Clinical trial NCT03789214
Conditions: Opioid Dependence Opioid Withdrawal Sleep Disturbance
Sponsor: Johns Hopkins University
Start date: 2019-07-01; Completion date: 2021-06-10
Enrollment: 90 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate whether a dual orexin-receptor antagonist approved by the FDA for sleep disturbance, suvorexant (SUVO; Belsomra), will increase total sleep time in patients with opioid use disorder (OUD) undergoing supervised withdrawal. This study is designed as a dose-finding study of SUVO compared to placebo. Briefly, OUD patients seeking supervised withdrawal will be admitted into a clinical research unit and stabilized onto buprenorphine for three days before being randomly assigned to study condition. All participants will then undergo a routine four-day buprenorphine taper, followed by a four-day post-taper phase. Participants will be randomized to receive either placebo, Low Dose SUVO, or High Dose SUVO and the investigators hypothesize that one or both doses of SUVO will improve total sleep time relative to placebo. Patients will attend a single follow-up session, 5-10 days following discharge.

Detailed description:

Arms: arm 1: Placebo sleep medication (Placebo oral capsule) arm 2: Low dose sleep medication arm 3: High dose sleep medication
Interventions: intervention 1: Placebo oral capsule intervention 2: Low Dose Suvorexant intervention 3: High Dose Suvorexant
Intervention descriptions: intervention 1: Placebo Sleep Medication intervention 2: Low Dose Suvorexant intervention 3: High Dose Suvorexant

Protocol documents:
ICF_001.pdf: 
 
Approved June 1, 2021 
Date: June 1, 2021 
Principal Investigator: Andrew Huhn, Ph.D. 
Application No.: IRB00198426 
 
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RESEARCH PARTICIPANT INFORMED CONSENT AND PRIVACY 
AUTHORIZATION FORM 
 
Protocol Title:  
Medical Management of Sleep Disturbance During 
Opioid Tapering  
 
 
Application No.:  
 
 
IRB00198426 
 
 
Sponsor/Supporter/Funded By:  
National Institute on Drug Abuse 
 
Principal Investigator:  
 
Andrew Huhn, Ph.D. 
 
 
 
5510 Nathan Shock Drive 
 
 
 
Baltimore, MD 21224 
 
 
 
Phone: 410-550-1971 
 
 
You are being asked to join a research study. Participation in this study is voluntary. Even if you decide 
to join now, you can change your mind later. 
 
1. 
Research Summary (Key Information): 
The information in this section is intended to be an introduction to the study only.  Complete details of 
the study are listed in the sections below. If you are considering participation in the study, the entire 
document should be discussed with you before you make your final decision.  You can ask questions 
about the study now and at any time in the future. 
 
The purpose of this study is to evaluate whether an FDA-approved medication for insomnia, suvorexant 
(Belsomra), can help treat sleep disturbance in patients with opioid use disorder (OUD) who are going 
through supervised opioid withdrawal in a residential treatment facility.  
 
The study consists of a screening visit, an 11-day residential stay at Johns Hopkins Bayview Medical 
Center, and a follow-up visit 5-10 days later. You will be stabilized on buprenorphine (Subutex) either 
during your screening visit or on the day you are admitted for your residential stay. During your stay, 
you will be maintained on buprenorphine/naloxone (Suboxone) for a 2-3 day period before being 
tapered off of Suboxone over a 4-day period.  We will ask you to stay on the unit with us for an 
additional 4 days after your final Suboxone dose so we can monitor any withdrawal you may be 
experiencing. It is expected that you will experience some level of opioid withdrawal as part of this 
study. Symptoms of opioid withdrawal include nausea, diarrhea or stomach cramping, muscle aches and 
pains, yawning, sweating, pupil dilation, minor increases in blood pressure, and runny nose/tearing eyes. 
 
If appropriate for this study, a scanned copy of 
the signed consent form should be uploaded to 
the participant’s Epic/EMR record. 
 
 
 
 
Patient I.D. plate 


 
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You will be asked to take the study drug during the opioid taper and after the opioid taper. The study 
drug will either be suvorexant (Belsomra) or placebo (an inactive material that does not contain any 
active drug).  The risks associated with suvorexant (Belsomra) are side-effects that could include 
sleepiness/drowsiness (7% of people), headache (7%), dizziness (3%), diarrhea (2%), dry mouth (2%), 
upper respiratory infection (2%), abnormal dreams (2%), and cough (2%). Serious adverse effects could 
include sleep paralysis (7%), somnolence (7%), and worsening of depression or suicidal ideation.  
 
There is no cost to you for participating in the study.  
 
2. 
Why is this research being done? 
This research is being done to evaluate whether a study drug called suvorexant (Belsomra) may help 
improve sleep in people who are tapering off of opioids.  
 
Belsomra works differently from other sleep medications. Most other sleep medications help you sleep 
by sedating you. Belsomra helps you sleep because it stops your natural “wake” cycle from being turned 
on. We think this may be a better way to help people sleep when they are withdrawing from opioids. 
Because of these differences, we also think that Belsomra will produce fewer negative side effects than 
those other medications.  
 
Are there any investigational drugs/devices/procedures? 
The use of Belsomra in this research study is investigational. The word “investigational” means that 
Belsomra is being used in a way that is not yet approved for marketing by the Food and Drug 
Administration (FDA). Specifically, although Belsomra is being administered to treat sleep, which is its 
approved indication, this study will administer Belsomra at doses that are higher than what the FDA has 
approved. The FDA is allowing us to administer Belsomra in this study. 
 
This study is designed to determine which dose of Belsomra increases sleep better than a placebo in 
patients who want to stop using opioids.  
 
Who can join this study? 
Only participants who are physically dependent on opioids and are interested in tapering off of them, 
and who are at least 18 years old, may join this study.  
 
How many people will be in this study?  
About 60 people will be enrolled into the study. 
 
3. 
What will happen if you join this study? 
If you agree to be in this study, we will ask you to do the following things: 
 
Screening Visit 
 
o You will be completing the screening visit today at the Behavioral Pharmacology Research Unit 
(BPRU).  We will ask you to complete several questionnaires to determine whether you are eligible 
to join the study.  The questionnaires will ask about things like your mood, emotional wellbeing, 
opioid use and withdrawal, drug use, and sleep. We will also ask you to provide a blood sample (no 
more than 2 tablespoons) that will be used to determine whether it will be medical safe for you to 
participate in our study and to provide a urine sample that will be tested for study eligibility, recent 
drug use, and pregnancy (if applicable). 
 


 
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o You may also complete an electrocardiogram (ECG) to make sure your heart is healthy. 
o At some point either today or during on Study Day 1, we will also ask you to meet with a medical 
staff member to complete a medical history and physical examination, and to ensure you have an 
opportunity to ask a medical team member any questions you may have about the study drug. 
 
Buprenorphine Induction 
 
If you are eligible for the study, we will need to induct you onto buprenorphine (Subutex) and transition 
you to buprenorphine/naloxone (Suboxone). In order to complete the induction, we will need you to 
arrive to the study in opioid withdrawal- we will not be able to administer the first dose of Subutex until 
you have started withdrawing from other opioids. You know your body best, so please time your final 
dose of opioids so that you will be experiencing mild-moderate withdrawal when you come into the 
clinic. During the induction, we will give you smaller doses of Subutex throughout the day. This is done 
to make sure you do not experience any negative side effects of Subutex. Because of this procedure, the 
induction may take a few hours, but we will aim to bring your withdrawal under control as quickly as 
possible.  
 
Ideally, we will complete this induction on the day that you are scheduled to be admitted into the 
residential clinical research unit that is described below.  However, sometimes it may not be possible for 
you to be immediately admitted into that unit. In those cases, we will be able to induct you onto 
Subutex, following the same procedures described above, and then provide you with some Suboxone to 
take yourself until you can be admitted into the unit. If this happens, we will provide you with a blister 
package that contains daily doses of Suboxone for you to take. You will need to come into the clinic 
weekly to pick up a new package. You will not receive more than 3 weeks’ worth of packages, and we 
will aim to have you admitted into the clinical research unit as soon as possible.  
 
Residential Stay Period 
 
If you are eligible to be in the study, you will be admitted to the residential clinical research unit that is 
located on our same campus for 11 days (10 nights).  During this time, if you are a smoker, you will be 
allowed to smoke cigarettes.   
 
During your stay, if you have not already been transitioned onto Suboxone then you will complete the 
induction described above. If you receive Suboxone from us before being admitted and have a dose 
higher than 16mg, then your dose will be reduced to 16mg on admission day. You will continue to take 
Suboxone for 2-3 days before beginning a Suboxone taper, which will be spread out over a 4-day period.  
We will ask you to staying on the unit with us for an additional four days after your final Suboxone dose 
so we can monitor any opioid withdrawal you may be experiencing.  
 
Study Days 1-3:  
 
o Beginning on Study Day 1 (the day you are admitted onto the residential unit), will ask you to begin 
wearing an accelerometer (also known as an Actigraph) on your non-dominant wrist (the wrist you 
do not write with) all day.  This device is the size of a watch and is used to measure sleep and daily 
activity. You will begin completing questionnaires and provide a saliva sample to measure your 
stress hormones several times a day each day.  
 
o Beginning on Study Day 1, we will also ask you to wear a wireless EEG monitor on your forehead 
every study night.  The EEG monitor is the size of a deck of cards and is used to measure sleep 
quality overnight. It works by placing self-adhesive sensors on your forehead, which are secured 
with a strap that goes around your head.  We will show you how to use the EEG monitor and nursing 
or research staff will be available to help you put it on at night as needed.  


 
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o At some point during Study Days 1 – 3, you will meet with a staff member to learn more about ways 
to help you sleep better. You will also complete a brief educational session about opioid-related 
overdose.  
 
o One Study Day 1 we will collect a blood sample from female participants that will be analyzed for 
hormone levels, and we will collect a blood sample from all participants on three study days (spread 
throughout the entire study) that will be used to analyze your stress hormone levels.  
 
Study Days 4-11:  
 
o Beginning on Study Day 4, your Suboxone dose will begin to decrease every day during Study Days 
4-7, and you will not receive any Suboxone on Study Days 8-11.  
 
o Beginning on Study Day 4, you will also begin receiving the study drug (either Belsomra or 
placebo), which will be administered in 2 capsules that you will swallow. Neither you nor the study 
staff working with you will know whether you are taking Belsomra or placebo.   
 
o Your capsules will consist of one of 3 potential options: a low dose of Belsomra, a high dose of 
Belsomra, or a placebo.  The study drug you receive will be determined randomly (by chance, with a 
method similar to drawing numbers from a hat).  The study drug will not change throughout your 
participation, and is designed to help you sleep while you are tapering off of opioids.  If you are 
uncomfortable with the study drug, you can speak to a study team member about reducing your dose, 
otherwise you will continue to take the study drug until the last night of the study (Study Day 10).  
 
o Since the study drug is designed to help you sleep, you should take it 30-60 minutes before you 
expect to go to sleep at night. The study drug will become available for you to take at 8:30 PM and 
you will need to ask the nurse for the study drug when you think you may go to sleep soon. If you 
have not yet started trying to sleep or asked for the study drug by 11:00 PM, then we will ask you to 
take the study drug at that time.   
 
o Through Study Days 4-11, additional medicines to help you manage symptoms of withdrawal will 
also be available to you. These medications are commonly used to help reduce some symptoms of 
opioid withdrawal (for example, Motrin) - to use them you will just need to ask the nurse to provide 
them to you.    
 
o At the end of the study and before discharge, we will provide you with a referral to additional 
treatments for opioid use disorder and an intranasal version of the medication naloxone (Narcan) 
that is used to reverse opioid-related overdoses, which we will instruct you on how to use.  
 
Follow-up Session:  
 
o You will be asked to come back to the research unit about 5-10 days after your residential stay for a 
brief follow-up session. Prior to the follow-up visit, we will ask some questions about your mood 
and drug use behaviors since leaving the unit over the phone. During the follow-up we will ask 
additional questions related to your mood since leaving the unit and ask you to provide a urine 
sample.  
 
 
 


 
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Will research test results be shared with you? 
It is uncertain if the research tests will produce results that would be relevant for your clinical care, so 
we will not share these results with you unless we identify a clinically significant result. If that happens, 
we will provide you with the information you need to consult a medical professional.  
 
How long will you be in the study? 
You may receive buprenorphine from us for up to 3 weeks while we are scheduling your stay in the 
residential unit, and once you are admitted onto the unit then you will stay there for 11 days and 10 
nights. There will be a brief follow-up session about 5-10 days after your residential stay.  
 
4. 
What happens to data and biospecimens that are collected in the study?  
 
What testing or procedures may be done with your biospecimens?  
Your biospecimens may be used for a variety of research purposes. The specific testing that will be part 
of this study includes blood, urine, and saliva, which may be tested for hormone levels, pregnancy, and 
drugs/medications. Most biospecimens contain DNA, which is the genetic code for each person. 
 
Johns Hopkins and our research partners work to advance science and public health.  The data and 
biospecimens we collect from you are important to this effort. 
 
We would also like to collect an optional genetic sample from all study participants. This will be 
collected as a saliva sample and will be stored for future genetic testing. The goal of this sample will be 
to help us learn more about whether genetics impacts response to different FDA-approved medications. 
This sample is optional and your decision about whether to provide the sample will not impact your 
eligibility for the study. If you decide to provide us with a genetic sample, you should know that the 
Genetic Information Nondiscrimination Act (GINA) is a federal law that helps reduce the risk of 
discrimination by health insurers or employers based on your genetic information. GINA does not 
protect you from discrimination if you apply for other types of insurance (such as life, disability or long-
term care). GINA also does not protect you against discrimination based on an already-diagnosed 
genetic condition or disease. 
 
Genetic information is unique to you and your family. Even without your name or other identifiers, it 
may be possible to identify you or other members of your family with your genetic information.  
Johns Hopkins follows procedures so that people who work with your DNA information for research 
cannot discover it belongs to you, unless you have given consent. However, new techniques may be 
developed that in the future make it easier to link your genetic data to you, so we cannot promise that 
your genetic information will never be linked to you. 
 
If you join this study, you will not own the data and/or biospecimens collected from you as part of this 
research study. If researchers use them to create a new product or idea, including those that may have 
commercial value, you will not benefit financially from these efforts. 
 
How will your data and/or biospecimens be shared now and in the future?  
Sharing data and/or biospecimens is part of research and may increase what we can learn from this 
study. 
  
Often, data/biospecimen sharing is required as a condition of funding or for publishing study results.  It 
also is needed to allow other researchers to validate study findings and to come up with new ideas. 
 


 
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Your data and/or biospecimens may be shared:  
 directly with research collaborators, other researchers, sponsors, government agencies, 
publishers of papers and other research partners  
 through government or other databases/repositories  
 
Data/biospecimen sharing could change over time, and may continue after the study ends. 
 
We will do our best to protect and maintain your data/biospecimens in a safe way.  Generally, if we 
share your data/biospecimens without identifiers (such as your name, address, date of birth) further 
review and approval by an IRB is not needed.  However, when we share data, we limit the uses of the 
information and whether these data can be shared with another research team.  If data/biospecimens are 
shared with identifiers, further IRB review and approval may be needed and the IRB will determine 
whether additional consent is required.  
 
Johns Hopkins researchers may also use the biospecimens collected in this study for future research 
purposes, which may include cell line development, gene sequencing, and genetic testing. Cell lines can 
be grown in the laboratory. This allows researchers to have an unlimited supply of your cells in the 
future without asking for more samples from you. Each cell contains your complete DNA.  Gene 
sequencing of your DNA provides researchers with the code to your genetic material. This future 
research may be unrelated to the current study and may include outside collaborators.  
 
Because science constantly advances, we do not yet know what future testing may include. If 
biospecimens are tested/used in ways not described above, further IRB review and approval may be 
needed and the IRB will determine whether additional consent is required. 
 
You can decline the collection and storage of any biospecimens for future research. You can also decline 
the collection and storage of the genetic biospecimen for future research.  
 
Will you allow us to store and use the biospecimens we collect for this study for future research? 
 
 
YES    ________________________  
 
______________ 
Signature of Participant 
 
 
Date 
 
 
 
 
NO     ________________________ 
 
______________ 
Signature of Participant 
 
 
Date 
 
Will you allow us to store and use genetic biospecimens we collect for this study for future research? 
 
 
YES    ________________________  
 
______________ 
Signature of Participant 
 
 
Date 
 
 
 
 
NO     ________________________ 
 
______________ 
Signature of Participant 
 
 
Date 
 


 
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5. 
What are the risks or discomforts of the study? 
Suvorexant (Belsomra®):   
The study drug may affect brain areas in ways that could increase sleep during opioid tapering.  You 
should not take this study drug if you have narcolepsy or sleep paralysis. You should also not take 
Belsomra® if you are taking other medications that either decrease or increase your liver enzymes 
(known as CYP 3A4). For this reason, it is important that you let us know all medications you are taking 
during the Screening visit.  
 
The most commonly reported side effects of suvorexant (Belsomra®) are: 
 Sleepiness or drowsiness (7% of people) 
 Headache (7% of people) 
 Dizziness (3% of people) 
 Diarrhea (2% of people) 
 Dry mouth (2% of people) 
 Upper Respiratory Infection (2% of people) 
 Abnormal dreams (2% of people) 
 Cough (2% of people) 
 Serious adverse events could include 
o Sleep paralysis (7% of people) 
o Somnolence (7% of people) 
o Worsening of depression or suicidal ideation  
 
Buprenorphine HCl (Subutex) or Buprenorphine/naloxone (Suboxone):   
Both of these drugs are FDA-approved for opioid withdrawal treatment and it is being used in the FDA-
approved manner in this study (in other words, there is nothing experimental about the use 
buprenorphine in this study).   
 
The most commonly reported side effects of buprenorphine are symptoms of opioid use or opioid 
withdrawal and include:  
 Headache (37%) 
 Withdrawal Syndrome (18% of people) 
 Pain (18% of people) 
 Nausea (15% of people)  
 Insomnia (14%) 
 Constipation (14% of people) 
 Sweating (13% of people) 
 Infection (12% of people) 
 Abdominal Pain (12% of people) 
 Runny Nose (10% of people) 
 Chills (8% of people) 
 Back Pain (8% of people) 
 Vomiting (8% of people) 
 Weakness or Lack of Energy (5% of people) 
 Diarrhea (5% of people) 
 Decreased Blood Pressure (4% of people) 
 
 


 
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Opioid Withdrawal: Since this is an opioid taper study, you should expect to experience some 
symptoms of opioid withdrawal during the study. Symptoms of opioid withdrawal include nausea, 
diarrhea or stomach cramping, muscle aches and pains, yawning, sweating, pupil dilation, minor 
increases in blood pressure, and runny nose/tearing eyes.  Due to the nature of this study, we cannot 
prevent you from experiencing some level of withdrawal, although we will try to minimize it as much as 
possible by making other medications that help reduce some symptoms of opioid withdrawal available 
to you by request.   
 
Risk of Opioid Overdose: You may be at an increased risk of experiencing an opioid overdose when 
you complete this study because your tolerance to opioids will have decreased.  To help protect you 
from experiencing an overdose, we will provide you with information about opioid overdose to inform 
you on how to identify and respond to overdoses, and we will also provide you with a take home dose of 
intranasal naloxone (Narcan®) as further protection against opioid overdose when you leave the study.    
 
Blood Draw: Taking blood may cause discomfort, bleeding, or bruising where the needle enters the 
body. In rare cases, it may result in fainting. There is a small risk of infection. 
 
Interviews or questionnaires: You may get tired or bored when we are asking you questions or you are 
completing questionnaires. You do not have to answer any question you do not want to answer. 
 
Identifiable private information: There is the risk that information about you may become known to 
people outside this study. 
 
Unknown risk: There may be side effects and discomforts that are not yet known.   
 
6. 
Are there risks related to pregnancy? 
The study drug is not yet approved for use in pregnancy or during breastfeeding.  Therefore, we will not 
enroll anyone who tests positive for pregnancy or is current breastfeeding into the study.   
 
It is unknown whether this research may hurt an embryo or fetus.  
 
7. 
Are there benefits to being in the study? 
You may or may not benefit from being in this study. If you are assigned to receive Belsomra, it is 
possible you will sleep better but this cannot be guaranteed. No benefit is expected if you are assigned to 
take placebo. If you take part in this study, you may help others in the future.   
 
8. 
What are your options if you do not want to be in the study? 
You do not have to join this study. Other options include seeking treatment for OUD or sleep 
disturbance from your health care provider. 
 
If you do not join, your care at Johns Hopkins will not be affected.  
 
9. 
Will it cost you anything to be in this study?   
You will receive a separate Insurance and Research Participant Financial Responsibility Information 
Sheet (Sheet). This Sheet will give you the following information: 
 The procedures, tests, drugs or devices that are part of this research and that will be paid for by 
the study (no cost to you).   
 The procedures, tests, drugs or devices that will be billed to you and/or your health insurer.  If 
you have health insurance, you will be responsible for any co-pays or deductibles not covered by 
your insurance.  


 
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10. 
Will you be paid if you join this study? 
You will have the potential to earn $30 for a Screening visit and up to $1430 for your participation; the 
payment information is described in more detail in a separate payment form that the staff will review 
with you. 
 
You may be required to provide your social security number to be paid for taking part in this study. 
Federal tax law requires that you report your research payments when you file your taxes. If your total 
payments from Johns Hopkins exceed $600 per year, Johns Hopkins will report these payments to the 
Internal Revenue Service and you will receive a 1099-MISC form from us. 
 
11. 
Can you leave the study early? 
 You can agree to be in the study now and change your mind later. 
 If you wish to stop, please tell us right away. 
 Leaving this study early will not stop you from getting regular medical care.  
 
If you leave the study early, Johns Hopkins may use or share your health information that it has already 
collected if the information is needed for this study or any follow-up activities.  
 
12. 
Why might we take you out of the study early?  
You may be taken out of the study if: 
 Staying in the study would be harmful. 
 You need treatment not allowed in the study. 
 You fail to follow instructions. 
 You become pregnant. 
 The study is cancelled. 
 There may be other reasons to take you out of the study that we do not know at this time.  
 
If you are taken out of the study early, Johns Hopkins may use or give out your health information that it 
has already collected if the information is needed for this study or any follow-up activities. 
 
13. 
How will your privacy be maintained and how will the confidentiality of your data 
be protected?  
 
HIPAA Authorization for Disclosure of Protected Health Information  
What information is being collected, used, or shared? 
To do this research, we will need to collect, use, and share your private health information.  By signing 
this document, you agree that your health care providers (including both Johns Hopkins Medicine and 
others) may release your private health information to us, and that we may use any and all of your 
information that the study team believes it needs to conduct the study.  Your private information may 
include things learned from the procedures described in this consent form, as well as information from 
your medical record (which may include information such as HIV status, drug, alcohol or STD 
treatment, genetic test results, or mental health treatment). 
 
Who will see, use or share the information?  
The people who may request, receive, or use your private health information include the researchers and 
their staff.  Additionally, we may share your information with other people at Johns Hopkins, for example 
if needed for your clinical care or study oversight.  To improve coordination of your research and clinical 
care, some information about the study you join will be included in your electronic medical record.   


 
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By signing this form, you give permission to the research team to share your information with others 
outside of Johns Hopkins.  This may include the sponsor of the study and its agents or contractors, 
outside providers, study safety monitors, government agencies, other sites in the study, data managers 
and other agents and contractors used by the study team.   
 
We try to make sure that everyone who sees your information keeps it confidential, but we cannot 
guarantee that your information will not be shared with others.  If your information is disclosed by your 
health care providers or the research team to others, federal and state confidentiality laws may no longer 
protect it.   
 
Do you have to sign this Authorization? 
You do not have to sign this Authorization, but if you do not, you may not join the study. 
 
How long will your information be used or shared?  
Your Authorization for the collection, use, and sharing of your information does not expire. 
Additionally, you agree that your information may be used for similar or related future research studies. 
 
What if you change your mind? 
You may change your mind and cancel this Authorization at any time.  If you cancel, you must contact 
the Principal Investigator in writing to let them know by using the contact information provided in this 
consent form.  Your cancellation will not affect information already collected in the study, or information 
that has already been shared with others before you cancelled your authorization. 
 
14. 
Will the study require any of your other health care providers to share your health 
information with the researchers of this study? 
As a part of this study, the researchers may ask to see your health care records from your other health 
care providers. You may be asked to give us a list of other health care providers that you use.  
 
15. 
What is a Certificate of Confidentiality? 
Your substudy information is protected by a Certificate of Confidentiality. This Certificate allows us, in 
some cases, to refuse to give out your information even if requested using legal means. 
 
It does not protect information that we have to report by law, such as child abuse or some infectious 
diseases. The Certificate does not prevent us from disclosing your information if we learn of possible 
harm to yourself or others, or if you need medical help. 
 
Disclosures that you consent to in this document are not protected. This includes putting research data in 
the medical record or sharing research data for this study or future research. Disclosures that you make 
yourself are also not protected. 
 
16. 
What treatment costs will be paid if you are injured in this study?  
Johns Hopkins and the federal government do not have programs to pay you if you are hurt or have 
other bad results from being in the study. However, medical care at Johns Hopkins is open to you as it is 
to all sick or injured people.   
 
The costs for any treatment or hospital care you receive as the result of a study-related injury that are not 
covered by a health insurer will be billed to you. 
 
By signing this form, you will not give up any rights you have to seek compensation for injury.  


 
Approved June 1, 2021 
Date: June 1, 2021 
Principal Investigator: Andrew Huhn, Ph.D. 
Application No.: IRB00198426 
 
Page 11 of 13 
Combined Parental Permission/Informed Consent/Authorization December 2018 Version 16 
17. 
What other things should you know about this research study? 
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. If you would like to review 
the information for this study, or a summary of the results, ask the study team doctor for the 
ClinicalTrials.gov study registration number. 
 
During this study, you will not have access to certain medical information and test results collected for 
study purposes.  If an emergency occurs while you are in the study, medical information needed for your 
treatment can be made available to your study doctor and other physicians who treat you.  When the 
study is completed, all the information in your medical record will be available to you. 
 
During the study, we will tell you if we learn any new information that might affect whether you wish to 
continue to participate. 
 
What is the Institutional Review Board (IRB) and how does it protect you?  
This study has been reviewed by an Institutional Review Board (IRB), a group of people that reviews 
human research studies. The IRB can help you if you have questions about your rights as a research 
participant or if you have other questions, concerns or complaints about this research study.  You may 
contact the IRB at 410-502-2092 or jhmeirb@jhmi.edu.  
 
What should you do if you have questions about the study, or are injured or ill as a result of being 
in this study?  
Call the principal investigator, Andrew Huhn, Ph.D. at 410-550-1971. If you wish, you may contact the 
principal investigator by letter. The address is on page one of this consent form. If you cannot reach the 
principal investigator or wish to talk to someone else, call the IRB office at 410-502-2092.   
 
If you have an urgent medical problem or think you are injured or ill because of this study, call 911 or 
go to your local emergency department.  You should also call Eric Strain, M.D. or Dr. Alexis Hammond 
at 410-550-0052 during regular office hours and at 410-550-0052 after hours and on weekends.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Approved June 1, 2021 
Date: June 1, 2021 
Principal Investigator: Andrew Huhn, Ph.D. 
Application No.: IRB00198426 
 
Page 12 of 13 
Combined Parental Permission/Informed Consent/Authorization December 2018 Version 16 
18. 
What does your signature on this consent form mean?  
Your signature on this form means that: You understand the information given to you in this form, you 
accept the provisions in the form, and you agree to join the study. You will not give up any legal rights 
by signing this consent form.  
 
 
WE WILL GIVE YOU A COPY OF THIS SIGNED AND DATED CONSENT FORM 
 
 
 
 
________________________________________________________________________________________________________________________ 
Signature of Participant  
 
 
 
 
(Print Name)  
 
 
 
 
Date/Time  
 
 
 
 
 
______________________________________________________________________________________________________________________ 
Signature of Person Obtaining Consent  
 
 
(Print Name)  
 
 
 
 
Date/Time 
 
 
 
 
NOTE: A COPY OF THE SIGNED, DATED CONSENT FORM MUST BE KEPT BY THE PRINCIPAL INVESTIGATOR AND A COPY 
MUST BE GIVEN TO THE PARTICIPANT.  IF APPROPRIATE FOR THIS STUDY, A SCANNED COPY OF THE SIGNED CONSENT 
FORM SHOULD BE UPLOADED TO THE PARTICIPANT’S EPIC/EMR RECORD (UNLESS NO MEDICAL RECORD EXISTS OR 
WILL BE CREATED).  
 
 
 


 
Approved June 1, 2021 
Date: June 1, 2021 
Principal Investigator: Andrew Huhn, Ph.D. 
Application No.: IRB00198426 
 
Page 13 of 13 
Combined Parental Permission/Informed Consent/Authorization December 2018 Version 16 
DOCUMENTATION OF PHYSICIAN/MID-LEVEL PROVIDER CONSENT PROCESS 
 
My signature below indicates that I have discussed the risks, benefits, and alternatives, answered any 
questions, and believe the participant is able to make an informed choice to join the study. 
 
 
 
________________________________________________________________________________________________________________________ 
Signature of Physician/Mid-Level Provider  
 
 
(Print Name)  
 
 
 
 
Date/Time  
 
 
 
 
________________________________________________________________________________________________________________________ 
Signature of Participant   
 
 
 
 
(Print Name)  
 
 
 
 
Date/Time     
 
 
NOTE: A COPY OF THE SIGNED, DATED CONSENT FORM MUST BE KEPT BY THE PRINCIPAL INVESTIGATOR AND A COPY 
MUST BE GIVEN TO THE PARTICIPANT.  IF APPROPRIATE FOR THIS STUDY, A SCANNED COPY OF THE SIGNED CONSENT 
FORM SHOULD BE UPLOADED TO THE PARTICIPANT’S EPIC/EMR RECORD (UNLESS NO MEDICAL RECORD EXISTS OR 
WILL BE CREATED).  
 

Prot_SAP_002.pdf: 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
Page 1 of 20 
MEDICAL MANAGEMENT OF SLEEP DISTURBANCE DURING OPIOID TAPERING 
(IRB00198426; UG3DA048734-01; NCT03789214) 
Protocol date: 08/04/2019 
Principal Investigators: Andrew S. Huhn, Ph.D., MBA, Kelly E. Dunn, Ph.D., MBA 
Co-investigators: Patrick Finan, Ph.D., Charlene Gamaldo, M.D., Eric Strain, M.D. 
Cecilia Bergeria, Ph.D., Alexis Hammond, M.D. 
Location: 
Behavioral Pharmacology Research Unit 
The Johns Hopkins University School of Medicine 
Johns Hopkins Bayview Medical Center 
5510 Nathan Shock Drive 
Baltimore, MD 21224 


 
 
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Page 2 of 20 
 
Date: 8.04.2019 
Principal Investigator: Andrew S. Huhn, Ph.D., M.B.A. 
Application Number: IRB00198426 
 
 
 
JHM IRB - eForm A – Protocol 
 
 
 
• Use the section headings to write the JHM IRB eForm A, inserting the appropriate material 
in each. If a section is not applicable, leave heading in and insert N/A. 
• When submitting JHM IRB eForm A (new or revised), enter the date submitted to the field at 
the top of JHM IRB eForm A. 
 
**************************************************************************************
************* 
 
 
1. 
Abstract 
 
This study will evaluate whether a dual orexin-receptor antagonist approved by the FDA for sleep 
disturbance, suvorexant (SUVO; BelsomraÒ), will increase total sleep time in patients with opioid use 
disorder (OUD) undergoing supervised withdrawal. The scientific premise of this study is based on 
substantial preclinical and human literature demonstrating that opioids modify the sleep-wake cycle. Acute 
doses of opioids disrupt sleep in animal and human models, and chronic opioid exposure produces 
persistent sleep disturbance in both animal and human models. In humans, chronic opioid use is associated 
with development of hypoxemia, sleep apnea, and disruptions in the hypothalamic-pituitary-adrenal axis in 
a manner that impairs sleep. These data are consistent with the fact that many OUD patients report 
substantial sleep disturbance. SUVO treats sleep disturbance by antagonizing the “wake cycle”. In addition 
there is a substantial preclinical literature shows that orexins influence the mesolimbic reward system that 
is broadly implicated in addiction. Interactions between the orexin and opioid systems suggest the orexin 
system could exert a clinically meaningful impact on the course of OUD. 
 
This study is designed as a dose-finding study of SUVO compared to placebo. Briefly, OUD patients 
seeking supervised withdrawal will be admitted into a clinical research unit and stabilized onto 
buprenorphine before being randomly assigned to study condition. All participants will then undergo a 
routine buprenorphine taper, followed by a post-taper phase. Participants will be randomized to receive 
either placebo, SUVO 20mg, or SUVO 40mg and we hypothesize that one or both doses of SUVO will 
improve total sleep time relative to placebo. The dose of SUVO identified as most efficacious in this study 
will be used in a subsequent study. This study is supported by power analyses that were conducted for both 
Aims 1 and 2. Primary outcomes of this study include total sleep time as measured via an ambulatory 
electroencephalography (EEG) device, wrist actigraphy, and self-reported sleep as well as abuse liability 
measures of SUVO. Participants will be referred to ongoing treatment following completion of the study 
and will be provided with opioid overdose education and Narcan as an additional prevention measure. 
 
2. 
Objectives (include all primary and secondary objectives) 
 
• Primary Aim 1: Evaluate whether 20mg and 40mg suvorexant, relative to placebo, improves total sleep 
time among patients undergoing routine opioid withdrawal, assessed via (a) EEG, (b) actigraphy, and 
(c) self-report.  


 
 
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• Primary Aim 2: Evaluate the abuse liability of 20mg SUVO versus 40mg SUVO relative to placebo 
using self-report ratings, and secondary measures that include a hypothetical purchase task and drug 
ratings.  
• Secondary Aim 1: Evaluate whether 20mg SUVO and 40mg SUVO decreases self-reported measures of 
drug effects and craving, opioid withdrawal, concomitant medication use, and self-reported stress; 
decreased diurnal salivary cortisol and serum cortisol/adrenocorticotropic releasing hormone; and 
improves treatment retention relative to placebo. 
 
3. 
Background (briefly describe pre-clinical and clinical data, current experience with procedures, 
drug or device, and any other relevant information to justify the research) 
 
Significance: OUD is a significant public health problem. More than 72,000 Americans died from drug 
overdose in 2017, the majority of which were opioid-related (Dunn et al., 2013). Individuals who are 
physically dependent on opioids experience an array of extremely aversive withdrawal symptoms upon 
opioid-removal, and most opioid treatment approaches are explicitly designed to minimize withdrawal 
severity. Thus, investigation into opioid withdrawal symptom management is critical for improving OUD 
treatment outcomes and has broad implications for many thousands of patients. For instance, the majority 
of the >500,000 people who sought OUD treatment from state-certified addiction treatment facilities in 
2016, received supervised opioid withdrawal treatment (also known as detoxification) (Substance Abuse 
and Mental Health Services Administration, 2016). Below we summarize the limited available literature on 
this topic to demonstrate that (a) sleep is directly impaired by opioids, (b) the orexin system may underlie 
sleep disturbance in persons with OUD, and (c) the dual-orexin receptor antagonist SUVO is an ideal 
medication to treat sleep disturbance in persons withdrawing from opioids.  
 
Sleep is directly impaired by opioids: There is a substantial preclinical and human literature 
demonstrating that opioids modify the sleep-wake cycle. Acute doses of opioids disrupt sleep in animal 
(Cronin, Keifer, Baghdoyan, & Lydic, 1995; Gauthier, Guzick, Brummett, Baghdoyan, & Lydic, 2011; 
Moreton, Roehrs, & Khazan, 1976; Watson, Lydic, & Baghdoyan, 2007) and human models (Dimsdale, 
Norman, DeJardin, & Wallace, 2007; Howe, Hegge, & Phillips, 1980; Kay, 1975a; Kay, Eisenstein, & 
Jasinski, 1969), and chronic opioid exposure produces persistent sleep disturbance in both animal  (Robert, 
Stinus, & Limoge, 1999; Young, Moreton, Meltzer, & Khazan, 1975) and human  (Dunn, Finan, Tompkins, 
& Strain, 2018; Kay, 1975b) models. In humans, chronic opioid use is associated with development of 
hypoxemia, sleep apnea (Charpentier, Bisac, Poirot, Vignau, & Cottencin, 2010; DeVido, Connery, & Hill, 
2015; Farney et al., 2013; Mogri, Desai, Webster, Grant, & Mador, 2009; Peles, Schreiber, Hamburger, & 
Adelson, 2011b; Schwarzer, Aichinger-Hinterhofer, Maier, Vollert, & Walther, 2015; Wang et al., 2005) 
and disruptions in the hypothalamic-pituitary-adrenal (HPA) axis  (Bunce et al., 2015) in a manner that 
impairs sleep. We know of only two studies that have empirically examined methods for improving sleep in 
OUD patients; these studies reported no benefit of electrostimulation or acute doses of methadone among 
patients being withdrawn from opioids (Gossop & Bradley, 1984) or the non-benzodiazepine trazodone in 
patients maintained on methadone (Stein et al., 2012b). Despite the lack of data, patients undergoing 
supervised withdrawal who experience sleep disturbance may first be prescribed hydroxyzine, then 
trazodone, and finally an antipsychotic such as quetiapine (Seroquel) (Pinkofsky et al., 2005).  
 
The orexin system may underlie sleep disturbance in persons with OUD: Orexinergic neurons are 
located in the lateral hypothalamus and activate a “wake cycle” that suppresses sleep. In addition to their 
well-known association with sleep, a substantial preclinical literature shows that orexins influence the 
mesolimbic reward system that is broadly implicated in addiction. Interactions between the orexin and 
opioid systems suggest the orexin system could exert a clinically meaningful impact on the subjective 
experience of opioids. A recent study in postmortem human brains found that long-term heroin users had 
54% more orexinergic neurons than age/sex matched healthy adults, suggesting that chronic opioid 
exposure is associated with increased orexin signaling (Thannickal et al., 2018). The proposed study is 


 
 
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significant because it targets a modifiable aspect of OUD (sleep) linked to a neurotransmitter system 
(orexin) that promotes drug craving and motivation to seek drug. 
 
The dual-orexin receptor antagonist SUVO is an ideal medication to treat sleep disturbance in 
persons withdrawing from opioids: Suvorexant (SUVO; Belsomra®) is a dual orexin receptor antagonist 
that is FDA-approved for insomnia. In contrast to benzodiazepines and other sleep aids that promote sleep 
through sedation, suvorexant SUVO prevents onset of the wake cycle. In clinical trials SUVO significantly 
increases sleep time, even among otherwise treatment-resistant patients. One within-subject, double-blind 
cross-over study reported SUVO improved ratings of sleep efficiency, wake after sleep onset, and latency 
to persistent sleep, as rated by PSG, over a 4-week period (Herring et al., 2012). A subsequent large-scale, 
Phase III randomized, controlled, double-blind trial reported significant improvements in subjective and 
PSG ratings of sleep relative to placebo (Herring et al., 2016a). Fewer people on SUVO, relative to other 
sleep aids, experience next-day sedation (Gotter et al., 2013). Because of this, SUVO has been suggested as 
a treatment for alcohol use disorder, however there is no controlled research in any substance use disorder 
population regarding the potential benefit of SUVO for drug or alcohol treatment (Campbell, Marchant, & 
Lawrence, 2018).  
 
SUVO acute dosing studies have repeatedly shown that sleep architecture changes following a single 
SUVO dose (Herring et al., 2016b; Sun et al., 2013), and that beneficial clinical outcomes are evident 
within 1 week (the earliest time point assessed; (Herring et al., 2016a; Herring et al., 2016b). These data 
suggest that SUVO has a quick onset of action, and are supported by a recent review/meta-analysis of 37 
available studies that found SUVO to improve sleep (Kishi, Matsunaga, & Iwata, 2015). EEG analyses 
have further revealed that, in contrast to the other common sleep aids gabapentin, zolpidem (Ambien), and 
trazodone (Oleptro), SUVO did not confer negative collateral effects on other transmitter systems (Ma et 
al., 2014; Snyder et al., 2016). The focused effect of SUVO on the orexin system may contribute to its 
impressive safety profile; clinical trials and meta-analyses report SUVO is well-tolerated and produces a 
low rate (<5%) of adverse events (Herring et al., 2016a; Herring et al., 2016b; Kishi et al., 2015), even 
following 1 year of chronic treatment (Michelson et al., 2014). Examination of SUVO effects on respiration 
among patients with and without sleep apnea showed no impairment in respiration or SpO2 levels, even 
when administered at doses twice what is recommended for clinical care (Sun et al., 2016; Uemura et al., 
2015). Although SUVO was designated a Schedule IV substance by the DEA based on a study comparing 
2-7.5 x the maximum dose of SUVO versus 1.5-3 x the maximum dose of zolpidem (Ambien), the abuse 
liability ratings from SUVO did not change in a dose-dependent manner (unlike zolpidem). In that study, 
SUVO also produced lower levels of feeling “high”, and fewer abuse-related adverse events (e.g. euphoric 
mood) than zolpidem. These data, combined with the absence of reports that SUVO is being diverted or 
abused, suggest the abuse liability of SUVO is lower than comparable Schedule IV substances. No studies 
have evaluated SUVO’s profile of effects in OUD patients (Pinkofsky et al., 2005).   
 
Summary: This study is significant not only because it evaluates the efficacy of SUVO for sleep 
disturbance in OUD patients, but also because sleep disturbance during supervised opioid withdrawal is 
pronounced and there is a dearth of indicated, effective pharmacotherapies.  
 
4. 
Study Procedures 
 
a. 
Study design: 
 
Screening Visits: Participants will be recruited from the community via flyers, newspaper postings, and 
other media outlets. Screening visits will take place on the Behavioral Pharmacology Research Unit at the 
Johns Hopkins Bayview Medical Center. Individuals will complete a phone-screen to assess for initial 
eligibility and will be invited for a clinic-based visit to confirm final eligibility. During this visit, 
participants will first review an informed consent form with a staff member and discuss the study before 


 
 
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providing voluntary informed consent to participate. Participants will then complete a series of measures to 
establish study eligibility, including a demographics questionnaire, self-reported opioid use and 
withdrawal, a past 30-day timeline follow back for drug and alcohol use, assessments of DSM-5 drug and 
alcohol use disorders, the Stop-Bang questionnaire assessment of sleep apnea, psychiatric functioning 
(MINI International Neuropsychiatric Interview [Sheehan et al., 1998]), and the Columbia Suicide Severity 
Rating Scale (Posner et al., 2011). Participants will provide a blood sample that will be tested for complete 
blood count and comprehensive metabolic panel, provide a urine sample that will be tested for evidence of 
opioid and other drug use, and pregnancy (when applicable). Either during the Screening or admission day, 
participants will complete a medical history and physical examination with qualified medical staff to 
determine final study eligibility. The physical examination will include an electrocardiogram (ECG) to 
determine if the participant has any heart abnormalities, and the Brief Pain Inventory to quantify current 
chronic pain issues (Cleeland et al., 1994). Opioid withdrawal scales will be collected at the end of the 
Screening visit to help confirm opioid physical dependence.  
 
Buprenorphine Induction and Stabilization: Participants will be inducted onto buprenorphine prior to 
beginning the buprenorphine taper. Induction may occur up to 3 weeks prior to admission to the CRU. 
Participants will be required to show evidence of opioid withdrawal (as per ratings on the COWS) and will 
receive incremental doses of buprenorphine throughout the day, up to a maximum of 16mg of 
buprenorphine on the induction day. The induction protocol will be conducted as clinically indicated, based 
upon medical team recommendations. To increase comfort during the induction, the medical team may 
administer the PRN concomitant medications that are approved for the taper protocol as well as clonidine. 
Participants may then be maintained on buprenorphine as an outpatient for up to 3 weeks before CRU 
admission. Briefly maintaining participants on buprenorphine will enable the study to retain participants 
between Screening and CRU admission, as the CRU has restricted access for protocols requiring weekend 
coverage. Participants who are maintained on buprenorphine as an outpatient will receive blister packages 
of sublingual buprenorphine for outpatient administration and may receive up to 24mg/day (beginning the 
day after induction) during this period.  During the stabilization period between Screening and Admission, 
participants will be required to visit the clinic on a weekly basis to exchange blister packages. Participants 
may receive assistance (e.g., bus tokens) from the study to help facilitate transportation to the BPRU on 
those days. Any participant receiving >16 mg as an outpatient will be transitioned to 16mg on the CRU 
admission day. Participants who are inducted onto buprenorphine on the CRU admission day will follow an 
identical induction procedure and will only receive up to 16mg. 
 
Clinical Research Unit (CRU): Following confirmation of eligibility, participants will be admitted onto a 
residential CRU that is located on the Bayview Medical Campus. Participants will reside on the CRU for 
up to 11 days (10 nights) and will be allowed to smoke cigarettes ad libitum in a designated smoking area 
during their stay.  Female participants will provide a sample of blood upon admission that will be analyzed 
for levels of progesterone and estrogen. 
Brief Sleep Hygiene Education: During stabilization, staff will conduct a brief educational session 
with participants to provide information regarding appropriate sleep hygiene (Doshi et al., 2017) . This 
session will ensure all participants have the same understanding of healthy sleep behaviors before the taper 
begins, to minimize the impact that differences in sleep hygiene has, and better isolate the impact of SUVO 
on study outcomes.  
Overdose Education: During the stabilization period, participants will also complete a brief opioid 
overdose prevention computerized education session (developed by Co-I Dunn under NIDA 
R21DA035327).  
Randomization to Group: Participants will be stratified into experimental group based on (a) 
baseline Pittsburg Sleep Quality Index (PSQI) (<5/>5) , (b) peak SOWS ratings during buprenorphine 
induction (<10/>10), (c) buprenorphine stabilization dose (<16mg/16mg), and (d) sex (M/F). 
Randomization will occur via a minimization procedure to balance the distribution of these characteristics 


 
 
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across the experimental groups. Study pharmacist staff, who have no direct participant contact, will oversee 
randomization and dispensing of study medications.   
 
Taper Phase (4 days): Participants will undergo an open-label, step-wise buprenorphine taper. An open-
label phase is necessary because buprenorphine placebo tablets/filmstrips are not available; however, this 
open-label design feature is of value because it increases the overall generalizability of the study results.   
Post-taper Phase (4 days): Participants will continue study participation for four days (three nights) 
following buprenorphine discontinuation, to capture the full course of opioid withdrawal.   
 
Study Medications: Double-blind study medication dosing will begin on the evening before Taper Day 
1. Study medications will either be 20mg SUVO, 40MG SUVO, or placebo, which will be administered 
prior to bedtime. Though participants will be reminded to practice good sleep hygiene, no contingencies or 
consequences will be associated with their sleep behavior. This is because our extensive experience 
suggests that participants who are unable to sleep at night will attempt to sleep during the day; all sleep 
attempts will be captured by wrist actigraphy and nightly questionnaires and evaluated as outcome data. 
Placing contingencies on sleep parameters (such as no day-time sleeping) could also prompt attrition.  
 
Upon study completion, participants will be discharged with referral to ongoing OUD treatment and will be 
provided with take-home dose of intranasal naloxone (Narcan, Adept Pharmaceuticals).  
 
Follow-up: Participants will also complete a follow-up visit approximately 5-10 days after study discharge, 
during which outcomes including adverse events, suicidality and depressive symptoms, need for additional 
OUD treatment referral, past 7-day day sleep, and illicit drug use (as assessed via self-report and a urine 
sample) will be collected.  
 
Study Measures 
 
Objective Sleep Measures:  
Sleep ProfilerTM Wireless EEG Monitor: The Sleep ProfilerTM (Advanced Brain Monitoring, Inc.) is an 
unobtrusive wireless EEG device that was designed for patients to use in their home sleep environment 
without the assistance of a professional technician. We will train our research staff and the CRU nursing 
staff to assist participants with application of the device nightly so we may ensure good measurement 
fidelity throughout the study. The Sleep ProfilerTM runs on a continuous charge for approximately 16 hours 
and provides three channels of frontal EEG, a pulse rate, and a sensor to detect head movement. The device 
is lightweight (2.5 oz) and utilizes three proprietary, pre-gelled, self-adhesive, snap electrodes. It can be 
comfortably applied and strapped to the forehead in 5 minutes and features a built-in impedance check to 
protect against poor connections, which audibly prompts the user to reaffix the electrodes when impedance 
is high. Participants will begin wearing the Sleep ProfilerTM on Stabilization day 1, which will familiarize 
participants with the product before they experience withdrawal, and provide baseline data for statistical 
comparison. Participants will be instructed to affix the Sleep Profiler after receiving their dose of study 
medication and to remove it upon waking every morning. 
 
 
Wrist Actigraphy: Participants will wear a triaxial accelerometer (Actigraph wGT3X-BT, Actigraph, LLC) 
on their non-dominant wrist for the entire duration of study enrollment. Wrist-worn actigraphy has been 
validated against PSG and provides an acceptable alternative measure of sleep continuity.  
 
Self-report Sleep Measures: Additional self-report measures of sleep will be collected as part of the 
Primary Study Aims to corroborate quantitative analyses and increase the breadth of sleep data available. 
These will include measures such as:    
1. 
Stanford Sleepiness Scale (Hoddes et al., , 1973) : A 7-point scale, which is a widely-used self-
report measure of daytime sleepiness that will be collected on a daily basis.  


 
 
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2. 
Daily Sleep Diary: Participants will be asked to document perceived sleep continuity and 
quality each morning. This method is widely used as an adjunct to objective measures of sleep (Carney 
et al., 2012) . 
3. 
Pittsburg Sleep Quality Index (PSQI; (Carpenter & Andrykowski, 1998) ): The PSQI is a 
widely-used self-reported measure of sleep quality and disturbance over the previous 30 days. It will be 
used at screening (past 30 day version) and on the final day of this study (related to study days only).  
 
Abuse Liability Measures: Medication abuse liability will be assessed as Primary Aim 3 and will include 
measures such as:  
1. 
Study Drug Abuse Liability Ratings: The abuse liability of the blinded study drug will be 
assessed each morning during the taper and post-taper phases by asking participants to rate questions 
pertaining to drug liking and drug effects on a 0-100 point visual analogue scale, as well as the 
perceived street value of the study drugs.   
2. 
Hypothetical Opioid Purchase Task: This is a validated method for assessing the abuse liability 
of opioids as well as other drugs of abuse (Aston, Metrik, & MacKillop, 2015; Jacobs & Bickel, 1999; 
Kiselica, Webber, & Bornovalova, 2016) .  
 
Opioid Withdrawal Measures: Withdrawal symptom severity will be evaluated daily, using measures such 
as: 
1. 
Visual Analog Ratings: Self-report ratings of drug effects that include withdrawal, nausea, sick, 
like how I feel, sleepiness, quality of sleep, and pain will be collected on a 0 (not at all) to 100 
(extremely) scale.  
2. 
Subjective Opiate Withdrawal Scale (SOWS) (Handelsman et al., 1987) : A 16-item widely-
used self-report measure that rates opioid withdrawal symptoms on a 4-point Likert scale.   
3. 
Clinical Opiate Withdrawal Scale (COWS) (Wesson & Ling, 2003) : An 11-item scale that 
includes some self-report items (e.g., muscle aches, nausea) and observer-rated measures of opioid 
withdrawal rated on unique ordinal scales.  
 
Secondary Study Outcomes: These measures are a comprehensive range of pharmacologically specific and 
general questions, and are the FDA standard for the measurement of drug effects in humans. We will use 
measures such as: 
1. 
Vital Signs: Physiological measurements of blood pressure, pulse, respiration, and oxygen 
saturation will be measured several times daily. 
2. 
Pupil Diameter: Physiological measure of autonomic nervous system activity that is a hallmark 
metric of opioid withdrawal. Will be assessed several times daily using a hand-held, ambulatory 
pupilometer (Neuroptics; Irvine CA). 
3. 
Retention in Treatment: Retention will be evaluated as number days completed (continuous) 
and being present on the final day of the study (yes/no). 
4. 
Opioid agonist/antagonist scale: A 37-item self-report measure of opioid effects on a 5-point 
Likert scale.  
 
Drug Specific Measures: Secondary aims will assess a variety of domains related to the study medication 
using measures such as:  
1. 
Drug Identification: Upon study discharge, participants will indicate whether they believe they 
are receiving SUVO or placebo. 
2. 
Drug Satisfaction: Upon study discharge, participants will be asked whether they would 
recommend the study medication (yes/no) to a family or friend experiencing sleep impairment while 
withdrawing from OUD.  
3. 
Adverse Event Ratings: We will follow standard FDA guidelines regarding recording of 
adverse events and will document all events on a daily basis. AEs will be summarized descriptively by 
severity and relatedness. 


 
 
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4. 
Neurocognitive Test Battery: Participants will complete a daily battery of cognitive tests to 
assess whether the study medication and/or sleep impairment is associated with changes in cognitive 
function and psychomotor agility during the course of withdrawal. The battery will consist of the 
Circular Lights test of fine motor movement, the Psychomotor Vigilance Task, the Digit Symbol 
Substitution Task (DSST) measure of psychomotor speed/pattern recognition, and the N-back measure 
of working memory. These tests were selected because they can be completed quickly, are not prone to 
practice effects, produce robust, reliable results, and have not been aversive to previous patients during 
opioid withdrawal.  
5. 
The Hamilton Depression scale (HAM-D): The HAM-D is a structured clinical interview that 
will be used multiple times throughout the study to provide a continuous measure of depressive 
symptomatology (Hamilton, 1960). 
 
Stress and Craving Measures: Several brief and validated measures (such as those below) will be used to 
inform potential mechanism underlying effects and whether prospective studies to examine these effects 
more thoroughly are warranted.  
1. 
Visual Analog Ratings: Self-report ratings of opioid craving (e.g. How much do you want to 
use right now? How much do you want to avoid using right now? How much control would you have 
over using if someone offered you opioids right now?) and stress (e.g. How stressed do you feel right 
now? How much is opioid withdrawal contributing to your stress?)   
2. 
Diurnal Cortisol: Salivary cortisol will be collected several times daily. Diurnal cortisol is a 
measure of HPA-axis function that affects the sleep-wake cycle  (Edwards, Evans, Hucklebridge, & 
Clow, 2001) .   
3. 
Additional HPA-axis Measures: One blood sample will be taken during the stabilization, 
withdrawal, and post-withdrawal periods to measure change in adrenocorticotropic hormone to cortisol 
ratios. These measures have been associated with treatment outcomes in other substance using 
populations including cocaine use disorder (Sinha, Garcia, Paliwal, Kreek, & Rounsaville, 2006) .    
 
b. Study duration and number of study visits required of research participants. 
 
The entire study will consist of one screening visit and a residential stay over the course of 11 days and 10 
nights. All study activities will take place at the BPRU and the Bayview CRU.  
 
c. Blinding, including justification for blinding or not blinding the trial, if applicable. 
 
The only blinded medication in this study is SUVO. Since this is the medication of interest, participants 
will be blinded to ensure study rigor and assess the utility of SUVO to treat sleep disturbance compared to 
placebo. The buprenorphine taper and concomitant medications will not be blinded in order to mimic the 
real-world experience of supervised opioid withdrawal and increase ecological validity. 
 
d. Justification of why participants will not receive routine care or will have current therapy stopped. 
 
Routine care for sleep disturbance during opioid withdrawal includes medications such as trazodone, which 
are not FDA approved for sleep (but commonly used). SUVO is an ideal medication for sleep disturbance 
in this population. Participants currently taking benzodiazepines for sleep disturbance will not be included 
in this study. Study participation will be stopped if participants opt out or if study physicians determine that 
it is unsafe for participants to continue in the study (at any time, including in serious adverse events). 
 
e. Justification for inclusion of a placebo or non-treatment group. 
 
Placebo sleep medication will be utilized to rigorously assess the efficacy of SUVO in OUD patients 
undergoing supervised withdrawal. This is necessary for the scientific integrity of the study. Patients 


 
 
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experiencing persistent sleep disturbance might experience discomfort, but will not be at increased risk for 
serious adverse events. 
 
f. Definition of treatment failure or participant removal criteria. 
 
Participants will be removed from the study if they opt out or if the medical team determines it is not safe 
to continue in the study or if they request to discharge from the study. Additional stopping rules will 
include not abiding by study policies and procedures, or engaging in behaviors towards staff or other 
participants that are abusive. Finally, development of an intercurrent illness or condition that changes the 
participant’s risk profile may result in a medically-related discharge from the study. 
 
g. Description of what happens to participants receiving therapy when study ends or if a participant’s 
participation in the study ends prematurely. 
 
Upon study completion, participants will be discharged with referral to ongoing OUD treatment. We have 
relationships with several local treatment providers and participants will be referred to a treatment that best 
matches their recovery goals. As a safety measure, participants will complete an overdose prevention 
training module prior to randomization and be discharged with internasal naloxone (Narcan).  
 
5. 
Inclusion/Exclusion Criteria 
 
Inclusion Criteria: 
· 
Aged >18 years old 
· 
Meets DSM-5 criteria for OUD with evidence of physical dependence on opioids. 
· 
Provides a urine sample that tests positive for opioids. 
· 
Seeking treatment to stop using illicit opioids. 
· 
Willing to comply with the study protocol. 
· 
Have no clinically significant chronic medical or surgical disorders or conditions that are judged by the 
investigators to prevent participation. 
 
Exclusion Criteria: 
· 
Seeking or currently enrolled in methadone or buprenorphine maintenance treatment for OUD 
· 
Pregnant or breast feeding. 
· 
Have evidence of physical dependence on alcohol or benzodiazepines that requires medical 
detoxification. 
· 
Have a known allergy to the study medications. 
· 
Past 30-day prescribed use of suvorexant or benzodiazepines for the indication of insomnia. 
· 
Current use of an SSRI or MAO inhibitor for depression or insomnia, or other medications that are 
contraindicated with suvorexant. 
· 
Current narcolepsy, restless leg syndrome, or sleep paralysis. 
· 
High risk for current sleep apnea as assessed via the Stop Bang questionnaire.   
· 
Current major depressive disorder.   
· 
Past year suicidal behavior as assessed via the Columbia Suicide Severity Rating Scale 
· 
Severe hepatic or renal impairment, defined as:   
o AST or ALT >3x ULN. 
o Total Bilirubin >2x ULN. 
o Creatinine >1.5x ULN. 
· 
Have circumstances that would interfere with study participation (e.g., impending jail). 
 
 
6. 
Drugs/ Substances/ Devices 


 
 
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a. The rationale for choosing the drug and dose or for choosing the device to be used. 
 
Suvorexant (SUVO): SUVO is FDA-approved for the treatment of insomnia and is an ideal candidate for 
evaluation because it is intended for PRN administration, improves sleep architecture after a single dose 
(Herring et al., 2016b; Sun et al., 2013) , and does not cause a withdrawal syndrome after abrupt 
discontinuation even when it has been administered chronically for several weeks (Herring et al., 2016b). 
This study utilizes two doses of SUVO (20 and 40mg) to evaluate which dose has a superior risk/benefit 
profile, although we do not anticipate a high rate of adverse events for either dose. The most effective dose 
can then be used in future clinical trials as well as in practice for the treatment of sleep disturbance during 
opioid withdrawal.  Participants will be given their medication dose in two weight and color-matched 
capsules, containing either two 20mg SUVO (40mg dose), two 10mg SUVO (20mg dose), or two placebo 
capsules.  As an added precaution, participants will be allowed to reduce their dose from two to one capsule 
(representing a 50% dose decrease) if they experience negative side-effects and would prefer a lower dose.  
 
Buprenorphine: Buprenorphine is FDA-approved for the treatment of OUD and it will be used according to 
that indication in this study. The buprenorphine stabilization and taper will be open label. Participants will 
be stabilized on buprenorphine for a maximum 3 week period before study admission, and will then 
complete a 3-day stabilization period (e.g., 8-16mg/day) and a 4-day step-wise taper. These approaches are 
standard clinical practice. This study utilized the open label taper approach in order to increase ecological 
validity of the supervised withdrawal paradigm.  
 
Concomitant Medications: Consistent with standard clinical practice treatment, the following concomitant 
medications will be available to patients upon request: ibuprofen, acetaminophen, loperamide, milk of 
magnesia, and simethicone. Clonidine may be provided during the induction period only. Concomitant 
medications introduce a necessary confound in opioid withdrawal research because they reduce the 
withdrawal symptom severity that is being evaluated as part of the primary study outcomes. However, our 
considerable experience with opioid withdrawal studies suggests that provision of some additional 
supportive medications is necessary to prevent treatment attrition. Following randomization to 
experimental group, patients will not receive additional sleep aids or clonidine. Concomitant medication 
use will be PRN and compared across groups as an outcome. 
 
b. Justification and safety information if FDA approved drugs will be administered for non-FDA approved 
indications or if doses or routes of administration or participant populations are changed. 
 
Suvorexant (SUVO): Suvorexant is approved by the FDA for the indication of insomnia at a 10mg and 
20mg dose, so an IND will be requested from the FDA for the doses (20mg, 40mg) proposed in this trial. 
The proposed 40mg dose is being evaluated because suvorexant has a broad therapeutic window, persons 
with OUD might have increased orexin signaling, as evidenced by postmortem studies citing 54% more 
orexinergic neurons in the lateral hypothalamus of persons with OUD compared to healthy controls, and 
because sleep disturbance during opioid withdrawal is severe and- as of yet- no sleep-promoting 
pharmacotherapies have been shown to be effective in human opioid withdrawal studies.  
 
Suvorexant has been examined in humans at doses up to 240mg and has been shown to produce minimal 
side effects (Belsomra product label). Several phase III trials have been conducted to support suvorexant’s 
approval. The first trial evaluated 10mg, 20mg, 40mg, 80mg doses (active N=243, placebo N=249) in 
persons with insomnia and reported dose-dependent effects on outcomes, with 10mg doses producing 
minimal improvement relative to placebo and higher doses producing larger magnitude improvements on 
numerous objective sleep measures (Herring et al., 2012). However, inspection of the data suggested that, 
whereas large differences existed between the 10, 20, and 40mg doses, only small improvements were 
gained by increasing the dose beyond 40mg to 80mg.  A subsequent phase III trial in persons with insomnia 
reported that suvorexant 40mg (N=322) relative to placebo (N=162) was effective at reducing insomnia and 


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produced a low rate of adverse events (69% vs. 64%, respectively) and SAEs (5% vs. 7%, respectively) 
following 1 year of continuous dosing (Michelson et al., 2014).  Two final phase III trials were conducted 
in persons with insomnia to further examine the effectiveness of the 20mg (N=493) and 40mg (N=770) 
suvorexant doses relative to placebo (N=767). Participants used suvorexant daily for 3 months, and results 
showed dose-dependent improvements in numerous objective sleep outcomes relative to placebo and a low 
rate of SAEs (0.6%, 0.8%, 2.1% for the 20mg, 40mg, and placebo doses, respectively) (Herring et al., 
2016). The NDA for suvorexant indicates that Merck intended to request the 40mg dose be approved, but 
decided to reduce the dose range to 10mg and 20mg because the FDA had just published concerns about 
next-day somnolence related to the sleep aid zolpidem (Ambien), which is not an orexin-antagonist. Thus, 
the FDA was not asked to rule on the safety or efficacy of 40mg suvorexant. Existing data support the 
evaluation and safety of the 40mg dose. This approach will help ensure that any lack of therapeutic benefit 
was not due to suvorexant doses that are below the therapeutic threshold in this population. This strategy is 
consistent with seminal trials evaluating suvorexant, and will also provide an opportunity to determine 
whether suvorexant may confer beneficial effects on other opioid-related outcomes, such as drug craving.  
7.
Study Statistics
a.
Primary outcome variable.
The first primary outcome for this study will be total sleep time during opioid withdrawal as determined by 
EEG, and supplemented by actigraphy and self-report.  
The second primary outcome for this study is abuse liability, which will be assessed via next day measures 
of Drug Liking measured on a 0-100 point VAS.  
b. Secondary outcome variables.
(1) Secondary outcomes from the Sleep Profiler EEG will include measures of sleep continuity and
architecture
(2) Secondary actigraphy outcomes will include sleep and activity-related outcomes
(3) Secondary self-report sleep ratings will include self-reported sleep measures
(4) Opioid withdrawal severity, assessed via the subjective opiate withdrawal scale.
(5) Other secondary outcomes include a hypothetical purchasing task, other self-report VAS measures of
abuse liability (e.g. drug effect, good effect, bad effect, perceived drug value), self-reported measures of
drug craving, VAS opioid withdrawal, stress; diurnal cortisol; vital signs; and retention in treatment.
c. Statistical plan including sample size justification and interim data analysis.
Power Analyses: In order to support the planned 2 and 3 group analyses (comparing 20mg SUVO, 40mg 
SUVO, and placebo), we used G-power to derive sample sizes from previously reported effect sizes in 
clinical trials on SUVO and hypothetical opioid purchase task data; both displayed large effect sizes 
(³0.70). A total sample size of 36 participants (12 per group) would provide 95% power to detect an effect 
size of 0.70 for difference in total sleep time (Primary Aim 1) and difference in the opioid demand curve 
(Secondary Aim 1). A study on the abuse liability of SUVO, zolpidem, and placebo in non-OUD patients 
(Schoedel et al., 2016) reported a medium to large effect size on drug liking (0.45), suggesting a total 
sample size of 34 would provide 90% power to detect an effect size of 0.45 for Primary Aim 2. To protect 
against participant drop out, we are proposing to enroll 15 participants per medication group (total N=45).  
Analyses: All Primary Outcomes (total sleep time, opioid withdrawal severity, and abuse liability) will be 
compared as a function of group (20mg SUVO, 40mg SUVO, and placebo; or SUVO [collapsed] vs 
placebo) and phase (taper vs. post-taper), as well as group by day (7 nights) using 2-factor Proc Mixed 
analyses with Tukey posthoc testing. Both peak values and Area-under-the-curve (AUC) values of total 
sleep time, SOWS scores, and Drug Liking 


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will be derived for (a) the entire study, (b) the taper period, and (c) the post-taper period.  These outcomes 
will be compared as a function of group and group x phase using independent groups t-tests and ANOVAs 
with Tukey post-hoc for pairwise comparisons. If data does not meet ANOVA assumptions, mixed model 
regressions will be used. 
Secondary outcomes from the Sleep Profiler EEG may include measures of sleep continuity (sleep latency, 
sleep efficiency [total sleep time/time spent in bed], wake after onset [WASO], number of awakenings) and 
architecture (time spent in stage 1, stage 2, stage 3, and rapid eye movement [REM] sleep).  (b) Secondary 
actigraphy outcomes may include wake after sleep onset (WASO), time spent napping, number of naps, 
and total activity. (c) Secondary self-report ratings may include subjective WASO, VAS sleepiness and 
quality of sleep, and Stanford Sleepiness Scale score. Analyses: All outcomes will be compared as a 
function of group (20mgSUVO, 40mg SUVO, and placebo) and phase (taper vs. post-taper), as well as 
group by day (7 nights) using 2-factor Proc Mixed analyses with Tukey posthoc testing. Area-under-the-
curve (AUC) values for the entire study and the taper and post-taper periods will then be derived and 
compared as a function of group and group x phase using independent groups t-tests and ANOVAs with 
Tukey post-hoc for pairwise comparisons. If data does not meet ANOVA assumptions, mixed model 
regressions will be used. 
Secondary actigraphy outcomes may include wake after sleep onset (WASO), time spent napping, number 
of naps, and total activity. Secondary self-report ratings may include subjective WASO, visual analogue 
scale (VAS) sleepiness and quality of sleep, and Stanford Sleepiness Scale score. All outcomes will be 
compared as a function of group (20mg SUVO, 40mg SUVO, and placebo) and phase (taper vs. post-
taper), as well as group by day (7 nights) using area-under-the-curve (AUC). The taper and post-taper 
periods will then be derived and compared as a function of group and group x phase using independent 
groups t-tests and ANOVAs with Tukey post-hoc for pairwise comparisons. If data does not meet ANOVA 
assumptions, mixed model regressions will be used. 
Secondary measures will be additional ratings on the hypothetical purchase task, SOWS and VAS ratings 
of opioid withdrawal, VAS ratings of abuse liability, self-reported craving, self-reported stress, perceived 
drug value, and diurnal salivary cortisol (measured via AUC values and mean daily cortisol) and 
cortisol/ACTH ratios. Purchase task data will be fit to opioid demand curves for comparison. Analyses: All 
outcomes will be compared as a function of group (20mg SUVO, 40mg SUVO, and placebo) and phase 
(taper vs. post-taper), as well as group by day (7 nights) using area-under-the-curve (AUC). The taper and 
post-taper periods will then be derived and compared as a function of group and group x phase using 
independent groups t-tests and ANOVAs with Tukey post-hoc for pairwise comparisons. If data does not 
meet ANOVA assumptions, mixed model regressions will be used. Exploratory analyses will include linear 
and multivariate regression models to examine the relationship between measures of sleep, stress, opioid 
withdrawal, and craving. Logistic regression will be used to examine the relationship between sleep, stress, 
opioid withdrawal, and craving on the likelihood of treatment attrition.  
d. Early stopping rules.
Patients will discontinue their study participation if they request to be discharged, have a serious adverse 
event, or if the study physicians decide it is in the patient’s best interest to be removed from the study. All 
patients will be discharged with naloxone, opioid overdose education, and referral to outpatient OUD 
treatment. 
8.
Risks
a.
Medical risks, listing all procedures, their major and minor risks and expected frequency.


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1. Risk associated with suvorexant (Belsomra®): Suvorexant is a Schedule IV dual orexin antagonist that is
FDA-approved for the treatment of insomnia. Suvorexant is 82% bioavailable and has a Tmax of 2 hours.
Tmax can be delayed by food though this does not impact the Cmax.  It is extensively metabolized by the
liver through CYP3A enzymes. The elimination half-life is 12 hours, and it is excreted through both renal
(23% unchanged) and fecal (66%) means. Suvorexant is contraindicated with other CNS depressants and
alcohol and strong CYP3A inhibitors. It is rated pregnancy category C, indicating insufficient data
available to make determination for human subjects. Suvorexant is contraindicated in patients with
narcolepsy, patients with recent suicidal behavior, or patients with severe hepatic impairment. There is no
evidence of potential overdose and a toxic dose has not been established. Clinical trials that administered
up to 240mg of suvorexant reported no overdose effects, though there was a dose-dependent increase in the
frequency and duration of next day somnolence. As per product label, most common side effects are
sleepiness/drowsiness (7% of people), headache (7%), dizziness (3%), diarrhea (2%), dry mouth (2%),
upper respiratory infection (2%), abnormal dreams (2%), and cough (2%). Serious adverse effects include
sleep paralysis (7%), somnolence (7%), and worsening of depression or suicidal ideation.
2. Risks associated with buprenorphine/naloxone: Participants in this study will be maintained on
buprenorphine/ naloxone briefly before beginning a 4-day buprenorphine/naloxone taper. Buprenorphine is
Schedule III FDA-approved medication that is approved for the indication of opioid withdrawal treatment.
Participants in this study will receive the generic sublingual tablet version of this product (which also has
naloxone). Buprenorphine is partial opioid agonist/antagonist at the opioid mu/kappa receptors
(respectively), has a low ceiling on its agonist effects, and a slow dissociation from the receptors that
results in a 26-hour elimination half-life. There is nothing experimental about the use of
buprenorphine/naloxone use in this study. All participants will receive the same buprenorphine/naloxone
detoxification schedule, and the highest potential dose (24mg) is well below what can be administered for
use on a daily basis (32mg). Buprenorphine/naloxone has very few contraindications, and is not
recommended for patients with respiratory distress (such as acute or severe bronchial asthma, or respiratory
depression), patients with a known allergy to buprenorphine, or patients with history of cardiac problems
such as long QT syndrome or severe hypotension. It is contraindicated for use with the opioid antagonist
naltrexone or other opioid agonists. It is rated in pregnancy category C, therefore all women who are
pregnant or breastfeeding will be excluded from study participation.  Buprenorphine/naloxone’s noted side
effects are minimal and rare (hyperhidrosis 14%, abdominal pain 11%, constipation 12%, nausea 15%,
headache 37%, insomnia 14%) and overlap significantly with known opioid withdrawal symptoms (e.g.,
abdominal pain, nausea).
3. Risk associated with opioid withdrawal: It is expected that participants will experience some level of
opioid withdrawal as part of this study. Symptoms of opioid withdrawal include nausea, diarrhea or
stomach cramping, muscle aches and pains, yawning, sweating, pupil dilation, minor increases in blood
pressure, and runny nose/tearing eyes.
4. Risk of opioid overdose: Patients are at an increased risk of experiencing an opioid overdose whenever
their tolerance to opioids has decreased. This includes completion of an opioid detoxification (or leaving
prison/jail).  The reason for this increased risk is really related to patient knowledge of how their tolerance
contributes to their opioid use, and patients who are not aware that their tolerance has decreased and relapse
to opioids by using the same dose they were using before they entered treatment are most susceptible to an
opioid-related overdose. 5. Risk associated with clonidine: Patients may receive clonidine during the
induction period only to assist with the transition from illicit opioids to buprenorphine/naloxone. Clonidine
will be administered per clinical recommendation and this study expects to use it in only a very small
number of patients.  The largest risk associated with clonidine is hypotension (experienced in 44.8% of
patients). Up to 38% of patients may also experience symptoms related to sedation, fatigue, and/or. Fewer
than 10% of patients experience symptoms related to GI upset (nausea, constipation), insomnia, respiratory,
neurologic, or psychiatric complications.  Clonidine has few contraindications, however given that it


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reduces blood pressure will not be administered to participants whose blood pressure is <80/60, however 
we expect this to be rare because hypertension is a symptom of opioid withdrawal.  
b. Steps taken to minimize the risks.
Adverse events will be assessed daily. The safety of participants is a priority of our research unit. The 
largest potential risks to participants on SUVO are worsening of depression and/or sleep paralysis. We will 
exclude any participant with current major depressive disorder, past year suicidal behavior, or self-reports 
of current sleep paralysis. Medical team members will be consulted about adverse events and we will 
follow all reporting guidelines. In the event of an SAE, appropriate courses of action may include 
observing the participant until the parameters return to normal or transferring the participant to the 
Emergency Department (ED). Our research unit, the location in which all study sessions will be conducted, 
is located across the street from the Johns Hopkins Bayview Medical Center (JHBMC) ED. Participants 
who can walk will be escorted to the ED by a study staff member. If there is any question in a participant’s 
ability to walk safely then 911 will be called to have an ambulance dispatched for the participant.  
Given the small sample size, the relatively short study duration, and the fact that medications are being 
administered as clinically-indicated, we are not planning an interim analysis. 
c.
Plan for reporting unanticipated problems or study deviations.
Adverse events may be identified by a member of the research staff, the Principal Investigators, or study 
co-investigators. The PI will be responsible for consulting a medical team member about adverse events  
The PI and research staff will meet on a weekly basis to review safety monitoring data and adverse events 
and to ensure that any safety concern has been addressed by medical staff and has been recorded 
appropriately.    
All SAEs will be reported to the JHM IRB within 3 working days after a study PI learns of the event. In 
addition, the study PI will notify the study co-investigators, the NIDA Program Official, and the FDA (if 
applicable).  The PI will coordinate dissemination of subsequent information obtained relating to the death 
(e.g., autopsy report, hospital records, toxicological analyses). 
The Johns Hopkins IRB will be provided with an annual summary of AEs and SAEs as part of the 
continuing review. If any SAEs requires a change to the protocol or consent form, the PI will make those 
changes promptly and submit the revised documents to the JHM IRB and appropriate other agencies. 
Important adverse events that are unanticipated, including pregnancy, will be reported to the Johns Hopkins 
IRB within 10 working days.  If the important adverse events requires changes to the protocol or consent 
form, the PI will make those changes promptly and submit the revised documents to the IRB and 
appropriate other agencies. 
d. Legal risks such as the risks that would be associated with breach of confidentiality.
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Consistent with these 
regulations a signed authorization will be obtained that informs each subject of the following:   
•
What protected health information (PHI) will be collected from subjects in this study
•
Who will have access to that information and why
•
Who will use or disclose that information
•
The rights of a research subject to revoke their authorization for use of their PHI.


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In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of subject authorization.  For 
subjects that have revoked authorization to collect or use PHI, attempts should be made to obtain 
permission to collect at least vital status (i.e. that the subject is alive) at the end of their scheduled study 
period. 
e.
Financial risks to the participants.
There are no financial risks to the patient. 
9.
Benefits
a.
Description of the probable benefits for the participant and for society.
This study will increase our understanding of the association between sleep and opioid withdrawal 
symptoms, the degree to which sleep impairment contributes to opioid treatment outcomes, and the degree 
to which a novel FDA-approved medication (suvorexant) with low abuse liability, high safety profile, and 
immediate onset of action has on sleep impairment during opioid withdrawal. This will be the first study to 
examine this medication in opioid use disorder (OUD) patients, the first to examine any sleep 
pharmacotherapy with OUD patients during a withdrawal procedure, and the first to use a rigorous 
unobtrusive, wireless, objective EEG monitor to collect sensitive objective data regarding sleep continuity 
and architecture.  These results will be rigorous and transparent and will advance our understanding of the 
role sleep may play in OUD and the value of evaluating the orexin system’s role in OUD more broadly, to 
ultimately provide an empirically-supported way to address the opioid epidemic. 
10.
Payment and Remuneration
a.
Participants will earn $30 for the screening visit. Participants who complete the study will earn
$100 per day for a total of $1100. Participants will also earn an adherence bonus of $30/day (up to
$300) for wearing the wireless EEG device throughout the night. The total maximum payment is
$1430 (See Payment Table).
Payment Schedule 
Daily 
Payments 
EEG 
Bonus 
Screen 
$30 
- 
Day 1 
$100 
- 
Day 2 
$100 
$30 
Day 3 
$100 
$30 
Day 4 
$100 
$30 
Day 5 
$100 
$30 
Day 6 
$100 
$30 
Day 7 
$100 
$30 
Day 8 
$100 
$30 
Day 9 
$100 
$30 
Day 10 
$100 
$30 
Day 11 
$100 
$30 
Follow-up 
$30 
- 
Total 
$1160 
$300 
Maximum Payment 
$1460 


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11.
Costs
a.
Detail costs of study procedure(s) or drug (s) or substance(s) to participants and identify who will
pay for them.
The participants in this study will not pay for any aspect of study participation. All study medications, 
residential treatment costs, and staff support is paid through the NIHA grant UG3DA048734-01. 


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