Clinical trial NCT03415581
Conditions: Opioid-use Disorder
Sponsor: New York State Psychiatric Institute
Start date: 2017-02-12; Completion date: 2019-12-23
Enrollment: 13 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Healthy, adult men and women, aged 21 to 59 years, who abuse opioids and are physically dependent on them will be recruited to participate in a study to examine the ability of doxazosin, an epinephrine receptor blocker, to alter the abuse potential of oxycodone. After participants complete the screening process, they will be scheduled for inpatient admission onto our clinical inpatient where they will reside during the 8-week study. During Weeks 1-2, participants will be transitioned from their normal opioid use regime onto oral morphine until withdrawal dissipates. At this time participants will also be stabilized on the first dose of doxazosin (0 or 16 mg/day; active doxazosin will be started at 4 mg and increased by 4 mg every 3 days). During Weeks 3-4, either active or placebo oxycodone will be available (in random order). Monday-Friday each these drugs will be tested using our sample and choice self-administration procedure. On Friday, participants will also complete a cue exposure session during which they will be presented drug cues to determine whether the study medication affects how participants react to them. To summarize, Weeks 1-2 and 5-6 will be stabilization weeks (0 or 16 mg doses of doxazosin administered in random order) and Weeks 3-4 and 7-8 will be test weeks under each of the doxazosin maintenance doses. At the conclusion of the study, participants will be given an exit interview, warnings about re-initiation of opioid use, and counseling about the different treatment options for Opioid Use Disorder. Within 1 week after discharge, investigators will assess adverse events using the a number of clinical assessments. At each weekly visits, investigators will assess participants' interest in treatment and drug use patterns.

Detailed description:
Healthy, adult men and women, aged 21 to 59 years, who abuse opioids and are physically dependent on them will be recruited to participate in a study to examine the ability of doxazosin, an alpha-1 adrenergic receptor antagonist, to alter the abuse liability of oxycodone. After participants complete the screening process, they will be scheduled for admission onto the General Clinical Research Unit on 5-South where they will reside during an 8-week study . During Weeks 1-2, participants will be stabilized on morphine and the first dose of doxazosin (0 or 16 mg/day; active doxazosin will be started at 4 mg and increased by 4 mg every 3 days; dosing will occur at 8pm each evening). During the stabilization periods, participants will be treated for emergent withdrawal symptoms with supplemental medications until withdrawal symptoms have dissipated.

During Weeks 3-4, either active or placebo oxycodone will be available (order of testing active or placebo oxycodone will be randomized). During active oxycodone weeks, participants will receive a sample dose of intransasal (IN) oxycodone (0, 12.5, 25, 50, or 100 mg/70kg) during morning sessions on Monday-Friday. The sampled reinforcer will be available during afternoon choice sessions using a modified progressive ratio self-administration procedure. During placebo oxycodone weeks, participants will receive a sample dose of placebo oxycodone (0 mg/70kg) during morning sessions on Monday-Thursday followed by afternoon choice sessions. On Friday, participants will receive 25 mg IN oxycodone during a sample session (the oxycodone dose on Fri morning will always be active). When self-administering oxycodone, participants will be instructed to insufflate the entire dose through one or both nostrils within 5-10 seconds. Following the sample session on Fri, participants will complete a cue exposure session during which they will be presented with neutral cues followed by drug cues. This procedure will allow the investigators to determine whether the study medication affects reactivity to drug-related cues after a period of no oxycodone availability. After the cue exposure session on Fri, participants will be given the opportunity to self-administer oxycodone. To summarize, Weeks 1-2 and 5-6 will be stabilization weeks (0 or 16 mg doses of doxazosin administered in random order) and Weeks 3-4 and 7-8 will be test weeks under each of the doxazosin maintenance doses. At the conclusion of the study, participants will be given an exit interview during which the study will be described. Those who are interested in treatment for their drug use at the end of the study will be offered referrals to studies at our Substance Treatment and Research Service or other treatment providers. Within 1 week after discharge, investigators will assess adverse events, pregnancy (using a urine pregnancy test), general health (complete blood count, blood chemistry, urinalysis, blood pressure, heart rate, body weight, EKG), and suicide (Columbia Suicide Severity Rating Scale).

Arms: arm 1: Maintenance on a daily dose of oral doxazosin (0 mg) for 4 weeks, followed by 4-week maintenance on active doxasozin (up to 16mg/day or the highest tolerated dose. During this time subjects complete testing sessions (Self-administration, Cue session) assessing the abuse potential of intranasal oxycodone. arm 2: Maintenance on a daily dose of oral doxazosin (16 mg, or the highest tolerated dose) for 4-weeks, followed by 4-week maintenance on placebo doxasozin. During this time subjects complete testing sessions (Self-administration, Cue session) assessing the abuse potential of intranasal oxycodone.
Interventions: intervention 1: Intranasal Oxycodone intervention 2: Cue Session
Intervention descriptions: intervention 1: Under each doxazosin maintenance condition the effects of intranasal oxycodone will be assessed in order to determine if doxazosin reduces dependent measures assessing its abuse potential. intervention 2: During the cue exposure session participants are presented with neutral cues followed by drug-related cues. This procedure will allow the investigators to determine whether the study medication affects reactivity to drug-related cues.

Protocol documents:
Prot_000.pdf: 
Signed copy on file at IRB 
 
             v. 4/19/13 
                                          NEW YORK STATE PSYCHIATRIC INSTITUTE         
INSTITUTIONAL REVIEW BOARD 
MEMORANDUM 
 
 
 
 
 
 
 
 
 
December 23, 2019 
TO: 
 
Dr.  Sandra D. Comer 
FROM: 
Dr. Edward Nunes, Co-Chair, IRB 
 
 
Dr. Agnes Whitaker, Co-Chair, IRB 
 
 
SUBJECT: 
APPROVAL NOTICE:  CONTINUATION   
 
 
Expedited per 45CFR46.110(b)(1)(f)(8)(c) 
 
Your protocol # 7547 entitled DOXAZOSIN: EVALUATION OF ITS ABILITY TO ALTER THE ABUSE 
LIABILITY OF OXYCODONE IN HUMANS (version date 12-23-19) and Consent Forms have been 
approved by the New York State Psychiatric Institute - Columbia University Department of 
Psychiatry Institutional Review Board from January 8, 2020 to January 7, 2021.   
 
Consent requirements: 
   
  X Not applicable: (RECRUITMENT COMPLETED. DATA BEING ANALYZED) 
    
   45CFR46.117 (c)(2) waiver of documentation of consent for the telephone interview.   
 
   Signature by the person(s) obtaining consent is required to document the consent process. 
 
   Documentation of an independent assessment of the participant’s capacity to consent is also required. 
 
       
    Approved for recruitment of subjects who lack capacity to consent:   No      Yes    
 
 
    Field Monitoring Requirements:  Routine      Special:                                    
 
√   Only copies of consent documents that are currently approved and stamped by the IRB 
may be used to obtain consent for participation in this study. 
√  A progress report and application for continuing review is required 2 months prior to the  
expiration date of IRB approval. 
√  Changes to this research may be not be initiated without the review and approval of the  
IRB except when necessary to eliminate immediate hazards to participants.  
√  All serious and/or unanticipated problems involving risks to subjects or others must be 
reported immediately to the IRB.  Please refer to the PI-IRB website at http://irb.nyspi.org 
for Adverse Event Reporting Procedures and additional reporting requirements.  
 
 
CC:  RFMH Business Office (U54DA037842; PI: Levin) 
 
 
 
 
 
 
EN/AW/Scr 


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Protocol Title:
Doxazosin: Evaluation of Its Ability to 
Alter the Abuse Liability of Oxycodone in 
Humans
Protocol Number:
7547
First Approval:
01/11/2018
Expiration Date:
01/07/2021
Version Date:
12/23/2019
Clinic:
Opioid Research Laboratory
Contact Principal Investigator:
Sandra Comer, PHD
Email: sdc10@cumc.columbia.edu
Telephone: 646-774-6146
Co-Investigator(s):
Jeanne Manubay, MD
Jermaine Jones, PHD
Shanthi Mogali, MD
Research Chief:
Frances Levin, MD
Cover Sheet
Choose ONE option from the following that is applicable to your study
If you are creating a new protocol, select "I am submitting a new protocol." As 5 Year Renewals are no 
longer required, this option remains for historical purposes.
I am submitting an annual continuation without modifications 
Division & Personnel
Division
What Division/Department does the PI belong to?
Division on Substance Use Disorders
Within the division/department, what Center or group are you affiliated with, if any? 
Opioid Laboratory
Unaffiliated Personnel
List investigators, if any, who will be participating in this protocol but are not affiliated with New York 


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State Psychiatric Institute or Columbia University. Provide: Full Name, Degrees and Affiliation.
Tanya Ramey, MD - Scientific Project Officer, NIDA
Application for Continuation of Research
Status
Current Status of Study: 
Study only involves secondary data analysis or chart record review of data.
Summary of Experiences to Date
Please provide a summary of scientific progress of the study and the experience of research participants, to 
date. This requirement is designed to allow for the investigator and the IRB to reassess the study’s risks and 
benefits in terms of developments in the field, changing practice patterns, and new IRB policies and 
procedures.
Funding for this study has ended, and we have thus ended enrollment and the running of participants. We 
are filing for a continuation of the study in order to review participant records and assess and report the 
causes behind the rate of participant discontinuation.
Funding
Have there been any changes in funding status since the prior approval? 
No
Have the principal investigator and other investigators made all required disclosures of financial interest in 
the study sponsor/product?
Yes
Summary
Have there been any study findings, recent literature, or untoward events occuring here or at other sites in 
the past year which might affect the analysis of the safety, risks or benefits of study participation? 
No
Have there been any serious adverse events (serious and/or unanticipated problems involving risks to 
subjects or others at this site which occured in the past year)? 
No
Have all study staff with a significant role in the design or implementation of the human subject components 
of this study received required training in human research subject protections?
No
Is the study covered by a certificate of confidentiality? 
Yes
Certificate expiration date (mm/dd/yyyy) 
12/15/2020


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Approved Sample and Progress
Approved sample size 
27
Total number of subjects studied since first approval
13
Have there been any significant deviations from the anticipated study completion estimates?
Yes
Describe actions taken or planned to address these problems.
A higher than anticipated dropout rate occurred because participants did not meet our blood pressure criteria 
for continuation in the trial. We made minor modifications to our blood pressure criteria but funding for this 
grant ended so we are no longer enrolling participants into this study. 
Comments / additional information 
Procedures
To create the protocol summary form, first indicate if this research will include any of the following 
procedures
   Medication Trial
   Administration of Substance of Abuse
   Off-label Use of Drug or Device
Population
Indicate which of the following populations will be included in this research
   Adults
   Adults over 50
   Substance Users
Research Support/Funding
Will an existing internal account be used to support the project?
No
Is the project externally funded or is external funding planned?
Yes
Select the number of external sources of funding that will be applicable to this study
Funding Source #1
Is the PI of the grant/contract the same as the PI of the IRB protocol? 


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No
Who is the PI of the grant/contract?
Levin, Frances, MD
Select one of the following
The grant/contract is currently funded
Source of Funding
Federal
Institute/Agency
NIDA
Grant Name
Shared Pharmacotherapeutic Strategies for Cannabinoid and Opioid Use Disorders
Grant Number
U54DA037842
Select one of the following
Single Site
Business Office
RFMH
Does the grant/contract involve a subcontract? 
Yes
Subcontracted?
To
Name institution(s)
Columbia University
Study Location
Indicate if the research is/will be conducted at any of the following
   NYSPI
This protocol describes research conducted by the PI at other facilities/locations
No
Lay Summary of Proposed Research 
Lay Summary of Proposed Research
Healthy, adult men and women, aged 21 to 59 years, who abuse opioids and are physically 
dependent on them will be recruited to participate in a study to examine the ability of doxazosin, 
an epinephrine receptor blocker, to alter the abuse potential of oxycodone. After participants 
complete the screening process, they will be scheduled for inpatient admission onto our clinical 
inpatient where they will reside during the 8-week study (Table 1). During Weeks 1-2, participants 
will be transitioned from their normal opioid use regime onto oral morphine until withdrawal 
dissipates. At this time participants will also be stabilized on the first dose of doxazosin (0 or 16 
mg/day; active doxazosin will be started at 4 mg and increased by 4 mg every 3 days). During 
Weeks 3-4, either active or placebo oxycodone will be available (in random order). Monday-Friday 


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each these drugs will be tested using our sample and choice drug vs money ($20) self-
administration procedure. On Friday, participants will also complete a cue exposure session 
during which they will be presented drug cues to determine whether the study medication affects 
how participants react to them. To summarize, Weeks 1-2 and 5-6 will be stabilization weeks (0 or 
16 mg doses of doxazosin administered in random order) and Weeks 3-4 and 7-8 will be test 
weeks under each of the doxazosin maintenance doses. At the conclusion of the study, 
participants will be given an exit interview, warnings about re-initiation of opioid use, and couseling 
about the different treatment options for Opioid Use Disorder.  Within 1 week after discharge, we 
will assess adverse events using the a number of clinical assessments.  Participants also will 
return weekly for their study payments for several weeks after study completion. At each of these 
weekly visits, we will assess participants’ interest in treatment and drug use patterns.
Background, Significance and Rationale
Background, Significance and Rationale
In addition to modulating opioid withdrawal effects, research suggests that noradrenergic
circuits may be involved in opioid reinforcement (Ventura et al., 2005). Doxazosin, an α1-
adrenergic receptor antagonist, is a safe, FDA-approved medication currently used to treat 
hypertension. Few studies have examined the effects of doxazosin in preclinical behavioral 
models, but numerous studies have evaluated the effects of prazosin, another α1-adrenergic 
receptor antagonist, on opioid-mediated responses. In preclinical models, prazosin reduced the 
acquisition and expression of morphine-induced conditioned place preference (Sahraei et al., 
2004; Zarrindast et al., 2002) and heroin self-administration (Greenwell et al., 2009). It also 
blocked morphine-induced dopamine release in the ventral striatum (Auclair et al., 2004), 
suppressed the development of tolerance to morphine (Kihara and Kaneto, 1986), and prevented 
naloxone-induced weight loss in morphine-dependent rats (Ozdogan et al., 2003). Prazosin did 
not share discriminative stimulus effects with morphine, and it did not alter morphine’s 
discriminative stimulus effects (Hughes et al., 1996). It had no analgesic effects of its own in 
rodents and either had no effect on (Kihara and Kaneto, 1986) or potentiated morphine-induced 
analgesia (Ozdogan et al., 2003). In addition to its effects on opioid self-administration, prazosin 
also reduced self-administration of cocaine (Wee et al., 2008), nicotine (Forget et al., 2010), and 
alcohol (Froehlich et al., 2013a; Rasmussen et al., 2009; Verplaetse et al., 2012; Walker et al., 
2008). And a low dose of prazosin given in combination with a low dose of naltrexone reduced 
alcohol drinking in rats at doses that were ineffective when given alone (Froehlich et al., 2013b). In 
humans, prazosin reduced alcohol craving, anxiety, and negative emotion following stress 
exposure (Fox et al., 2012), and in a small (N=17 men), randomized, placebo-controlled treatment 
trial, prazosin reduced the number of drinking days per week, and number of drinks per week 
during the last 3 weeks of the study relative to placebo (Simpson et al., 2009). Like prazosin, 
doxazosin produced dose-related decreases in self-administration of alcohol in rats (O’Neil et al., 
2013). And when doxazosin was given in combination with the β receptor antagonist propranolol, 
it reduced cue-induced reinstatement of responding for cocaine (Smith and Aston-Jones, 2011). In 
cocaine-dependent
humans, doxazosin decreased cocaine-induced ratings of liking and desire to use cocaine 
(Newton et al., 2012) and improved treatment outcomes in a placebo-controlled trial for cocaine 


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dependence (Shorter et al., 2013). To date, no clinical studies have examined the effects of either 
prazosin or doxazosin on opioid self-administration or withdrawal. Although substantially more 
research has been conducted with prazosin, we decided to evaluate doxazosin instead because 
while both medications produce a similar side-effects profile (Torvik and Madsbu, 1987), 
doxazosin has a longer half-life and thus can be given once daily rather than 2-3 times each day, 
which may increase adherence in clinical outpatient settings.
Specific Aims and Hypotheses
Specific Aims and Hypotheses
       Specific Aim 1: Assess the ability of doxazosin to alter oxycodone self-administration behavior 
(measured by average progressive-ratio breakpoint values) and positive subjective responses 
(measured by visual analog scales). 
       Hypothesis 1: Doxazosin will be superior to placebo in reducing oxycodone's reinforcing and 
positive subjective effects. 
       Specific Aim 2: Assess the ability of doxazosin to affect opioid craving (measured by ratings of 
"I Want Heroin") and physiological response (galvanic skin response, skin temperature, and 
heart rate) to drug cues. 
       Hypothesis 2: Doxazosin will be superior to placebo in reducing drug craving, as well as 
physiological and subjective reactivity to drug cues.
       Exploratory Aim: Assess the ability of doxazosin to alter withdrawal symptoms, as measured 
by the SOWS, that may occur during Weeks 3, 4, 7, and 8.
Description of Subject Population
Sample #1
Specify subject population
Non-treatment-seeking participants with moderate-severe opioid use disorder
Number of completers required to accomplish study aims
27
Projected number of subjects who will be enrolled to obtain required number of completers
56
Age range of subject population


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21-59
Gender, Racial and Ethnic Breakdown
The proposed study seeks to include women and minorities; the study does not exclude any
potential participants on the basis of race or gender. Both males and females will be recruited.
Based on previous studies, it is estimated that the sample will be 70% male, 50% Caucasian,
25% Black or African-American, 20-25% Hispanic or Latino, 0-5% Asian and Pacific Islander
and less than 1% Native American. All efforts will be made to ensure that representation of
women and ethnic minorities are in proportion to the population of the city of New York.
Description of subject population
Participants meeting DSM-5 criteria for moderate-severe OUD and physical dependence on 
opioids will be enrolled.
Recruitment Procedures
Describe settings where recruitment will occur
All in-person screening and assessments (drug interview, psychiatric evaluation, medical 
examination, and naloxone challenge) will occur within the facilities of the Substance Use 
Research Center (SURC), located on the 3rd floor of the NYSPI.
How and by whom will subjects be approached and/or recruited? 
Initial telephone interviews will be carried out by research assistants and nurses; 2) drug interview 
and general assessment related to study issues will be conducted by a psychologist; 
3) Psychiatric Examinations will be performed by a psychiatrist or psychiatric nurse practitioner, 
clinical psychologist. 4) SCIDs will be performed by a nurse or psychologist. Telephone screens 
will be recorded either electronically or on paper forms.
How will the study be advertised/publicized? 
Recruitment is primarily through word-of-mouth and advertisements in local newspapers such as 
the Village Voice and AM New York, as well as electronic media (e.g., Facebook, Google, 
StudyKik, and websites that drug users frequent such as Bluelight and Erowid). The study will also 
be advertising and publicized on the New Jersey Transit Bus stops. The study will be advertising 
on the New York MTA Subway Train system. We will also be advertising in the New Jersey 
Journal's online platform. The study will be using RecruitMe as a platform for recruitment. 
Do you have ads/recruitment material requiring review at this time? 
Yes
Does this study involve a clinical trial?
Yes
Please provide the NCT Registration Number
NCT03415581
Concurrent Research Studies
Will subjects in this study participate in or be recruited from other studies? 
Yes


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Describe concurrent research involvement
6723: Risks and Benefits of Overdose Education and Naloxone Prescribing to Heroin Users (PI:
Sandra Comer, Ph.D.)
Inclusion/Exclusion Criteria
Name the subject group/sub sample
Participants with OUD
Create or insert table to describe the inclusion criteria and methods to ascertain them
Inclusion Criterion                                                               Method of Ascertainment 
 
1. 21-59 years of age
Self-reported age and/or verification 
with legal identification
2. Diagnostic criteria for Opioid Use 
Disorder moderate-severe (304.00) as 
per DSM-V 
Clinical interviews (telephone, 
psychologist, nurse, physician), 
naloxone challenge test/visual 
evidence of opioid withdrawal
3. No current or past diagnosis of 
schizophrenia, schizoaffective 
disorder, or other psychotic disorder; 
bipolar I or bipolar II disorder, other 
major mood, psychotic, or anxiety 
disorder that might interfere with the 
study
Clinical interview with physician or 
nurse
4. Physically healthy
Clinical interview with physician, 
laboratory tests (urinalysis, blood 
chemistry, 12-lead ECG), physical 
examination, self-reported medical 
history
5. Able to perform study procedures
Practice session or Clinical 
Judgement (Psychologist or 
Physician)
6. Normal body weight
Body mass index < 30
7. Current or history of intranasal 
opioid use
Clinical interviews (telephone, 
psychologist, physician, or 
Psychiatric NP)
8. Current intranasal or intravenous 
use of opioids in amounts and/or 
Clinical interviews (telephone, 
psychologist, Psychiatric NP, or 


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frequencies that meet or exceed those 
used in the proposed study (e.g., 3-4 
tablets of a prescription opioid 
medication per day or 1-2 bags of 
heroin per day)
physician)
9. If female and using oral 
contraceptives, must use alternative 
forms of contraception as well (e.g. 
condoms in combination with 
spermicide)
Clinical interview (psychologist, 
nurse, physician), physical 
examination
10. Has not participated in another 
opioid laboratory study within the past 
3 months
Clinical interview (psychologist, 
physician,or Psychiatric NP), review 
of laboratory records
Create or insert table to describe the exclusion criteria and methods to ascertain them
Exclusion Criterion                                                              Method of Ascertainment
1. Meeting DSM-V criteria for 
substance use disorder (moderate-
severe) on drugs other than opioids, 
nicotine or caffeine (must be less than 
500 mg caffeine daily)
Clinical interview with physician or  
Psychiatric NP, urine screen, 
observation
2. Participants requesting treatment
Self-report during interview
3. Treatment with any investigational 
drug during the last 30 days
Self-report during interview
4. Participants on parole or probation
Self-report during interview, criminal 
background check upon admission. 
5. Currently pregnant or trying to 
conceive, or currently lactating
Blood pregnancy testing at 
screening, on admission and (beta-
hCG), and self-report during 
interview and study visits
6. Current or recent history of 
significant violent or suicidal behavior 
and/or suicidal/homicidal risk
Clinical interview with a psychiatrist 
or Psychiatric NP, & C-SSRS, MINI, 
and Beck Depression Inventory
7. Cannot read or understand the self-
report assessment forms unaided, or 
cannot comply with the requirements of 
the study
Clinical interview (psychologist, 
physician, or Psychiatric NP), or 
practice session


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8. Elevated liver function tests (i.e., AST 
and ALT > 3 times the upper limit of 
normal (ULN); bilirubin > 2x ULN; 
hepatitis B or chronic hepatitis C)
 
Laboratory tests
9. Physical disorders that might make 
participation hazardous such as AIDS, 
cancer, baseline hypotension, 
orthostatic hypotension or syncope, 
hypertension (blood pressure > 
140/90), uncontrolled diabetes, 
pulmonary hypertension or heart 
disease (please note that participants 
will be asked about previous visits to a 
cardiologist, chest pain, or strong 
palpitations; if these exist, they will be 
referred to a cardiologist and excluded 
unless cleared for participation by a 
cardiologist)
Clinical interview (psychologist, 
physician,or Psychiatric 
NP) physical examination, 12-lead 
ECG
10. Current major Axis I 
psychopathology other than opioid 
use disorder (e.g., mood disorder with 
functional impairment or suicide risk, 
schizophrenia), that might interfere 
with ability to participate in the study
Clinical interviews (psychologist, 
physician,or Psychiatric NP) 
11. Sensitivity, allergy, or 
contraindication to opioids, doxazosin, 
adrenergic antagonists or agonists, or 
similar compounds
Clinical interview (psychologist, 
physician,or Psychiatric NP)
12. Planning to conceive within 6 months 
of study participation
Clinical interviews (psychologist, 
physician,or Psychiatric NP)
      13. The use of prescription or       over-
 the- counter medication that       can affect 
CYP3A4 activity, 7       days       prior  to  the 
anticipated       study start       date; or  the 
use of       phosphodiesterase inhibitors and 
      MAOIs  14 days prior to the study.
 Medical History, Clinical Interview 
(psychologist, physician,or Psychiatric NP)
Waiver of Consent/Authorization


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Indicate if you are requesting any of the following consent waivers
Waiver of consent for use of records that include protected health information (a HIPAA waiver of 
Authorization) 
No
Waiver or alteration of consent
Yes
Waiver of documentation of consent 
No
Waiver of parental consent 
No
Consent Procedures
Is eligibility screening for this study conducted under a different IRB protocol?
No
Describe procedures used to obtain consent during the screening process 
Upon the participant's first visit to NYSPI, the general study procedures are described by a
research assistant. If the participant is still interesting in screening for the study, (s)he is given a
screening consent for to review. After giving the participant time to review the screening consent
form, (s)he meets with a research nurse, psychologist or physician to sign the screening consent
for to initiate screening procedures detailed in the document.
Describe Study Consent Procedures
A physician or psychiatric NP conducts the physical and psychiatric examinations, reviews the 
inclusion/exclusion criteria, and obtains consent to study participation. As a result of our ongoing 
consent procedures throughout screening with various personnel, the date that the participant 
signs the study consent form sometimes will differ from the date that the physician or psychiatric 
NP signs the study consent form.
 
Blevins, Derek MD
Brezing, Christina, MD
Comer, Sandra, PhD
Jones, Jermaine, PhD
Kidd, Jeremy MD
Manubay, Jeanne, MD
Mogali, Shanthi, MD
Murray, Janet RN
Shulman, Matisyahu, MD
Tindall, Claudia NP
Wai, Jonathan MD
Williams, Arthur MD
Woolfolk, Vincent MA
Suky Martinez MA
Muhammad Iqbal MD


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Ben Srivastava MD
Ida Holt RN
Indicate which of the following are employed as a part of screening or main study consent procedures
   Consent Form
   Consent Script
Justification for Waiver or Alteration of Consent
Waiver of consent is requested for the following
As per 45CRF46.116(d) of the Code of Federal Regulations, we are requesting a waiver of
consent for our telephone screen.
Explain why your research can not be practicably carried out without the waiver or alteration
Participants first respond to study advertisements via telephone.
Describe whether and how subjects will be provided with additional pertinent information after participation
If participants meet the initial inclusion/exclusion criteria based on the telephone interview, they
will be invited to the laboratory for in-person screening visits where the study procedures will be
explained again in detail by multiple staff members.
Persons designated to discuss and document consent
Select the names of persons designated to obtain consent/assent
Blevins, Derek
Brezing, Christina, MD
Evans, Suzette, PHD
holt, ida
Iqbal, Muhammad
Jones, Jermaine, PHD
Kidd, Jeremy
Levin, Frances, MD
Manubay, Jeanne, MD
Mogali, Shanthi, MD
MURRAY, JANET
Shulman, Matisyahu, MD
Srivastava, A Benjamin
Tindall, Claudia
Wai, Jonathan, MD
Williams, Arthur
Type in the name(s) not found in the above list


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Study Procedures
Describe the procedures required for this study
Healthy, adult men and women, aged 21 to 59 years, who abuse opioids and are physically 
dependent on them will be recruited to participate in a study to examine the ability of doxazosin, 
an alpha-1 adrenergic receptor antagonist, to alter the abuse liability of oxycodone. After 
participants complete the screening process, they will be scheduled for admission onto the 
General Clinical Research Unit on 5-South where they will reside during an 8-week study (Table 
1). 
 
During Weeks 1-2, participants will be stabilized on morphine and the first dose of doxazosin (0 or 
up to 16 mg/day; active doxazosin will be started at 4 mg and increased by 4 mg every 3 days if 
tolerated based on blood pressure assessments up to a maximum dose of 16 mg/day; dosing will 
occur at 8pm each evening). Doxazosin maintenance may be delayed until after morphine 
stabilization based on the judgement of the medical director. During the stabilization periods, 
participants will be treated for emergent withdrawal symptoms with supplemental medications 
(e.g., clonazepam, compazine, ketorolac tromethamine, ondansetron, ibuprofen or 
acetaminophen, trazodone, and/or zolpidem) until withdrawal symptoms have dissipated, based 
on physician or Nurse Practitioner  judgment and using SOWS scores as a guide. Because 
numerous participants in previous studies have reported insomnia during similar procedures, oral 
doses of trazodone or zolpidem will be available on request at bedtime throughout the proposed 
study to alleviate the insomnia that may occur. We will offer a standing dose of trazodone only 
(100 mg), and a prn dose of 5 mg Ambien if participants continue to have problems with insomnia. 
If a participant has a history of non-response to trazodone, he or she will be offered 10 mg Ambien 
each night at bedtime. When withdrawal symptoms have dissipated, based on self-report and 
observer ratings, supplemental medications, with the exception of trazodone or zolpidem, will no 
longer be available and experimental sessions will begin. If participants are still experiencing side 
effects from doxazosin, additional days may be required to achieve stability; a previous study 
demonstrated that participants can become stable, with few adverse effects, after 2 weeks 
(Rodgman et al., 2016). Colace will be given to all participants as a standing order, in order to 
treat constipation, which is a common side effect of opioid administration. Liver function tests will 
be performed upon admission, every other week throughout the study, and at 1-week follow-
up. Because of the effects of opoid withdrawal on orthostatic hypotension, daily orthostatic 
assessments will not begin until after morphine stabilization. 
 
During Weeks 3-4, either active or placebo oxycodone will be available (order of testing active or 
placebo oxycodone will be randomized). During active oxycodone weeks, participants will receive 
$20 and a sample dose of intransasal (IN) oxycodone (0, 12.5, 25, 50, or 100 mg/70kg) during 
morning sessions on Monday-Friday (Table 2). The sampled dose/$ will be available during 
afternoon choice sessions using a modified progressive ratio self-administration procedure. During 
placebo oxycodone weeks, participants will receive $20 and a sample dose of placebo oxycodone 
(0 mg/70kg) during morning sessions on Monday-Thursday followed by afternoon choice 
sessions. On Friday, participants will receive $20 and 25 mg IN oxycodone during a sample 
session (the oxycodone dose on Fri morning will always be active). When self-administering 


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oxycodone, participants will be instructed to insufflate the entire dose through one or both nostrils 
within 5-10 seconds. Following the sample session on Fri, participants will complete a cue 
exposure session during which they will be presented with neutral cues followed by drug cues. 
This procedure will allow the investigators to determine whether the study medication affects 
reactivity to drug-related cues after a period of no oxycodone availability. After the cue exposure 
session on Fri, participants will be given the opportunity to self-administer oxycodone and/or 
money. 
 
To summarize, Weeks 1-2 and 5-6 will be stabilization weeks (0 or up to 16 mg doxazosin 
administered in random order) and Weeks 3-4 and 7-8 will be test weeks under each of the 
doxazosin maintenance doses. At the conclusion of the study, participants will be given an exit 
interview during which the study will be described. Those who are interested in treatment for their 
drug use at the end of the study will be offered referrals to studies at our Substance Treatment 
and Research Service or other treatment providers. Participants will return weekly for their study 
payments for several weeks after study completion. At each of these weekly visits, we will assess 
participants’ interest in treatment and drug use patterns (via self-report and urine drug toxicology). 
Within 1 week after discharge, we will assess adverse events, pregnancy (using a urine 
pregnancy test), general health (complete blood count, blood chemistry, urinalysis, blood 
pressure, heart rate, body weight, EKG), and suicide (Columbia Suicide Severity Rating Scale).
  
You can upload charts or diagrams if any
Criteria for Early Discontinuation  
Criteria for Early Discontinuation
Participants will be withdrawn from the study if they 1) do not comply with unit policies or study 
procedures, 2) are deemed medically at risk for further study participation, or 3) express a strong 
desire to receive treatment for their drug use. All participants who are withdrawn from the study 
will be offered referrals to treatment facilities and our Substance Treatment and Research Service. 
Those participants who are discontinued from study participation because of sensitivity to the 
respiratory effects of the opioids administered during the study will receive a special de-briefing by 
the study physician or Psychiatric NP prior to discharge. Specifically, participants will be warned of 
the risks, namely overdose and death, associated with continued opioid use.
 
Potential Cases of Drug-Induced Liver Injury
Liver function tests will be performed upon admission and every other week throughout the study. 
Abnormal values in aspartate transaminase (AST) and/or alanine transaminase (ALT) levels 
concurrent with abnormal elevations in total bilirubin level that meet the criteria outlined below in 
the absence of other causes of liver injury are considered potential cases of drug-induced liver 
injury (potential Hy’s law cases) and will be considered important medical events. The threshold of 
laboratory abnormalities for a potential case of drug-induced liver injury will depend on the 
subject’s individual baseline values and underlying conditions. Subjects who present with the 


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following laboratory abnormalities will be evaluated further to definitively determine the etiology of 
the abnormal laboratory values:
· Subjects with AST or ALT and total bilirubin baseline values within the normal range who 
subsequently present with AST or ALT values >3 times the upper limit of normal (3X ULN) 
concurrent with a total bilirubin value >2X ULN with no evidence of hemolysis and an alkaline 
phosphatase value >2X ULN;
· For subjects with preexisting ALT or AST or total bilirubin values above the ULN, the following 
threshold values will be used in the definition mentioned above:
· For subjects with preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2X the baseline values and >3X ULN, or >8X ULN (whichever is smaller).
 
Concurrent with
· For subjects with preexisting values of total bilirubin above the normal range: Total bilirubin level 
increased from baseline by an amount of at least 1X ULN or if the value reaches >3X ULN 
(whichever is smaller). The subject will be evaluated again, within 48 hours from awareness of the 
abnormal results. This evaluation will include laboratory tests, detailed history, and physical 
assessment. In addition to repeating measurements of AST and ALT, laboratory tests will include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase, 
prothrombin time (PT)/ international normalized ratio (INR), and alkaline phosphatase. A detailed 
history, including relevant information, such as review of ethanol, acetaminophen, recreational 
drug and supplement consumption, family history, occupational exposure, sexual history, travel 
history, history of contact with a jaundiced person, surgery, blood transfusion, history of liver or 
allergic disease, and work exposure, will be collected. Further testing for acute hepatitis A, B, or C 
infection and liver imaging (e.g., biliary tract) will be performed as warranted. All cases confirmed 
on repeat testing as meeting the laboratory criteria defined above, with no other cause for liver 
function test (LFT) abnormalities identified at the time, will be considered potential Hy’s law cases 
irrespective of availability of all of the results of the investigations performed to determine etiology 
of the abnormal LFTs. Such potential Hy’s law cases will be reported as SAEs and discontinued 
from the study.
 
Hypotension  
Vital signs are monitored daily on the inpatient unit  in seated, supine, and standing position and 
during laboratory sessions, and if a consistent pattern of clinically significant hypotension is 
observed, in the opinion of the clinical physicians on 5-South and the study's medical director, the 
participant will be discontinued from the study. 
 
Criteria for Testing Sessions:
 
a. Do not administer study drug if: Heart Rate <60 or >130 bpm, Systolic Pressure <90 or >165 
mm Hg, Diastolic Pressure < 60 or >100 mm Hg, or if a subject has orthostatic vital signs as 
follows: a supine BP of 85/55 or less, a seated BP of 85/55 or less, or an orthostatic decrease of 
>20 systolic and >15 diastolic upon standing.
 
b. Discontinue a session if a single reading is: Heart Rate <50 or > 175 bpm, Systolic Pressure 
<90 or >180 mm Hg, Diastolic Pressure or < 55 or >120 mm Hg.


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c. Notify the study MD if Heart Rate < 50 bpm, Systolic Pressure < 90 mm Hg, Diastolic Pressure 
< 55 mm Hg.
 
d.  We will perform orthostatic assessments prior to oxycodone administration and 1 hour after. If 
a subject has a HR < 55, a supine BP of 85/55 or less, a seated BP of 85/55 or less, or an 
orthostatic decrease of >20 systolic or >15 diastolic upon standing, or a HR > 35 bpm upon 
standing, oxycodone will not be administered, and the laboratory session will be postponed a day. 
We will not continue lab sessions until orthostatic vital signs are normal. If orthostatic hypotension 
occurs, the subject will be offered water or Gatorade, and asked to remain seated. Orthostatic vital 
signs will then be checked hourly, and the study MD will be notified for further management. 
 
Criteria for Discontinuing Enrollment  
If at any time hypotension or orthostatic hypotention occurs with clinical symptomology such as: 
dizziness, lightheadedness, blurred vision, weakness, fatigue, nausea, palpitations, or headache, 
an adverse event will be recorded. If at any time, hypotension or orthostatic hypotension occurs 
with clinical symptomology such as: dizziness, lightheadedness, blurred vision, weakness, fatigue, 
nausea, palpitations, or headache, an adverse event will be recorded. If > 3 AE’s from orthostasis 
occurs, the subject will be stabilized on a lower dose of doxazosin. If symptomatic orthostatic 
hypotension occurs on the lowest active doxazosin dose (4 mg), the participant will be 
discontinued from the study and treated based on the study MD’s assessment. If the subject’s vital 
signs decrease by >30 systolic or >15 diastolic from BP recorded on admission, and if a subject 
develops orthostatic symptoms, the subject will be discontinued. 
 
 
Blood and other Biological Samples
Please create or insert a table describing the proposed collection of blood or other biological specimens
During the screening process and within 1 week following discharge, blood will be drawn for 
laboratory testing and, for women, pregnancy testing. Liver function tests will be performed upon 
admission and every other week throughout the study. Approximately 40 cc (3 tablespoons) blood 
will be drawn for these purposes. 
 
Urine drug testing will be performed at each screening visit, thrice weekly while participants are 
inpatient, and during each post-study visit. Urine pregnancy tests will be performed upon 
admission and monthly during the inpatient period.   
 
 


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Assessment Instruments
Create a table or give a brief description of the instruments that will be used for assessment
See Table 3 for a summary of events. 
 
Screening Instruments
Telephone Interview: 10 min
General Health Questionnaire: 5 min
Medical History Questionnaire: 10 min
Drug History Questionnaire: 10 min
Short Michigan Alcohol Screening Test: 5 min
Beck Depression Inventory: 15 min
Clinical Drug/History Interview: 30 min
Demographic Information (e.g., age, race, ethnicity, gender, marital status, family income, 
occupation, etc.): 45 min
Self-reported Trauma Assessments (e.g., Life Events Checklist, Modified Sexual Experiences 
Survey, Trauma Symptom Inventory, Distress Tolerance Scale): 30 min
Physical and Psychiatric Examination including a Mental Status Evaluation: 1 hr
Laboratory Hospital Tests: 2-3 hr
Columbia-Suicide Severity Rating Scale (C-SSRS): 5 min
MINI: 30 min
36-Item Short Form Survey Instrument (SF-36) Health Survey: 5 min
Lifestyle Profile: 2 min
Sleep Quality Assessment: 5 min
Insomnia Severity Index: 2 min
Locally developed Sleep Questionnaire: 2 min
Quality of Life Enjoyment and Satisfaction Questionnaire: 5 min 
 
Subjective and Performance Tasks and Sleep Assessments
Digit-Symbol Substitution Task: 3 min
Divided Attention Task: 10 min
Subjective Effects Measures*: 5 min
*Four questionnaires will be used to assess subjective effects during laboratory sessions (see 
Comer et al., 1999 for details). The first questionnaire is a 26-item visual analog scale designed to 
assess subjective and physiological effects. The first 18 lines are labeled with adjectives 
describing mood states ("I feel...alert, anxious, a bad drug effect, depressed, energetic, a good 
drug effect, gooseflesh, high, irritable, mellow, muscle pain, nauseated, restless, sedated, sleepy, 
social, stimulated, talkative") and 4 additional lines are labeled with questions about the dose just 
received ("The dose was potent," "The dose was of high quality," "I liked the dose," "For this dose 
I would pay..."). Participants also indicate, by making a mark along a 100 mm line, how much they 
want each of the following drugs: heroin, cocaine, alcohol, and tobacco. Participants rate each 
item on the visual analog scale from "Not at all" (0 mm) to "Extremely" (100 mm), except for the 
"For this dose, I would pay" question, which ranges between $0 (0 mm) and $20 (100 mm). The 
second questionnaire is a 12-item opioid symptom checklist consisting of true/false questions 


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designed to measure opioid effects ("I feel normal," "My skin is itchy," "I feel relaxed," "I feel like I 
am coasting," "I feel like I am nodding," "I feel high," "I feel sleepy," "I feel drunken," "I feel 
nervous," "I have a lot of drive," "I feel like I am 'on a soapbox' (need to talk)," "My stomach is 
turning," and "I am feeling a pleasant sick"). The visual analog scale and opioid symptom checklist 
together constitute the subjective-effects battery. The third questionnaire is the 16-item Subjective 
Opiate Withdrawal Scales. Participants rate each item on a scale from 0 to 4, with 0 being "Not at 
all" and 4 being "Extremely" ("I feel anxious," "I feel like yawning," "I'm perspiring," "My eyes are 
tearing," "My nose is running," "I have gooseflesh," "I am shaking," "I have hot flashes," "I have 
cold flashes," "My bones and muscles ache," "I feel restless," "I feel nauseous," "I feel like 
vomiting," "My muscles twitch," "I have cramps in my stomach," "I feel like shooting up now"). The 
fourth questionnaire is a 6-item Drug Effects Questionnaire. Specific items on the Drug Effects 
Questionnaire are: "How strong a drug effect are you feeling right now?" "Do you feel any good 
effects from the drug?" "Do you feel any bad effects from the drug?" "Which one of the drugs listed 
below is the drug most like?" "Rate the degree to which you would be willing to take today's drug 
again." "Do you like the way the drug makes you feel right now?" Participants describe drug 
effects by selecting among a series of possible answers ranging from 0 ("No (good, bad, etc.) 
effects at all") to 4 ("Very strong effects"). Ratings of drug type are: "Placebo (No drug), Stimulant, 
Sedative or Tranquilizer." Ratings of drug liking range between -4 ("Dislike very much") and 4 
("Like very much"). In addition to the above items, an Opioid Craving Questionnaire (OCQ) will be 
administered each evening throughout the study. Each question on the OCQ will be rated on a 7-
point scale with "Strongly Disagree" at one end and "Strongly Agree" at the other end. Total 
scores can range between 0 and 70. 
 
A 7-item sleep questionnaire (Haney et al., 2004) asking about the quantity and quality of the 
previous night's sleep will also be administered each morning. In addition, an objective sleep 
measure (sleep efficiency: percentage of time spent asleep) will be collected each night via an 
Actiwatch.
 
Drug Exposure. On Fridays during some test weeks at 10 am, participants will receive a single 
dose of 25 mg oxycodone and $20. The subjective, performance, and physiological effects of 
oxycodone will be measured repeatedly during these sessions. Cue Exposure. On Fri during 
placebo oxycodone test weeks, beginning at 1 pm, participants will be presented with neutral cues 
followed by drug cues. Two opaque pitchers will be placed on the participant’s desk at the 
beginning of the session. Hidden under one pitcher will be a glass of water. Hidden under the 
second pitcher will be a straw and a glycine packet filled with lactose. There will be two 3-min 
exposure trials separated by 5 min of relaxation. During the first exposure trial, participants will be 
exposed to the neutral cues. After a 5-min relaxation period, participants will be exposed to the 
drug cues. Immediately after each cue presentation, participants will complete an Opioid Craving 
Questionnaire. Physiological measures (heart rate, respiratory rate, blood pressure, skin 
temperature (ST), and galvanic skin response (GSR)) will be collected during cue presentation. 
Participants will be informed that after completion of the questionnaires, they will have the option 
to choose the dose of oxycodone that they received during the morning session or money. 
Progressive Ratio (PR) Choice. Immediately following the Cue Exposure procedure, participants 
will be given the opportunity to respond for up to $20 or 25 mg oxycodone after completing a 10-
trial modified progressive-ratio procedure. During each trial, participants will work for $2 or 1/10th 


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of the dose that they received during the Drug Exposure Session. The number of responses 
(finger presses on a computer mouse) required to receive the first 1/10th of the dose will be 25, 
followed by 50, 100, 200, 400, 800, 1600, 3200, 6400, and 12800 responses. Thus, it becomes 
increasingly difficult for participants to receive drug each time they choose the drug option. The 
motivation to respond for drug will be assessed by the breakpoint value, which is the last ratio 
completed for drug (i.e., lower drug breakpoint value = lower propensity to relapse). After 
participants complete the task or stop responding, they will receive whatever fraction of the money 
and/or dose that they earned. Using similar procedures in previous studies in our laboratory, we 
have shown that Bup/Nx and SR-NTX produced dose-related reductions in heroin self-
administration (Comer et al., 2002, 2005). In our ongoing trial using this procedure, breakpoint 
values on Fri were approximately 2000 when active heroin was available. That is, participants 
chose the drug option on 7-8 of the 10 choice trials during the modified progressive ratio task. 
 
Actiwatch (Philips Respironics): ~10 hr
 
In addition to the above, the following questionnaire will be completed weekly throughout the 
study: Cognitive and Physical Functioning Questionnaire (CPFQ): 2 min
Impulsivity Assessments (to be completed after admission to 5-South)
Barratt Impulsiveness Scale: 5 min
Impulsivity Questionnaire: 5 min
Sensation-Seeking Scale: 5 min
UPPS Impulsive Behavior Scale: 5 min
Immediate Memory Task/Delayed Memory Task: 20 min
GoStop Task: 15 min
Subject Opiate withdrawal symptoms (SOWS) - 5 min
 
Please attach copies, unless standard instruments are used
Off label and investigational use of drugs/devices
Choose from the following that will be applicable to your study 
   Drug
Select the number of drugs used in this study
1
Drug #1
Name of the drug 
Doxazosin
Manufacturer and other information
Cardura XL; doxazosin mesylate extended release tablet in combination with oxycodone
Approval Status
IND is approved


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IND#
137123
Who holds the IND/IND sponsor?
IND is held by PI/CU Investigator
Comer, Sandra, PHD
Research Related Delay to Treatment
Will research procedures result in a delay to treatment?
No
Treatment to be provided at the end of the study
This is not a treatment study. However, counseling about different treatment options and referrals 
for treatment are available to participants at any time before, during, or after their participation in 
this study. Participants will also be informed that they do not have to participate in this study in 
order to get a referral to help stop taking drugs. Furthermore, our lab is an official New York State 
Dept. of Health naloxone training and distribution site, therefore, they can receive overdose 
education and naloxone without engaging in any study procedures.  Prior to discharge, 
participants will receive counseling about the different treatment options for opioid use disorder 
(Vivitrol, buprenorphine, methadone, behavioral therapy etc.). Additionally, our standard discharge 
procedure includes education about the risks of opioid overdose, how to identify opioid overdose, 
and how to use a naloxone kit provided to them as certified opioid overdose responders. For those 
participants requesting outpatient treatment, appropriate arrangements will be made, including 
placement in an outpatient treatment study at our Substance Treatment and Research Service 
(STARS), if they are eligible, or participation in group therapy at STARS or Narcotics Anonymous. 
Induction onto Suboxone or Vivtrol treatment will also be available to all participants prior to 
discharge.
Clinical Treatment Alternatives
Clinical treatment alternatives
This study is not a treatment study. Participants expressing interest in treatment will be 
immediately referred to an appropriate treatment provider, and will not be included in the study.
Risks/Discomforts/Inconveniences 
Risks that could be encountered during the study period
1) Opioid Administration During Laboratory Sessions
In the current proposal, an intranasal dose of up to 100 mg will be used. The most frequently 
reported adverse experiences associated with oxycodone administration are: lightheadedness, 
dizziness, sedation, nausea, and vomiting. Hypotension, respiratory depression, mood changes 
(euphoria, dysphoria), constipation, skin rash, and pruritis have also been reported. The most 


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serious possible adverse effect is respiratory depression. However, our careful participant 
selection and selection of doses should preclude the occurrence of such an event. We have safely 
tested a bolus dose of 50 mg intravenous oxycodone in a previous study, so we do not anticipate 
significant respiratory depression to occur. During the laboratory session, vital signs (heart rate, 
blood pressure, and arterial oxygen saturation) will be monitored. Prior to drug administration, 
blood oxygen saturation must be within acceptable ranges (> 92%) for drug administration to 
occur. If respiratory difficulty is observed, then, with the exception of vital signs monitoring, the 
session will be discontinued. Careful attention will be paid to oxygen saturation and, for safety, 
oxygen will be available for emergency use during the experimental session. We will ask 
participants to take a deep breath if their oxygen saturation falls below 85%. Such requests are 
effective in restoring normal oxygen saturation in preoperative patients given opioids. In the 
unlikely event that prompted breaths do not bring the oxygen saturation above 90% within 1 min, 
supplemental oxygen will be administered through a nasal cannula and the flow rate adjusted as 
necessary. In addition, resuscitation equipment and naloxone injection will be available in the 
testing area if respiration was seriously depressed (i.e., if a research participant was no longer 
able to respond to verbal commands to take deep breaths). In such an event, naloxone (0.4 mg to 
0.8 mg intravenously) would be administered, followed by subsequent doses every 1 min until an 
individual responds to verbal commands to breathe deeply (with the total naloxone dose not to 
exceed 10 mg). During the time of apnea, participants will be ventilated with an Ambu Bag by a 
trained research nurse. If significant respiratory depression did occur, the affected individual would 
be monitored for three hours for signs of recurrent respiratory depression. 
2) Doxazosin
Doxazosin (Cardura ®XL; doxazosin mesylate extended release tablet) was approved by the U.S. 
Food and Drug Administration in 2005 for the treatment of benign prostatic hyperplasia (enlarged 
prostate gland). The most common adverse events related to treatment with doxazosin are 
dizziness, nausea, runny nose, headache, weight gain, and feeling tired or drowsy. Less common 
side effects include: floppy iris syndrome, yellowing eyes/skin, dark urine, easy bleeding/bruising, 
fever, and persistent sore throat. Serious side effects of doxazosin include hives or other signs of 
an allergic reaction, fainting, pounding heartbeat, trouble breathing, swelling in the ankles, hands, 
or feet, vision changes, slurred speech, and an erection that is painful or lasts 4 hours or longer. 
Participants will be informed about the possible side effects of doxazosin and will be told to notify 
a nurse or physician if they begin to experience any of them. Medical staff will note which 
symptoms are present, their severity, and make a decision whether to continue the participant in 
the study.
 
3) Hypotension
We will follow stringent guidelines for monitoring vital signs during titration of doxazosin dose and 
throughout the study. Just before the 8pm dose and 2 hours after dosing (10pm), and at 7am and 
1pm, orthostatic assessments of heart rate (HR) and blood pressure (BP) will be measured. Prior 
to dosing, a HR < 55, a supine BP of 85/55, a seated BP of 85/55, or an orthostatic decrease of 
>20 systolic or >15 diastolic upon standing, or an increase in HR of >30 bpm upon standing, will 
be considered an adverse event of “hypotension” and result in holding the doxazosin dose. In 
order to be considered an AE these measurements must be accompanied by clinical symptoms 
such as: dizziness, lightheadedness, blurred vision, weakness, fatigue, nausea, palpitations, or 


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headache.  The subject will be offered water or Gatorade, and orthostatic vital signs will be 
checked again in one hour. The study MD will be called to provide further management. The 
subject will be required to have normal vital signs for 3 consecutive days on a given dose of 
doxazosin XL, before titrating upward. We will titrate the doxazosin XL dose gradually to a 
tolerated dose (but no more than 16 mg) to determine what might be an appropriate dose in this 
population.
 
 
4) Increased Sensitivity to Opioids 
Participants who were dependent upon admission may be less tolerant to the effects of opioids at 
discharge. Participants will be counseled about the risks of decreased tolerance to opioids prior to 
discharge, and made aware that they may be more sensitive to the effects of opioids upon 
completion of the study. They will be told that this increased sensitivity to opiates could result in 
overdose and death, and that extreme caution must be exercised after they leave the hospital, if 
they choose to use any opioid again.
 
5) Morphine Stabilization Period
The major risk of the initial stabilization period is the emergence of opioid withdrawal symptoms 
such as sweating, anxiety, nausea, vomiting, diarrhea, stomach upset, changes in blood pressure, 
weakness, restlessness, feelings of changes in temperature, sneezing, runny nose, watery eyes, 
gooseflesh, and insomnia. If participants experience withdrawal symptoms, we will prescribe 
medications to alleviate those symptoms.
 
6) Naloxone Challenge Test
To determine whether or not participants are dependent on opioids before admission into the 
study, we may administer up to 3.0 mg naloxone intramuscularly (by injection) which may produce 
a number of withdrawal symptoms. Participants may experience certain effects such as: sweating, 
restlessness, stomach pain, diarrhea, headache, anxiety, nausea, vomiting, dizziness, runny 
nose, yawning, muscle aches, or tremors. We will monitor their reactions to naloxone for up to 45 
min. At the end of this period, we may prescribe oral morphine sulfate (up to 50 mg) to alleviate 
those symptoms. The doses of morphine have been carefully selected to be below dangerous 
levels, but participants will be informed that they may experience side effects which may include: 
drowsiness, itchiness, dry mouth, sweating, restlessness, constipation, headache, anxiety, slowed 
breathing, nausea, vomiting, dizziness, sedation, or tremors. To ensure that participants can 
safely undergo this procedure, it is only completed following the physical examination.
 
7) Confidentiality
Potential participants divulge information that is sensitive and may have adverse social
consequences if released. This would include information released to insurance companies, 
health care agencies, or family members, or information made public in any way. We deal with 
issues of confidentiality by using coded records, storing signed consent forms in a locked safe, 
and trying to the best of our ability to maintain confidentiality.
 
8). Fall Risks


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Fall precautions will be in place throughout the study. When subjects are on the inpatient unit, the 
unit staff will follow their fall precaution protocol. Staff conduct “fire rounds” every 30 minutes to 
check on every patient on the unit for safety purposes. The inpatient unit also has common areas 
that have glass windows, which ensures that subjects are easily seen. Additionally, this protocol 
requires subjects to wear special clothes with short pant legs, non-skid slippers or shoes, and 
ensures monitoring while a subject showers or is ambulating. When subjects are in lab, staff will 
be monitoring vital signs more frequently and will escort subjects to the bathrooms. 
 
Describe procedures for minimizing risks
1) Study Procedures
Participants are fully informed of the potential side effects of the drugs and the risks of the 
procedures. Should a woman become pregnant during the experimental protocols, she will be 
excluded from further participation. We will perform a blood pregnancy test at screening, and urine 
pregnancy tests upon admission and monthly during the study, and will advise female participants 
to use an effective method of birth control prior to admission into all protocols. Participants are 
monitored by trained medical staff during experimental sessions. Emergency medical equipment 
is available in our laboratory and, as well, we are located in a hospital where a full medical 
emergency back-up team is constantly available. We anticipate, however, that careful participant 
selection, dose selection, and participant monitoring will eliminate the need for such emergency 
care. In addition, we have developed guidelines for opioid administration such that oxygen 
saturation dictates whether supplemental oxygen will be administered. Naloxone is available 
during all laboratory sessions in the event of serious respiratory depression. 
We will monitor subjects for depression and suicidality throughout the protocol with the BDI and C-
SSRS. At discharge, participants will be offered treatment with sustained-release naltrexone or a 
clinically effective dose of sublingual buprenorphine/naloxone (e.g., 8-16 mg) Additional doses of 
buprenorphine/naloxone will be given to subjects to bridge them until they are able to meet with a 
treatment provider who will manage their maintenance therapy. We will not offer detoxification, 
unless participants wish to transition to sustained-release naltrexone. All participants will be 
warned of the risks of opioid overdose, particularly overdose on fentanyl. They will be offered 
training on how to recognize an opioid overdose and how to reverse it with naloxone. All subjects 
will be provided with a kit containing naloxone. 
During the follow up period after discharge, subjects will complete a self-report drug use 
questionnaire, urine drug toxicology, BDI, and C-SSRS. Participants deemed at risk by virtue of 
the emergence of depressive symptoms meeting criteria for a Major Depressive Episode (as 
assessed by a psychiatrist), or reporting current active suicidal ideation (“Yes” to CSSRS 
questions 4 or 5) that was not present before and constitutes a change will be withdrawn from the 
study and treated for their depressive symptoms according to the clinical judgment of the study 
physicians or psychiatric nurse NP, including as necessary antidepressant treatment. Participants 
withdrawn from the study during the inpatient phase for reasons of depressed mood or suicidality 
will be maintained on the clinical research unit and treated clinically until a psychiatrist or 
Psychiatric NP determines that they no longer require inpatient treatment. They will then be 
discharged into outpatient treatment if required.


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Participants endorsing clinically significant depressive symptoms on the BDI or suicidal ideation or 
behavior since the previous visit on the CSSRS to be assessed by a study psychiatrist during the 
follow-up session. Any participant judged to meet criteria for Major Depression, or who is 
experiencing significant depressive symptoms according to the psychiatrist's or Psychiatric NP's 
clinical judgment will be provided with referrals for treatment for their depression. Any participant 
judged to be at emergent risk due to suicidal thoughts or behavior will be escorted by a research 
staff member and security to the NY Presbyterian Hospital Emergency Room. The researcher will 
remain with the participant until he or she is taken for assessment.
The formal study completion day will be the last visit (there are several visits, depending on how 
much participants earn - they get paid a maximum of $600 per week). If participants are leaving 
the state (some travel following the study) and request payment by mail, we will recommend that 
they stay to complete the follow-up period for safety reasons. If they decline to do so, we will mail 
them their payment in $600 weekly increments as mail order checks (they will not receive the 
extra $25 for each follow-up visit). Our research group has been conducting inpatient and 
outpatient clinical pharmacology research for more than 20 years and our careful precautionary 
measures should ensure that no serious adverse events occur.
 
2) Recruitment and Informed Consent
Participants will be recruited via newspaper and online advertisements, as well as posting of flyers 
and word-of-mouth. The first phase of recruitment is a structured telephone interview. Those 
volunteers passing the initial interview visit the laboratory and receive a brief description of the 
study and are asked to consent to be screened. This screening consent form covers all interviews, 
questionnaires, and collection of appropriate medical information. They receive a physical exam 
(including blood and urine tests), ECG, medical history evaluation, and psychiatric interview. Only 
those judged psychiatrically and physically healthy are accepted to continue. They are given the 
opportunity to ask questions and discuss participation at length. Those who pass this screening 
will have the study described to them in detail by one of the investigators, and then will sign a 
study consent form. Volunteers report to the laboratory prior to admission to practice the study 
performance tasks used during the study. We find that this multi-consent process provides 
participants with substantially more information at each decision point. They always have 
information about the study for which they are volunteering, and have engaged in the behaviors 
that will be required. Such a procedure provides fully informed consent.
 
3) Confidentiality
A Certificate of Confidentiality will be obtained for the current study and procedures for protecting 
confidentiality of records will be followed. Specifically, all data records containing identifying 
information will be kept in locked files and on password-protected computers. Only the study 
investigators will have access to the codes linking the participant to their identifying information. 
Only the primary investigator and other core study staff will have access to identifiable information, 
which will be maintained on site under lock and key. All computer data are stored without names 
or other uncoded identification. Patients will be identified only through a numerical code in all 
electronic databases.
 


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Comer, Sandra
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Methods to Protect Confidentiality
Describe methods to protect confidentiality
We have obtained a Certificate of Confidentiality for this study from NIDA. The records for this 
study will be kept confidential and will only be accessible to study staff. Screening information, 
which may include the participant's name, will be kept in a locked filing cabinet. Once a participant 
is enrolled into the study all further documents will be identified solely by initials and an assigned 
number.
Will the study be conducted under a certificate of confidentiality?
Yes, we have already received a Certificate of Confidentiality
Direct Benefits to Subjects  
Direct Benefits to Subjects
There are no direct benefits to subjects for participating in this study. 
Compensation and/or Reimbursement 
Will compensation or reimbursement for expenses be offered to subjects?
Yes
Please describe and indicate total amount and schedule of payment(s). 
Include justification for compensation amounts and indicate if there are bonus payments.
Participants will be paid $50/day with a $50/day bonus for completion of the study. Use of a per 
diem bonus is necessary to keep participants from leaving the study during the last several days 
when the money remaining to be earned would otherwise be proportionately small. In addition to 
the per diem payment, participants have the opportunity to earn money during the experimental 
sessions ($20 per sample session plus up to $20 per self-administration session). Participants will 
also be paid for completing the screening process ($25/visit), one training session prior to 
admission ($25), a naloxone challenge test ($25), and a follow-up evaluation 1 week after the 
completion of the experiment ($25). Payments will be in cash, separated into several installments 
($600 per week) at the end of the study in order to prevent large one time payments. Total 
payments will be between approximately $6550 and $7350. On some occasions, it may be 
necessary to repeat sessions (e.g., due to catheter failure).
References
References


Protocol Summary Form
7547
Comer, Sandra
Page 26 of 26
Comer, S.D., Collins, E.D., Kleber, H.D., Nuwayser, E.S., Kerrigan J.H., and Fischman, M.W.: 
Depot naltrexone: Long-lasting antagonism of the effects of heroin in humans. 
Psychopharmacology. DOI 10.1007/s002130100909, 2001; Psychopharmacology 159: 351-360, 
2002.
 
Comer, S.D., Walker, E.A., Collins, E.D.: Buprenorphine/naloxone reduces the reinforcing and 
subjective effects of heroin in heroin-dependent volunteers. Psychopharmacology 181(4): 664-
675, 2005.
Rodgman, C., Verrico, C.D., Holst, M., Thompson-Lake, D., Haile, C.N., De La Garza, R., 
Raskind, M.A., Newton, T.F.: Doxazosin XL reduces symptoms of posttraumatic stress disorder in 
veterans with PTSD: A pilot clinical trial. J Clin Psychiatry 77(5) e561-e565, 2016.
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