Clinical trial NCT04094584
Conditions: Alcohol Use Disorder Substance Use Alcohol Abuse or Dependence
Keywords: Emergency Department Naltrexone
Sponsor: University of California, San Francisco
Start date: 2020-08-14; Completion date: 2022-05-01
Enrollment: 179 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a phase 4, open-label, feasibility study of extended release naltrexone (Vivitrol, Alkermes Pharmaceutical) and case management for treatment of alcohol use disorders in the ED.

Excess alcohol use is a major cause of morbidity and mortality and contributes to a large number of emergency department (ED) visits. The rate of alcohol-related ED visits is increasing, and there is evidence that this increase may be driven by a subset of patients who frequently visit the ED due to an underlying alcohol use disorder (AUD). The proposed study will assess the feasibility of implementing a multimodal treatment for AUD in the emergency department for 25 patients with AUD. The rationale for including each component of the multimodal treatment is outlined below.

Pharmacotherapy is recommended as the standard of care for alcohol use disorders. Of the four drugs approved by the FDA for treatment of alcohol use disorder, extended release naltrexone has been found to be superior at reducing healthcare utilization, increasing detoxification facility use, and reducing total cost. Fewer than 1 in 4 patients with AUD currently receives treatment with an FDA approved agent and use of these drugs in EDs is virtually non-existent.

ED patients with alcohol use disorders frequently suffer from multiple medical, mental health, and social problems that influence their health. Providing such patients with case management services has shown promise in improving health related outcomes while curbing ED utilization and healthcare costs.

Regardless of comorbidity, limited access to substance use and mental health services is a significant barrier to receiving treatment, and large disparities exist in access based on income level. Facilitated referrals, where a healthcare worker communicates with the patient and service providers and assists the patient with obtaining follow up, have been used effectively to improve access to specialty care after ED discharge. Case managers are familiar with community treatment resources and are well versed in providing facilitated referrals.

The primary hypothesis is that implementing this multimodal treatment will be feasible in an ED setting and will reduce alcohol use. Feasibility measures (recruitment, retention, continuation of treatment after the trial) are the primary outcomes. The intent of the intervention is to change drinking behavior in a way that benefits participants' health and quality of life. As such, we will conduct a limited efficacy assessment. Treatment efficacy will be assessed by comparing alcohol consumption, quality of life, and life consequences related to alcohol use before and after the intervention.

The primary efficacy outcome is change in total alcohol consumption measured by a 2 week timeline follow back. Change from baseline will be assessed after the 3 month intervention period, and at the conclusion of the study follow up period for all outcomes.

Detailed description:

Arms: arm 1: The intervention is multimodal and consists of:

1. Intramuscular injections of 380mg extended-release Naltrexone, given once monthly for 3 months.
2. Case Management services
Interventions: intervention 1: Vivitrol (Extended Release Naltrexone)
Intervention descriptions: intervention 1: Monthly Injections of 380mg Extended-Release Naltrexone, case management services as needed tailored to the individual participant

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Emergency Department Ini0ated Extended-Release Naltrexone and Case 
Management for the Treatment of Alcohol Use Disorder 
 
 
 
NCT04094584 
 
 
 
Study Protocol 
3/11/2020 


Murphy Raven Naltrexone Pilot 3-11-2022
1
Treatment of alcohol use disorders with extended-release naltrexone and tele-addiction 
assessment initiated in the emergency department.
I.
Scope of the Problem:
Alcohol use disorders are common and represent a significant public health problem. In the 
United States 88,424 deaths annually and 1 in 10 deaths of working-aged adults age 20-64 can be 
attributed to excessive alcohol use [1,2]. This represents 2.5 million years of potential life lost 
and an annual cost of $249 billion [3]. Over the past 9 years, alcohol- related visits to the 
emergency department (ED) have increased by 47% with an annual cost increase of $4.1 billion 
to $15.3 billion [4]. During this time the number of people using alcohol in the United States and 
the total amount of alcohol consumed has not changed, suggesting that this increase in alcohol-
related ED use may be due to increased consumption among a subset of frequent ED users [4].
ED visits can be leveraged as teachable moments to intervene with patients in times of crisis, and 
because of the large proportion of alcohol-related ED visits relative to other medical specialties, 
emergency providers are well-positioned to offer interventions that address substance use, such 
as Screening Brief Intervention and Referral to Treatment (SBIRT) and pharmacotherapy 
[7].  Further, EDs commonly employ social workers alongside medical providers to help link 
patients to outpatient services, including treatment for drug and alcohol use disorders.  In 
addition, many patients with alcohol use disorders are marginalized from traditional primary care 
settings or have difficulty accessing effective treatment in non-ED settings.  As a result, EDs are 
often the primary point of contact with the healthcare system for individuals with alcohol use 
disorder [7]. 
Screening, brief intervention, and referral to treatment (SBIRT) has demonstrated efficacy in 
reducing risky alcohol use and reducing net healthcare costs. SBIRT is strongly recommended 
for use in the emergency department by the CDC, the US Preventive Services Task Force, and 
the National Institute on Alcohol Abuse and Alcoholism [10]. Despite these recommendations, 
SBIRT is rarely utilized due to numerous barriers to implementation including time and cost 
[11].  Emergency department use of SBIRT paired with facilitated referrals where ED staff 
ensure eligibility, insurance clearance, and assist in scheduling and transportation to follow up 
visits has demonstrated feasibility and may reduce the barriers to accessing treatment [7]. 
Even though pharmacotherapy is recommended as the standard of care for alcohol dependence, 
fewer than 1 in 4 dependent patients receives treatment with an approved agent [6] and its use in 
EDs is virtually non-existent. Of the four drugs approved for treatment of alcohol dependence, 
extended release naltrexone (XR-NTX) has been found to be superior at reducing healthcare 
utilization, increasing detoxification facility use, and reducing total cost [5]. It may also be 
perceived by providers as a more feasible treatment to administer [6]. While there is a growing 
body of evidence supporting the efficacy of ED-initiated, medication-assisted treatment (MAT) 
of opiate use disorders [7], little research exists on ED-initiated MAT for alcohol use 
disorders.  We propose to address this knowledge gap via a pilot study to examine the feasibility 
of ED-initiated XR-NTX paired with telemedicine SBIRT for frequent ED users with alcohol use 
disorders. Enrolled patients will receive up to 3 consecutive months of XR-NTX. A dedicated 
research case manager will be available for all participants. The research case manager will 


Murphy Raven Naltrexone Pilot 3-11-2022
2
outreach to the participants in the community to coordinate monthly injections. An addiction 
specialist from a community organization familiar the drug will administer the XR-NTX. 
This study aims to address CARESTAR’s Funding Priority to “support nonprofit health 
advocacy organizations, state and local agencies, providers of care and community partners in 
the development and implementation of meaningful, impactful and sustainable health related 
initiatives that improve care and expand access to emergency and trauma services, particularly 
with vulnerable populations.”
II.
Study Design and Procedures:
Overview of Design:
This is a phase 4 open label feasibility study of extended release naltrexone (Vivitrol, Alkermes 
Pharmaceutical), case management and tele-addiction medicine for treatment of alcohol use 
disorders in the ED. The planned study period is 2 years. During this time we will conduct 
necessary department staff training and recruit 25 patients. Each patient will be followed for 12 
months from index visit by our study staff, with case management provided by a full-time 
research case manager. Patients will be enrolled consecutively, 24 hours a day, 7 days a week. 
Recruitment will take place in the UCSF Emergency Department, Parnassus campus. Follow up 
visits may occur in the UCSF ED or an outpatient setting agreed upon by the patient and the 
research case manager. Patients who drop out of the study will be replaced with new patients; 
enrollment will end once 25 patients have been retained in the study or at the planned end date.
Initial Screening:
All adult patients presenting to the University of California San Francisco ED during the study 
period with will be screened for frequent ED utilization (defined as 3 or more ED visits in the 
past 12 months including the index visit) by electronic medical record review conducted by the 
treating physician or member of the research team. UCSF, San Francisco General, and several 
other academic and community emergency departments in the San Francisco Bay Area share an 
electronic platform called the Emergency Department Information Exchange, or EDIE, that 
documents dates of ED visits and diagnoses.  UC emergency providers can view visits at each of 
these sites, and ED visits to any hospital will be counted towards this 3-or-more threshold.
Determination of Eligibility:
An ED provider or staff (including physicians, advanced health practitioners, nurses, social 
workers, and case managers) may alert the PI or research study staff of potentially eligible 
patients based on the initial screen. The research team member will then determine eligibility as 
described below.
The PI Dr. Raven, research fellow Dr. Murphy or study staff (the research case manager) can all 
determine study eligibility. Initial eligibility will be determined based on chart review during the 
time of an ED visit. During study hours, the above mentioned faculty and staff will examine the 


Murphy Raven Naltrexone Pilot 3-11-2022
3
ED trackboard to determine if any patients currently in the ED at UCSF have made at least 4 ED 
visits in the past 12 months to UCSF or a combination of UCSF, ZSFG, or other hospitals based 
on shared data in our emergency department information exchange platform. If an individual is 
determined to be eligible based on these criteria, the faculty or study staff will review the chart 
for the most recent lab results including liver function tests (AST, ALT), platelets, and urine or 
serum pregnancy tests and urine toxicology testing specifically the presence of opioids including 
fentanyl (see exclusion criteria for specific cut off values). They will also review the past 
medical history and allergies in the electronic medical record to determine if the patient has 
cirrhosis or a document allergy to naltrexone or inactive ingredients contained in naltrexone XR. 
When a patient is determined to meet criteria inclusion by electronic record review, a study staff 
member will discuss the case with the ED provider caring for the patient to confirm the patient is 
willing to be approached, is clinically sober, and medically stable. The ED provider will then 
introduce the patient to the research staff who will discuss the study with the patient. The 
research staff member will assess the patient's willingness to participate. If a patient expresses 
interest in participating the research staff member will confirm the accuracy of information 
obtained from the medical record review that pertains to inclusion and exclusion criteria. If no 
discrepancies are found the research team member describe the study in detail and will perform a 
capacity assessment using the University of California San Diego Brief Assessment of Capacity 
to Consent to Research (UBACC) if there are any concerns about the participant’s capacity to 
consent, such as ongoing alcohol or drug intoxication or withdrawal. 
Capacity Assessment:
The UBACC is a validated 10-item questionnaire used previously in this population [16,17]. It 
rates the basic elements of capacity (understanding, appreciation, reasoning, and ability to 
express a choice) to identify subjects with questionable capacity to consent to a specified 
research project. Administration of the UBACC will occur after informing the patient about the 
study. The consenter will review each page of the informed consent document with the patient, 
pausing to reassess comprehension throughout the process. Then they will administer the 
UBACC. Once the patient's understanding is confirmed by the UBACC, the consenter will 
request the patient’s signature and provide the patient with a copy of the signed consent 
document. If the consenter doubts the patient's comprehension of the study procedures the 
patient will not be enrolled at that time, but may be eligible in the future. Once capacity is 
established the patient will be asked to provide informed consent. 
Consent:
Patients deemed to be eligible for enrollment after electronic record review may be approached 
by a member of the research team to assess willingness to participate. For patients interested in 
participating consent will occur only after the patient is clinically sober as judged by the treating 
ED provider and their capacity to consent has been established by the consenter, using the 
UBACC if necessary. The consenter will provide patients with information about the study, 
including risks and benefits of treatment with extended release naltrexone both verbally and in 
print. If the patient wishes to enroll in the study they will be consented by a member of the 
research team (research case manager, PI, research fellow) and sign the consent document. 


Murphy Raven Naltrexone Pilot 3-11-2022
4
With the exception of the research case manager, all members of the research team are practicing 
Emergency Medicine Physicians who frequently obtain informed consent for a variety of 
procedures performed while caring for patients in the emergency department and have completed 
required human subjects research training. 
The research case manager will be trained in obtaining informed consent by completing the 
required training modules for UCSF human subjects researchers and be trained in the teach back 
method and use of the UBACC by the study PI, Dr. Raven.
Enrollment:
Patients identified as frequent ED users will undergo an alcohol use disorder screening 
conducted by the research case manager, PI, or research fellow using a validated screening tool, 
the Alcohol Use Disorder Identification Test (AUDIT) which constitutes the screening 
component of SBIRT. The AUDIT places patients into one of four categories: low risk, risky, 
harmful, and severe. Brief intervention and pharmacotherapy have previously been shown to be 
most effective in those with harmful or severe use disorders [12].  Patients found to have at least 
harmful alcohol use based on the screening will be offered enrollment (AUDIT score ≥ 8). 
Enrollees will have blood and urine samples collected to screen for active opiate use including 
fentanyl, platelet counts, pregnancy, or significant liver disease (see exclusion criteria below) if 
no results are available in EHR. With the exception of urine pregnancy screening these tests are 
done as part of the routine care of emergency department patients with alcohol use disorders who 
are interested in accessing treatment. The results will be used to confirm inclusion/exclusion 
criteria are met. Patients meeting all criteria will be enrolled into the study and will receive 
380mg of extended-release naltrexone as an intramuscular injection in the ED.
Naltrexone training and administration: 
Study staff will compose and send e-mail before the start of the study, with input from UCSF ED 
nursing leadership, to all ED RNs informing of the intent and responsibilities of the study. 
Subsequently, during RN sign out (twice daily at 7am and 7pm) study staff will remind ED RNs 
about the study protocol to ensure as much staff as possible is aware of RN involvement and 
responsibilities. The shift-change information session will be performed for a two week run in 
period to assure all RNs are oriented. 
The ED is staffed by clinical pharmacists 12-16 hours per day and will be present during study 
enrollment hours. They will be trained on the specifics of the study protocol by our Zlatan 
Coralic, an ED pharmacist at our Parnassus ED. RNs will be able to consult Zlatan or any of the 
other ED pharmacists on the specifics of medication procurement, administration, and 
monitoring during the study period.  Similarly, ED resident physicians and attending physicians 
will be informed of the study protocol and will receive didactic teaching about physician 
involvement and responsibilities via email and during resident conference and the monthly 
Department of Emergency Medicine faculty meeting. 


Murphy Raven Naltrexone Pilot 3-11-2022
5
Medication storage and distribution: 
We will work with UCSF Investigational Drug Storage (IDS) to store all drug doses.  The initial 
dose will be given in UCSF ED and for all doses, we will create a study-specific link in our 
electronic medical record system (Apex) for order entry, which will link to the study supply. Our 
study team will verify consent prior to verification and the study consent to be uploaded into 
Apex. IDS will generate an Rx form that can be used to request the subsequent clinic or other 
community-based doses (“clinic supply) drug for an enrolled subject. 
The clinic supply will be labeled for the subject and picked up from UCSF IDS by study staff for 
transport to clinic or community site for administration. The clinic supply will be given 7-day 
expiration at room temperature from time of dispensing per FDA labeling.  (Store unopened kit 
at 2°C to 8°C (36°F to 46°F). Kit may be kept at room temperature of ≤25°C (77°F) for ≤7 days 
prior to use; do not freeze. Following reconstitution of the suspension, administer immediately) 
and the drug will be transported at ambient temperatures.  Insulated cooler to be used if 
ambient temperature are expected to exceed 25C. If the clinic dose is not used, unused study 
drug will be returned to UCSF IDS for accountability and disposal.
Index ED visit: 
The case manager will obtain baseline data using a HIPAA compliant database REDCap used for 
multiple ongoing research studies at UCSF.  Baseline data will be collected for the purposes of 
the study and for ongoing case management including information on where the patient lives or 
stays (if unhoused), contact information (phone numbers, family member contacts, email, etc.) 
and preferred mode of communication. Those without cellphones who choose to enroll and who 
agree will be provided with a cell phone at the time of enrollment for the purposes of 
maintaining touch with research case manager and research team. We will track the rate of cell 
phone issuance, loss, and use for study purposes as one of our feasibility metrics. The case 
manager will also use REDCap to collect a detailed substance use history using validated 
questions from the Addiction Severity Index (ASI), and assess social, occupational, and 
psychological alcohol related problems using the Short Inventory of Problems (SIP-2R). Alcohol 
use will be quantified using the timeline follow back method [18,19]. 
Index visit follow up:
The research case manager and the patient will coordinate a follow-up plan for the next injection 
visit. ED social workers routinely refer patients to case management and other outpatient 
services including drug and alcohol treatment programs. The facilitation of referral to ongoing 
care by the study case manager will simply represent a new option for securing outpatient 
follow-up for enrolled patients. This coordination of follow-up care will be outlined in the 
informed consent document and explained as a part of study enrollment.
Prior to leaving the ED after the index visit the research case manager will provide the patient 
with a medical bracelet or wallet card that identifies them as study participant using extended 
release naltrexone and provides the contact information for the PI and research case manager. 


Murphy Raven Naltrexone Pilot 3-11-2022
6
The medical bracelet or wallet card will alert providers that opiate dosing adjustments may be 
necessary to adequately treat acute pain should the patient require treatment during the study 
period. It will provide information about the added precautions necessary should that patient 
require opioid pain management. Specifically, as the amount of opioid required to achieve 
adequate analgesia may be increased any resulting respiratory depression may be deeper and 
more prolonged. Therefore a fast acting agent is preferred and the amount of opioid analgesic 
should be titrated to the clinical effect in a setting equipped for cardiopulmonary resuscitation. 
The PI will be available by phone for emergency consultation at any time.
Visit 2-3 study procedures: 
Patients will receive a monthly intramuscular injection of extended release naltrexone for up to 3 
consecutive months during visits for which the research case manager will outreach to the 
participants in the community. Injections will be administered in an outpatient setting by an 
addiction community provider familiar with XR-Naltrexone, or in the UCSF ED depending on 
patient preference.  A 20-dollar gift card incentive will be used to encourage follow-up at the 
time of each injection. We will follow participants for 12 months from the time of enrollment (an 
additional 9 months after the final dose of XR-NTX administered on behalf of the study). 
Specimens for alcohol biomarker testing will be collected at follow up visits.
At each of the monthly follow up visits we will collect data on a) feasibility measures and b) 
study outcomes. During the follow-up period, the research case manager will track all 
participants and we will continue to collect data on study outcomes using REDCap including ED 
and inpatient hospital use, substance use, readiness to change, and engagement in substance use 
recovery/rehabilitation via community treatment programs, as well as subsequent doses of XR-
Naltrexone administered. This data will be collected by administering the same validated 
questionnaires used in the index visit (AUDIT, ASI, SIP-2R). The PI and research fellow will 
also query the EDIE system and UCSF EHR monthly in order to identify any emergency 
department visits that could be related to the study procedures.
Follow up procedures after visit 3:
Following completion of the 3rd injection visit the patient will no longer receive XR-Naltrexone 
through the study. They will be encouraged to continue engaging with other community health 
providers to continue treatment, but are not required to do so. During the 9 months after the final 
injection visit the patient will contacted by phone approximately once a month by a member of 
the research team to collect outcome data as well as to discuss any ongoing treatment or changes 
in their health that occurred after the completion of the treatment period. At the end of the 12 
month study period a data analyst will conduct a final review of the EHR and EDIE network to 
complete the collection of outcome data.
Case management services between study visits 1-3:
Between injection visits, the research case manager will be available to participants to assist with 
their needs including being connected to longer term case management services, connection with 
a primary care provider, or other services they may need related to food, clothing, and shelter.  If 
participants who have chosen to follow up with community providers are having difficulty 


Murphy Raven Naltrexone Pilot 3-11-2022
7
making appointment, for example because they cannot find transportation, the research case 
manager can facilitate transportation to appointment. Participants can also choose to switch from 
following up in the UCSF ED to community providers of XR-NTX at any time. In such cases, 
the research case manager will coordinate referral to an alternative provider in San Francisco 
who can administer XR-NTX. Participants will be able to contact the study case manager by 
phone or meet in person depending on the case manger’s availability.
Transition to ongoing care:
Patients who wishes to receive treatment with XR-Naltrexone after completing their 3 injections 
or after dropping out of the study will have the following options:
1. If the patient has been receiving injections during the study from a community provider they 
may continue treatment after the 3rd injection or choosing to drop out of the study.
2. If the patient has been receiving injections during the study in the UCSF ED they can be 
referred to a community site that administers XR-Naltrexone to establish treatment.
Handling of missed injection visits:
Patients who miss scheduled follow up injection visits will be contacted and asked to reschedule 
their injection visit as soon as possible. If they are able to reschedule within 2 weeks then no 
changes to study procedure are necessary. If they are able to reschedule within 2-4 weeks then 
they will be asked if they have used any opiates (including fentanyl) in the past 7 days. If they 
have not used opiates in the past 7 days then they will resume treatment, provided they are not 
endorsing any signs or symptoms of liver injury. If they endorse signs or symptoms of liver 
injury they will undergo screening as outlined above. If they endorse using opiates then they will 
not be allowed to resume treatment through the study. If a patient is unable to reschedule a 
missed injection appointment within one month they will not be allowed to continue in the study. 
If a patient is unable to resume treatment through the study then they will be provided with 
alternative follow up options (see transition to ongoing care).
Participant Payment:
A 20-dollar gift card incentive will be used to encourage attendance at the 6 monthly follow up 
visits required for XR-Naltrexone injections. Gift cards will be given at each of the six visits. 
The total value of gift cards available to each participant during the study period is $120.00. Gift 
cards will be issued for locations that do not sell alcohol (e.g. Starbucks coffee).
  
Study Subjects:
The target population is patients with frequent ED visits for alcohol related complaints who may 
benefit from ED-initiated XR-NTX. The accessible population is all people in the San Francisco 
Bay Area presenting to the ED with an alcohol related complaint. The study sample will be adult 


Murphy Raven Naltrexone Pilot 3-11-2022
8
patients presenting to the UCSF ED with active hazardous or high risk alcohol use and ≥4 ED 
visits in the past 12 months for alcohol related complaints.
Inclusion Criteria:
•
Age ≥ 21
•
AUDIT score ≥ 8
•
Frequent emergency department visits, defined as: At least 3 emergency department visits for 
in the past 12 months, including the index visit.
Exclusion Criteria:
•
Opioid use: currently receiving opioid analgesics, self-report of opioid use in past 7 days, 
current physiologic opioid dependence, patients in acute opioid withdrawal, urine toxicology 
screen positive for opiates including fentanyl
•
History of hypersensitivity to naltrexone, polylactide-co-glycolide (PLG), 
carboxymethylcellulose, or any other components of the diluent 
•
LFTs > 5x upper limit of normal or known cirrhosis
•
Platelets less than 100,000 per cubic mm
•
Acute condition at the time of enrollment that necessitates medical therapy with opioids
•
Pregnant 
•
Incarcerated 
Management of acute alcohol withdrawal:  
XR-NTX is not a treatment for acute alcohol withdrawal. Acute alcohol withdrawal management 
will be left to the discretion of the treating physician.  
Patients admitted to the hospital:
Hospital admission will not exclude an individual from study participation.  The study 
medication will be delivered in the ED and the research case manager will follow the patient 
while he/she is an inpatient, and coordinate a follow-up plan with the admitting team at the time 
of hospital discharge.
III.
Safety:
Adverse Events:
Serious adverse events have been reported to occur in ~5% of those treated with XR-NTX, 
which is similar to placebo [15]. Adverse events tend to be mild or moderate, with injection site 
pain, nausea, headache and fatigue being the most frequent.
The research case manager will collect information about adverse events at each monthly follow 
up visit and enter the data into RedCap data collection forms. Any unanticipated problems 
related to the study activities identified by the research team will be entered into the RedCap 
form as well. This data will be reviewed quarterly by the PI, who will determine if the event was 
expected, the severity of the event, and the likelihood that the event was related to the research 
study activities. Any serious adverse events will be reported to the PI immediately by the 


Murphy Raven Naltrexone Pilot 3-11-2022
9
research case manager, or any member of the research team who identifies a serious adverse 
event. The PI will report all serious adverse events resulting in death or possible life threatening 
events to the UCSF IRB immediately. All other adverse and unexpected events will be reported 
using the iRIS adverse event reporting forms within 5 business days of the PI becoming aware of 
the event.
Risks and risk minimization strategy:
Injection site pain, mild swelling, and possible ecchymosis are possible. The smallest acceptable 
needle size will be used and patients will be treated with non-narcotic oral analgesics as needed 
for bothersome injection site pain 
XR-Naltrexone carries the risk of inducing opiate withdrawal in patients with opiate dependance. 
Urine drug screening and direct questioning about opiate usage will be used to exclude any 
patients with possible active opiate use disorders.
XR-Naltrexone is an mu-opioid receptor antagonist and thus may limit the analgesic efficacy of 
these medications should the patient require them for an unexpected acute medical or surgical 
condition. The antagonist effect can be overcome by increasing the dose of opioid analgesic. 
This confers a theoretical increased risk of respiratory depression. Participants will be provided 
with a medical bracelet and/or wallet card that carries relevant clinical information for providers 
as well as contact information for the PI and research team (see previous description under Index 
ED visit)
XR-Naltrexone carries a risk of drug induced hepatitis. Patients will be screened with liver 
function tests, questioned about medical history of liver disease, and have their medical record 
reviewed by the emergency medicine provider to screen for history of liver disease. Patients with 
cirrhosis or aminotransferase levels (AST, ALT) greater than 5x the upper limit of normal will be 
excluded. Participants will be questioned at subsequent XR- NTX administration visits about 
signs and symptoms of liver injury (upper abdominal pain, abdominal bloating, vomiting, 
yellowing of the skin or eyes, severe fatigue/weakness, joint and muscle pain).  Answers to these 
questions will be reviewed weekly by the PI and clinical research fellow. If the PI and/or fellow 
believe the participant is exhibiting evidence of liver injury, they will arrange a follow up visit 
at the UCSF ED within one week. At that visit if the PI or fellow feels there is sufficient clinical 
concern for liver injury, then laboratory testing of liver function will be conducted during the 
visit. Any liver function testing that occurs as a result of the PI/fellow's concern for liver injury 
will be considered research specific testing and outside routine clinical care. The results of any 
laboratory tests done to evaluate for XR-NTX induced organ injury will be followed up by the PI 
or clinical research fellow. Subsequent injections of XR-NTX will not be given until the 
PI/clinical fellow have the results and confirmed that it is safe for the patient to continue 
treatment. If the liver aminotransferase concentrations rise to >5 times the upper limit of normal 
the study medication will be discontinued and the aminotransferases will be repeated in one 
week. If on repeat testing the amiotransferase elevation is again above 5 times the upper limit of 
normal the patient will be referred for Hepatology evaluation.


Murphy Raven Naltrexone Pilot 3-11-2022
10
XR-Naltrexone is a deep intramuscular injection and additionally carries some risk of lowering 
platelet counts, typically by less than 20,000 per cubic mm. Patients with platelet counts below 
100,000 per cubic mm. will be excluded in order to minimize the risk of  bleeding.
 
As with any medication, XR-Naltrexone intramuscular injection carries a risk of allergic 
reactions including anaphylaxis. Patients with known allergy to naltrexone or any of the inactive 
ingredients of the injection will be excluded.
Data collected for this study includes details about alcohol and recreational drug use as well as 
information about employment and housing status. These topics may be sensitive to discuss, but 
are part of routine medical interviewing. Information collected by the research team will be take 
place in a private room and data stored securely (see data management plan).
No EDs in San Francisco administer Naltrexone, so there is no concern that a patient will receive 
extra doses during ED visits at locations other than UCSF.  There are community sites, such as 
the San Francisco sobering center, SF street medicine and Health Right 360, where XR-
Naltrexone is available and is administered to patients. These community sites are key 
stakeholders in the treatment of patients with AUD.  One of the aims of this study is to establish 
a robust referral network for ongoing treatment of AUD once patients are discharged from the 
hospital/ED by mobilizing key stakeholders. We will coordinate with leadership and staff of 
community organizations that treat AUD throughout the study timeframe by forming a 
stakeholder committee that includes representatives from SF Street medicine, Health Right 360, 
and UCSF providers about both facilitators of and barriers to continuity of care after the initial 
ED visit and throughout the study. The committee with also serve as a venue for stakeholders to 
express any safety concerns, and will review any adverse events. The committee will meet 
quarterly and will record meeting proceedings and create a meeting summary. 
Risk/Benefit balance:
XR-Naltrexone is FDA approved for the treatment of alcohol use disorders and has an excellent 
established safety profile. The serious adverse drug event rates are low and the drug is generally 
well tolerated. Based on available evidence, it is the most effective pharmacotherapy for alcohol 
use disorders. The benefits to participants of receiving a safe, established, effective treatment for 
their alcohol use disorder include reduction in total alcohol consumed, reduction in heavy 
drinking days, and increased success with achieving sobriety if desired. Based on current 
research literature, reduced days of heavy drinking and total alcohol use can be reasonably 
expected to lower the risk of alcohol related disease and alcohol related trauma. These are 
associated with significant cost, both personal and financial, to both patients and society.
IV.
Analysis, Measurements, and Outcomes:
Because this is a feasibility study, primary outcomes of interest are recruitment (consent) rate, 
time required to complete initial tele-medicine assessment in the ED, time needed to administer 
XR-NTX in the ED, total ED length of stay, time to first follow up after the initial ED encounter, 
number of cell phones issued by the study, retention and follow up rates over the 3-month study 


Murphy Raven Naltrexone Pilot 3-11-2022
11
period, retention rate with other providers in San Francisco, number of doses of XR-NTX 
received during the study period and intervals between doses, and barriers to and facilitators of 
follow-up after the initial ED visit.
We will also collect pilot data on the following for statistical analysis:
Predictor Variable: Multi-modal treatment with Extended Release Naltrexone and case 
management
Primary Outcome: Change in the number of Emergency Department visits for alcohol-related 
complaints. [(# of ED visits for alcohol related complaint in 12 months after enrollment) - (# of 
ED visits for alcohol related complaint in 12 months before enrollment)].  
Secondary Outcomes: number of standard alcoholic drinks consumed per week, number of days 
of heavy drinking, overall substance use severity (change in AUDIT score), change in alcohol-
related social/occupational/psychological problems identified on SIP-2R, change in PEth, and 
change in urine ethyl glucuronide
Cost analysis: This study will not provide precise estimates of efficacy or costs. However, we 
will use our results to perform a basic cost analysis to guide future research. We will estimate: 
overall cost and cost per patient (medications, case management, follow-up visits), cost per 
avoided ED visit, cost per avoided hospitalization, program cost vs expected medical cost saved. 
All costs will be estimated at the societal perspective
Potential confounding variables or covariates, justifications:
There are several potential confounders which we will measure such as number of doses of XR-
NTX received, willingness to change, engagement in other, baseline substance use severity, 
housing status, psychiatric and medical comorbidity, and basic demographic variables such as 
age and sex. The primary strategy employed to combat these cofounders is the selection of the 
primary outcome. Since the outcome is a change from the patient’s baseline ED usage from the 
prior year each patient serves as their own control. Thus they are matched for many of the 
possible confounders.
The risk of bias is substantial given that all enrollees are to be treated with XR-NRT and the 
study is not randomized or blinded and the population of interest is at high risk of being lost to 
follow up. We intend to conduct both an intention to treat analysis and a per protocol analysis, 
though our sample size may limit the utility of this approach. We will employ an independent 
data analyst to collect the ED visit counts and perform the final statistical analysis.
Statistical issues:
Statistical Test: Paired T Test
Hypothesis: 


Murphy Raven Naltrexone Pilot 3-11-2022
12
ED initiated Treatment of alcohol use disorders with multi-modal therapy reduces alcohol related 
ED visits in patients with frequent ED visits for alcohol related complaints
Sample Size:
We will enroll 25 patients. As a feasibility study our sample size was chosen as it represents a 
reasonable patient load for a single case manager. Because this population is difficult to retain in 
treatment, we anticipate the drop-out rate will be significant. Patients who drop out of the study 
(either withdraw or are lost to follow up) will be replaced with new enrollees until 25 patients 
have been recruited into the study. The goal of this practice is to maximize the benefit to the 
patient population, avoid wasting donate study medication, and to allow the research team to  
optimize recruitment and retention strategies.
Last year 42 patients presented to the UCSF Emergency Department at least 4 times for an 
alcohol related complaint. Of this group the mean number of visits was 8.49 with a SD of 8.58. 
The median number of visits was 6. The number of visits ranged from 4-47. After excluding 2 
outliers (40 and 47 visits, each > 3SD above the mean) the mean was 6.78 visits with a SD of 3.5 
visits.
We estimate a standardized effect size of 0.584 would represent 2-5 emergency visits for alcohol 
related complaints. This equates to a 29-59% reduction in ED utilization, which is clinically 
relevant. 
Data management plan:
The research case manager will use a tablet device to enter data into data entry forms in 
REDCap. The research case manager will also maintain a back-end Microsoft Access database. 
The REDCap data collection system is secure will be accessible only to members of the study 
team.  The back-end Access database will be maintained on MyResearch in a folder accessible 
only to members of the study team. REDCap and MyResearch are on secure servers and are 
backed up regularly.  When data are exported to STATA for statistical analysis, patients will be 
identified by a SubjectID that has no meaning external to the database. No dates will be 
exported.
Interim analysis: 
We will conduct a qualitative analysis after 10 enrolled patients to 
assess enrollment (enrollment rate, number of patients who do not meet inclusion criteria, 
unanticipated barriers to enrollment), retention (study retention rate, unanticipated barriers to 
retention, proportion of follow up visits in ED vs at patient's home or in the community), and 
adverse events that might be related to the study at that time including adverse reactions to the 
study drug. We do not anticipate adverse events occurring as a result of this study, because of the 
safety profile of the study drug and the fact that we are offering new, additional services to assist 
patients with treatment for alcohol use disorder, which are low-risk activities.  


Murphy Raven Naltrexone Pilot 3-11-2022
13
V.
Personnel, resources, and partnerships:
UCSF will provide a full-time research fellow (board eligible Emergency Medicine physician), 
as well as other board certified Emergency Medicine physicians, RNs, and pharmacists, to assist 
with screening and enrolling patients, administering and storing medication, coordinate follow 
up, and perform data analysis.
Procedures other than injection of the study drug carried out as part of routine care during the 
index visit and with community healthcare providers services occurring after the index visit will 
be charged to the participant’s insurance.
The cost of procedures done for research purposes only including urine drug screening, urine 
fentanyl screening, and repeat liver function testing for participants with suspected liver injury 
will be paid for by the study.
The study will pay for all doses of the study drug administered as part of this study (up to 3 per 
participant). 
VI.
Brief Proposed Timeline:

May-July 2019- Submit for IRB approval and grant proposals

October 2019-December 2019 hiring and training of research case manager and 
Emergency staff

March 2020-June 2021 enrollment and data collection period

June 2021-August 2021- data analysis

September 2021- Begin writing manuscripts, submitting abstracts, developing proposal 
for follow up randomized control trial
References:
1. Centers for Disease Control and Prevention (CDC). Alcohol-Related Disease Impact (ARDI). 
Atlanta, GA: CDC.
2. M Stahre. Contribution of excessive alcohol consumption to deaths and years of potential life 
lost in the United States. Prev Chronic Dis 2014;11:130293.
3. JJ Sacks et al. 2010 National and State Costs of Excessive Alcohol Consumption. Am J Prev 
Med 2015; 49(5):e73–e79.
4.  White et al. Trends in Alcohol-Related Emergency Department Visits in the United States: 
Results from the Nationwide Emergency Department Sample, 2006 to 2014. Alcohol Clin Exp 
Res. 2018    Jan 2.
5. D Hartung, Extended-release Naltrexone for Alcohol and Opioid Dependence: A Meta-
Analysis of Healthcare Utilization Studies, J Subst Abuse Treat. 2014 Aug; 47(2): 113–121.
6. AJ Ober, Assessing and improving organizational readiness to implement substance use 
disorder treatment in primary care: findings from the SUMMIT study, BMC Fam Pract. 2017; 
18: 107.


Murphy Raven Naltrexone Pilot 3-11-2022
14
7. D’Onofrio et al. Emergency department-initiated buprenorphine/naloxone treatment for opioid 
dependence: a randomized clinical trial. JAMA. 2015 Apr 28;313(16):1636-44. doi: 
10.1001/jama.2015.3474.
8. DH Gustafson et al. A smartphone application for alcoholism recovery: A randomized 
controlled trial. JAMA: Psychiatry. 2014; 71:5
9. MA Celio et al. Using Video Conferencing to Deliver a Brief Motivational Intervention for 
Alcohol and Sex Risk to Emergency Department Patients: A Proof-of-Concept Pilot Study. 
Addict Res Theory. 2017; 25(4): 318–325.
10.  ED Boudreaux et al. The Remote Brief Intervention and Referral to Treatment Model: 
Development, Functionality, Acceptability, and Feasibility. Drug Alcohol Depend. 2015 Oct 1; 
155: 236–242.
11. RM Cunningham et al. National survey of emergency department alcohol screening and 
intervention practices. Ann Emerg Med. 2010 Jun;55(6):556-62
12. E Goplerud, T McPherson. Implementation Barriers To And Facilitators Of Screening Brief 
Intervention Referral And Treatment (SBIRT) In Federally Qualified Health Centers.
13. B Kiluk, The Short Inventory of Problems – Revised (SIP-R): Psychometric properties 
within a large, diverse sample of substance use disorder treatment seekers. Psychol Addict 
Behav. 2013 Mar; 27(1): 307–314.
14. S Piano et al. Assessment of alcohol consumption in liver transplant candidates and 
recipients: the best combination of the tools available. Liver Transpl. 2014 Jul;20(7):815-22.
15. Garrett JC et al. Efficacy and tolerability of long-long-acting injectable naltrexone for 
alcohol dependence: a randomized control trial. JAMA. 2005 Apr 6;293(13):1617-25
16. Jeste DV et al. A new brief instrument for assessing decisional capacity for clinical research. 
Archive  General Psychiatry. 2007 Aug;64(8):966-74.
17. McCormack RP et al. Including Frequent Emergency Department Users With Severe 
Alcohol Use Disorders in Research: Assessing Capacity. Annals of Emergency Medicine. 2015 
Feb;65(2):172-177
18.Sobell, L.C., & Sobell, M.B., (1992). Timeline followback: A technique for assessing self-
reported alcohol consumption. In R.Z. Litten & J. Allen (Eds.), Measuring alcohol consumption: 
Psychosocial and biological methods (pp. 41-72). New Jersey: Humana Press.
19.Sobell, L. C., & Sobell, M. B. (1995). Alcohol consumption measures. In J. P. Allen & M. 
Columbus (Ed.), Assessing alcohol problems: A guide for clinicians and researchers. (pp. 55-73). 
Rockville, MD: National Institute on Alcohol Abuse and Alcoholism.