Clinical trial NCT01788306
Conditions: Opioid Overdose
Keywords: Elevated risk opioid overdose
Sponsor: University of Washington
Start date: 2013-01-01; Completion date: 2018-10-01
Enrollment: 256 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This prospective, randomized emergency department trial will study the effectiveness of an intervention that combines opioid overdose prevention, education and intervention that includes take home naloxone with brief behavioral change counseling. The study will recruit both heroin users (n=500) and pharmaceutical opioid users at elevated risk for overdose (n=500). Outcomes of interest include subsequent opioid overdoses and overdose risk behaviors.

Primary Aims

The primary aims are to test whether those who receive the intervention compared to standard care have: 1) Lower rates of opioid non-fatal and fatal overdose; 2) Reduce drug use, inappropriate medication use, and other overdose risk behaviors.

Secondary Aims

The secondary aims are to test whether those who receive the intervention compared to standard care have: 3) More appropriate health care utilization (e.g. fewer emergency department visits and admissions to inpatient care); 4) Lower total health care costs; 5) Determine the prevalence of HIV risk behaviors among heroin and pharmaceutical opioid users at risk for overdose and whether the intervention impacts these behaviors.

Detailed description:
Fatal overdoses involving pharmaceutical opioids have increased dramatically over the past decade, surpassing those related to heroin, and are the leading cause of drug overdose in much of the U.S. In Seattle-King County, 75% of drug overdoses involved pharmaceutical opioids and/or heroin in 2009. Opioid overdoses, heroin and pharmaceutical, are preventable and reversible. Research indicates that drug users and their partners can be successfully trained to recognize and reverse overdoses with naloxone (an opioid antagonist medicine or "antidote").

Despite active heroin overdose prevention, education and intervention programs with naloxone (OOPEN) in 15 states with thousands of overdose reversals and no serious adverse events, rigorous studies of these programs on rates of subsequent heroin overdoses have not been conducted. No OOPEN programs or studies have yet been implemented for pharmaceutical opioid users at elevated risk for overdose. The Emergency Department (ED) setting holds great promise for identifying and recruiting those at elevated risk of both heroin and pharmaceutical opioid overdose: 1) the ED study site for this proposal provides most services to those needing care for acute opioid related medical problems in Seattle, and 2) patients' need for urgent medical attention may heighten their concern about potential harms from opioids.

Unique to this setting is the potential to identify high risk pharmaceutical opioid users, a population that is difficult to locate and engage. ED interventions using brief behavior change counseling (BBCC) have been shown to significantly improve health behaviors such as alcohol use and injury, to increase entry into drug treatment as well as to reduce costs. Evidence is promising, but limited, regarding the impact of BBCC on opioid related risk behaviors.

This prospective, randomized ED trial will study the effectiveness of an intervention that combines OOPEN with BBCC for both heroin users (n=500) and pharmaceutical opioid users at elevated risk for overdose (n=500). The primary outcome is subsequent opioid overdoses, ascertained by follow up interviews conducted at 3, 6 and 12 months as well as via administrative records for up to 24 months (i.e. medical records, ambulance responses, and death certificates).

Primary Aims

The primary aims are to test whether those who receive the intervention compared to standard care have: 1) Lower rates of opioid non-fatal and fatal overdose; 2) Reduce drug use, inappropriate medication use, and other overdose risk behaviors.

Secondary Aims

The secondary aims are to test whether those who receive the intervention compared to standard care have: 3) More appropriate health care utilization (e.g. fewer emergency department visits and admissions to inpatient care); 4) Lower total health care costs; 5) Determine the prevalence of HIV risk behaviors among heroin and pharmaceutical opioid users at risk for overdose and whether the intervention impacts these behaviors.

Arms: arm 1: Study intervention, overdose prevention, education, intervention, brief behavioral change counseling, take-home naloxone, referral to local available resources. arm 2: Standard of care, referral to local available resources.
Interventions: intervention 1: OOPEN+BBCC
Intervention descriptions: intervention 1: Take-home naloxone is offered as part of a behavioral prevention intervention to reduce the occurrence of future opioid overdose.

Protocol documents:
Prot_SAP_000.pdf: 
Project OOPEN Study Protocol v1.9 8-22-2014 
 
Page 1 of 22 
Project OOPEN, Opioid Overdose Prevention, Education and Intervention 
Study Protocol 
1R01 DA030351-01A1, (A Trial to Prevent Opioid Overdose: E.D. Based Intervention & Take-home Naloxone) 
Caleb Banta-Green, 
PhD, MSW, MPH 
Principal Investigator 
Alcohol and Drug Abuse 
Institute 
206-543-0937 
Joseph Merrill, MD, 
MPH 
Acting Assistant 
Professor 
UW School of Medicine 
206-744-1834 
Dennis Donovan, PhD 
Director 
UW Alcohol and Drug 
Abuse Institute 
206-543-0937 
Phillip Coffin, MD, MIA 
Director of Substance 
Abuse Research 
San Francisco 
Department of Public 
Health  
415-554-8176 
Christopher Dunn, PhD 
Associate Professor 
Psychiatry and 
Behavioral Sciences 
206-251-4890 
Norbert Yanez, PhD 
Associate Professor 
School of Public Health 
206-543-8027 
Jeanne Sears, PhD, RN 
Senior Research 
Scientist 
Health Services 
206-543-1360 
Lauren Whiteside, MD 
Acting Clinical 
Instructor 
Harborview Medical 
Center 
206-744-8464 
Anthony Floyd, PhD, CIP 
Project Director 
Alcohol and Drug Abuse 
Institute 
206-616-7382 
Melissa Phares, MSW 
Interventionist 
Alcohol and Drug Abuse 
Institute 
206-543-0937 
Jonnae Tillman 
 
Interventionist 
Alcohol and Drug Abuse 
Institute 
206-543-0937 
Paul Grekin, MD 
Medical Director 
Evergreen Treatment 
Services 
206-223-3644 
Michelle Peavy, PhD 
Assistant Treatment 
Director 
Evergreen Treatment 
Services 
206-223-3644 
Esther Ricardo-Bulis, MA 
Research Coordinator 
Evergreen Treatment 
Services 
206-223-3644 
 
 
 
 


Project OOPEN Study Protocol v1.9 8-22-2014 
 
Page 2 of 22 
Abstract 
Fatal overdoses involving pharmaceutical opioids have increased dramatically over the past 
decade, surpassing those related to heroin, and are the leading cause of drug overdose in much 
of the U.S. In Seattle-King County, 75% of drug overdoses involved pharmaceutical opioids 
and/or heroin in 2009. Opioid overdoses, heroin and pharmaceutical, are preventable and 
reversible. Research indicates that drug users and their partners can be successfully trained to 
recognize and reverse overdoses with naloxone (an opioid antagonist medicine or “antidote”).  
Despite active heroin overdose prevention, education and intervention programs with naloxone 
(OOPEN) in 15 states with thousands of overdose reversals and no serious adverse events, 
rigorous studies of these programs on rates of subsequent heroin overdoses have not been 
conducted. No OOPEN programs or studies have yet been implemented for pharmaceutical 
opioid users at elevated risk for overdose..  
Unique to this setting is the potential to identify high risk pharmaceutical opioid users, a 
population that is difficult to locate and engage. Interventions using brief behavior change 
counseling (BBCC) have been shown to significantly improve health behaviors such as alcohol 
use and injury, to increase entry into drug treatment as well as to reduce costs. Evidence is 
promising, but limited, regarding the impact of BBCC on opioid related risk behaviors.  
This prospective, multi-site, randomized trial will study the effectiveness of an intervention that 
combines OOPEN with BBCC for both heroin users (n=500) and pharmaceutical opioid users at 
elevated risk for overdose (n=500). The primary outcome is subsequent opioid overdoses, 
ascertained by follow up interviews conducted at 3, 6 and 12 months as well as via 
administrative records for up to 24 months (i.e. medical records, ambulance responses, and 
death certificates). Hypotheses to be investigated include that the intervention recipients will 
have: 1) lower rates of opioid overdose, 2) reduced drug use and overdose risk behaviors, 3) 
more appropriate health care utilization, and 4) lower total health care costs. We will also 
explore whether the intervention impacts HIV risk behaviors. 
Introduction 
This research proposes the first prospective, clinical trial to test the effectiveness of an 
intervention to prevent opioid overdoses among pharmaceutical opioid users and heroin users. 
Naloxone distribution programs for heroin users are widespread and descriptive studies have 
been conducted, but prospective, randomized studies necessary to prove effectiveness have 
not been conducted. To date no research has been published on how to prevent overdoses 
among pharmaceutical opioid users, now the largest group represented in fatal drug overdoses 
nationally.  The intervention combines two widely used interventions for related health 
behaviors that have not previously been combined: 1) opioid overdose prevention, education 
and intervention with naloxone (OOPEN) for heroin users, and 2) brief behavior change 
counseling (BBCC) which has been shown to prevent future harms for a range of substances. 


Project OOPEN Study Protocol v1.9 8-22-2014 
 
Page 3 of 22 
Opioid overdose is increasingly common, associated with substantial morbidity and mortality 
and should be responsive to prevention and intervention programs.  Brief behavior change 
counseling is likely to increase the effect of these programs. There is an urgent need for 
evidence based interventions that can readily access and engage people at elevated risk for 
overdose, including the under-studied population of pharmaceutical users.  Evidence of the 
impact of interventions on overdose rates, overdose risk behaviors, health care utilization and 
potential costs savings is needed. 
Background and Rationale 
Use, misuse and abuse of pharmaceutical opioids and heroin are relatively common and 
negative health consequences are severe, often fatal, and increasingly frequent. Opioid 
overdoses involving heroin persist, while overdoses related to pharmaceutical opioids have 
increased dramatically over the past decade and have surpassed those related to heroin both 
locally and throughout much of the United States. Health care utilization and costs associated 
with caring for those with problematic opioid use are substantial and increasing.  
Recent, local data indicate the following:  
• Of 256 drug caused deaths in Seattle-King County, Washington in 2008, 195 involved 
pharmaceutical opioids and/or heroin. The opioid caused death rate in Washington State is 
higher than the national average and the overall drug caused death rate in King County has 
increased significantly over the past decade, driven by the increase in pharmaceutical opioid 
involved deaths.   
• Non-fatal opioid overdose was reported by 16% of heroin users, with 41% reporting 
witnessing an overdose, in the prior year according to a 2009 survey conducted at Seattle 
area syringe exchanges.   These rates are likely conservative as evidence suggests that 
syringe exchange users have lower overdose rates than non-users. 
• Heroin related visits to the Harborview Medical Center (HMC) emergency department (ED) 
in 2008 totaled at least 966 and at least 768 for pharmaceutical opioid users who did not 
report current heroin use (case types included: drug abuse, overmedication, adverse 
reaction, and seeking detox). The rate of ED visits for non-medical uses of pharmaceutical 
opioids was higher in the Seattle area than any other metropolitan area included in the U.S. 
Drug Abuse Warning Network (DAWN) in 2007 and Seattle ranked fourth nationally for 
heroini. 
• Naloxone (opioid antidote) was administered approximately once a day in Seattle by medics 
attending to opioid overdoses in 2011. Almost all are transported to the HMC ED. 
• On August 22, 2012 the Director of the Office of National Drug Control Policy, Gil 
Kerlikowske, called for increased action to prevent drug overdose deaths, including wider 
distribution of naloxone. 


Project OOPEN Study Protocol v1.9 8-22-2014 
 
Page 4 of 22 
Objectives 
Primary Aims 
The primary aims are to test whether those who receive the intervention compared to standard 
care have: 
1) Lower rates of opioid non-fatal and fatal overdose  
2) Reduce drug use, in appropriate medication use, and other overdose risk behaviors 
Secondary Aims 
The secondary aims are to test whether those who receive the intervention compared to 
standard care have: 
3) More appropriate health care utilization (e.g. fewer emergency department visits and 
admissions to inpatient care) 
4) Lower total health care costs 
5) Determine the prevalence of HIV risk behaviors among heroin and pharmaceutical opioid 
users at risk for overdose and whether the intervention impacts these behaviors. 
 
 


Project OOPEN Study Protocol v1.9 8-22-2014 
 
Page 5 of 22 
Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This prospective, multi-site, randomized clinical trial will compare standard care to a novel 
intervention that combines OOPEN with BBCC for heroin users (n=500) and pharmaceutical 
opioid users at elevated risk for overdose (n=500). The study will take place at Harborview 
Medical Center (HMC) , University of Washington Medical Center (UWMC), and Evergreen 
Treatment Services. The primary outcomes are subsequent opioid overdoses, ascertained by 
self-report interviews at 3, 6 and 12 months after recruitment as well as via administrative 
records for at least 24 months and self-reported drug use and other overdose risk behaviors. 
Secondary outcomes include: health care utilization, direct health care costs and impact on HIV 
risk behaviors.  
HEROIN USERS 
Intervention
OOPEN + BBCC 
Standard Care
PHARMACEUTICAL OPIOID, 
NOT HEROIN, USERS
Randomization 
(n=500)
OOPEN= Opioid overdose prevention, education and intervention
BBCC= Brief behavior change counseling 
Outcomes
Interviews                Admin. Data
(3, 6 & 12 months)      (Up to 10 years) 
Screening 
Eligible & Interested
Baseline Assessment
Informed consent
Baseline data collected
Potential Subjects Identified
Intervention
OOPEN + BBCC
Standard Care
Randomization 
(n=500)
Outcomes
Interviews                Admin. Data
(3, 6 & 12 months)     (Up to 10 years) 
Screening
Eligible & Interested
Baseline Assessment
Informed consent 
Baseline data collected
Potential Subjects Identified
 Screening consent 
  
Screening consent 


Project OOPEN Study Protocol v1.9 8-22-2014 
 
Page 6 of 22 
Eligibility Criteria 
Inclusion for all subjects: 
1) Meets study definition of elevated risk of future opioid overdose 
•  Reason for visit is opioid overdose (regardless of frequency of use), or 
• Use of pharmaceutical opioids not prescribed to the patient 2 or more times in the 
prior month, or 
• Use of other opioids, alcohol, benzodiazepines or stimulants within two hours of 
using opioids 2 or more times in the prior month, or  
• Average daily dose of prescribed opioids consumed is greater than10 mg morphine 
equivalent analgesic dose or higher for 15 or more days in the last 30.    
• Enrolled in opioid substitution program (e.g. methadone or suboxone) and receiving 
doses. 
Inclusion for heroin users: 
2) Use of heroin through any route of administration at least 2 times in the last 30 days (or if 
institutionalized recently, in the most recent month they were not institutionalized) with or 
without other risks being present. 
Inclusion for prescription-type opioid users: 
3) Use of pharmaceutical opioids at least 2 times in the last 30 days (or if institutionalized 
recently, in the most recent month they were not institutionalized) with other risks being 
present. 
Inclusion for opiate registry users: 
4) Average daily dose of prescribed opioids consumed is 30 mg morphine equivalent 
analgesic dose or higher without other risks being present. 
In the case of known pregnancy, subjects will not be excluded and will be offered naloxone if 
randomized to the intervention arm.  
Exclusion criteria 
1) Unwilling to allow further access to medical or drug treatment records.  
2) Inability to communicate in English.  
3) Current active suicidal ideation. 
4) Significant cognitive or psychiatric impairment (per judgment of clinical staff) 
5) Inability to provide adequate contact information to assist with follow-up.  
6) Under age 18 or over age 70 at time of recruitment.  
7) Not currently living in Washington State or planning to move from Washington State 
within the following year.   


Project OOPEN Study Protocol v1.9 8-22-2014 
 
Page 7 of 22 
8) Receiving treatment for sexual assault.  
9) Have non-expired take-home naloxone at home, on their person, or in their possessions. 
Participation in the study is not appropriate for subjects under care for terminal illness, as 
known reduced life expectancy may skew study results, and the use of high doses of opioid 
medications may be used during end of life care. 
Potential Subjects Identified 
Some subject will be identified through prescreening of intake records and medical history for 
patients admitted to hospital, including those admitted for overdose, or in transit to the ER for 
overdose. In the emergency departments several large monitors display information related to 
admission. Some subjects initially seen in the ER will be admitted to the main hospital, but will 
be listed in ER medical records for the past 3 days. Some subjects may bypass emergency 
services and be admitted directly into inpatient care. Medical records would again be screened 
for eligibility. Finally some patients will be recruited through flyers and word of mouth without 
the use of medical records screening. 
We will use this information in combination with information available from prescreening 
medical records to identify potential subjects. We will communicate with clinical staff pointing 
out potential subjects identified in prescreening, and reminding clinical staff of potential 
subjects to be aware of for inclusion. Study staff will regularly attend staff meetings to educate 
them about the study, enlist their help in identifying potential subjects and obtain feedback on 
recruitment protocols. 
Clinical staff will be asked to look for patients who have experienced overdose, exhibit physical 
symptoms of drug use (such as abscesses or track marks), present for care with symptoms of 
pain without apparent injury, or exhibit signs of overmedication (such as pinpoint pupils) for 
admissions unrelated to drug use or overdose. Clinical staff will also be asked to look for 
subjects who use opioid medications, have a high number of prescriptions or prescribers for 
controlled substances (such as opioids or benzodiazepines), or high emergency room utilization 
or admissions.  
If a potential subject is appropriate and medically stable clinical staff may either inform the 
subject of the availability of the study or confirm that research staff may make the initial 
approach with subjects. A study flyer will also be made available to clinical staff. If patients 
express interest, we will approach the potential subject.      
 
 


Project OOPEN Study Protocol v1.9 8-22-2014 
 
Page 8 of 22 
 
 
Subject Approach and Consent for Screening 
If the potential subject is interested in hearing more about the study, research staff will briefly 
explain the study purpose. To assist with the presentation of the study, a brief video slideshow 
with audio narration that describes the study and requests permission for eligibility screening 
will be presented. Subjects will listen to the narration using closed headphones with disposable 
one-time use covers. After the presentation, we will review the written material, address any 
questions and concerns the subject may have and confirm their agreement to answer screening 
questions with a signed consent document. 
Eligibility Screening 
Subjects will be asked to complete an eligibility screening questionnaire. The items covered are 
general, such as proximity to the research settings, drug use questions, and medical health 
questions. Screening questions will be completed by the subject, with assistance from research 
staff, if required. Research staff will assist subjects with the calculation of their average 
morphine equivalent dose if the only opioids used are those prescribed to them (not including 
subjects in opioid substitution treatment).   
Subjects who endorse the broader question about having thoughts of being better off dead or 
of hurting oneself will be asked 5 follow-up questions related to active suicidal ideation using 
the Modified Scale for Suicidal Ideation (MSSI). Subjects with MSSI values above cut-off levels 
will be excluded and referred to clinical staff for further care. 
We hope to afford as much privacy as possible for subjects who would like to hear more about 
the study. Screening data will be kept for all subjects whether eligible or not and whether 
enrolled or not. 
Obtain Informed Consent 
Written informed consent will be obtained from all subjects who wish to continue further with 
the study. Subjects will also be asked to complete HIPAA authorization agreements for medical 
records information from their ED or inpatient visit along with medical care and drug treatment 
records from secondary data sources.  
Baseline Assessments 
Eligible subjects will undergo baseline assessments and provide information on personal 
information and health: 


Project OOPEN Study Protocol v1.9 8-22-2014 
 
Page 9 of 22 
1) Education, Employment, Income and Housing: This assessment captures other 
demographic information related to subject’s resources and social stability. 
2) Overdose Risk Assessment: This assessment is used to determine the potential for 
future overdose based on prior overdose history, current drug use practices and social 
context for current drug use. This assessment is not standardized but is compiled from 
individual items of known risk factors for overdose.  
3) World Health Organization Quality of Life (WHOQOL-BREF). This is a short assessment to 
measure general health and physical, social and emotional functioning. 
4) World Health Organization Alcohol, Smoking and Substance Involvement Screening Test 
(WHO-ASSIST v.3). This is a multi-item tool to determine areas of substance use and 
misuse. This assessment battery screens for recent and lifetime use of a variety of 
substances, including illicit drugs, alcohol, pharmaceuticals and tobacco products. 
5) Age of First Use: Subjects are asked to provide the ages they first used a variety of 
substances. 
6) HIV Risk Assessment Battery: This assessment is used to determine the potential for 
contracting HIV, hepatitis and other blood-borne illnesses based on drug use and sexual 
use behaviors. 
7) Overdose History: This assessment will collect information related to any prior overdose 
that the subject has experienced or witnessed. 
8) EQ-5D-3L: This validated quality of life measure asks about problems in mobility, self-
care, usual activities, pain and discomfort, anxiety and depression and overall health. 
Locator information: 
Subjects will be asked to provide a number of sources to ensure they can be contacted for 3, 6 
and 12 month follow-up visits. However, because we anticipate a number of high risk subjects 
to be indigent, subjects may be enrolled if they provide at least one primary source of locator 
information. 
Randomization 
Subjects will be randomized to receive either standard of care or the study intervention. We 
will recruit equal numbers of subjects in the intervention and control arms of the study, 
meeting eligibility criteria as heroin user or primarily pharmaceutical opioid users. 
Follow-up Visits 
Follow-up visits will occur at 3, 6 and 12-month after enrollment. All interviews will be by 
phone. Most assessments given at the baseline interview will be repeated at each follow-up 


Project OOPEN Study Protocol v1.9 8-22-2014 
 
Page 10 of 22 
point. In addition to the assessments subjects will be asked questions about whether they have 
naloxone and, if not, what happened to any naloxone that was given to them. 
Secondary Data Sources 
Secondary data on health care and drug treatment utilization will be obtained from Washington 
State (separate IRB action pending) using the following sources: 
• Treatment and Assessment Report Generation Tool (TARGET) for drug treatment 
admissions data  
• The Comprehensive Hospital Abstract Reporting System (CHARS) for hospital 
admissions 
Information on any ambulance transports will be obtained from the Seattle Fire Department’s 
Medic 1 unit. 
In the event of a subject death during the study will we request information on cause of death 
from the King County Medical Examiner’s Office. If a subject cannot be located we will also 
check this source to see if they have died and if so to obtain data on the cause of death. If we 
are unable to locate a subject during the course of the study or at final follow-up we will utilize 
the King County Jail Inmate Look-up Service. At no time will subjects be contacted or study 
procedures attempted while the subject is incarcerated. 
Intervention Description 
Standard care for patients who have used opioids would vary according to individual clinical 
need and might include referral to drug treatment or detoxification services.  Standard care 
would not include OOPEN and BBCC interventions as specified in this grant.  After baseline data 
are obtained subjects assigned to the intervention undergo the following procedures: 
A brief behavior change counseling (BBCC) session 
• Conveys subjects’ risk for overdose, based on the baseline measures 
• Engages them in a reflective discussion of the pros and cons of their current patterns of use  
• Has the patients identify behavior change(s) they are interested in making to improve their 
health 
• Encourages them to share opioid overdose prevention and intervention information and 
materials with their family, friends, housemates, and/or drug using partners. 
Education and training on opioid overdose prevention and intervention with naloxone (OOPEN) 
• Subjects will view a training video on study laptops that reviews: 
o Information on risk factors for overdose and how to prevent and reduce the risk of 
overdose 


Project OOPEN Study Protocol v1.9 8-22-2014 
 
Page 11 of 22 
o How to recognize an opioid overdose 
o The importance of calling 911  
o How to intervene in an overdose 
 Positioning a victim in rescue position 
 Brief overview of rescue breathing  
 Training on how and when to administer naloxone 
• Subjects will be given a study brochure that covers the information in the video and reviews 
the Washington State 911 Good Samaritan overdose law which provides immunity from 
prosecution for drug possession charges to overdose victims and bystanders who seek aid in 
an overdose event.  
• Prescribing and dispensing overdose rescue kits including 2 doses of intra-nasal naloxone, a 
disposable rescue breathing mask, and disposable gloves.  
• Subjects in the intervention group will be informed that they may have one replacement of 
the naloxone kit (2 doses) during the 12 month study period. 
We expect the intervention to take 30-45 minutes on average based on our experience and that 
this is feasible and reasonable for subjects and interventionists. 
Fidelity assessment for the BBCC will be done with the shortened Motivational Interviewing 
Treatment Integrity (MITI) instrument.  
Schedule of and Sources Data Obtainment 
DATA SOURCES AND TIMING 
Interview 
Administrative 
Case Report Form 
  
  
MEASURES 
Base-
line 
3 & 6 
mos. 
12 
mo.  
Up to 
10 yrs. 
Up to 
10 yrs. 
PRIMARY AIMS 
  
  
  
  
  
Aim 1: Overdose 
  
  
  
Subject overdosed prior 3/6* months    Y/N 
x 
x 
x 
  
  
Subject overdosed       Y/N  &   Date 
  
  
x 
Aim 2: Drug use and other overdose risk behaviors 
  
  
  
Alcohol/Drugs 3/6 month use frequency  
x 
x 
x 
  
  
 
 
 
 
 
 
Opioid use following interruption past 3/6 months 
x 
x 
x 
  
  
Using opioids without others present 
x 
x 
x 
  
  
Avg. daily opioid dose- Prescribed Opioid Users 
x 
x 
x 
  
  
Opioid substitution drug treatment prior 3/6 
x 
x 
x 
  
x 
Other drug treatment sought or used prior 3/6 
x 
x 
x 
  
x 
SECONDARY AIMS 
  
  
  
  
  
Aim 3: Health care utilization 
  
  
  


Project OOPEN Study Protocol v1.9 8-22-2014 
 
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ED, Outpatient, Inpatient and Ambulance- # & 
  
x 
x 
Aim 4: Health care costs 
  
  
  
Hospital-based total direct health care costs 
 
x 
x 
Aim 5: HIV Risk Behaviors 
x 
x 
x 
 
 
CO-VARIATES & POTENTIAL EFFECT MODIFIERS 
  
  
  
  
  
Demographics 
x 
  
  
Employment, health insurance, income, housing 
x 
x 
x 
  
  
Alcohol/Drugs ages of first use 
x 
  
  
Medical status and satisfaction (WHO QOL BREF,           
EQ-5D- 3L) 
x 
x 
x 
  
  
Behavior change plans and readiness 
x 
  
  
Overdose lifetime history 
x 
  
  
Possessed, "carried" naloxone, # of days past 3/6 
x 
x 
x 
  
  
Overdose # witnessed events past 3/6 months 
x 
x 
x 
  
  
Source of naloxone- Study, other 
x 
x 
x 
  
  
Subject had naloxone administered to them, #, by 
x 
x 
x 
  
x 
Disposition of naloxone 
x 
x 
x 
  
  
Subject had negative/allergic reaction to naloxone 
x 
x 
x 
  
  
FIDELITY ASSESSMENT OF BASELINE 
  
  
  
  
  
Overdose prevention & intervention training. Item 
x 
  
  
Motivational Interviewing Treatment Integrity 3.1.1 
x 
  
  
  
  
*Past 3 months timeline for 3 and 6 month follow ups, past 6 months used at 12 month 
follow up. 
Brief Behavioral Change Counseling (BBCC) 
The BBCC will be conducted according to the demeanor and guidelines of Motivational 
Interviewing (MI), a style for counseling patients about sensitive behaviors and for giving them 
information to enhance their health and safety in a non-judgmental manner. MI has been 
widely implemented in brief intervention studies for drug use and other behavior change. MI is 
non-confrontational and respectful of subjects’ autonomy to discuss or not discuss sensitive 
topics The BBCC will consist of 4 elements:  
1) The interventionist will show to the patient an approximately 8-minute video on 
overdose prevention, recognition and intervention, which subjects will view on a laptop 
while they are using headphones. The interventionist will debrief the video with 
subjects and answer questions.  
2) Next, the interventionist will review with subjects their overdose risk. This task involves 
informing subjects of the “good news” about overdose risks they are NOT incurring in 
their current behaviors for the purpose of reinforcing and hopefully continuing more 
positive health behaviors (e.g., not inappropriately mixing other drugs or alcohol with 


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opiates). Next, the interventionist will respectfully and in a neutral tone review with 
subjects the behaviors that currently place them at risk for opiate overdose (e.g., using 
opiates when alone or after a long period of abstinence).  
3) From the video and risk feedback, the interventionist will segue into an open discussion 
of any changes subjects are thinking of making to increase their safety from overdosing. 
If at any time during the interview, subjects indicate that they would prefer to quit 
opiates or to seek opiate detox or treatment, the interventionist will help with these 
referrals. The discussion will culminate in a summary of healthy changes, if any, that 
subjects intend to make. Subjects will take with them a handout that has been 
customized to summarize any changes subjects indicate that they want to make. 
4) Finally, the Overdose Prevention Kit will be shown to the patient. This involves a hands 
on demonstration of how to set up and administer the naloxone nasally, with the goal of 
subjects’ learning this well enough to be able to use or teach significant others to 
administer naloxone to the subjects, if ever needed. The entire intervention is 
conducted in a Motivational Interviewing style of counseling. The interventionist will 
then summarize the conversation. 
All interventions will be audio recorded if subjects permit, allowing the trainer/supervisor of the 
interventionists to monitor MI and overdose education fidelity throughout the course of the 
study. 
Study Medication 
The medication, naloxone, is being used for an indicated condition, opioid overdose. The 
specific formulation of Naloxone we plan to use is a 2mg/ml-2ml syringe that is made by 
International Medication Systems in El Monte, California (NDC # 00548336900). 
The device used to deliver the medication nasally is a mucosal atomizer device (MAD300). The 
mucosal atomization device is licensed for intranasal atomization of prescription medications.   
At usual doses, naloxone is relatively free of adverse effects. Because the duration of action of 
naloxone may be shorter than that of the narcotic being reversed, patients being treated for 
opioid intoxication with symptoms of respiratory depression should be closely monitored as 
additional doses of naloxone may be required.  Administration of naloxone to opioid-
dependent patients may provoke an acute withdrawal syndrome (including body aches, 
diarrhea, tachycardia, fever, runny nose, sneezing, piloerection, sweating, yawning, nausea or 
vomiting, nervousness, restlessness or irritability, shivering or trembling, abdominal cramps, 
weakness, and increased blood pressure). Withdrawal reaction are not life threatening. Agitation 
and paresthesia have been infrequently reported with the postoperative use of naloxone 
hydrochloride injection. 


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Hypersensitivity reactions, such as allergic reactions, are theoretically possible, but have never 
been documented with naloxone.  We will ask about allergic reactions to naloxone during the 
baseline interview and at each of the three follow up interviews. Any allergic reactions will be 
reported to the University of Washington’s human subjects division and the sponsor the 
National Institute on Drug Abuse. 
Several articles have been published showing the effectiveness of nasally administered 
naloxone in overdose situations and the comparability of effect between intranasal 
administration with other routes of administration for naloxone. The intra-nasal route of 
delivery of naloxone with a mucosal atomization device has been used in 1,000’s of reversals 
safely and effectively by both medical professionals and lay persons. 
According to the naloxone package insert “When administered in usual doses and in the 
absence of opioids or agonistic effects of other opioid antagonists, it exhibits essentially no 
pharmacologic activity.” Its use on an unconscious person who did not use opioids is very likely 
to be benign. 
There is no known mechanism by which naloxone could potentially be converted into an opioid 
agonist that could be abused. Nothing has ever been published that suggests such a conversion 
of naloxone has been accomplished and discussions with professors in schools of medicine (Dr. 
Andy Saxon) and pharmacology (Dr. Charles Chavkin) at the University of Washington indicated 
no evidence that naloxone has ever been modified in such a way as to facilitate its being 
abused. According to the naloxone package insert:  “NARCAN is an essentially pure opioid 
antagonist, i.e., it does not possess the "agonistic" or morphine-like properties characteristic of 
other opioid antagonists. “ 
Subjects will be educated about withdrawal reactions. The overdose intervention training and 
all education materials will clearly and strongly encourage calling 911 during any suspected 
overdoses.  Emergency medical services are well equipped to handle any withdrawal reactions. 
Intra-nasal administration of naloxone generally results in more mild withdrawal symptoms 
than other routes of administration.   
Regulatory Compliance and Safety 
Regulatory binder 
The regulatory files should contain all required documents, study-specific documents, and all 
important communications. Regulatory files will be checked for compliance prior to study 
initiation, throughout the study, as well as at study closure. 
Study documentation includes all case report forms, data collection forms, workbooks, source 
documents, monitoring logs and appointment schedules, sponsor-investigator correspondence, 
and signed protocol and amendments, or Institutional Review Board correspondence and 
approved current and previous consent forms and signed participant consent forms.  


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Source documents include all reports and records necessary for the evaluation and 
reconstruction of the clinical research study. The original recording of an observation should be 
retained as the source document. Because direct data entry through the REDCap electronic 
data capture system will be employed relatively few source documents are anticipated for the 
collection of primary data. 
 
Data Safety Monitoring Oversight Committee 
The Data Safety Monitoring Oversight Committee will have three representatives who have 
clinical and research expertise relevant to the study.  They are not directly involved in the study. 
They will meet during the period of study planning, one month after the study is initiated and 
quarterly from then on.  The committee will receive regular reports on the progress of the 
study, including the number and characteristics of subjects and those who declined to 
participate.  Any serious adverse events (SAE) will be discussed with the committee to 
determine if the risks of SAE could be modified by any changes in study procedures.  Other 
reports will be provided as the committee requests.  
The committee will include two physicians: Andy Saxon, MD a psychiatrist at the Veterans 
Affairs Puget Sound Health Care Network, where he is the medical director of addiction 
treatment services, he is also a Co-Investigator for medication studies for the Pacific Northwest 
Node of NIDA’s Clinical Trials Network and conducts clinical trials and medical trainings on 
Suboxone- a medication which contains naloxone. The other physician member is Matthew 
Golden, MD the director of HIV/STD programs for Public Health- Seattle & King County and 
Associate Professor of Medicine at the University of Washington. An additional committee 
member will have expertise in community based substance abuse treatment and the 
epidemiology of opioid abuse: T. Ron Jackson, MSW is the director of Evergreen Treatment 
Services a methadone maintenance clinic serving more than 1,000 patients in the Seattle area, 
he is also the co-investigator for community treatment programs for the Pacific Northwest 
Node of NIDA’s Clinical Trials Network. 
Drug accountability 
Study medication will be ordered, stored, maintained and dispensed by the Investigational Drug 
Service Pharmacies at Harborview Medical Center and UW Medical Center and the clinical 
dispensary at Evergreen Treatment Services. Upon receipt, the investigator, pharmacist, or 
authorized designee is responsible for taking inventory of the investigational agent. A record of 
this inventory will be kept and usage will be documented. Any unused or expired investigational 
agent shall be accounted for. 
 


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Adverse event reporting 
 
The risks expected from trials employing behavioral interventions are presumed minimal and 
the medication being prescribed for possible future use is designed to be used to prevent a 
fatal overdose with side effects being rare. However, given the nature of ongoing drug and/or 
medication use the population studied in this trial is possibly at risk for an overdose.  Adverse 
events (AEs) will be categorized as serious or non-serious, as related or not related to the study, 
and as expected or unexpected. An AE is defined as any reaction, side effect, or untoward event 
that occurs during the course of the clinical trial. Stable chronic conditions, such as substance 
abuse, which are present prior to clinical trial entry and do not worsen, are not considered AEs. 
Common, minor ailments and complaints will be excluded from any type of documentation. 
These may include: colds, flu’s, cuts, scrapes, coughs, headaches, stomach complaints, and 
general fatigue.  
Serious adverse events (SAEs) are defined as any fatal event, any immediately life threatening 
event, any permanent or substantially disabling event, any event that requires or prolongs 
inpatient hospitalization, congenital anomaly or birth defect, or any event requiring 
intervention to prevent any of the previously listed serious events. Hospital visits that do not 
result in admittance are not considered SAE’s (e.g. emergency room visit for a non- study-
related injury that does not result in admittance). Normal childbirth and pre-planned elective 
procedures are not considered SAEs. AE/SAE’s will be elicited by interventionists/research 
interviewers at each assessment visit by asking the participants if they have noticed any new 
problems or existing problems that have gotten worse (using the Adverse Events Worksheet).  
Disclosure of an AE/SAE may also occur in an unsolicited manner to a research or clinical staff 
member. The interviewers should be focused on gathering data to aid in determining study 
relatedness. Study-relatedness will be determined by the interviewers in consultation with one 
of the investigators. All AEs and SAEs will be recorded in the AE/SAE log and entered into the 
secured project database. AEs that are not study related do not require any further paperwork 
documentation besides the AE Log. In this study, potential AEs that may be related to the study 
would be an increase in emotional distress in relation to discussion of past or current drug use 
behaviors or side effects of naloxone.  
University of Washington Adverse Events reporting requirements 
The term adverse event is generally used to refer to any untoward or unfavorable medical 
occurrence in a human subject, including any abnormal sign (for example, abnormal physical 
exam or laboratory finding), symptom, or disease, temporally associated with the subject's 
participation in the research, whether or not considered related to the subject's participation in 
the research. Adverse events encompass both physical and psychological harms. They occur 


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most commonly in the context of biomedical research although, on occasion, they can occur in 
the context of social and behavioral research. 
Unanticipated problems, in general, include any incident, experience, or outcome that meets all 
of the following criteria: 
1. unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document; and (b) the characteristics 
of the subject population being studied; 
2. related or there is a reasonable possibility that the incident, experience, or outcome 
may have been caused by the procedures involved in the research; and 
3. suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
The adverse event report form is to be used to report an adverse event where there is a 
reasonable probability that the event was attributable to a study procedure. The UW IRB 
defines reasonable probability as "more likely than not" - that is, there is a greater than 50% 
likelihood of the event having been caused or partially caused by the research or arising from 
the circumstances of the research. 
Per HSD policy the form is required to be submitted as soon as possible but no later than 10 
business days after becoming aware of the event. 
Data security  
Data will be uploaded to ADAI servers weekly. Only authorized individuals are permitted access 
to the project database. Data are backed up nightly so there is minimal risk of data loss. Any 
edits to previously saved data are fully tracked in an electronic audit table and include the 
date/time stamp and user ID of the person making the edit. Ongoing data monitoring will be 
the responsibility of the research coordinator. 
Confidentiality 
We will obtain a federal Certificate of Confidentiality (CoC), protecting participants against 
disclosure of sensitive information (e.g., drug use). The Department of Health and Human 
Services (HHS) office that issues the CoC will be advised of any changes in the CoC application 
information.  
Participant records will be kept confidential by the use of study codes for identifying 
participants on data collection forms, secure separate storage of any documents that have 


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participant identifiers, and secure computing procedures for entering and transferring 
electronic data. 
Study monitoring 
The monitoring of study records will be conducted on a regular basis by the research 
coordinator. The purpose of these visits is to encourage and assess regulatory compliance and 
to document the integrity of the trial progress. Monitoring activity will assure that submitted 
data are accurate and in agreement with source documentation and will also review 
regulatory/essential documents such as correspondence with the IRB. Areas of particular 
concern will be participant informed consent, protocol adherence, safety monitoring, IRB 
reviews and approvals, regulatory documents, participant records, study drug accountability, 
and principal investigator supervision and involvement in the trial. The research coordinator 
will ensure that staff are trained and able to conduct the protocol appropriately and that study 
procedures are properly followed. If additional training of study personnel is needed, project 
staff will undertake or arrange for that training.  
Data monitoring 
Study data will be entered by interventionists directly into password protected, study specific 
laptop computers.  Data will be captured using the REDCap electronic data capture system 
which uses a secure connection to local REDCap servers located at ITHS. Only authorized users 
will be allowed access to the data entry system and no identifiable data will be entered into 
REDCap. Research staff will use password protected UW works for data entry.  
Data completion will be verified when study interviews are completed. Baseline data and study 
arm assignment will be captured by secure data servers at ITHS as data are collected in REDCap.  
Data will be managed by the principal investigator and research coordinator, who will access 
study data from desktop computers connected via local area network to computer servers that 
are in a locked room in a locked office suite at the Alcohol and Drug Abuse Institute (ADAI). 
Similarly, follow-up interview data will be entered directly into password protected, study 
specific laptop computers using REDCap, with data uploaded to servers at ADAI weekly.   
Health services and cost data will be obtained, cleaned and made into analytic data sets by Dr. 
Sears. Data will be transferred securely and stored on ADAI servers which are backed up nightly. 
The research coordinator will be responsible for the integrity of all study data and will prepare 
regular reports for the 3-person data and safety monitoring oversight committee which will 
review any adverse events as well as monitor study progress to ensure that study results are 
scientifically valid. 
The research coordinator for the study will conduct software programming and data 
management activities. Data will be stored on computer servers at ADAI that are fully HIPAA-


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compliant in accordance with the University of Washington School of Medicine. The senior 
computer specialist at ADAI maintains nightly tape backups and active disaster recovery 
protection and procedures. The research coordinator will develop data collection forms used by 
research staff.  These forms will also have a companion data dictionary which comprehensively 
defines each data element. The data dictionary specifies missing, illogical, out of range, and 
inconsistent value checks for each data element, in addition to logic checks and assists the 
project data analysis. 
Intervention fidelity monitoring 
The primary threat to the integrity of the intervention is that the intervention may not be 
delivered as intended. This potential problem is minimized because the intervention is highly 
structured and intervention fidelity will be regularly monitored by co-investigators who will 
monitor audio recordings of intervention sessions after the interventionist has initially been 
approved to conduct interventions without supervision. 
Data Analysis 
Sample Size Calculation 
The study was powered to address aim 1, the impact of the intervention on non-fatal overdose. 
For the study of each opioid user type (heroin and pharmaceutical opioids) the number of 
subjects needed in each arm of the study (intervention and comparison) to achieve power of 
0.80 to detect a decline in the overdose rate from 20% to 10% at a confidence level of 0.05, is 
219 subjects. To increase power somewhat and account for potential loss to follow up, we plan 
to enroll more subjects, 250 in each arm of each study, for a total of 500 heroin using subjects 
and 500 pharmaceutical opioid, non-heroin using subjects. Other outcomes to be analyzed 
include drug use and services utilization. Data on brief interventions in ED’s shows declines in 
drug use and ED utilization of at least 40%. Specifically in Washington State, the Screening and 
Brief Intervention Referral and Treatment (SBIRT) found a 45% reduction in average days of 
drug use among high risk heroin users who received a brief intervention in an ED (from 15.8 
days to 8.7 days in the prior month) and 41% reduction among high risk pharmaceutical opioid 
users (12.8 to 7.5 days).   
Assumptions behind the power estimate are based upon an annual rate of non-fatal heroin 
overdose estimated to be a median of 25% across studies and for fatal overdoses 
approximately 1%. For the purposes of this sample size estimate we are conservatively 
assuming a total annual overdose rate for heroin users of 20%.  We believe that a reduction of 
the OD rate by 50% may be possible based on the potential for additive effects of the OOPEN 
and the BBCC interventions. Preliminary data on overdose rates for pharmaceutical opioid 


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abusers (no regular heroin use) indicates a rate approximately half that of heroin users based 
upon analyses conducted by Dr. Banta-Green of interviews from 1,661 clients entering 
methadone maintenance treatment which indicate a lifetime overdose rate for pharmaceutical 
opioid abusers (25%) that is half the rate of heroin abusers (49%). These findings were 
extrapolated to a 50% lower rate of annual overdose, the validity of which cannot currently be 
determined, but will be ascertained at the conclusion of this proposed study. We are assuming 
an annual overdose rate of 10% for pharmaceutical opioid users, or 20% over two years which 
is the amount of time over which follow up via administrative data will be collected. The power 
estimates above therefore address one year overdose rates for heroin and 2 years for 
pharmaceutical opioid users. 
 
Planned methodology 
Intent to treat analyses will be the primary analytic approach used to analyze the data resulting 
from this randomized controlled study.  Intent to treat analyses compare those assigned to the 
intervention group to those in the standard care group, regardless of whether those in the 
standard care group receive some amount of the intervention.  
Planned analyses 
Aim 1 Test whether the intervention group has lower rates of opioid overdose and longer time 
to occurrence of overdose. Overdose will be ascertained at 12 months via self-report and across  
at least 24 months via administrative data. Because randomized controlled studies are designed 
to account for potential confounding factors by distributing confounders, measured and 
unmeasured, equally across comparison and intervention groups, the initial unadjusted analysis 
will be a logistic regression analysis comparing the probability of opioid overdose in the two 
study arms. To examine differences in the time to overdose and to account for time varying 
covariates, such as overdose risk factors, survival analyses will be conducted with the outcome 
time to overdose(s). A Cox proportional hazards model will be used to investigate the possible 
association between these factors and event time. We will use sandwich standard error 
estimates in all statistical tests. Multivariable logistic regression analyses will be conducted to 
examine the association between predictors and moderators and of the odds of overdose 
occurrence. Predictors will include treatment assignment and overdose risk factors such as 
concomitant drug use, interruption in tolerance and homelessness. Potential effect 
modification will be assessed by including interaction terms for the treatment assignment by 
severity of opioid and other substance use as measured by the ASSIST. For the pharmaceutical 
opioid only group, effect modification by opioid user type will be assessed; opioid user 
typologies will be based upon which inclusion criteria subjects met. 
Aim 2 Test whether the intervention group has fewer overdose risk behaviors. These are 
measured as both binary and continuous data. Binary data will be examined with logistic 


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regression and continuous data analyzed with ordinary least-squares regression. Analyses will 
adjust for the overdose risk behavior level or frequency reported at baseline as a concomitant 
variable, the outcome is the overdose risk behavior at 12 months, and the primary predictor is 
the treatment group assignment. We will compute robust standard error estimates for each 
model and use them in all hypothesis tests and confidence intervals. 
Aims 3 and 4 Test whether the intervention group has more appropriate health care utilization 
and lower total health care costs. We will analyze utilization for three separate outcomes: ED 
visits, outpatient visits, and inpatient hospital admissions as we would expect the intervention 
to result in declines in ED and inpatient care with concomitant increases in outpatient care over 
time as patients stabilize their health status. For these analyses we will use a rate modeling 
approach (negative binomial or Poisson regression, with an exposure adjustment should there 
be a need to account for differing amounts of follow-up time). We will examine health care 
costs (combined hospital and ambulance costs) from the health care system perspective. 
 Mean-per-month health care costs will be calculated for both pre- and post-randomization 
periods for each individual. We will assess the difference in health care costs across the two 
study arms by regressing post-randomization mean health care costs on study arm, and 
controlling for pre-randomization mean health care costs (which should reduce variance and 
increase power) along with other important covariates. We expect that 500 per arm will be an 
adequate number to support the use of Ordinary Least-Squares (OLS) regression to model 
mean cost differences, but will use Generalized Linear Models (GLM) models to examine the 
sensitivity of OLS results. In addition, we will calculate unadjusted and adjusted cost offsets by 
adding the cost of the intervention to health care costs and comparing average monthly total 
costs of services for the intervention group to the average for the standard care group. 
Aim 5 Test whether the intervention group has fewer HIV risk behaviors. These are measured as 
both binary and continuous data. Binary data will be examined with logistic regression and 
continuous data analyzed with ordinary least-squares regression. 
Other analyses 
In order to determine whether there is recruitment reactivity, whether those enrolled in either 
arm of the study have a change in behaviors compared to those not enrolled, we will examine 
ED re-visit rates at two years for those receiving standard care compared to those with similar 
demographic characteristics, CPT codes and ED visit dates, but were not enrolled. While this will 
not directly measure the impact of recruitment on overdose, it will provide some information 
about recruitment reactivity. Subsequent to intent to treat analyses we will examine whether 
any subjects in the standard care group received take-home naloxone and overdose prevention 
and intervention training i.e. “crossed over”. If so, it is possible that this intermediate group 
might be more similar to the intervention than the standard care group. Crossovers will be 
identified by as interview question, such as “Did you possess or have ready access to naloxone 
during the past 3/6 months?” If there is a group that crossed over, post-hoc analyses will 
compare overdose rates at two years for the cross over group compared to each of the other 
two study arms. Completion level of administrative data will be assessed by the interview 
questions at each follow up that document what types of services, in broad categories, were 


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obtained at non-HMC or non-UWMC facilities or ambulance services not in Seattle-King County. 
This will allow for an evaluation of ascertainment bias, that is, how complete data based on 
HMC/UWMC and King County ambulance data are and whether there are differential levels of 
data completion by study arm assignment. 
Missing data and dropouts 
Missing data will be minimized by the study procedures described above. However, missing 
data are inevitable and could lead to biased results.  Baseline data values and study arm 
assignment will be examined to determine the relationship with missingness. Sensitivity 
analyses will be conducted that assume any person lost to follow up had constant levels of drug 
use based upon their most recent measurement point. This will provide some guidance as to 
the amount of bias possibly introduced by missing data.