDA receptor is 
associated with increased intracellular calcium levels, and calcium channel blockers (CCBs) have been 
shown to alleviate opioid withdrawal [64-68]. Thus, CCBs may have utility for improving treatment for opioid 
withdrawal.  
CCBs have been shown to alleviate opioid withdrawal in opioid-treated nonhumans [67]. Moreover, the 
L-type CCBs verapamil, nimodipine, and nifedipine have been shown to alleviate withdrawal in clinical trials 
of opioid detoxification [69, 70]. In a human model of opioid withdrawal, isradipine, which is an L-type CCB, 
was most effective among the CCBs tested for their efficacy to block naloxone-induced behavioral effects 
[71-73]. Importantly, isradipine showed greater dose-related efficacy than the alpha2-adrenergic agonist 
clonidine or tizanidine [72-74]. For instance, clonidine partially attenuated naloxone-occasioned responding 
in a manner not related to dose and somewhat attenuated naloxone-induced changes in self-report 
measures, including opioid-antagonist ratings [74]. When combined with naloxone, isradipine significantly 
attenuated naloxone-occasioned responding without increasing novel-appropriate responding occasioned 


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when given alone, and significantly attenuated naloxone-induced increases in ratings of opioid-receptor 
antagonist and in ratings measuring sedation (data not shown) [72]. These results suggest that isradipine 
may be more effective than clonidine as a nonopioid pharmacotherapy for treating opioid withdrawal. Thus, 
the proposed project will determine the preliminary efficacy and tolerability of isradipine in opioid-dependent 
participants undergoing 10-day BUP detoxification.  
Evidence suggests that BUP is among the most effective detox agents, but relapse rates are still high 
post-taper [30] and ancillary medications are ineffective in improving outcomes [75]. Thus, adjunct treatment 
with a pharmacologically relevant medication is needed. Our pilot studies and those of others suggest that 
agents acting on non-opioid pharmacological targets implicated in the expression of opioid withdrawal may 
have utility (see Rationale section below). Given that calcium channel blockers (CCBs) have been shown to 
alleviate opioid withdrawal [64-68], we will examine the efficacy of a CCB to improve outcomes during BUP 
detox.  
Various calcium channel subtypes have been identified and are grouped according to their distinct 
electrophysiological and pharmacological properties into T-, N-, L-, P/Q, and R-types (see [76]), of which the 
L-type CCBs have been the most commonly studied for opioid withdrawal. Yet these agents may have 
limited utility for outpatient detox due to the potential for hypotensive effects [70, 72], as in the case of the 
alpha2-adrenergic agonist clonidine [27, 77], and the feasibility and preliminary efficacy of the L-type CCB 
isradipine is currently being studied in a pilot trial (R21DA035325; Oliveto, PI). This application focuses on 
an N-type CCB, due to the fact that N-type CCBs have less impact on blood pressure while alleviating 
certain pain conditions (see [78]). GBP, an N-type CCB [79, e.g., 80, 81] and gamma-aminobutyric acid 
(GABA) analogue that promotes release of GABA [82, 83], has been shown to attenuate morphine-induced 
conditioned place preference in rats [84]; enhance the analgesic effect of morphine in rats [85] and healthy 
volunteers [86]; decrease postoperative morphine consumption and movement-related pain after radical 
mastectomy [87]; and block, as well as reverse, tolerance to the anti-nociceptive effects of morphine in the 
rat paw-pressure and tail-flick tests [88]. These findings indicate a relationship between GBP and the opioid 
system that is similar to that observed with L-type CCBs [e.g., 89] and should be explored further. 
     Given that the GABA system has been implicated in the expression of withdrawal [e.g. 90, 91-93], the 
GABA-ergic actions of GBP may also contribute to its efficacy in attenuating withdrawal. GBP has low 
abuse liability [94], a favorable side effect profile, minimal drug interactions, and a relatively short 
elimination half-life (5-9 hours) [95]. GBP has also been shown to decrease naloxone-induced ratings of 
drug strength in opioid-maintained humans [96]. In addition, GBP at 1200-1800 mg/day, but not 900 mg/day 
[97], has been shown to alleviate withdrawal symptoms in both uncontrolled [98-100] and placebo- 
controlled [31] opioid agonist-assisted detox trials. Thus, GBP may be a promising adjunct medication for 
opioid withdrawal. 
 
Despite the scope of the prescription opioid problem, a paucity of data still exists regarding characteristics 
of the prescription opioid dependent population as well as those subpopulations of prescription opioid 
abusers most likely to benefit from a particular treatment [13, 14, 33, 101]. Moreover, results of medications 
development trials have shown that potential treatment agents such as NTX [102, 103] or alpha-adrenergic 
agents [22, 104] have modest efficacy in the whole sample, indicating the need to identify potential factors 
that may impact treatment response. Yet few studies have examined predictors, mediators, and moderators 
of outcomes in medication treatment for opioid dependence [34, 101, 105-107]. To determine whether we 
can identify subpopulations of prescription opioid -dependent patients who are most likely to benefit from 
GBP and transition to NTX, we will assess several types of measures at baseline and/or during the course 
of the trial, including demographic, drug dependence severity, level of opioid use, treatment history, 
retention, and comorbid psychiatric and substance use disorders. Other major prognosticators we will 
examine are gender, distress tolerance, readiness to change, and anxiety: 1) Gender: Women are as likely 
as men to misuse prescription opioids [108], and almost half of treatment admissions with opioids other than 
heroin as the primary drug of abuse are women [109]. To our knowledge, one large clinical trial for 
prescription opioid dependence showed sex differences in baseline characteristics but not treatment 
outcomes [107]. Given that sex differences have been observed in response to other pharmacological 


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interventions during medication trials [110, 111] and laboratory studies [112, 113], we will examine whether 
sex differences in response to GBP versus placebo occur. 2) Distress tolerance: Psychological distress 
tolerance is defined as the ability to persist in goal-directed activity while experiencing psychological 
distress [114, 115]. Distress tolerance has been shown to be negatively associated with a range of 
problematic behaviors, including drug and alcohol use [116, 117]. Moreover, drug or alcohol treatment 
outcomes are poorer in individuals with low distress tolerance [118, 119]. Because detox and NTX therapy 
can produce symptoms that are uncomfortable or “distressing,” we will examine whether baseline objective 
and subjective measures of distress tolerance predict subsequent treatment response. We will also 
measure distress tolerance at several time points to determine whether distress tolerance changes as a 
function of study phase. 3) Readiness to change: Motivation to change drug-using behaviors has been 
associated with treatment retention and outcomes [120, 121] and is thought to predict patient behaviors 
during treatment. We will assess whether “readiness to change,” measured by a validated instrument [122], 
will predict treatment response during the detox as well as successful transition to and maintenance on NTX 
therapy. We will also reassess this construct at several time points to determine whether motivation 
changes during participation, as has occurred previously [48]. 4) Anxiety: Anxiety is prevalent in opioid-
dependent populations [106] and is associated with craving for opioids during opioid withdrawal [123]. 
Higher anxiety and craving ratings also occur during early abstinence in former heroin users [124]. In 
addition, anxiety sensitivity (i.e., fear of anxiety-related bodily sensations, arising from a belief that such 
sensations have harmful personal consequences) is associated with greater likelihood of dropping out of 
residential treatment programs [125] as well as greater sedative use among methadone-maintained women 
[126]. On the other hand, severe anxiety symptoms at baseline doubled the likelihood of treatment success 
during medically supervised opioid withdrawal procedures [106]. Meanwhile, impaired decision-making in 
opioid-dependent patients has been shown to be influenced by current levels of anxiety and by the 
personality markers trait anxiety and self-directedness rather than drug use per se [127]. Given the dearth 
of data on the prevalence and prognostic relevance of anxiety in prescription opioid abusers, we will obtain 
several measures of anxiety at baseline and during the study. 
 
 5. Significance or Importance of Proposed Research: 
 
The clinical significance of this research is clear. Despite current treatments that are available to 
date, prescription opioid dependence is a chronic, often relapsing, disorder with medical, social, and legal 
complications and opioid withdrawal is implicated in relapse to opioid use. This study will help shed light on 
whether the N-type CCB gabapentin may be a useful adjunct medication during detoxification from BUP as 
well as the feasibility of transition to injection NTX. The results of this study, if positive, will support further 
examination of the utility of N-type CCB’s like gabapentin as adjunct medications during BUP detoxification, 
transition to NTX and other situations where opioid withdrawal may be of concern. 
 
6. Experimental Subjects: 
 
Up to 200 individuals (18-64 yrs old) who are seeking treatment for prescription opioid dependence 
will be recruited until 150 eligible participants have enrolled into the study proper.  
A. Inclusion criteria 
1) be between the ages of 18-64 
2) be available to attend clinic 3 - 6 days a week for approximately 30-120 minutes per day during the first 
3 weeks 
3) fulfill DSM-5 criteria for moderate to severe Opioid Use Disorder. These criteria will be ascertained in 
the following manner:  the physician will determine whether the individual is appropriate based on 
several clinical assessments that are routinely employed by methadone program physicians, including 
history and severity of opioid use, presence of track marks, prior treatment history, self-reported and/or 
observed signs and symptoms of opioid withdrawal. If any individual’s severity of opioid use disorder is 


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questionable, that person will be excluded from further consideration as a participant. 
4) submit a urine sample negative for benzodiazepines or barbiturates prior to starting the study.  
B. Exclusion criteria 
1) report having had a severe adverse reaction to study medications 
2) have an unstable medical condition or stable medical condition that would interact with study 
medications or participation, including a current chronic pain or other medical condition that requires 
ongoing opioid agonist treatment (determined by physician assessment)  
3) conditions such as chronic obstructive pulmonary disease (COPD) that reduce lung function 
4) have a major psychiatric disorder (psychosis, schizophrenia, bipolar) 
5) current suicidal ideation or suicidal attempt in the past 12 months 
6) have a seizure disorder 
7) physiological dependence on alcohol or drugs other than opioids, tobacco or marijuana (as determined 
by physician assessment) 
8) are pregnant, plan to become pregnant, have inadequate birth control, if relevant, or lactating 
9) report ongoing use of OTC or prescription drug (including Maalox) that would have major interaction 
with study drugs, including CNS depressants (e.g., anxiolytics, antidepressants, antihistamines). 
10) have any of the following: liver function tests >3 times normal, BUN and Creatinine outside normal 
range; ECG abnormalities including but not limited to: bradycardia (<50 bpm); prolonged QTc interval 
(>450 msec); Wolff-Parkinson White syndrome; wide complex tachycardia; 2nd degree, Mobitz type II 
heart block; 3rd degree heart block; left or right bundle branch block; pre-existing severe gastrointestinal 
narrowing (pathologic or iatrogenic).  
Individuals with anxiety or depression and not taking exclusionary medications will be included unless 
findings during screening indicate a need for immediate treatment determined by the study physician 
and/or the Columbia–Suicide Severity Rating Scale [128].  
C. Initial Diagnostic Evaluation  
1) Medical—Care will be taken to exclude medically ill participants from the clinical trial by having 
participants undergo a comprehensive evaluation, including physical, psychiatric, and neurological 
examinations. Routine laboratory studies will ensure that participants are medically acceptable for 
participation (CBC, BUN/creatinine, electrolytes, liver-function tests, pregnancy test for women, 
urinalysis, ECG). Liver function tests will be repeated at week 4. A physician will review laboratory data 
and ECG prior to study entry. Women of childbearing potential will have a pregnancy test before starting 
the study and prior to oral NTX. If a woman suspects she has conceived during the study a pregnancy 
test will be done at her request. 
2) Psychiatric/Behavioral—Care will be taken to assure that participants meet diagnostic criteria by means 
of a screening interview by one of the physician investigators.   
 
7. Experimental Methods: 
 
A. Entry into Treatment. If we are recruiting for more than one study at a time, then screening procedures 
will be done under screening protocol # 204167. If a person is eligible to participate, then all screening 
materials will be transferred to this protocol. Participants will be recruited by word-of-mouth, public 
service announcements through local radio and TV stations, internet ads, flyers, newspaper 
advertisements, social media, and AR Research. Otherwise, triage will be done by a staff member and 
take about 60 minutes. It will cover the basic inclusion and exclusion criteria, as well as a brief 
description of the study, to determine if the participant is interested in participating. Treatment 
alternatives as described below will also be offered to the prospective participant. If (s)he is appropriate 
and agrees to the study, full screening will be completed typically within that week.  
Intake will be done by a research staff member and take about 2-4 hours to cover explanation of the 
study, evaluation of exclusion criteria, screening for opioid or other drug dependence, and obtaining 
informed consent. A physical exam will be completed by a study physician and laboratory examination 


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will include urinalysis, urine toxicology screen, ECG (which will be completed by a research assistant or 
research nurse), and blood evaluation (SMA-20, CBC—these and any other laboratory test mentioned in 
this protocol will be outsourced to Quest Diagnostics and/or Redwood Laboratories). TB test status will 
be assessed during the physical exam; individuals who report a history of positive TB test results will be 
required to provide documentation from the Arkansas Department of Health verifying a negative chest x-
ray in the past year. HIV testing is available if requested by the participant. A study physician will then 
interview the participant for psychiatric diagnosis and review of medical data for starting medication. 
This screening would typically be complete within one week; however, this process may take longer in 
cases where a person needs to submit documentation about a medical issue that requires resolution 
prior to study entry, etc. Those who present for screening in severe withdrawal will be referred to the 
Emergency Department. Also, if a physician determines that abnormal screening results may be linked 
to withdrawal, the tests will be redone. Then participants undergo our intake procedure, which can take 
up to 4 hours to complete, including obtaining informed consent for the specific study (if participants was 
screened under IRB#204167) and intake assessments (see assessment section).  
B. Experimental Procedures.  During the detox phase (weeks 1-3), participants will attend the Center for 
Addiction Services and Treatment on the 4th floor of PRI 3-6 days per week to receive study medication, 
attend a weekly therapy session, and complete assessments (Table 1). During the NTX induction (week 
4), participants will attend clinic 4-5 days. On day 1 (either Monday or Tuesday) of week 4, participants 
will submit a urine sample that may need to be opioid-negative in order to start NTX induction. (If the 
urine sample is positive for opioids then the decision to start NTX induction will be made by a study 
physician). Upon daily confirmation of an opioid-negative urine sample or determination by study 
physician to proceed with NTX induction, participants will be administered clonidine, followed by oral 
NTX (6.25 mg). Participant’s orthostatic vital signs and symptoms will be monitored prior to and 20 
minutes following clonidine administration as well as 2 hours after initial oral naltrexone administration. If 
the participant experiences lightheadedness or dizziness and has evidence of orthostatic hypotension 
with BP drop of > 20 mm Hg for systolic or >10 mg Hg for diastolic, accompanied by an increase in 
pulse of more than 20 beats per minute, then the vitals will be repeated in 30 minutes. If the orthostatic 
changes persist at the time of the second measurement prior to naltrexone administration, then 
naltrexone will not be administered and vitals will be repeated every 30 min until they are within study 
parameters for release.  
If participants receive naltrexone 6.25 mg on day 1 (either Monday or Tuesday depending on clinic 
closures and scheduling), they return the following day and several of the procedures from the previous 
day will be repeated, including a drug screen for recent opioid use and vitals to include orthostatic 
measurements. If the drug screen is negative for opioids and no orthostasis is present, then the 
participant will be administered clonidine, followed 20-40 min later by oral NTX (6.25 mg if Tuesday or 
12.5 mg if Wednesday). Participant’s orthostatic vital signs and symptoms will be monitored prior to and 
20 minutes following clonidine administration as well as 2 hours after oral naltrexone administration. 
Procedures for release from the clinic will occur as in day 1. Participants will return on two subsequent 
days to undergo several procedures as before and receive clonidine followed 20-30 min later by 
increasing doses of oral NTX under observation, and receive the NTX injection on day 5. Participants 
then attend clinic once per week for up to 8 weeks (weeks 5-12). 
If participants do not receive naltrexone on day 1 of week 4 (e.g., Monday was a holiday so did not 
attend clinic) then the following will occur: Participants will attend clinic on day 2 of week 4 and submit a 
urine sample that may need to be opioid-negative in order to start NTX induction. (If the urine sample is 
positive for opioids then the decision to start NTX induction will be made by a study physician; 
participants have up to day 3 to be inducted onto NTX). Upon confirmation of an opioid-negative urine 
sample or determination by study physician to proceed with NTX induction, participants will be 
administered clonidine, followed by oral NTX (6.25 mg). If the sample is negative or regular use is not 
indicated, participant’s orthostatic vital signs and symptoms will be monitored prior to and 20 minutes 
following clonidine administration as well as 2 hours after initial oral naltrexone administration. If the 
participant experiences lightheadedness or dizziness and has evidence of orthostatic hypotension with 


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BP drop of > 20 mm Hg for systolic or >10 mg Hg for diastolic, accompanied by an increase in pulse of 
more than 20 beats per minute, then the vitals will be repeated in 30 minutes. If the orthostatic changes 
persist at the time of the second measurement, then the transition to NTX will be halted on that day. The 
participant will be invited to return on day 3 and the procedures from the previous day will be repeated 
including a drug screen for opioids and vitals to include orthostatic measurements. If drug screen is 
negative for opioids and no orthostasis is present, then the participant will resume the process that was 
attempted on day 1 or 2, except that they receive 12.5 mg of NTX on day 3 and proceed with the dose 
escalation above on subsequent days. If orthostatic changes recur, then the participant will not be 
transitioned to NTX, and his/her study participation may be ended and s/he will be referred to alternative 
treatment, if desired. Those participants that are opioid abstinent but choose not to receive the NTX 
injection, may otherwise proceed in the study through week 8, attending weekly clinic visits for individual 
psychotherapy and assessment completion. If there is no evidence of opioid relapse at week 8 as 
determined by a study physician, these individuals may proceed in the study through week 12. 
Participants who successfully transition to NTX injection in week 4 will be offered the opportunity to 
receive one additional NTX injection in week 8. In order to be eligible for the second NTX injection, 
participants submit a urine sample that may need to be opioid-negative to receive NTX injection during 
week 8. If the urine sample is positive for opioids then the decision to give the second NTX injection will 
be made by a study physician. If the study physician determines that the participant will not receive the 
second NTX injection, they will be referred to appropriate alternative treatment, if desired. Otherwise, 
participants continue in the study as before, attending weekly clinic visits for individual psychotherapy 
and completion of assessments. All participants will attend their last clinic visit during week 12 to 
complete final assessments, terminate therapy, and receive aftercare referrals as determined during the 
course of treatment. A follow-up interview will be conducted during week 16 (+/- 1 week). Participants 
will receive an appointment reminder at least one day prior to each appointment during the NTX phase 
to increase attendance. Participants will be asked to supply names and phone numbers of at least two 
stable contact people whom staff can call if the participant can’t be reached post-participation. Staff will 
maintain at least monthly contact with participants who have been discharged from the trial to enhance 
follow-up rates. In advance of the scheduled follow-up appointment, a reminder letter will be sent to 
each participant’s most recently recorded address.  
  Assessments will typically be obtained once or thrice weekly (more often during week 4). A 
supervised urine sample will be obtained and self- and observer-ratings completed. Blood samples will 
also be drawn during week 4 to determine buprenorphine and gabapentin levels. 
C. Drugs. The UAMS Research Pharmacy will prepare medications during the study. BUP mono tablets 
(sublingual), oral NTX tablets, clonidine tablets, depot NTX (Vivitrol), GBP and placebo (microcrystalline 
cellulose) will be purchased through the UAMS Hospital and a bulk supply of gabapentin and placebo 
capsules will be prepared by the UAMS Research Pharmacy. Study medications for Phase I 
(buprenorphine detox) will be brought to the CAST Pharmacy and stored in the research vault of the 
CAST dispensary for dispensing through the CAST medication window. Study medications for phase II 
(naltrexone induction) will be stored in a refrigerator and/or wall-mounted narcotics lock box in the NTX 
induction room on the 4th floor of PRI. 
   Detox procedures are similar to those performed previously by our group [31]. The 12 mg dose of BUP 
has been used successfully in our prior trial and has been shown to be associated with minimal 
withdrawal symptoms [31]. We have shortened the BUP maintenance prior to GBP induction in order to 
start the 10-day detox on Wednesday of week 2. This allows us to better characterize symptomology 
during the second half of the detox as well as end the taper on Friday of the following week, thereby 
providing a 3-day window over the weekend before initiating NTX induction on Monday (see below). 
During the detox phase, participants will typically attend the clinic either 6 days per week (Monday–
Saturday) per current protocol or thrice weekly truncated study visits due to COVID-19. Buprenorphine 
dosing will begin Monday or Tuesday of Week 1. During Week 1, all participants will receive 4 mg of 
buprenorphine on Monday (or Tuesday), followed by another 4 mg dose 30 minutes later, and 12 mg 
(maintenance dose) per day on Tuesday (Wednesday)–Friday; on Saturday, participants will receive a 


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double dose (24 mg) of BUP. Participants with truncated study visits due to COVID-19 will receive a 
lockbox for medications taken on days when they do not attend clinic (Tuesday, Thursday, and 
weekends) during the detox phase. Staff will ensure that participants sign medication accountability 
logs. Participants receive 12 mg of BUP on days 1 and 2 of week 2. Beginning on day 3 (Wed) of week 
2, all participants will begin a 10-day BUP detox schedule [129], such that they receive 8 mg for two 
days, 6 mg for 1 day, 12 mg dose on Sat (double dose to cover Sun, or 6 mg doses on Saturday and 
Sunday if they are receiving take –home medications due to COVID-19), 4 mg on day 1 of week 3, 2 mg 
on days 2 and 3, and 1 mg on days 4 and 5 (Thur-Fri) of week 3. Participants may receive take-home 
dose(s) of buprenorphine to ensure participants are receiving the medication according to the dosing 
regimen on holidays and holiday weekends when the clinic is closed. This may also occur when 
inclement weather is forecast and the decision is made to have the clinic close on a given day. If a 
participant initially experiences side effects (e.g., feeling high) on the 8 mg dose of buprenorphine 
(which does occur during the first day or two of buprenorphine induction in a subset of opioid dependent 
patients), the physician may delay the increase to 12 mg depending on symptoms severity and duration; 
however, the participants will typically be on a stable dose of buprenorphine before day 3 of week 2. If a 
participant cannot tolerate the 12 mg dose of buprenorphine their dose will be reduced to no less than 8 
mg/day and the detox schedule will be adjusted accordingly. If the participant cannot tolerate 8 mg of 
buprenorphine they will be discharged from the study. In the event that a participant is quarantined due 
to COVID-19 during phase I BUP detox, they will be discharged from the protocol and the study 
physician will provide them with take-home BUP taper individually tailored according to where in phase 
1 the participant was at the time of quarantine. 
   During the detox phase, morning GBP/placebo ingestion will occur under supervision 6 days per 
week, and a take-home dose will be given each day for evening ingestion (3 take-home doses on Sat to 
also cover Sun). For participants on the truncated schedule due to COVID-19 (thrice weekly), lockboxes 
with BUP and GBP/Placebo will be given on the same schedule to be taken on days when not 
presenting to clinic (Tues, Thurs, weekends) with specific instructions provided by CAST nurse, in 
addition to drug accountability logs signed by the participant. Additional take-home doses of 
GBP/placebo will be given to take on holidays, days when clinic is closed due to inclement weather and 
holidays to ensure adequate blood levels of GBP are maintained. The initial dose of GBP at 100 mg will 
be given on day 3 of week 1, and a 100 mg dose provided to take home. The GBP dose will increase to 
200 mg BID on day 4, 400 mg BID on day 5, 600 mg BID on day 6, and 800 mg BID (1,600 mg/day) on 
day 7 of week 1. Participants will remain on 1600 mg/day through day 2 of week 5 (during NTX therapy, 
GBP/placebo capsules will be given in weekly blister packs). Then GBP will be reduced to 1200 mg/day 
on day 3, 800 mg/day on day 4, 600 mg on day 5, 400 mg on day 6, and 200 mg on day 7. On days 1 
and 2 of week 6, all participants will receive placebo. If GBP side effects are too severe at the 800-mg 
BID dose, GBP will be decreased to no less than 1200 mg/day, given data that 900 mg/day of GBP is 
ineffective [97]. If GBP side effects are too severe at 1200 mg/day, GBP will be discontinued and the 
participant will be discharged from the study and referred to local treatment agencies. During transition 
to NTX (week 4), if a) the participant’s urine sample is opioid-negative and/or regular opioid use is not 
indicated, and b) orthostatic vital signs and symptoms are within limits specified below (Section 14, 
Protection of Participants, B. Protections Against Risk): On day 1 of week 4, participants will receive 0.1 
mg of clonidine followed 20-30 min later by 6.25 mg of oral NTX. If tolerated, the person will return on 
day 2, receive 0.1 mg of clonidine followed 20-30 min later by 6.25 mg of oral NTX. On day 3, 
participants will receive 12.5 mg of NTX 20-30 min after clonidine. (For those who do not start induction 
until day 2 or 3: Starting on day 2, NTX will be given at the 6.25 mg dose 20-30 min after clonidine. On 
day 3, NTX will be given at the 12.5 mg dose 20-30 min after clonidine.) On day 4, 25 mg of NTX will be 
given 20-30 min after clonidine. If 25 mg is tolerated, then on the morning of day 5, participants will 
receive the depot NTX injection.  (Participants have up to day 3 of week 4 to start the transition to NTX. 
For those who do not start induction until day 2 or 3: Starting on day 2, NTX will be given at the 6.25 mg 
dose 20-30 min after clonidine. Starting on day 3, NTX will be given at the 12.5 mg dose 20-30 min after 
clonidine. In such cases, dosing/administration on subsequent days will be as specified above.) Those 


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who received the first NTX injection, and who have been determined to be eligible for the second NTX 
injection and choose to receive a second NTX injection, will do so during their week 8 clinic visit. If a 
participant is required to quarantine due to COVID-19 during phase II, they may remain on protocol and 
complete assessments and therapy sessions remotely (by phone or teleconference). If this occurs, urine 
drug screens and the COWS assessment will be recorded as missed until they are no longer required to 
quarantine. If a participant is unable to provide a urine drug screen at week 8 due to quarantine, they will 
not be eligible for the second Vivitrol injection and will be discharged from protocol and offered referrals 
to treatment as necessary. 
 
D. Medication Compliance. During the detox phase/week 4 oral NTX phase, compliance with BUP, oral 
NTX, and GBP/placebo (AM dose) will be assured by observing participants as they ingest the 
medication and/or providing lockboxes and accountability logs signed by participants that are in the 
protocol on the truncated schedule due to COVID-19. Compliance with take-home doses of GBP during 
the detox and weekly blister packs of GBP during/immediately following week 4 depot NTX will be 
monitored by pill counts, self-report, and/or week-4 blood levels of GBP. Riboflavin will be added to 
capsules and weekly urine samples will be stored for back-up quantitative urinalysis of riboflavin levels, 
especially if GBP blood levels are disparate. The research nurse will perform depot NTX injections. 
E. Randomization of sample. To increase the likelihood that treatment groups are balanced with respect to 
key baseline variables (opioid-withdrawal symptom severity, marijuana-use status, anxiety ratings and 
tobacco-use status), males and females (with and without prescribed psychoactive medication) will be 
separately assigned to treatment groups with “urn” randomization, using a Microsoft Access program 
developed and used in previous studies [130, 131]. In urn randomization, an algorithm modifies ongoing 
randomization probabilities based on prior composition of treatment groups, maximizing multivariate 
equivalence of treatment groups [132]. Thus, urn randomization balances allocation of important 
prognostic variables in treatment groups, while retaining other benefits of random assignment [133, 
134]. 
F. Maintenance of the Double Blind - A code will be kept in a locked cabinet, in a special file in the data 
manager’s or PI’s office, and pharmacy matching participants with the active/placebo study medications. 
This code will be available 24 hours a day and will be broken at the request of outside health 
professionals in the event of a medical emergency. To prevent any of the investigators from 
inadvertently discovering the medication assignments of other participants in the special file needs to be 
opened, a psychiatrist not directly involved with the study participants will open the special file. Once the 
code is broken, that participant will be dropped from the study. Although we do not anticipate difficulties 
maintaining the double blind, we will evaluate the adequacy of the double blind by having each 
participant and a research staff member report the medication (placebo or gabapentin) they believe is 
being administered. 
G. Counseling Guidelines - Several components of Behavioral NTX therapy [135] will be employed in the 
present study. During the BUP/GBP induction and detox phase, all participants will be scheduled to 
meet weekly, either in person, via telephone or video conference, with a research therapist typically for 
60 minutes. Content of these sessions will include education and support, medication management, 
techniques to enhance motivation for abstinence or NTX therapy, and review of contingency 
management procedures. The session also provides an opportunity to review critical issues and 
problem areas. During NTX treatment, weekly sessions with the research therapist will include Cognitive 
Behavioral Treatment, manual-driven [136, 137] as a controlled element of the study. Modules will focus 
on relapse prevention and engagement in community support groups (e.g., Narcotics Anonymous). 
Although the involvement of a significant other in the treatment process will be encouraged, it will not be 
required for participation. The research therapist will monitor number and duration of scheduled 
treatment sessions, including frequency and reason for extra-session telephone calls, subjects' 
involvement in any ancillary treatments, and other clinically significant events and formal treatment 
concurrent with their study treatment (including self-help meetings). At the end of the study, participants 
will be given treatment referrals.  


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H. Program Termination - Any participant choosing not to take the study medication will be discharged from 
the study with appropriate referrals. During the detox phase and NTX transition week, participants 
missing medications on three successive days (or any two days during week 1) or do not complete 
assessments will be administratively discharged. If participating under the truncated schedule due to 
COVID-19, participants will be discharged if they miss any clinic visits during week 1 and miss 1 clinic 
day during weeks 2 and 3 due to the take-home medication schedule, therefore, they cannot miss 
Friday visits. Participants will be discharged if they do not receive their take-home medication blister 
packs by day 5 of week 4. Participants who cannot provide an opioid-free urine on either day 1, 2, or 3 
of week 4 during oral NTX induction may be deemed ineligible to continue onto depot NTX therapy as 
determined by the study physician. Similarly, if participants are unable to provide an opioid-free urine at 
the week 8 visit, a study physician will determine if participants will be eligible to continue in the study 
with or without the second NTX injection. A participant will be discharged if PIs believe a subject’s health 
or wellbeing may be threatened by continuation in the study. If a participant is required to quarantine 
due to COVID-19 during the phase I BUP detox, they will be discharged from the protocol, and the study 
physician will provide take-home BUP taper for detox. If a participant is required to quarantine due to 
COVID-19 during phase II, they may remain on protocol and complete assessments and therapy 
sessions remotely (by phone or teleconference). If this occurs, they will be unable to provide urine drug 
screens or complete the COWS assessment until they are no longer required to quarantine. If a 
participant is unable to provide a urine drug screen at week 8 due to quarantine, they will not be eligible 
for the second Vivitrol injection and will be discharged from protocol and offered referrals to treatment as 
necessary. If a pregnancy test becomes positive, the participant will be withdrawn from the study and 
referred to an appropriate treatment program. Participants who relapse following BUP detox or NTX 
therapy, as determined by physician assessment, will be offered referrals to the UAMS Center for 
Addiction Services and Treatment, a residential therapeutic community, an inpatient treatment program, 
or others, as appropriate. Participants administratively discharged will also be referred to local treatment 
programs, if desired. 
I. Dependent Measures. The purpose and timing of assessments are shown in Table 1. Assessments will 
be presented via computer whenever possible with responses entered directly into the computer (with 
paper copies as backup in case of computer malfunction or unavailability). If an assessment is missed at 
any time point, whether due to participants missing appointments, glitches with computer or staff error, 
the assessments will be completed at the next earliest visit as possible and appropriate. If not, the 
assessment will be considered missed. 
 The primary outcome measure is illicit opioid use (typically obtained thrice weekly during weeks 1-4, 
weekly during weeks 5-12, and once at the week 16 follow-up interview, biologically verified by the 
Redwood Toxicology Laboratory and/or Lochness Medical Supplies dipstick and/or EMIT assay). 
Secondary outcomes include craving ratings, retention, self- and observer-rated opioid withdrawal 
symptoms, adverse events, sleep quality, withdrawal signs (blood pressure, body temperature), mood, 
heart rate variability (HRV), decision making, and prescription opioid and other drug use, including 
alcohol, tobacco and caffeine. We chose assessment techniques as recommended in NIDA’s A 
Diagnostic Source-book for Drug Abuse Treatment and Research to use comparable assessments by 
different investigators in substance abuse [138]. Our set of screening instruments will provide general 
patient information, including demographic data; medical history; and history of substance use, family 
substance abuse, and psychiatric treatment [130, 131]. Other assessments include the following: 1) 
Weekly Drug Use (done weekly), which uses a timeline recall method that we developed in previous 
studies to assess self-reported use of opioids and other drugs [130, 131]; 2) PRISM 5 (done at intake or 
during week 1), a computerized structured clinical interview (software package will be purchase) from 
completed to determine several DSM-V psychiatric diagnoses [139, 140]; 3) Medication Side Effects 
Checklist (done weekly), consisting of multiple items describing side effects specific to GBP, BUP or 
NTX [141] rated on a scale from 0 (not at all) to 4 (very much); 4) Subjective Opiate Withdrawal Scale 
(SOWS) (done thrice weekly during weeks 1-3, daily (5 days) during week 4, and weekly thereafter), 
consisting of 16 items describing possible opioid withdrawal symptoms that are rated on a scale from 0 


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(not at all) to 4 (extremely) [142]; 5) Clinical Opiate Withdrawal Scale (COWS) (done thrice weekly 
during weeks 1-3, daily (5 days) during week 4, and weekly thereafter), an observer-rated opioid 
withdrawal scale that consists of 11 items describing withdrawal symptoms [142]; 6) the Stages of 
Change Readiness and Treatment Eagerness Scale (SOCRATES) [122]; 7) measures of distress 
tolerance, including Breath Holding Endurance [143], in which the length of time (seconds) that 
participants can hold their breath is measured, and the Distress Tolerance Scale [144]; 8) measures of 
anxiety/depression, including the State Trait Anxiety Inventory (purchased through Mind Garden, Inc) 
[145], the Anxiety Sensitivity Index (purchased at anxietysensitivityindex.com from IDS Corporation, 
Inc.), a reliable and valid 16-item self-report questionnaire that assesses the degree to which an 
individual is concerned about the possible negative consequences of arousal-based anxiety symptoms 
[146], and the Hamilton Anxiety and Depression Scales [147, 148]; 9) measures of sleep quality, 
including the Pittsburgh Insomnia Rating Scale [149] and Pittsburgh Sleep Quality Index [150]; 10) 
measures of known physiological indicators of withdrawal (vital signs, body temperature); and 11) the 
Endpoint Rating Form, which assesses functional level at termination and reason for termination. To 
assess potential adverse effects of the study medication, participants will be asked at every visit whether 
they are experiencing any symptoms, which will be recorded on a Symptoms Form. 
 
Decision Making Assessment. Delay discounting will be assessed via paper survey at intake and at the 
end of detoxification (week 3, day 5) [151, 152]. Participants will complete 27 fixed-choice options 
between immediate, smaller and delayed, larger hypothetical amounts of money (e.g., “Would you 
prefer (a) $54 today or (b) $80 in 30 days?”). Delayed amounts of money range from small ($25-$35), 
medium ($50-$60), to large ($75-$85). Rates of delay discounting will be characterized by calculating k 
values based on Mazur’s hyperbolic discounting function [153] for choices in each of the three delayed 
monetary categories. For this study, k values will be averaged across the three monetary categories and 
log transformed. Higher average k values indicate increased delay discounting. 
 
Heart Rate Variability (HRV). On day 2 or 3 of weeks 1-2 and day 5 of week 3, participants undergo a 10 
min assessment of Heart Rate Variability (as a noninvasive measure of relative autonomic nervous 
system imbalance such as stress versus relaxation) while sitting, standing and sitting while performing 
measured breathing prior to receiving that day’s medication. Participants will be asked to secure a belt 
with sensors around their torso as well as place another sensor on their finger and to refrain from talking 
during the assessment. After approximately 30 seconds after settling down, participants will be given 
instructions to sit quietly and their HRV will be recorded for 2 minutes. Then the participant is instructed 
to stand quietly and their HRV will be recorded for 2 minutes. Finally, the participant will be instructed to 
sit quietly and follow a measured breathing indicator (i.e., inhaling and exhaling) on the computer screen 
while their HRV is recorded for 2 minutes. HRV will be measured using the HRV System - ProComp2 
with Biograph 2,069.10 2,069.10 Infiniti & HRV Suite Software with 1 BVP Sensor/1 Respiration Sensor. 
Objective Distress Tolerance Tasks. On day 3 of week 1 prior to receiving active/placebo study 
medication, participants will be invited to complete two computerized games. The purpose of this 
preliminary testing is to test the relevance of a quantitative measure of affective distress tolerance 
(mirror tracing task) and effortful performance (EffRT) with Opioid Use Disorder severity, to self-report 
measures of distress tolerance, and treatment outcomes. 
1) Mirror Tracing Task. This task measures distress tolerance as persistence on the task. In this task, 
participants use a computer mouse to move a cursor around a monitor to trace over a star shape 
without leaving the shape’s lines. The mouse is programmed to move the red dot in the reverse 
direction. If the participant moves the red dot outside of the lines of the star, or stalls for more than 2 
sec, the red dot returns to the starting position and there is a loud buzzing noise. There is a simple 


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practice task before the experimental task. In the experimental task, participants can end the task at any 
time, but the longer they persist in the task the more points they earn. This task lasts up to 20 min.  
2) Effort Expenditure for Reward Task (EffRT). This task measures effort-based decision making. On 
each trial, participants choose between two different task difficulty levels to obtain monetary rewards. 
For all trials, participants make repeated manual button presses within a short amount of time. Each 
button press raises the level of a “bar” viewed onscreen. If the bar is raised to the top within the allotted 
time period, the participants wins the points for that trial. Each trial offers a choice between two levels of 
difficulty: a “hard” task and an “easy” task. Hard task trials required the subject to make 100 button 
presses using the non-dominant little finger within 21 seconds, while easy task trials require the subject 
to make 30 button presses using the dominant index finger within 7 seconds. Completion of easy task 
trials will earn 1 point. Hard task trials could earn between 1.24 and 4.30 points. However, the 
probability of earning the points for successful task completion is 88%, 50%, or 12%. The probability of 
earning points is indicated onscreen at the start of each trial. At the end of each trial, participants are 
shown whether they completed the task on time or not, and earned the points or not. Participants have 
20 min to play as many trials as they are able. 
For completing these optional tasks, participants will be compensated $20 plus they can earn up to an 
additional $5 per task ($30 total) based on their performance. 
 
Table 1. Summary of the Schedule and Purpose of Assessments. 
PURPOSE/INSTRUMENT 
Rater 
TIME OF ADMINISTRAION 
Phase I BUP/GBP 
Phase II GBP/NTX 
Pre-
TX 
3 X 
Weekly 
Weekly 
(typically 
Day 3) 
Day 5 
Week 3 
Days 1 and/or 
2 NTX 
transition 
Days 4 and/or 
5 NTX 
transition 
Weekly 
(typically 
Day 3) 
Week 16 
(+/- 1 
week) 
Screening Variables and Predictors 
of Outcomes 
 
 
 
 
 
 
 
 
 
Demographics Form 
RS 
X 
 
 
 
 
 
 
 
Medical History 
RS 
X 
 
 
 
 
 
 
 
Substance Use History 
RS 
X 
 
 
 
 
 
 
 
PRISM-5 
RS 
X^ 
 
 
 
 
 
 
 
Distress Tolerance Scale 
P 
X^ 
 
 
X 
 
 
X** 
X 
Breath-holding Endurance  
RS 
X^ 
 
 
X 
 
 
X** 
X 
Mirror tracing task 
RS 
X^ 
 
 
 
 
 
 
 
EffRT task 
RS 
X^ 
 
 
 
 
 
 
 
State Trait Anxiety Inventory 
P 
X^ 
 
 
X 
 
 
X** 
X 
Anxiety Sensitivity Index 
P 
X 
 
 
X 
 
 
X** 
X 
SOCRATES 
P 
X^ 
 
 
X 
 
 
 
 
Columbia Suicide Severity Rating 
Scale 
P 
X+ 
 
 
 
 
 
 
 
Assessment of Outcome: Substance Use 
Urine Drug Screens (12 panel) 
P 
X 
X 
 
 
X 
X 
X  
X 
Weekly Drug Use 
RS 
X 
 
X 
 
 
 
X 
X 
Weekly Craving 
RS 
 
 
X 
 
 
 
X 
X 
Physical/Psychological Symptoms 
Subjective Opiate Withdrawal Scale 
(SOWS) 
RS 
X 
X 
 
 
X 
X 
X 
X 
Medication Side Effects Checklist 
RS 
 
 
X 
 
X 
X 
X 
 
Clinical Opiate Withdrawal Scale 
(COWS) 
RS 
 
X 
 
 
X 
X 
X 
X 
Vitals (BP, HR, RR, T)  
RS 
X 
 
X 
 
X+* 
X+* 
X+* 
 
Symptoms Form 
RS 
 
X+ 
 
 
X 
X 
X 
 
Pittsburg Insomnia Rating Scale 
RS 
 
 
X 
 
 
 
X 
X 
Pittsburg Sleep Quality Index 
RS 
X^ 
 
 
X 
 
 
X** 
X 
Hamilton Anxiety Scale 
RS 
 
 
X 
 
 
 
X 
X 
Hamilton Depression Scale 
RS 
 
 
X 
 
 
 
X 
X 


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Other 
Blood Chemistries (CBC, Chem 20 to 
include LFT’s) and Urinalysis  
P 
X 
 
 
 
X* 
 
 
 
Pregnancy Test (women) 
P 
X 
 
 
 
X 
 
 
 
Breath sample to test alcohol levels 
P 
 
+ 
 
 
 
 
 
 
Buprenorphine blood level 
RS 
 
 
 
 
X 
 
 
 
Gabapentin blood level 
RS 
 
 
 
 
X 
 
 
 
ECG 
RS 
X 
 
 
 
 
 
 
 
Heart Rate Variability Assessment 
RS 
 
 
X 
 
 
 
 
 
Employment Assessment 
RS 
X 
 
 
 
 
 
 
X 
Endpoint Rating Form 
RS 
 
 
 
 
 
 
X++ 
 
Monetary Choice Questionnaire 
RS 
X 
 
 
X 
 
 
 
 
RS—Research Staff; P—Participant. X=assessment performed (at specified time point). [ ^ = during intake or week 1]  [ *=Liver function tests, bup and GBP 
levels only]  
[ ** = only at week 8 and 12]  [+*=orthostatic vitals, week 4 only] [ +=completed during the trial as clinically necessary] [++=Completed after discharge from 
active treatment protocol] 
 
An Employment Assessment form consisting of up to 3 questions regarding employment activities 
during the past 7 and/or 30 days will be administered at intake and at the 16-week follow-up. The 
Columbia–Suicide Severity Rating Scale [128] will be done at either screening or intake as well as 
during the study if clinically indicated. Breath analysis for alcohol will be performed as clinically indicated 
at any time point, although current alcohol physiological dependence is among the exclusion criteria. 
One of the coded urine samples obtained each week during weeks 2- 5 will be frozen, and those from 
individuals in the GBP group will be sent to the core laboratory of Dr. Hendrickson to determine 
quantitative urine riboflavin levels, especially if GBP blood levels are disparate. Blood chemistries (SMA 
20, CBC, which will be done using Quest Diagnostics) and ECG as well as a general physical 
examination (completed by the study physician) will be performed during screening. A blood sample for 
liver function tests will also be drawn and results obtained from Quest Diagnostics prior to week 4 NTX 
injection. Blood samples obtained during week 4 will be processed, frozen and stored until sent to Dr. 
Hendrickson’s laboratory for analysis of BUP and GBP levels.  
At every visit, participants are asked whether they are experiencing any symptoms. The onset, 
duration, quality, and severity of any symptoms are recorded on the Symptoms Form and tracked to 
resolution. If symptoms are severe, then the medical staff is notified immediately. These symptoms are 
also discussed at weekly team meetings to ascertain whether the symptoms meet criteria for an adverse 
event. If so, attribution and severity are also determined. 
The hypothesis posed under Specific Aim 1 (regarding efficacy and tolerability of GBP during and 
immediately following BUP detox) will be tested by comparing drug-screen results, withdrawal 
measures, craving, sleep quality and adverse events between GBP and placebo groups during weeks 2-
3 and day 1 of week 4. The hypothesis posed under Specific Aim 2 (regarding acceptability/feasibility 
of transition to NTX therapy) will be tested by determining retention, reasons for dropout, drug-screen 
results and side effects during the oral NTX induction (week 4) and depot NTX therapy (weeks 4-8). 
Queries posed under Specific Aim 3 (regarding prognosticators) will determine whether salient factors 
such as sex, other drug use, dependence diagnoses, distress tolerance measures, caffeine use, etc.: a) 
differentially impact response to GBP vs. placebo on outcomes during detox, b) are associated with 
differential outcomes during transition to NTX and c) are associated with differential longer-term 
outcomes at week 16. 
 
J. Timeline. We estimate that we will develop standard operating procedures during months 1–3 and enroll 
2-4 participants/month during months 4–53, allowing for major holidays and staff vacations. All study 
procedures will be completed by month 55 and follow-up interviews by Month 58. We will complete data 
analyses and manuscript preparation by Month 60. These data, if positive, will be used to support further 
research on adjunct GBP during BUP detox as well as provide preliminary feasibility data for outpatient 
transition to NTX therapy. 
 


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8. Data Analysis Methods: 
 
We will compare baseline characteristics of the two groups using the intent-to-treat sample with 
analyses of variance for continuous variables (e.g., age) and Chi2 analyses for categorical variables (e.g., 
sex, race) to determine whether any significant baseline differences have accrued despite randomization. In 
addition, given that later phases (i.e., transition, depot NTX therapy) may have different sample 
configurations due to anticipated dropout, we will similarly compare the two groups on participant 
characteristics. If we find significant baseline differences in variables within a phase or at each subsequent 
phase relative to the one prior, these differences will be informative of factors associated with treatment 
outcomes. For those variables found to affect outcome, we will use contingency tables with stratification or 
add these factors to the appropriate random regression models to adjust for these differences.  
   Specific Aim 1: Efficacy and tolerability of GBP versus Placebo during and immediately following BUP 
detox. For data during the BUP taper (weeks 2-3), dependent variables obtained at several time points 
(e.g., urine sample results for opioids, opioid withdrawal symptoms scores) will be entered into random 
regression models, also known as hierarchical linear models (HLMs), to determine whether scores change 
differentially across treatment groups [154, 155]. Continuous data will be analyzed longitudinally with 
MIXREG, an HLM modeling program for continuous measures [156]. Dichotomous urine results (i.e., 
negative or positive) will be analyzed longitudinally using the SAS procedure GLIMMIX, which allows an 
HLM modeling program for ordinal outcome measures [157]. We will use all available data in our analyses 
and will make no attempt to interpolate missing data. HLM methodologies fit a regression line for each 
participant, effectively interpolating missing data, before deriving final estimates. This approach of modeling 
repeated measures is specifically designed for use in repeated measures designs with missing data, 
allowing for intra-participant serial correlation and unequal variance and covariance structures over time. 
These problems, common to clinical trial data, are solved by incorporating available trend data for each 
individual with information on the behavior of the group from which the participant is drawn. If there are any 
significant baseline differences, the variable will be added as a cofactor in the HLM analyses. We will 
examine differences in retention using Kaplan-Meier Survival Analysis. Analyses will be done on those who 
participated long enough to start the BUP taper, as well as during GBP induction to detect possible 
differential dropout before the taper. To determine whether treatment group differences occurred in 1) 
success of retention from the BUP detox to the NTX transition and 2) eligibility to undergo oral NTX 
induction, we will build 2 X 2 contingency tables using percentages of participants in the GBP vs. placebo 
groups who 1) return on day 1 of week 4 versus drop out after completing the taper, and 2) test negative 
versus positive for opioids. The type, severity, and frequency of adverse events will be compared across 
groups. All analyses will employ a significance level of α = 0.05, and all tests are two-tailed.  
   Specific Aim 2: Acceptability and feasibility of outpatient transition to and maintenance on depot NTX 
therapy. Because there are two phases to NTX therapy transition (i.e., 4-day oral induction and up to 8-
week depot NTX), data obtained during these phases will be analyzed separately. For the oral NTX 
induction, descriptive statistics will be used to report the percentage of abstinent participants who receive 
the 4-day oral dosing. Urine data collected each day during the 4-day induction will be entered into random 
regression models similar to those above to determine whether changes in illicit opioid or other drug use 
occurred over time. To obtain pilot data on the association between treatment group (GBP vs. placebo) and 
successful induction, data regarding the percentage of those receiving oral NTX and the NTX injection or 
not in the GBP vs. placebo groups will be entered into a 2 X 2 contingency table. The type, severity, and 
frequency of opioid withdrawal and/or adverse events will be compared across groups. Reasons for not 
receiving the NTX injection will be summarized. 
   For the NTX phase (weeks 4-12), dependent variables obtained at weekly time points (e.g., urine sample 
results for opioids and other drugs, side effect scores, opioid withdrawal scores, etc.) will be entered into 
random regression models (HLMs) to determine whether scores change differentially over time [154, 155]. 
Continuous data will be analyzed longitudinally with MIXREG [156]. Dichotomous urine results (i.e., 
negative or positive) will be analyzed longitudinally using the SAS procedure GLIMMIX [157]. We will 
examine differences in study dropout during this phase using Kaplan-Meier Survival Analysis. Our principal 


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analyses will be done on those who participated long enough to start the depot NTX therapy. The type, 
severity, and frequency of adverse events will be recorded and summarized.  
   Specific Aim 3: Identify prognosticators of treatment outcomes. Predictors of treatment efficacy during 
each phase will be examined using baseline assessments (e.g., sex, level of opioid use, distress tolerance 
scores, etc.). We will evaluate general predictors of successful outcomes (with success as defined above) 
regardless of treatment type and predictors of differential response to treatments. Depending on the 
distribution of participants with moderate versus severe opioid dependence, severity of opioid dependence 
will also be examined as a prognosticator. Our basic analytic strategy will be to dichotomize groups into the 
presence and absence of a dichotomous predictor variable (e.g., female or alcohol dependence diagnosis) 
and then to examine the relative predictive values on treatment outcomes by adding each factor to the log 
linear analyses for single time point outcomes and HLM for longitudinal measures such as frequency of self-
reported drug use, opioid-negative urines and craving measures. Each continuous measure (e.g., HAM-A, 
distress tolerance scores) will be entered as a covariate in the above analyses. 
Longer-Term Outcomes. Continuous data from the 16-week follow-up interview will be initially entered 
into repeated measures ANOVA’s with group (GBP vs. placebo), successful completion of detox (yes vs. 
no), successful induction onto oral NTX therapy (yes vs. no), and successful transition to depot NTX therapy 
(yes vs. no) as factors. Dichotomous follow-up data will be entered into Chi2 tables for each phase. 
Longitudinal data captured during each phase of the study and at follow-up will be entered into random 
regression models as above, and piece-wise comparisons will be made between each phase. For all 
analyses, a p value <0.05 will be used to infer statistical significance. 
Sample Size. PASS (Power Analysis & Sample Size) Software was used to estimate power. Sample 
size for the intent-to-treat sample was determined based on having enough power during and immediately 
following the BUP taper to detect group differences in the primary outcome of illicit drug use and identify 
potential prognosticators. Based on the proportion of participants in the GBP versus placebo groups having 
opioid-free urines on the last day of the BUP taper from our pilot trial with GBP [31, 129], treating the one 
missing value as positive, a difference in the percentage of participants with opioid-free urines at the end of 
detox as well as immediately prior to initiating NTX therapy will be detected with >90% power with an 
analysis sample size of 106 total participants anticipated to remain for NTX transition. Thus, our sample size 
is adequate to detect differences for our primary outcome during and immediately following the 
detoxification. Meanwhile, there has been minimal, if any, study of sex (or other bivariate prognosticator) 
differences for the effect of an adjunct medication for opioid dependence, much less for prescription opioid 
dependence. This study will provide unique data to quantify a potential difference. Given our expected 
sample size of 150 participants entering the BUP detox phase, the study will have >80% power for an effect 
size of 0.29 (small effect size), and 106 participants eligible for NTX transition will have >80% power to 
detect an effect size of 0.35 (considered a "medium" effect size). 
 
9. Location of Study: 
 
The study will be located on the fourth floor of the Psychiatric Research Institute at UAMS. 
 
10. Payment to Participant: 
 
Participant retention can be challenging for detox and NTX therapy studies. To facilitate attendance 
and offset inconvenience, participants in our study will have the opportunity to earn both fixed monetary 
payments (for attendance at longer visits and study medication container returns) and compensation based 
on a low-cost “fishbowl” contingency management procedure (for clinic visits) that has been shown to 
enhance retention and attendance [158, 159]. Contingency management is increasingly used in community 
treatment settings for this purpose [160-164]. In the fishbowl procedure, participants will have the 
opportunity to draw chips, according to an escalating ratio schedule. Chips have varying dollar amounts 
from $1.00-$100.00 (or “Good Job!”) written on them. Participants can receive, on average, up to $35 for 
participating in the screening, $90 for bottle returns and attendance at all required appointments during the 


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detox phase, $150 for attendance at all required appointments during the transition to NTX injection, $480 
for returning blister packs and attendance at all required appointments during NTX therapy, and $50 for 
attending the week 16 follow-up interview. In our previous studies at Yale University and UAMS, we have 
developed and implemented procedures to successfully recruit, enroll, and ensure the safety of participant 
populations. To help ensure good follow-up rates, staff will check in with participants or their contacts 
monthly post-participation to make certain contact information is up-to-date. 
 
11. Source of funds: 
 
NIDA 
 
12. Probable Duration: 
 
Up to Five Years 
 
13. Risks and Benefits: 
 
1. Buprenorphine. Buprenorphine is approved by the Food and Drug Administration (FDA) to treat opioid 
dependence. Common side effects of buprenorphine include sedation, nausea, dizziness/vertigo, 
sweating, hypotension, vomiting, miosis, hypoventilation, confusion, blurred vision, euphoria, 
gastrointestinal distress, headache, weakness/fatigue, dry mouth, nervousness, depression, slurred 
speech, paresthesia, hypertension, tachycardia, bradycardia, constipation, pruritus, diplopia, visual 
abnormalities, urinary retention, dreaming, flushing/warmth, chills/cold, tinnitus, conjunctivitis, 
Wenckebach block, psychosis [141] and sleep disturbances. 
 
2. Detoxification with Buprenorphine. In an opioid-dependent individual, slowly decreasing the 
buprenorphine dose over time can produce temporary signs and symptoms of opioid withdrawal such as 
malaise, nausea, nasal congestion, abdominal symptoms, anxiety, myalgia, insomnia, sweating, 
diarrhea, tremor, body ache, muscle spasms, rhinorrhea, and piloerection. These symptoms can be 
unpleasant, but are not medically dangerous [141]. 
 
3. Gabapentin. The most commonly reported side effects of gabapentin include somnolence, 
nausea/vomiting, gastrointestinal distress, ataxia, and vertigo [165]. Other side effects include asthenia, 
peripheral edema, infection, fever, confusion, accidental injury (due to a fall, for instance), worsening of 
depression, suicidal thoughts, peripheral edema, diarrhea, dry mouth, constipation, clumsiness, loss of 
muscle coordination, abnormal gait, conjunctivitis, abnormal thinking, abnormal vision[165], and possibly 
vivid and disturbing dreams. The dose of gabapentin (1600 mg/day) chosen for this study was based on 
1) results of our prior study showing that this dose was well tolerated and alleviated craving and opioid 
use in prescription opioid-dependent patients stabilized on BUP [31, 129]; 2) results of other studies 
showing that gabapentin at 1200-1800 mg/day, but not 900 mg/day, appeared to improve outcomes 
during opioid detoxification [97-100]; and 3) a review by Ho et al. [166] that showed a typical dose of 
gabapentin that was used adjunctively with opiates to treat postoperative pain was 1200 mg, while some 
studies did use doses as high as 1800 mg. 
According to a safety communication by the Food and Drug Administration (FDA) on 12/19/19, serious 
breathing difficulties may occur in patients who have respiratory risk factors and using gabapentinoids 
such as gabapentin. Risk factors include the use of opioid pain medicines and other drugs that depress 
the central nervous system, and conditions such as chronic obstructive pulmonary disease (COPD) that 
reduce lung function. The elderly are also at higher risk. 
 
4. Buprenorphine plus Gabapentin. There have been no reports of interactions or serious adverse 
reactions between buprenorphine and gabapentin. In our pilot study [31], the following adverse events 


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occurred during gabapentin induction that were at least possibly study-related and showed a greater 
incidence in the gabapentin than placebo group: nausea/vomiting (gabapentin: N=2/16; placebo: 
N=1/14), somnolence (gabapentin: N=2/16; placebo: N=0/14), sleep disturbances (gabapentin: N=2/16; 
placebo: N=0/14), loss of motor skills (gabapentin: N=1/16; placebo: N=0/14), and lightheadedness 
(gabapentin: N=1/16; placebo: N=0/14). All events were mild and did not require an intervention, except 
for the lightheadedness, which occurred on day 4 during induction onto gabapentin. Even though vital 
signs were within the normal range, because this was a pilot study, a conservative approach was used 
and the gabapentin induction discontinued for this participant. Thus, we anticipate no pharmacokinetic 
interactions between these agents. There has also been one case study looking at gabapentin and 
buprenorphine and there was no adverse reaction. This case study was based on a previous 2006 
review that showed that gabapentin produced a decrease in opioids consumed postoperatively [166, 
167]. Nevertheless, based on the 12/19/19 safety report by the FDA, serious breathing difficulties may 
occur as a result of combined use of gabapentin and opioid pain medicines. 
 
5. Clonidine. The use of clonidine to alleviate symptoms of opioid withdrawal is a standard clinical practice. 
Clonidine produces side effects such as dry mouth, drowsiness, sedation, dizziness, headache, fatigue, 
and changes in heart rate and blood pressure. The dose employed is within the recommended daily 
dose range [168].  
 
6. Naltrexone. Both oral and injection formulations of naltrexone are approved by the FDA to treat formerly 
physiologically dependent opioid abusers. Oral doses of naltrexone may be associated with an opioid 
withdrawal-like symptom complex consisting of tearfulness, mild nausea, abdominal cramps, 
restlessness, bone or joint pain, myalgia, and nasal symptoms. Other commonly reported side effects 
include difficulty sleeping, anxiety, nervousness, abdominal pain/cramps, low energy, joint and muscle 
pain, diarrhea, constipation, increased thirst, increased energy, feeling down, irritability, dizziness, skin 
rash, delayed ejaculation, decreased potency, and chills. If participants do not keep well hydrated, these 
symptoms can result in moderate to severe dehydration that can lead to low blood pressure. Patients 
taking naltrexone may not benefit from opioid containing medicines, such as cough and cold 
preparations, antidiarrheal preparations, and opioid analgesics [169]. The remaining precautions for oral 
naltrexone are similar to those for Injectable Naltrexone and are outlined below. 
Naltrexone injectable is contraindicated in patients who have previously exhibited hypersensitivity to 
naltrexone, PLG, carboxymethylcellulose, or any other components of the diluent of the injection [169]. 
Other potential risks include eosinophilia pneumonia, unintended precipitation of opioid withdrawal, and 
opioid overdose following an attempt to overcome opiate blockade. Other precautions include 
depression and suicidality, injection site reactions, renal impairment, use in patients with 
thrombocytopenia or any coagulation disorder, and use in patients who are pregnant, plan to become 
pregnant, or are breastfeeding. Furthermore, the most common side effects associated with the use of 
injectable naltrexone include injection site reactions, nausea, tiredness, headache, dizziness, vomiting, 
decreased appetite, and muscle cramps. Studies in alcoholic populations and in volunteers in clinical 
pharmacology studies have suggested that a small fraction of patients may experience an opioid 
withdrawal-like symptom complex consisting of tearfulness, mild nausea, abdominal cramps, 
restlessness, bone or joint pain, myalgia, and nasal symptoms. Other commonly reported side effects 
include difficulty sleeping, anxiety, nervousness, abdominal pain/cramps, low energy, joint and muscle 
pain, diarrhea, constipation, increased thirst, increased energy, feeling down, irritability, dizziness, skin 
rash, delayed ejaculation, decreased potency, and chills. Patients taking naltrexone may not benefit 
from opioid containing medicines, such as cough and cold preparations, antidiarrheal preparations, and 
opioid analgesics. Naltrexone and its primary metabolite are excreted primarily in the urine, and caution 
is recommended in administering the drug to patients with renal impairment. The risk of suicide is 
increased in patients with substance abuse with or without concomitant depression. This risk is not 
abated by treatment with naltrexone. In a situation requiring opioid analgesia, the amount of opioid 
required may be greater than usual, and the resulting respiratory depression may be deeper and more 


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prolonged. While naltrexone is a potent antagonist with a prolonged pharmacologic effect, the blockade 
produced by naltrexone is surmountable. This is useful in patients who may require analgesia, but poses 
a potential risk to individuals who attempt, on their own, to overcome the blockade by administering 
large amounts of exogenous opioids. Indeed, any attempt by a patient to overcome the antagonism by 
taking opioids is very dangerous and may lead to a fatal overdose. Naltrexone has the capacity to cause 
hepatocellular injury when given in excessive doses. Naltrexone is contraindicated in acute hepatitis or 
liver failure. The margin of separation between the apparently safe dose of naltrexone and the dose 
causing hepatic injury appears to be only five-fold or less. Naltrexone does not appear to be a 
hepatotoxin at the recommended doses. Patients will be warned of the risk of hepatic injury and advised 
to stop the use of Naltrexone and seek medical attention if they experience symptoms of acute hepatitis. 
The risk of overdose on opioids is transiently increased as naltrexone’s effects diminish due to 
naltrexone-induced increases in sensitivity to opioids. Patients will also be warned not to use opioids 
due to the risk of overdose during the first two weeks after the effects of depot NTX (or several days 
after oral NTX) have worn off. 
 
7. Naltrexone plus Clonidine. Clonidine has been shown to alleviate some of the signs and symptoms of 
opioid withdrawal associated with very low doses of naltrexone [170]. The most common side effects 
included dizziness, fatigue and gastrointestinal upset [171].  
 
8. Naltrexone plus Clonidine plus Gabapentin. Gabapentin with clonidine may increase clonidine-induced 
dizziness and drowsiness as well as produce difficulty thinking. Gabapentin and clonidine have shown a 
synergistic effect on inhibiting allodynia in a spinal nerve ligation model in the rat [172]. Gabapentin has 
also been shown to potentiate clonidine-induced anti-nociception in the formalin test [173]. Thus, we 
expect that gabapentin will potentiate clonidine’s impact on alleviating naltrexone-induced withdrawal 
symptoms. This combination may also produce greater sedation and stomach upset. 
 
9. Naltrexone plus Gabapentin. To our knowledge, no laboratory studies have examined the interaction 
between gabapentin and naltrexone. However, gabapentin at doses up to 1,200 mg/day was examined 
concomitantly with oral naltrexone in alcoholic patients [174]. Side effects were mild to moderate in 
severity and included dizziness (both naltrexone alone and naltrexone plus gabapentin), daytime 
somnolence, blurred vision and premature ejaculation.  
 
10. Other risks. 
a. Blood Drawing. Participants will have approximately 40 cc of blood drawn as a result of their 
participation in the study. Blood drawing can cause some pain and result in a hematoma.  
 
b. 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 these 
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 PI or Data Manager. 
c. Riboflavin. The addition of riboflavin to the capsules may turn the participants’ urine bright yellow. 
d. Performance Tasks. There may be some affective discomfort during the performance of the Mirror 
Tracing Tasks. Participants are allowed to end the task at their discretion. 
 
14. Protection of Participants: 
 
A. Participant Recruitment and Consent Procedures.  
Opioid-dependent participants seeking detoxification from opioids and short-term NTX therapy will 
be recruited via newspaper ads, radio ads, flyers, word-of-mouth, online ads, social media, email, and 
referrals. A research staff member experienced in obtaining informed consent will interview participants 
to determine interest in participating in this trial. Aspects of the study procedures, risks, and potential 
benefits will be explained, and any questions will be answered. The participant will be asked questions 


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to ensure an adequate understanding of the study and encouraged to read through the consent form a 
second time. The participant is asked to read aloud a section of informed consent to ensure that s/he 
can read (if the person is illiterate, a witness will be found to be present for the entire informed-consent 
process). If the participant indicates any hesitation about signing the consent form, s/he will be 
encouraged to leave with the consent form to consider the matter at leisure. If a participant indicates a 
desire to sign the consent form, both the participant and staff member will sign the form. The staff 
member will document that the informed-consent process occurred and whether the person’s questions 
were addressed to his/her satisfaction. If at any time the participant exhibits intoxication, sedation, over-
agitation, or some form of inattentiveness, the consenting process will be stopped and the interview 
rescheduled. After obtaining written informed consent for participation in the study and completing all 
screening procedures, a study physician will interview the participant and review all medical and 
psychiatric data prior to admitting the participant and beginning medication. 
 
B. Protections Against Risk. 
 
1. Our inclusion and exclusion criteria will be applied by experienced professionals, who will be carefully 
trained and monitored in order to accept only appropriate participants into the study. Thus, effective 
screening will exclude participants who would be placed at a greater risk. Risk level is determined by 
the medical and psychiatric history, drug use history, the physical examination, and the laboratory 
studies done prior to beginning this research protocol.  
 
2. The close monitoring of objective and subjective drug effects by direct observation, interviewing, and 
self-ratings will allow objective evaluation of the effects of gabapentin on detoxification from 
buprenorphine and transition to depot NTX therapy.  If at any point during the trial adverse reactions 
become excessive, the participant will be removed from the study. If the participant drops out of the 
study, alternative treatment will be offered. If a person relapses to opioid use following the BUP detox 
or following NTX therapy as determined by a study physician, he or she will be offered BUP as a 
rescue medication (2 mg) and referred to the Center for Addiction Services and Treatment opioid 
agonist maintenance program. Those who do not transition to NTX but are opioid abstinent will be 
offered alternative treatment as well as the option to continue to participate in the study without NTX 
therapy. 
 
3. Based on current recommendations by the manufacturer, pregnant women will be excluded by history 
and urine pregnancy test. They may, however, have the opportunity to enter the UAMS methadone or 
buprenorphine maintenance program. Women capable of becoming pregnant will be asked to use 
effective birth control in order to participate and to inform the study physician if their birth control plans 
change after being accepted into the study.  Participants who become pregnant will be transferred to 
an area program. 
 
4. On each day of transition to oral NTX, participants may need to submit an opioid-negative urine 
sample in order to receive the medication (if relapse to regular opioid use is indicated as determined 
by physician assessment, participants will not receive NTX). If positive, the participant may be invited 
to return the next day. If the sample is negative or regular use is not indicated, on all days that include 
clonidine administration (days 1-4), participants’ orthostatic vital signs and symptoms will be monitored 
prior to and following clonidine administration as well as 2 hours following initial naltrexone 
administration, to assure orthostatic hypotension does not occur at severity indicating increased risk. If 
the participant experiences lightheadedness or dizziness and has evidence of orthostatic hypotension 
with BP drop of > 20 mm Hg systolic or >10 mg Hg diastolic, accompanied with an increase in pulse 
>20 beats per minute, then the vitals will be repeated in 30 minutes. If the orthostatic changes persist 
at the time of the second measurement, then the transition to NTX will be halted on that day. The 
participant will be invited to return the following day and the procedures from the previous day will be 


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repeated, including a drug screen for opiates and vitals to include orthostatic measurements. If drug 
screen is negative for opiates and no orthostasis is present, then the participant will resume the 
process that was attempted on day one. If orthostatic changes recur, then the participant will not be 
transitioned to NTX; his/her study participation may be ended, in which case s/he will be referred to 
alternative treatment, if desired. 
 
5. During the NTX induction week, participants will be reminded to hydrate prior to clinic attendance. 
Drinks containing electrolytes will be provided to participants each day of the induction and 
participants will be encouraged to drink at least 20 oz during their 2+ hour visit. Clonidine will be given 
each day of the oral NTX induction to ease some of the typical discomfort experienced by participants 
during this time. 
 
6. Breathalyzer readings will be taken if alcohol use is suspected. If a participant has a breath-alcohol 
concentration of ≥0.08%, they cannot receive study medication until it drops below 0.08%. If the 
participant wishes, s/he can come back for a repeat alcohol breath analysis reading before the end of 
clinic dosing hours. 
 
7. Research staff members monitor participant’s status on at least a thrice-weekly basis during weeks 1-
4 and weekly during weeks 5-12. The research counselor will monitor psychiatric symptoms such as 
depression and anxiety on a weekly basis. Should symptoms worsen, the study physician will evaluate 
the participant to determine whether he/she could safely continue in the study. We will evaluate 
suicidality using the Columbia Suicide Severity Rating Scale during either screening or intake and as 
clinically indicated thereafter. Those who answer yes to the second question regarding current 
(meaning last 30 days) suicidal thoughts AND to at least one of questions 3, 4, and 5 about plans or 
intention to attempt suicide in the past month or answers Yes to question 6 in the past 12 months will 
be excluded during screening. If current suicidal ideation or a suicide attempt occurs during the study, 
the physician will be notified, campus police and/or MEMS called (if this occurs on campus) or 911 
called (if this occurs off campus) and the participant removed from the study. Participants will be given 
telephone numbers to call 24 hours a day in case of emergency.  An on-call study physician will be 
available at the after-hours number. 
 
8. Confidentiality will be protected by having all records identified by code number only, with the master 
file that matches subjects’ names with their study doses kept under lock by the data manager and 
pharmacy. To prevent any of the investigators from inadvertently discovering the medication dose 
assignments of participants, drug records will be maintained by ID code only in the pharmacy and will 
be made accessible to research staff only after a participant has completed the study. A Certificate of 
Confidentiality will be obtained from the Department of Health and Human Services when the protocol 
is approved by the IRB and will be submitted to the IRB prior to participant enrollment. 
 
9. Participants will be removed from the study if they experience any of the following: loss of 
consciousness, moderate-to-severe muscle weakness, seizure, or syncope, as determined by study 
physician. If at any point the participant is found to have orthostatic hypotension after complaining of 
lightheadedness or dizziness, then the vitals will be repeated within 30 minutes. If orthostatic 
hypotension has not resolved, then the physician will be notified for further instructions. If a participant 
is required to quarantine due to COVID-19 during phase I BUP detox, they will be discharged from 
protocol and study physician will provide a take-home BUP detox taper individually tailored to where in 
the phase 1 protocol the participant is. If a participant is required to quarantine due to COVID-19 
during phase II, they may remain on protocol and complete assessments remotely (by phone or 
teleconference). If this occurs, urine drug screens and COWS assessments will not be able to be done 
until participants are no longer required to quarantine. If a participant is unable to provide a urine drug 
screen at week 8 due to quarantine, they will not be eligible for the second Vivitrol injection, be 


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discharged from protocol and be offered referrals to treatment as necessary.  
 
10. All participants will be instructed to refrain from opioid use for at least 24–48 hours prior to their first 
dose of buprenorphine or naltrexone in order to decrease the likelihood of precipitating opioid 
withdrawal symptoms. If the participant had used within the window, this is discussed with the 
physician and the decision will be made with the participant to either continue with the induction (with 
the participant understanding they may experience withdrawal) or reschedule. Participants are 
monitored after the initial buprenorphine dose to ensure withdrawal symptoms don’t emerge (if they 
do, participants will be supported and a physician will be available to evaluate if symptoms become 
severe.) If symptoms emerge, the second dose of buprenorphine on day of induction may be held, as 
determined by physician. Buprenorphine doses will almost always be ingested at the clinic (except 
during holiday weekends, inclement weather, or if participating under truncated visit schedule due to 
COVID-19) in order to decrease the likelihood of diversion and/or intravenous use. Participants will 
also be advised of the increased risk of overdose on opioids should they use opioids during the first 
two weeks after the effects of depot naltrexone (several days after oral naltrexone if participants did 
not transition to the depot formulation) have worn off.  
 
11. Participants will be issued a card at admission that states that the holder is in a UAMS research study 
during a certain time period, is potentially receiving study medications that should not be stopped 
abruptly and/or may block the effects of opioid medications, and, if, for any reason, the holder cannot 
make the scheduled appointment, then s/he should call the appropriate phone numbers listed on the 
card. If a participant notifies us that s/he is incarcerated and will be detained for at least 3 days, we will 
discharge the person from the study, break the blind, and inform the participant which medication s/he 
was taking as well as what types of symptoms to be watchful for. The participant also will be told that 
s/he should notify the prison medical or other authority if symptoms develop. The consent form will 
provide participants with telephone numbers to call 24 hours a day. Upon injection with Vivitrol, 
participants will be issued a similar card specific to Vivitrol; name/contact information of the study 
physician will be recorded on the card in case of medical emergency. 
 
12. The trial will be stopped if investigators discharge 15 participants (10% of total sample) from the study 
due to study-related adverse effects. The trial will be stopped if 3 participants experience study-related 
serious adverse events or if 3 participants experience serious gabapentin/opioid-related events of a 
behavioral or physical nature. This requirement to terminate the study is based on 5 out of 150 active 
participants (3.0%). 
 
13. All personnel involved in this project will undergo biannual training in protection of human 
subjects. 
 
Potential Benefits and Risk/Benefit Ratio. The risks associated with this study include the effects of the 
study medications, detoxification, naltrexone transition and blood sampling. In addition, participants will 
have the inconvenience of participating in the study. Benefits offsetting these risks include that participants 
will undergo a medical evaluation, will be tapered off opioids will receive short-term naltrexone therapy and 
psychotherapy, and may experience abstinence from illicit opioids. The information gained in this study can 
assist us in developing more effective strategies for treating prescription opioid dependence, which 
ultimately would be of great benefit to society. We believe that the benefits more than justify the risks of 
participating in this study. 
 
15. Data and Safety Monitoring Plan  


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A. Data Acquisition, Collection, Transmission, and Entry 
Each research staff member is instructed on the timing of assessments for each individual. Checklists 
are used to ensure that assessments are obtained at the time indicated and are reviewed by the data 
manager, therapist and/or principal investigators.  
For the computerized assessments, the programs were created in such a way that 1) each participant 
has his/her own template of questionnaires that are prescheduled based on the timing of assessments 
outlined in the protocol, 2) each question must be answered in order to go to the next task or question, 3) 
each answer has a “built in” range of appropriate values such that out-of-range answers will not be 
accepted. The computer data will be backed up onto a secure server or flash sticks and brought to the 
data manager’s office, who will then export the date to excel or SPSS and check for missing data. The 
devices(s) used to collect data will be kept in a locked office when not in use. 
For paper assessments, the research assistant reviews the assessments for missing/out-of-range 
values and then brings them immediately to the data manager and/or principal investigator(s) to review as 
well. If any missing or inaccurate values are found, the participant will be asked to complete those again. 
Paper data will be entered into the computer independently by two different research staff trained to 
perform data entry, and the data manager will employ a verification program to determine and correct any 
discrepancies based on source data. If the data manager notices recurring data entry errors, he/she will 
inform the person(s) responsible and retrain them as necessary. 
For urine data, participants will be observed by a member of the same sex (or nurse) while they 
provide a urine sample to ensure that the sample truly came from a particular participant. In addition, 
research assistants check the temperature of the container of the urine sample to discern whether the 
container is cooler than normal. When a urine sample is suspect, the participant is asked to submit 
another sample. Urine data will be downloaded from the Redwood Toxicology Laboratory into an excel 
document. Research staff trained in phlebotomy will obtain blood samples. Riboflavin, gabapentin and 
buprenorphine assay results will be entered into the computer independently by two different research 
staff members as before. 
 Prior to statistical analyses, the data manager and/or principal investigator will check the data for 
mislabeling, missing data, out-of-range data, etc., and change/correct as appropriate based on source 
data. The data manager will also assign study condition per study ID for analysis purposes. A master data 
set will be created with at least two back-ups. One of these back-up disks will be given to the statistician, 
with a data assessment dictionary, for analysis.  
 
B. Procedures in Place to Ensure the Validity and Integrity of the Data 
The research assistant will have at least a Bachelor's level education and the research therapists at 
least a Masters level education (or relevant experience) and previous experience in clinical rating and/or 
interviewing. Under the direct supervision of the principal investigators and/or data manager, the rater will 
receive one month of training on the assessments, including the PRISM CV-V. Training may include 
viewing videotapes, observation of interviews and ratings, co-rating and interviewing with the supervisor 
present.  In order to conduct interviews for this study, it is required that the rater complete three 
consecutive conjoint interviews on which DSM V diagnoses are in complete agreement with those of more 
experienced raters. After training, reliability will be spot-checked on a semi-annual basis.  
 As for training on the other scales, the investigators and/or data manager first provides a training 
session on the background of the particular scale and how it is to be completed. Then the staff member 
observes the completion of the assessment by an experienced rater on at least 3 occasions. Afterwards, 
the staff member completes the assessment in the presence of an experienced rater on at least 3 
occasions, with feedback given each time until the supervisor is confident that the person understands the 
assessment and completes it properly. Thereafter, assessments are checked on a continuous basis for 
appropriate completion and constructive criticism is given as necessary. Staff members also undergo a 
refresher on assessments every 6 months. 


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C. Collection and Reporting of Adverse Events (AEs) and Serious Adverse Events (SAEs).  
All adverse events (AEs) occurring during the course of the study must be collected, documented, and 
reported to the PIs. The occurrence of AEs will be assessed in an ongoing way. Each week study 
investigators will review the AEs from the previous week for events that were reported as new or 
continuing. The study investigators will follow all AEs to the point of satisfactory resolution. A list of all AEs 
will be included in the annual progress report to NIDA. 
The PIs and the Co-Investigators will determine whether an event meets the criteria of a serious 
adverse event (SAE) and/or an unanticipated problem involving risks to subjects or others (UPIRTSO). 
The PI will report AEs and SAEs on an annual basis and UPIRTSOs to the IRB in a timely fashion. The PI 
will report all SAEs such as deaths, hospitalizations and unexpected toxicity, whether or not study-related, 
to NIDA within 72 hours. The procedures for reporting these SAEs to NIDA include written documentation 
using the clinical notes related to the adverse event and specific forms detailing the event with a sign-off 
by all appropriate supervisory personnel. Outcomes of SAEs will be periodically reported to NIDA. A 
summary of the AEs, SAEs and UPIRTSOs that occurred during the year will be included in an annual 
report to NIDA. 
The IRB communicates recommendations and decisions to the PI in a timely manner. In the event that 
the IRB takes an action that impacts the day-to-day operations of the trial (e.g., suspends recruitment, 
halts the trial), the PI will report those actions to the NIDA officer both verbally and in writing. 
 
D. Data and Safety Monitoring (DSM) Plan 
The PIs will be ultimately responsible for monitoring the safety and efficacy of the trial, executing the 
DSM plan, and complying with reporting requirements. The trial also has a study monitor, Michael Mancino, 
M.D. A Data and Safety Monitoring Board (DSMB) will also monitor this study. Members will be given a 
copy of the DSM plan prior to study initiation and will have the opportunity to make any recommendations at 
that time. DSM will occur in an ongoing way throughout the study. In addition, DSM will be formally 
reviewed when 33%, 67% and 100% of individuals have been enrolled. The PI will provide a summary of 
the DSM report to NIDA on an annual basis as part of the progress report. The DSM report will include a 
brief description of the trial, baseline sociodemographic characteristics, retention data, disposition of study 
participants, Q.A. issues, regulatory issues, AEs and SAEs along with assessments of attribution and 
severity, any actions or changes with respect to the protocol, and efficacy analyses, if conducted. This 
report will be given to the members of the DSMB for review when 33%, 67% and 100% of individuals have 
been enrolled or more frequently as necessary. The DSM Board will meet upon review of the DSM report 
generated when 33%, 67% and 100% of individuals have been enrolled or more frequently as necessary. 
Whether risks of participation remain acceptable under the present protocol or modifications to the protocol 
are necessary while still maintaining scientific integrity of the project will be determined. Interim analyses will 
not be performed unless clinically indicated. All SAEs, such as death, hospitalization, and unexpected 
toxicity, will be reported to the IRB, FDA, and NIDA under expedited reporting. The procedures for this 
reporting include written documentation using the clinical notes related to the adverse event and specific 
forms detailing the event with a sign-off by all appropriate supervisory personnel. We will report major 
protocol amendments or changes in the informed consent to NIDA, as well as any temporary or permanent 
suspension of patient accrual.   
 
16. References: 
 
1. 
Substance Abuse and Mental Health Services Administration, Results from the 2009 National 
Survey on Drug Use and Health: Volume I. Summary of National Findings. , N.S.H.-A. Office of 
Applied Studies, HHS Publication No. SMA 10-4856Findings, Editor. 2010: Rockville, MD. 
2. 
SAMHSA, Drug Abuse Warning Network, 2009: National Estimates of Drug-Related Emergency 
Department Visits. HHS Publication No. (SMA) 11-4659. DAWN Series D-35. S. A. a. M. H. S. 
Administration. 2011: Rockville, MD. 


Improving treatment outcomes for prescription opioid dependence                                         PI: Alison Oliveto, Ph.D. 
 
V.26 
26 of 33  
7/24/2020 
3. 
DuPont, R.L., Prescription Drug Abuse: An Epidemic Dilemma. Journal of Psychoactive Drugs, 
2010. 42(2): p. 127-132. 
4. 
McCabe, S.E., et al., Does early onset of non-medical use of prescription drugs predict subsequent 
prescription drug abuse and dependence? Results from a national study. Addiction, 2007. 102(12): 
p. 1920-1930. 
5. 
Cai, R., et al., Emergency department visits involving nonmedical use of selected prescription drugs-
United States, 2004-2008. Journal of the American Medical Association, 2010. 304(5): p. 514-516. 
6. 
Coben, J.H., et al., Hospitalizations for poisoning by prescription opioids, sedatives, and 
tranquilizers. American Journal of Preventive Medicine, 2010. 39(6): p. 613-U27. 
7. 
Paulozzi, L.J. and Y.L. Xi, Recent changes in drug poisoning mortality in the United States by urban-
rural status and by drug type. Pharmacoepidemiology and Drug Safety, 2008. 17(10): p. 997-1005. 
8. 
Hanson, K., A pill problem: Prescription drug abuse is the fastest growing form of substance abuse. 
State legislatures, 2010(March): p. 22-25. 
9. 
Hanson, K., A pill problem: prescription drug abuse is the fastest growing form of substance abuse. 
State Legislatures, 2010. 36(3): p. 22-5. 
10. 
Weiss, R.D., et al., Adjunctive counseling during brief and extended buprenorphine-naloxone 
treatment for prescription opioid dependence: A 2-phase randomized controlled trial. Archives of 
General Psychiatry, 2011. 68(12): p. 1238-1246. 
11. 
Moore, B.A., et al., Primary care office-based buprenorphine treatment: Comparison of heroin and 
prescription opioid dependent patients. Journal of General Internal Medicine, 2007. 22(4): p. 
527−530. 
12. 
Brands, B., et al., Prescription opioid abuse in patients presenting for methadone maintenance 
treatment. Drug and Alcohol Dependence, 2004. 73(2): p. 199−207. 
13. 
Sigmon, S.C., Characterizing the emerging population of prescription opioid abusers. The American 
Journal on Addictions, 2006. 15(3): p. 208−212. 
14. 
Zacny, J., et al., College on Problems of Drug Dependence taskforce on prescription opioid non-
medical use and abuse: Position statement. Drug and Alcohol Dependence 2003. 69: p. 215 -232. 
15. 
Knudsen, H.K., L.J. Ducharme, and P.M. Roman, Controlled-release oxycodone admissions in 
public and private substance abuse treatment: Associations with organizational characteristics. 
Journal of Addictive Diseases, 2007. 26(1): p. 41-50. 
16. 
Stotts, A.L., C.L. Dodrill, and T.R. Kosten, Opioid dependence treatment: options in 
pharmacotherapy. Expert Opinion on Pharmacotherapy, 2009. 10(11): p. 1727-1740. 
17. 
Friedmann, P.D., et al., Medication-assisted treatment in criminal justice agencies affiliated with the 
criminal justice-drug abuse treatment studies (CJ-DATS): availability, barriers, and intentions. 
Substance Abuse, 2012. 33(1): p. 9-18. 
18. 
Hamza, H. and E.O. Bryson, Buprenorphine maintenance therapy in opioid-addicted health care 
professionals returning to clinical practice: a hidden controversy. Mayo Clinic Proceedings, 2012. 
87(3): p. 260-267. 
19. 
Cicero, T.J., et al., Relationship between therapeutic use and abuse of opioidanalgesics in rural, 
suburban, and urban locations in theUnited States. Phamacoepidemiology and Drug Safety, 2007. 
16(8): p. 827−840. 
20. 
O'Connor, P.G., et al., Three methods of opioid detoxification in a primary care setting. Annals of 
Internal Medicine, 1997. 127(7): p. 526−530. 
21. 
Winstock, A.R., N. Lintzeris, and T. Lea, "Should I stay or should I go?" Coming off methadone and 
buprenorphine treatment. International Journal of Drug Policy, 2011. 22(1): p. 77-81. 
22. 
Kleber, H.D., et al., Clonidine in outpatient detoxification from methadone maintenance. Archives of 
General Psychiatry, 1985. 42(4): p. 391-394. 
23. 
Kosten, T.R., B.J. Rounsaville, and H.D. Kleber, Comparison of clinician ratings to self reports of 
withdrawal during clonidine detoxification of opiate addicts. Am J Drug Alcohol Abuse, 1985. 11(1-2): 
p. 1-10. 


Improving treatment outcomes for prescription opioid dependence                                         PI: Alison Oliveto, Ph.D. 
 
V.26 
27 of 33  
7/24/2020 
24. 
Rounsaville, B.J., T. Kosten, and H. Kleber, Success and failure at outpatient opioid detoxification. 
Evaluating the process of clonidine- and methadone-assisted withdrawal. J Nerv Ment Dis, 1985. 
173(2): p. 103-10. 
25. 
Jasinski, D.R., R.E. Johnson, and T.R. Kocher, Clonidine in morphine withdrawal. Differential effects 
on signs and symptoms. Archives of General Psychiatry, 1985. 42(11): p. 1063-1066. 
26. 
Gossop, M., et al., Lapse, relapse and survival among opiate addicts after treatment. A prospective 
follow-up study. British Journal of Psychiatry, 1989. 154: p. 348-353. 
27. 
Gowing, L.R., et al., Alpha2-adrenergic agonists in opioid withdrawal. Addiction, 2002. 97(1): p. 49-
58. 
28. 
Amato, L., et al., Methadone at tapered doses for the management of opioid withdrawal. Cochrane 
Database of Systematic Reviews, 2005. Jul 20(3): p. CD003409. 
29. 
Gowing, L., R. Ali, and J.M. White, Buprenorphine for the management of opioid withdrawal. 
Cochrane Database of Systematic Reviews, 2009(3). 
30. 
Kleber, H.D., Pharmacologic treatments for opioid dependence: detoxification and maintenance 
options. Dialogues in Clinical Neuroscience, 2007. 9(4): p. 455-70. 
31. 
Sanders, N.C., et al., Randomized, placebo-controlled pilot trial of gabapentin during an outpatient, 
buprenorphine-assisted detoxification procedure. Experimental and Clinical Psychopharmacology, 
2013. 21(4): p. 294-302 [PMC3972066]. 
32. 
Gowing, L.R. and R.L. Ali, The place of detoxification in treatment of opioid dependence. Current 
Opinion in Psychiatry, 2006. 19: p. 266-270. 
33. 
Sigmon, S.C., et al., Brief buprenorphine detoxification for the treatment of prescription opioid 
dependence: A pilot study. Addictive Behaviors, 2009. 34: p. 304-311. 
34. 
Sigmon, S., et al., A randomized, double-blind evaluation of buprenorphine taper duration in primary 
prescription opioid abusers. JAMA Psychiatry, 2013. 70(12): p. 1347-1354. doi: 
10.1001/jamapsychiatry.2013.2216. 
35. 
Dean, A.J., et al., Does naltrexone treatment lead to depression? Findings from a randomized 
controlled trial in subjects with opioid dependence Journal of Psychiatry and Neuroscience, 2006. 
31(1): p. 38-45. 
36. 
Mysels, D.J., et al., The association between naltrexone treatment and symptoms of depression in 
opioid-dependent patients. The American Journal of Drug and Alcohol Abuse, 2011. 37: p. 22-26. 
37. 
Hulse, G.K., H.T. Ngo, and R.J. Tait, Risk Factors for Craving and Relapse in Heroin Users Treated 
with Oral or Implant Naltrexone. Biological Psychiatry, 2010. 68: p. 296-302. 
38. 
Carreno, J.E., et al., Maintenance treatment with depot opioid antagonists in subcutaneous implants: 
an alternative in the treatment of opioid dependence. Addiction Biology, 2003. 8: p. 429-38. 
39. 
Minozzi, S., et al., Oral naltrexone maintenance treatment for opioid dependence (Review). 2011, 
The Cochrane Collaboration. 
40. 
Sullivan, M.A., et al., Management of relapse in naltrexone maintenance for heroin dependence. 
Drug & Alcohol Dependence, 2007. 91: p. 289-292. 
41. 
Sullivan, M.A., et al., Predictors of Retention in Naltrexone Maintenance for Opioid Dependence: 
Analysis of a Stage I Trial. The American Journal on Addictions, 2006. 15: p. 150-159. 
42. 
Ritter, A.J., Naltrexone in the treatment of heroin dependence: relationship with depression and risk 
of overdose. Australian and New Zealand Journal of Psychiatry, 2002. 36: p. 224-28. 
43. 
Brooks, A.C., et al., Long-Acting Injectable Versus Oral Naltrexone Maintenance Therapy With 
Psychosocial Intervention for Heroin Dependence: A Quasi-Experiment. Journal of Clinical 
Psychiatry, 2010. 71(10): p. 1371-78. 
44. 
Reece, A., Psychosocial and treatment correlates of opiate free success in a clinical review of a 
naltrexone implant program. Substance Abuse Treatment, Prevention, and Policy, 2007. 2(35): p. 1-
15. 
45. 
Reece, A., Favorable mortality profile of naltrexone implants for opiate addiction. Journal of 
Addictive Diseases, 2010. 29(1): p. 30-50. 


Improving treatment outcomes for prescription opioid dependence                                         PI: Alison Oliveto, Ph.D. 
 
V.26 
28 of 33  
7/24/2020 
46. 
Hulse, G.K. and R.J. Tait, A pilot study to assess the impact of naltrexone implant on accidental 
opiate overdose in ‘high-risk’ adolescent heroin users. Addiction Biology, 2003. 8: p. 337-42. 
47. 
Hulse, G.K., et al., Reducing hospital presentations for opioid overdose in patients treated with 
sustained release naltrexone implants. Drug & Alcohol Dependence, 2005. 79: p. 351-57. 
48. 
Carroll, K.M., et al., Contingency Management to Enhance Naltrexone Treatment of Opioid 
Dependence: A Randomized Clinical Trial of Reinforcement Magnitude. Experimental and Clinical 
Psychopharmacology, 2002. 10(1): p. 54-63. 
49. 
DeFulio, A., et al., Employment-based reinforcement of adherence to an FDA approved extended 
release formulation of naltrexone in opioid-dependent adults: A randomized controlled trial. Drug & 
Alcohol Dependence, 2012. 120: p. 48-54. 
50. 
Bisaga, A., et al., A placebo controlled trial of memantine as an adjunct to oral naltrexone for opioid 
dependence. Drug & Alcohol Dependence, 2011. 119: p. e23– e29. 
51. 
Schottenfeld, R.S., Maintenance treatment with buprenorphine and naltrexone for heroin 
dependence in Malaysia: a randomised, double-blind, placebo-controlled trial. The Lancet, 2008. 
371: p. 2192-2200. 
52. 
Ngo, H.T., R.J. Tait, and G.K. Hulse, Comparing Drug-Related Hospital Morbidity Following Heroin 
Dependence Treatment With Methadone Maintenance or Naltrexone Implantation. Archives of 
General Psychiatry, 2008. 65(4): p. 457-65. 
53. 
Kunoe, N., et al., Retention in naltrexone implant treatment for opioid dependence. Drug & Alcohol 
Dependence, 2010. 111: p. 166-69. 
54. 
Koob, G.F., R. Maldonado, and L. Stinus, Neural substrates of opiate withdrawal. TINS, 1992. 15(5): 
p. 186-191. 
55. 
Nestler, E., Molecular mechanisms of drug addiction. Journal of Neuroscience, 1992. 12: p. 2439-
2450. 
56. 
Redmond, D.E. and J.H. Krystal, Multiple mechanisms of withdrawal from opioid drugs. Annual 
Review of Neuroscience, 1984. 7: p. 443-478. 
57. 
Williams, J.T., et al., Cellular and synaptic adaptations mediating opioid dependence. Physiological 
Reviews, 2001. 81(1): p. 299-343. 
58. 
Macdonald, J., et al., Where is the locus of opiod withdrawal? TiPS, 1997. 18: p. 134-140. 
59. 
Akaoka, H. and G. Aston-Jones, Opiate withdrawal-induced hyperactivity of locus coeruleus neurons 
is substantially mediated by augmented excitatory amino acid input. Journal of Neuroscience, 1991. 
11: p. 3830-3839. 
60. 
Ennis, M. and G. Aston-Jones, Activation of locus coeruleus from nucleus paragiganto-cellularis: A 
new excitatory amino acid pathway in brain. J Neurosci, 1988. 8: p. 3644-3657. 
61. 
Rasmussen, K. and G.K. Aghajanian, Withdrawal-Induced activation of locus coeruleus neurons in 
opiate-dependent rats: Attenuation by lesions of the nucleus paragigantocellularis. Brain Research, 
1989. 505: p. 346-350. 
62. 
Rasmussen, K., et al., Opiate withdrawal and the rat locus coeruleus: Behavioral 
electrophysiological, and biochemical correlates. J Neurosci, 1990. 10: p. 2308-2317. 
63. 
Mayer, M.L. and R. Miller, Excitatory amino acid receptors, 2nd messengers and regulation of 
intracellular Ca2+ in mammalian neurons. Trends Pharmacol Sci, 1990. 11: p. 11: 254. 
64. 
Bongianni, F., et al., Calcium channel inhibitors suppress the morphine-withdrawal syndrome in rats. 
British Journal of Pharmacology, 1986. 88: p. 561-567. 
65. 
Baeyens, J.M., et al., Effects of peripheral and central administration of calcium channel blockers in 
the naloxone-precipitated abstinence syndrome in morphine-dependent rats. European Journal of 
Pharmacology, 1987. 137: p. 9-13. 
66. 
Ramkumar, V. and E.E. El-Fakahany, Prolonged morphine treatment increases rat brain 
dihydropyridine binding sites: Possible involvement in development of morphine dependence. 
European Journal of Pharmacology, 1988. 146: p. 73-83. 
67. 
Seth, V., et al., Role of calcium in morphine dependence and naloxone-precipitated withdrawal in 
mice. Journal of Experimental Pharmacology, 2011. 3: p. 7-12. 


Improving treatment outcomes for prescription opioid dependence                                         PI: Alison Oliveto, Ph.D. 
 
V.26 
29 of 33  
7/24/2020 
68. 
Silverstone, P.H., C. Done, and T. Sharp, Clonidine but not nifedipine prevents the release of 
noradrenaline during naloxone-precipitated opiate withdrawal: An in vivo microdialysis study in the 
rat. Psychopharmacology, 1992. 109: p. 235-238. 
69. 
Jimenez-Lerma, J.M., et al., Nimodipine in opiate detoxification: a controlled trial. Addiction, 2002. 
97(7): p. 819-824. 
70. 
Shulman, A., et al., Calcium channel blocking drugs in the management of drug dependence, 
withdrawal and craving. A clinical pilot study with nifedipine and verapamil. Australian Family 
Physician, 1998. 27 Suppl 1: p. S19-24. 
71. 
Oliveto, A., et al., Effects of verapamil and diltiazem in methadone-maintained humans under a 
naloxone novel-response discrimination procedure. Presented at the 2009 Annual Meeting of the 
College on Problems of Drug Dependence, Reno/Sparks, NV. 2009. 
72. 
Oliveto, A., et al., Isradipine and dextromethorphan in methadone-maintained humans under a 
naloxone discrimination procedure. European Journal of Pharmacology, 2004. 491(2-3): p. 157-168. 
73. 
Oliveto, A.H., et al., Effects of tizanidine and nifedipine in methadone-maintained humans under a 
naloxone novel-response discrimination procedure. Presented at the 2011 Annual Meeting of the 
College on Problems of Drug Dependence. Hollywood, FL: 
http://www.cpdd.vcu.edu/Pages/Meetings/CPDD11AbstractBook.pdf. 2011. 
74. 
Oliveto, A., et al., Clonidine and yohimbine in opioid-dependent humans responding under a 
naloxone novel-response discrimination procedure. Behavioural Pharmacology, 2003. 14(2): p. 97-
109. 
75. 
Hillhouse, M., et al., Provision of ancillary medications during buprenorphine detoxification does not 
improve treatment outcomes. Journal of Addictive Diseases, 2010. 29(1): p. 23-29. 
76. 
Duka, T., H.S. Crombag, and D.N. Stephens, Experimental medicine in drug addiction: towards 
behavioral, cognitive and neurobiological biomarkers. Journal of psychopharmacology, 2011. 25(9): 
p. 1235-1255. 
77. 
Verster, J. and L. de Haan, The 2D:4D digit ratio: a biomarker of alcohol and drug abuse? Current 
Drug Abuse Reviews, 2011. 4(2): p. 65-6. 
78. 
Alguacil, L.F., E. Salas, and C. Gonzalez-Martin, Identification of New Drug Targets and Biomarkers 
Related to Obesity and Eating Disorders: an Approach Based on Reward Deficit and Addiction. 
Current Pharmaceutical Design, 2011. 17(5): p. 462-470. 
79. 
Eroglu, C., et al., Gabapentin receptor alpha2delta-1 is a neuronal thrombospondin receptor 
responsible for excitatory CNS synaptogenesis. Cell, 2009. 139(2): p. 380-92. 
80. 
Maneuf, Y.P., et al., Cellular and molecular action of the putative GABA-mimetic, gabapentin. 
Cellular and Molecular Life Sciences, 2003. 60(4): p. 742-50. 
81. 
Snutch, T.P., K.G. Sutton, and G.W. Zamponi, Voltage-dependent calcium channels--beyond 
dihydropyridine antagonists. Current Opinions in Pharmacology, 2001. 1(1): p. 11-6. 
82. 
Bertrand, S., F. Morin, and J.C. Lacaille, Different actions of gabapentin and baclofen in 
hippocampus from weaver mice. Hippocampus, 2003. 13(4): p. 525-8. 
83. 
Kuzniecky, R., et al., Modulation of cerebral GABA by topiramate, lamotrigine, and gabapentin in 
healthy adults. Neurology, 2002. 58(3): p. 368-72. 
84. 
Andrews, N., et al., Effect of gabapentin-like compounds on development and maintenance of 
morphine-induced conditioned place preference. Psychopharmacology, 2001. 157(4): p. 381-7. 
85. 
Shimoyama, M., et al., Gabapentin enhances the antinociceptive effects of spinal morphine in the rat 
tail-flick test. Pain, 1997. 72(3): p. 375-82. 
86. 
Eckhardt, K., et al., Gabapentin enhances the analgesic effect of morphine in healthy volunteers. 
Anesthesiology and Analgesia, 2000. 91(1): p. 185-91. 
87. 
Dirks, J., et al., A randomized study of the effects of single-dose gabapentin versus placebo on 
postoperative pain and morphine consumption after mastectomy. Anesthesiology, 2002. 97(3): p. 
560-4. 
88. 
Gilron, I., et al., Gabapentin blocks and reverses antinociceptive morphine tolerance in the rat paw-
pressure and tail-flick tests. Anesthesiology, 2003. 98(5): p. 1288-92. 


Improving treatment outcomes for prescription opioid dependence                                         PI: Alison Oliveto, Ph.D. 
 
V.26 
30 of 33  
7/24/2020 
89. 
Santillan, R., et al., Nimodipine-enhanced opiate analgesia in cancer patients requiring morphine 
dose escalation: a double-blind, placebo-controlled study. Pain, 1998. 76(1-2): p. 17-26. 
90. 
Hack, S.P., C.W. Vaughan, and M.J. Christie, Modulation of GABA release during morphine 
withdrawal in midbrain neurons in vitro. Neuropharmacology, 2003. 45(5): p. 575-84. 
91. 
Williams, J.T., M.J. Christie, and O. Manzoni, Cellular and synaptic adaptations mediating opioid 
dependence. Physiological Reviews, 2001. 81(1): p. 299-343. 
92. 
Kruszewska, A., The role of GABA in morphine abstinence in rats. Drug and Alcohol Dependence, 
1988. 21(1): p. 37-41. 
93. 
Zarrindast, M.R. and E. Mousa-Ahmadi, Effects of GABAergic system on naloxone-induced jumping 
in morphine-dependent mice. European Journal of Pharmacology, 1999. 381(2-3): p. 129-33. 
94. 
Ewan, E.E. and T.J. Martin, Rewarding electrical brain stimulation in rats after peripheral nerve 
injury: Decreased facilitation by commonly abused prescription opioids. Anesthesiology, 2011. 
115(6): p. 1271-1280. 
95. 
Bourgeois, B.F., Pharmacokinetic properties of current antiepileptic drugs: what improvements are 
needed? Neurology, 2000. 55(11 Suppl 3): p. S11-6. 
96. 
Oliveto, A., et al., Effects of cycloserine and gabapentin in methadone-maintained humans under a 
naloxone novel-response discrimination procedure. Presented at the 2010 Annual Meeting of the 
College on Problems of Drug Dependence, Scottsdale, AZ. 2010. 
97. 
Kheirabadi, G.R., et al., Effect of add-on gabapentin on opioid withdrawal symptoms in opium-
dependent patients. Addiction, 2008. 103(9): p. 1495-9. 
98. 
Freye, E., J.V. Levy, and L. Partecke, Use of gabapentin for attenuation of symptoms following rapid 
opiate detoxification (ROD) - correlation with neurophysiological parameters -. Neurophysiologie 
clinique, 2004. 34: p. 81-89. 
99. 
Martinez-Raga, J., et al., Add-on gabapentin in the treatment of opiate withdrawal. Progress in 
Neuro-Psychopharmacology & Biological Psychiatry, 2004. 28: p. 599-601. 
100. 
Salehi, M., et al., Importance of gabapentin dose in treatment of opioid withdrawal. Journal of clinical 
psychopharmacology, 2011. 31(5): p. 593-6. 
101. 
Dreifuss, J.A., et al., Patient characteristics associated with buprenorphine/naloxone treatment 
outcome for prescription opioid dependence: Results from a multisite study Drug and Alcohol 
Dependence, 2013. http://dx.doi.org/10.1016/j.drugalcdep.2012.12.010. 
102. 
Comer, S.D., et al., Injectable, Sustained-Release Naltrexone for the Treatment of Opioid 
Dependence. Archives of General Psychiatry, 2006. 63: p. 210-18. 
103. 
Fantoma, A., G. Gerra, and A. Zaimovic, Naltrexone and buprenorphine combination in the 
treatment of opioid dependence. Journal of Psychopharmacology, 2006. 20: p. 806-14. 
104. 
Yu, E., et al., A Phase 3 placebo-controlled, double-blind, multi-site trial of the alpha-2-adrenergic 
agonist, lofexidine, for opioid withdrawal Drug and Alcohol Dependence, 2008. 97: p. 158–168. 
105. 
Morral, A., et al., Natural classes of treatment response. J. Consult. Clin. Psychol, 1997. 65(4): p. 
673-685. 
106. 
Ziedonis, D.M., et al., Predictors of outcome for short-term medically supervised opioid withdrawal 
during a randomized, multicenter trial of buprenorphine-naloxone and clonidine in the NIDA clinical 
trials network drug and alcohol dependence. Drug & Alcohol Dependence, 2009. 99(1-3): p. 28-36. 
107. 
McHugh, R.K., et al., Gender differences in a clinical trial for prescription opioid dependence. 
Journal of Substance Abuse Treatment, http://dx.doi.org/10.1016/j.jsat.2012.12.007, 2013. 
108. 
Brands, B., et al., Nonmedical use of opioid analgesics among Ontario students. Canadian Family 
Physician, 2010. 56: p. 256-262. 
109. 
DHHS and SAMHSA. Treatment Episode Data Set (TEDS) 1999-2009: State Admissions to 
Substance Abuse Treatment Services. 2011. 
110. 
Nich, C., et al., Sex differences in cocaine-dependent individuals' response to disulfiram treatment. 
Addict Behav, 2004. 29(6): p. 1123-8. 
111. 
Kosten, T.A., et al., Gender differences in cocaine use and treatment response. J Subst Abuse 
Treat, 1993. 10(1): p. 63-6. 


Improving treatment outcomes for prescription opioid dependence                                         PI: Alison Oliveto, Ph.D. 
 
V.26 
31 of 33  
7/24/2020 
112. 
Chopra, M.P., et al., Sex and opioid maintenance dose influence response to naloxone in opioid-
dependent humans: a retrospective analysis. Pharmacology Biochemistry and Behaviour, 2008. 
90(4): p. 787-96. PMCID: PMC2577173. 
113. 
Singha, A.K., et al., Sex differences in self-reported and physiological response to oral cocaine and 
placebo in humans. American Journal on Drug and Alcohol Abuse, 2000. 26(4): p. 643-57. 
114. 
Brown, R.A., et al., Distress tolerance and duration of past smoking cessation attempts. J. Abnorm. 
Psychol, 2002. 111: p. 180-185. 
115. 
Lejuez, C.W., C.W. Kahler, and R.A. Brown, A modified computer version of the paced auditory 
serial addition task (PASAT) as a laboratory-based stressor. J. Behav. Ther. Exp. Psychiatry, 2003. 
29: p. 290-293. 
116. 
Daughters, S.B., et al., The relationship between distress tolerance and antisocial personality 
disorder among male inner-city treatment seeking substance users. J. Personal. Disorders, 2008. 
22: p. 245–509. 
117. 
Howell, A.N., et al., Anxiety sensitivity, distress tolerance, and discomfort intolerance in relation to 
coping and conformity motives for alcohol use and alcohol use problems among young adult 
drinkers. Addict. Behaviours, 2010. 35: p. 1144-1147. 
118. 
Daughters, S.B., et al., Psychological distress tolerance and duration of most recent abstinence 
attempt among residential treatment-seeking substance abusers. Psychol. Addict. Behav, 2005. 19: 
p. 208–211. 
119. 
Daughters, S.B., et al., Distress tolerance as a predictor of early treatment dropout in a residential 
substance abuse treatment facility. J. Abnorm. Psychology, 2005. 114: p. 729-734. 
120. 
Joe, G.W., D.D. Simpson, and K.M. Broome, Effects of resdiness for drug abuse treatment on client 
retention and assessment of process. Addiction, 1998. 93(8): p. 1177-1190. 
121. 
Hesse, M., The readiness ruler as a measure of readiness to change poly-drug use in drug abusers. 
Harm Reduction Journal, 2006. 3(3). 
122. 
Miller, W.R. and J.S. Tonigan, Assessing drinkers' motivations for change: The Stages of Change 
Readiness and Treatment Eagerness Scale (SOCRATES). Psychology of Addictive Behaviors, 
1996. 10: p. 81-89. 
123. 
Swift, R.M. and R.L. Stout, The relationship between craving, anxiety, and other symptoms in opioid 
withdrawal. Journal of Substance Abuse, 1992. 4(1): p. 19-26. 
124. 
Shi, J., et al., Time-dependent neuroendocrine alterations and drug craving during the first month of 
abstinence in heroin addicts. American Journal of Drug & Alcohol Abuse, 2009. 35(5): p. 267-272. 
125. 
Lejuez, C.W., et al., Anxiety sensitivity: a unique predictor of dropout among inner-city heroin and 
crack/cocaine users in residential substance use treatment. Behaviour Research and Therapy, 
2008. 46(7): p. 811-818. 
126. 
Hearon, B.A., et al., Anxiety sensitivity and illicit sedative use among opiate-dependent women and 
men. American Journal of Drug & Alcohol Abuse, 2011. 37(1): p. 43-47. 
127. 
Lemenager, T., et al., Impaired decision making in opiate addiction correlates with anxiety and self-
directedness but not substance use parameters. Journal of Addiction Medicine, 2011. 5(3): p. 203-
213. 
128. 
Posner, K., et al., The Columbia–Suicide Severity Rating Scale : Initial validity and internal 
consistency findings from three multisite studies with adolescents and adults. American Journal of 
Psychiatry, 2011. 168: p. 1266-1277. 
129. 
Sanders, N.C., et al., Effects of gabapentin in opioid-dependent individuals during a 10-day 
buprenorphine detoxification. The 2012 Annual Meeting of the College on Problems of Drug 
Dependence. Palm Springs, CA. 2012. 
130. 
Kosten, T., et al., Desipramine and contingency management for cocaine and opiate dependence in 
buprenorphine maintained patients. Drug Alcohol Depend, 2003. 70(3): p. 315-25. 
131. 
Oliveto, A., et al., Efficacy of dose and contingency management procedures in LAAM-maintained 
cocaine-dependent patients. Drug Alcohol Depend, 2005. 79(2): p. 157-65. 


Improving treatment outcomes for prescription opioid dependence                                         PI: Alison Oliveto, Ph.D. 
 
V.26 
32 of 33  
7/24/2020 
132. 
Stout, R.L., et al., Ensuring balanced distribution of prognostic factors in treatment outcome 
research. J Stud Alcohol Suppl, 1994. 12: p. 70-5. 
133. 
Wei, L.J., An application of an urn model to the design of sequential controlled clinical trials. Journal 
of the American Statistical Association, 1978. 73: p. 559-563. 
134. 
Wei, L.J. and J.M. Lachin, Properties of the urn randomization in clinical trials. Controlled Clinical 
Trials, 1988. 9(4): p. 345-64. 
135. 
Rothenberg, J.L., et al., Behavioral naltrexone therapy: an integrated treatment for opiate 
dependence. Journal of Substance Abuse Treatment, 2002. 23: p. 351-60. 
136. 
Carroll, K.M., A cognitive-behavioral approach: treating cocaine addiction. 1998, NIDA: Rockville, 
MD. p. 98-4308. 
137. 
Carroll, K.M., Cognitive-Behavioral Coping Skills Treatment for Cocaine Dependence. 1996, New 
Haven, CT: Yale University Psychotherapy Development Center. 
138. 
Rounsaville, B.J., A diagnostic sourcebook for drug abuse treatment and research, in NIDA 
Research Monograph Series. 1993, NIH Pub. p. 1-10. 
139. 
Hasin, D., et al., Diagnosis of comorbid psychiatric disorders in substance users assessed with the 
Psychiatric Research Interview for Substance and Mental Disorders for DSM-IV. American Journal 
of Psychiatry, 2006. 163: p. 689–696. 
140. 
Hasin, D.S., et al., Psychiatric Research Interview for Substance and Mental Disorders (PRISM): 
reliability for substance abusers. American Journal of Psychiatry, 1996. 153: p. 1195–1201. 
141. 
Physicians' desk reference. 58th ed. 2008, Montvale, NJ: Thomson PDR. 
142. 
Handelsman, L., et al., Two new rating scales for opiate withdrawal. American Journal of Drug and 
Alcohol Abuse, 1987. 13(3): p. 293-308. 
143. 
Hajek, P., M. Belcher, and J. Stapleton, Breath-holding endurance as a predictor of success in 
smoking cessation. Addictive Behaviors, 1987. 12(3): p. 285-8. 
144. 
Simons, J.S. and R.M. Gaher, The distress tolerance scale: Development and validation of self-
reported measure. Motivation and Emotion, 2005. 29(2): p. 83-102. 
145. 
Spielberger, C.D., Manual for the State-Trait Anxiety Inventory: STAI (Form Y) in Consulting 
Psychological Press, Inc. 1983: Palo Alto, CA. 
146. 
Peterson, R.A. and S. Reiss, Anxiety Sensitivity Index manual (2nd ed. rev.). 1992: Worthington, 
OH: International Diagnostic Systems. 
147. 
Hamilton, M.A., A rating scale for depression. J Neurol Neurosurg Psychiatry, 1960. 23: p. 56-82. 
148. 
Hamilton, M., The assessment of anxiety states by rating. British Journal of Medical Psychology, 
1959. 32: p. 50–55. 
149. 
Moul, D.E., et al., Preliminary study of the test-retest reliability and concurrent validities of the 
Pittsburgh Insomnia Rating Scale (PIRS). Sleep 25 Abstract Supplement, 2002: p. A246-A247. 
150. 
Buysse, D.J., et al., The Pittsburgh Sleep Quality Index: A new instrument for psychiatric practice 
and research. Journal of Psychiatric Research, 1989. 28(2): p. 193–213. 
151. 
Kirby, K.N., N.M. Petry, and W.K. Bickel, Heroin addicts have higher discount rates for delayed 
rewards than non-drug-using controls. J Exp Psychol Gen, 1999. 128(1): p. 78-87. 
152. 
Acheson, A., et al., Greater discounting of delayed rewards in young adults with family histories of 
alcohol and drug use disorders: studies from the Oklahoma family health patterns project. 
Alcoholism: Clinical and Experimental Research, 2011. 35(9): p. 1607-13. 
153. 
Mazur, J.E., An adjusting amount procedure for studying delayed reinforcement, in Quantitative 
Analysis of Behavior: The Effects of Delay and of Intervening Events on Reinforcement Value, 
J.E.M. M.L. Commons, J.A. Nevin and H. Rachlin, Editor. 1987, Lawrence Erlbaum Associates: 
Hillsdale. p. 55-73. 
154. 
Bryk, A.S. and S.W. Raudenbush, Application of hierarchical linear models to assessing change. 
Psychol Bull, 1987. 101: p. 147-158. 
155. 
Gibbons, R.D., et al., Some conceptual and statistical issues in analysis of longitudinal psychiatric 
data. Application to the NIMH treatment of Depression Collaborative Research Program dataset. 
Arch Gen Psychiatry, 1993. 50(9): p. 739-50. 


Improving treatment outcomes for prescription opioid dependence                                         PI: Alison Oliveto, Ph.D. 
 
V.26 
33 of 33  
7/24/2020 
156. 
Hedeker, D. and R.D. Gibbons, MIXREG: A computer program for mixed-effects regression analysis 
with autocorrelated errors. Computer Methods and Programs in Biomedicine, 1996. 49(3): p. 229-
252. 
157. 
Hedeker, D. and R.D. Gibbons, MIXOR: A computer program for mixed-effects ordinal regression 
analysis. Computer Methods and Programs in Biomedicine, 1996. 49(2): p. 157-176. 
158. 
Petry, N.M., Effects of increasing income on polydrug use: a comparison of heroin, cocaine and 
alcohol abusers. Addiction, 2000. 95(5): p. 705-17. 
159. 
Petry, N.M. and B. Martin, Low-cost contingency management for treating cocaine- and opioid-
abusing methadone patients. J Consult Clin Psychol, 2002. 70(2): p. 398-405. 
160. 
Lott, D.C. and S. Jencius, Effectiveness of very low-cost contingency management in a community 
adolescent treatment program. Drug Alcohol Depend, 2009. 102(1-3): p. 162-5. 
161. 
Olmstead, T.A. and N.M. Petry, The cost-effectiveness of prize-based and voucher-based 
contingency management in a population of cocaine- or opioid-dependent outpatients. Drug and 
Alcohol Dependence, 2009. 102(1-3): p. 108-115. 
162. 
Petry, N.M. and F. Simcic, Recent advances in the dissemination of contingency management 
techniques: clinical and research perspectives. Journal of Substance Abuse Treatment, 2002. 23(2): 
p. 81-86. 
163. 
Petry, N.M., S.M. Alessi, and D.M. Ledgerwood, Contingency management delivered by community 
therapists in outpatient settings. Drug and Alcohol Dependence, 2012. 122(1-2): p. 86-92. 
164. 
Walker, R., et al., Disseminating contingency management to increase attendance in two community 
substance abuse treatment centers: Lessons learned. Journal of Substance Abuse Treatment, 2010. 
39(3): p. 202-209. 
165. 
Pfizer, Neurontin - Gabapentin [Package Insert]. In: Division of Pfizer Inc., Parke-Davis Db (ed) Vol. 
LAB-0397-6.0, pp 1-22.  Revised 9/14. New York, 2014. 
166. 
Ho, K.Y., T.J. Gan, and A.S. Habib, Gabapentin and postoperative pain--a systematic review of 
randomized controlled trials. Pain, 2006. 126(1-3): p. 91-101. 
167. 
Tay, K.H., Gabapentin and opioid craving. Pain Med, 2009. 10(4): p. 774. 
168. 
Economics, M., Physicians Desk Reference \. 1998, Montvale, NJ: Medical Economics Company, 
Inc. 
169. 
PDR, Physicians Desk Reference. 2013, Montvale, New Jersey: PDR Network, LLC. 
170. 
Mannelli, P., et al., The combination very low-dose naltrexone-clonidine in the management of opioid 
withdrawal. American Journal of Drug & Alcohol Abuse. , 2012. 38(3): p. 200-5. 
171. 
Mannelli, P., et al., Effectiveness of Low-Dose Naltrexone in the Post-Detoxification Treatment of 
Opioid Dependence. Journal of Clinical Psychopharmacology, 2007. 27(5): p. 468-74. 
172. 
Yamama, Y., et al., Intrathecal gabapentin and clonidine synergistically inhibit allodynia in spinal 
nerve-ligated rats. Life Sciences, 2010. 87(17-18): p. 565-571. 
173. 
Yoon, M.H., J.I. Choi, and S.H. Kwak, Characteristic of interactions between intrathecal gabapentin 
and either clonidine or neostigmine in the formalin test. Anesthesia & Analgesia, 2004. 98(5): p. 
1374-1379. 
174. 
Anton, R.F., et al., Gabapentin combined with naltrexone for the treatment of alcohol dependence. 
American Journal of Psychiatry, 2011. 168(7): p. 709-717. 
 

SAP_001.pdf: 
 
 
 
 
 
Statistical Analysis Plan 
 
 
Study Title: Improving Treatment Outcomes for Prescription Opioid Dependence 
 
NCT Number: NCT02543944 
 
Date last reviewed by IRB: 10/4/2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Data Analysis Methods: 
 
We will compare baseline characteristics of the two groups using the intent-to-treat sample with 
analyses of variance for continuous variables (e.g., age) and Chi2 analyses for categorical variables (e.g., sex, 
race) to determine whether any significant baseline differences have accrued despite randomization. In 
addition, given that later phases (i.e., transition, depot NTX therapy) may have different sample configurations 
due to anticipated dropout, we will similarly compare the two groups on participant characteristics. If we find 
significant baseline differences in variables within a phase or at each subsequent phase relative to the one 
prior, these differences will be informative of factors associated with treatment outcomes. For those variables 
found to affect outcome, we will use contingency tables with stratification or add these factors to the 
appropriate random regression models to adjust for these differences. 
Our primary outcome is changes in opioid positive urines over time during the detox phase. Other major 
outcomes are: percentage of detox phase completers, naltrexone phase initiators and vivitrol receivers. 
Specific Aim 1: Efficacy and tolerability of GBP versus Placebo during and immediately following BUP detox. 
For data during the BUP taper (weeks 2-3), dependent variables obtained at several time points (e.g., urine 
sample results for opioids, opioid withdrawal symptoms scores) will be entered into random regression models, 
also known as hierarchical linear models (HLMs), to determine whether scores change differentially across 
treatment groups [154, 155]. Continuous data will be analyzed longitudinally with MIXREG, an HLM modeling 
program for continuous measures [156]. Dichotomous urine results (i.e., negative or positive) will be analyzed 
longitudinally using the SAS procedure GLIMMIX, which allows an HLM modeling program for ordinal outcome 
measures [157]. We will use all available data in our analyses and will make no attempt to interpolate missing 
data. HLM methodologies fit a regression line for each participant, effectively interpolating missing data, before 
deriving final estimates. This approach of modeling repeated measures is specifically designed for use in 
repeated measures designs with missing data, allowing for intra-participant serial correlation and unequal 
variance and covariance structures over time. These problems, common to clinical trial data, are solved by 
incorporating available trend data for each individual with information on the behavior of the group from which 
the participant is drawn. If there are any significant baseline differences, the variable will be added as a 
cofactor in the HLM analyses. We will examine differences in retention using Kaplan-Meier Survival Analysis. 
Analyses will be done on those who participated long enough to start the BUP taper, as well as during GBP 
induction to detect possible differential dropout before the taper. To determine whether treatment group 
differences occurred in 1) success of retention from the BUP detox to the NTX transition and 2) eligibility to 
undergo oral NTX induction, we will build 2 X 2 contingency tables using percentages of participants in the 
GBP vs. placebo groups who 1) return on day 1 of week 4 versus drop out after completing the taper, and 2) 
test negative versus positive for opioids. The type, severity, and frequency of adverse events will be compared 
across groups. All analyses will employ a significance level of α = 0.05, and all tests are two-tailed. 
Specific Aim 2: Acceptability and feasibility of outpatient transition to and maintenance on depot NTX 
therapy. Because there are two phases to NTX therapy transition (i.e., 4-day oral induction and up to 8-week 
depot NTX), data obtained during these phases will be analyzed separately. For the oral NTX induction, 
descriptive statistics will be used to report the percentage of abstinent participants who receive the 4-day oral 
dosing. Urine data collected each day during the 4-day induction will be entered into random regression 
models similar to those above to determine whether changes in illicit opioid or other drug use occurred over 
time. To obtain pilot data on the association between treatment group (GBP vs. placebo) and successful 
induction, data regarding the percentage of those receiving oral NTX and the NTX injection or not in the GBP 
vs. placebo groups will be entered into a 2 X 2 contingency table. The type, severity, and frequency of opioid 
withdrawal and/or adverse events will be compared across groups. Reasons for not receiving the NTX injection 
will be summarized. 
For the NTX phase (weeks 4-12), dependent variables obtained at weekly time points (e.g., urine sample 
results for opioids and other drugs, side effect scores, opioid withdrawal scores, etc.) will be entered into 
random regression models (HLMs) to determine whether scores change differentially over time [154, 155]. 
Continuous data will be analyzed longitudinally with MIXREG [156]. Dichotomous urine results (i.e., negative or 
positive) will be analyzed longitudinally using the SAS procedure GLIMMIX [157]. We will examine differences 
in study dropout during this phase using Kaplan-Meier Survival Analysis. Our principal analyses will be done 
on those who participated long enough to start the depot NTX therapy. The type, severity, and frequency of 
adverse events will be recorded and summarized. 
Specific Aim 3: Identify prognosticators of treatment outcomes. Predictors of treatment efficacy during 
each phase will be examined using baseline assessments (e.g., sex, level of opioid use, distress tolerance 


scores, etc.). We will evaluate general predictors of successful outcomes (with success as defined above) 
regardless of treatment type and predictors of differential response to treatments. Depending on the 
distribution of participants with moderate versus severe opioid dependence, severity of opioid dependence will 
also be examined as a prognosticator. Our basic analytic strategy will be to dichotomize groups into the 
presence and absence of a dichotomous predictor variable (e.g., female or alcohol dependence diagnosis) and 
then to examine the relative predictive values on treatment outcomes by adding each factor to the log linear 
analyses for single time point outcomes and HLM for longitudinal measures such as frequency of self-reported 
drug use, opioid-negative urines and craving measures. Each continuous measure (e.g., HAM-A, distress 
tolerance scores) will be entered as a covariate in the above analyses. 
Longer-Term Outcomes. Continuous data from the 16-week follow-up interview will be initially entered into 
repeated measures ANOVA’s with group (GBP vs. placebo), successful completion of detox (yes vs. no), 
successful induction onto oral NTX therapy (yes vs. no), and successful transition to depot NTX therapy (yes 
vs. no) as factors. Dichotomous follow-up data will be entered into Chi2 tables for each phase. Longitudinal 
data captured during each phase of the study and at follow-up will be entered into random regression models 
as above, and piece-wise comparisons will be made between each phase. For all analyses, a p value <0.05 
will be used to infer statistical significance. 
Sample Size. PASS (Power Analysis & Sample Size) Software was used to estimate power. Sample size for 
the intent-to-treat sample was determined based on having enough power during and immediately following 
the BUP taper to detect group differences in the primary outcome of illicit drug use and identify potential 
prognosticators. Based on the proportion of participants in the GBP versus placebo groups having opioid-free 
urines on the last day of the BUP taper from our pilot trial with GBP [31, 129], treating the one missing value as 
positive, a difference in the percentage of participants with opioid-free urines at the end of detox as well as 
immediately prior to initiating NTX therapy will be detected with >90% power with an analysis sample size of 
106 total participants anticipated to remain for NTX transition. Thus, our sample size is adequate to detect 
differences for our primary outcome during and immediately following the detoxification. Meanwhile, there has 
been minimal, if any, study of sex (or other bivariate prognosticator) differences for the effect of an adjunct 
medication for opioid dependence, much less for prescription opioid dependence. This study will provide 
unique data to quantify a potential difference. Given our expected sample size of 150 participants entering the 
BUP detox phase, the study will have >80% power for an effect size of 0.29 (small effect size), and 106 
participants eligible for NTX transition will have >80% power to detect an effect size of 0.35 (considered a 
"medium" effect size).