REVIEW

Naltrexone Initiation in the Inpatient Setting

for Alcohol Use Disorder: A Systematic
Review of Clinical Outcomes
Robert W. Kirchoff, MD; Norhan M. Mohammed, MD;
Jack McHugh, MB BCh BAO; Matej Markota, MD; Thomas Kingsley, MD, MPH, MS;
Jonathan Leung, PharmD RPh; M. Caroline Burton, MD;
and Rahul Chaudhary, MBBS

Abstract

Alcohol use disorder (AUD) is a highly prevalent health issue in the United States. The number of those
receiving medication-assisted treatment (MAT) is limited, despite strong evidence for their effectiveness.
The inpatient setting may represent an important opportunity to initiate MAT. The goal of this study was
to summarize the data on naltrexone initiation in the emergency department or inpatient setting for the
management of AUDs. We searched ClinicalTrials.gov, Ovid EBM Reviews, Ovid Embase, Ovid Medline,
Ovid PsycINFO, Scopus, and Web of Science from inception through October 31, 2019. Search strategies
were created using a combination of keywords (Supplemental Appendix 1, available online at http://www.
mcpiqojournal.org) and standardized index terms related to naltrexone therapy for medically hospitalized
patients with AUD. Two uncontrolled pre-post study designs evaluated naltrexone prescription rates, 30-
day readmission rates, and rehospitalization rates. Two authors independently abstracted data on study
characteristics, results, and study-level risk of bias. The research team collaborated to assess the strength of
evidence across studies. Two studies reported that implementing a protocol for naltrexone initiation
increased MAT rates, with one study noting a substantial decrease in 30-day hospital readmissions.
Overall, we found that there is a paucity of data on naltrexone initiation in the inpatient setting for AUDs.
This likely reflects the nature of current clinical practice and prescriber comfortability. There is a need for
further studies evaluating MAT initiation in the inpatient setting. Furthermore, efforts to increase provider
knowledge of these therapeutic options are in need of further exploration.
ª 2021 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/) n Mayo Clin Proc Inn Qual Out 2021;5(2):495-501

From the Department of

A
lcohol use disorder (AUD) is a highly 50% of patients admitted for alcohol with-
Internal Medicine (R.W.K.,
prevalent and critical health issue in drawal will be readmitted for the same reason N.M.M., J.M., T.K., M.C.B.,
the United States. Alcohol-induced within 30 days.4 R.C.), Department of Psy-
death rates have accelerated overall and partic- Alcohol use disorder treatment is highly chiatry and Psychology
(M.M.), and Department
ularly in women.1 In 2018, an estimated 14.8 heterogeneous, with a large proportion of pa- of Pharmacy (J.L.), Mayo
million persons had AUD, corresponding to tients spontaneously remitting and some Clinic, Rochester,
5.4% of the population. Of this group, only needing long-term psychosocial and medication Minnesota.

4.6% received treatment in a specialty treat- interventions.3 Compared with other substance
ment facility (hospital, rehabilitation center, use disorders, AUD has several US Food and
or mental health facility).2 It is estimated that Drug Administration (FDA)eapproved and
20% of patients who attend the emergency off-label pharmacological options available to
department (ED) suffer from an AUD.3 Hospi- assist patients with sobriety. Currently, there
talists frequently encounter alcohol with- are 3 FDA-approved medication-assisted treat-
drawal admissions and are often tasked with ment (MAT) options: naltrexone, acamprosate,
providing short counseling sessions on AUD and disulfiram. These agents have been studied
owing to time constraint. Furthermore, up to in renal and hepatic insufficiency, pregnancy

Mayo Clin Proc Inn Qual Out n April 2021;5(2):495-501 n https://doi.org/10.1016/j.mayocpiqo.2021.01.013 495
www.mcpiqojournal.org n ª 2021 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. This is an open access article under
the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 MAYO CLINIC PROCEEDINGS: INNOVATIONS, QUALITY & OUTCOMES

or illicit, as naltrexone can precipitate opioid

ARTICLE HIGHLIGHTS withdrawal in those who are actively using,
and should be avoided in such patients. How-
d Alcohol use disorder and the related comorbidities are
ever, naltrexone is also approved for opioid
commonly encountered in the inpatient setting, with this patient abstinence, making it a dual purpose medica-
population representing a source of frequent readmissions. tion in patients with both alcohol and opioid
d Therapeutic options to reduce relapse are available but rarely use disorders.
used in the hospital setting. A 2005 Cochrane review of 50 random-
ized controlled trials (RCTs), including 7793
d Naltrexone and other medication-assisted treatment options
patients, found that naltrexone reduced the
are well studied in the outpatient setting; however, there are risk of heavy drinking to 83% of that in the
few studies exploring their initiation in the inpatient medical placebo group13 and was associated with an
setting. overall decrease in drinking days. Although
its effectiveness has been adjudged as equiva-
lent to that of acamprosate,8 naltrexone is
and lactation, central nervous system toxicity, given as a once daily dose vs thrice daily, mak-
and drug abuse and therefore can be tailored ing it more convenient for daily use. These fea-
to specific patient populations, depending on tures combined with its favorable safety profile
their comorbidites.5 For example, acamprosate have led to naltrexone’s role as a first-line
can be used in liver failure but not in renal insuf- agent for MAT of AUDs, prompting investiga-
ficiency whereas naltrexone should be avoided tion into its potential value as a predischarge
in liver failure but is permitted in renal insuffi- intervention for patients who are admitted
ciency. Dosing and routes can also influence for alcohol withdrawal.
which MAT to use. Two additional agents that Despite these favorable findings, there ap-
have been approved by the European Medicines pears to be limited use of naltrexone in the
Agency include nalmefene and gamma- acute setting when a patient is evaluated in
hydroxybutyrate. The efficacy of nalmefene the ED or admitted to the hospital.
has not been found to be any better than pla- The inpatient setting offers an opportunity
cebo in clinical trials in the United States.6 to initiate treatment and possibly prevent sub-
The abuse potential of gamma- stance use disorder progression, which may
hydroxybutyrate has led to caution with pre- otherwise go untreated if left unaddressed.
scribing in Europe, and it is not FDA approved Furthermore, deferring treatment with
for AUD.7 naltrexone or other MAT to the outpatient
Naltrexone, a long-acting opioid antago- setting may lead to patients being lost to
nist, is one of the most extensively studied follow-up and a missed opportunity to initiate
medications to treat any substance use disor- a potentially beneficial medication. There is a
der, with several decades of research support- lack of data on the implications of inpatient
ing its use5,8,9 and an FDA approval dating vs outpatient initiation of MAT. In our review,
back to 1994.10 Naltrexone is unique in that we focus on studies investigating the initiation
it is available in both oral and long-acting of naltrexone in the inpatient setting.
injectable forms. In addition to evidence sug- The objective of this study was to system-
gesting effectiveness in reduction of heavy atically review the published literature on
drinking, this medication has a relatively naltrexone (oral or injectable) initiated in the
benign adverse effect profile, and remains a acute setting for the management of AUDs.
first-line pharmacological treatment choice
for AUDs. The mechanism proposed is a
METHODS
reduction of dopamine release from the nu-
cleus accumbens in the setting of opioid recep- Data Sources
tor occupancy.11,12 An important caveat is that We searched ClinicalTrials.gov, Ovid EBM Re-
attention must be paid to the patient’s medica- views, Ovid Embase (1974þ), Ovid Medline
tion and substance use history to ensure there (1946þ, including epub ahead of print, in-
is no co-occurring use of opioids, prescribed process, and other nonindexed citations),

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NALTREXONE INITIATION IN THE INPATIENT SETTING

Ovid PsycINFO (1806þ), Scopus (1970þ), RESULTS

and Web of Science (1975þ) from initiation A total of 2102 records were identified. All re-
to October 31, 2019. We also sought addi- sults were exported to a citation manager, in
tional studies by reviewing the reference lists which 984 obvious duplicates were removed,
of the included articles. Search strategies leaving 1118 unique citations. Forty full-text
were created using a combination of keywords articles were assessed for eligibility (Figure).
(Supplemental Appendix 1, available online at A total of 2 trials met the inclusion criteria.
http://www.mcpiqojournal.org) and standard- Both trials were uncontrolled pre- and postin-
ized index terms related to naltrexone therapy tervention studies in which providers were
for medically hospitalized patients with AUD. educated about naltrexone prescribing. Both
trials were adjudged to have a serious risk of
bias (Table). Naltrexone prescription rates in
Data Selection addition to 30-day hospital readmissions and
We included both RCTs and non-RCTs in 30-day ED revisits were the common
which naltrexone was initiated during hospital outcomes.
course or upon discharge and was compared
with a placebo as well as studies in which Naltrexone Prescription Rates
readmissions were identified. Studies without Two studies examined prescription rates of
measureable outcomes, studies performed in naltrexone pree and posteeducational inter-
outpatient, residential, or partial outpatient vention. Wei et al16 implemented a discharge
programs, studies in which psychiatric comor- planning tool for all patients admitted with
bidity was the primary focus, and those that an alcohol-related diagnosis. This intervention
examined use of naltrexone for anything other led to an increase in oral
than AUD were excluded. naltrexoneeprescribing rates from 0% to
64% (P<.001). Likewise, Stephens et al17
developed an algorithm for assessing eligibility
Data Extraction, Quality, and Applicability for oral naltrexone, which included the addi-
Assessment tion of related smart phrases to the electronic
Two authors (N.M.M., J.M.) independently medical record. An increase in naltrexone-
abstracted data on study design; setting; pop- prescribing rates from 1.6% to 28.1% was
ulation characteristics (sex, age, race/ethnicity, noted after these interventions.
comorbid conditions, and coronary anatomy);
eligibility and exclusion criteria; numbers of
patients screened, eligible, enrolled, and lost Thirty-Day Hospital Readmissions
to follow-up; method of outcome assessment; Both studies examined all-cause inpatient
and results for each outcome. Each study readmissions at 30 days. Wei et al16 found
was assessed for bias independently, and that rates of readmission decreased from
consensus was reached by discussion. Dis- 23.4% (15 of 64) to 8.2% (4 of 49)
agreements in study selection and issues (P¼.042) after the implementation of the
related to data extraction were resolved by dis- naltrexone-prescribing program. Stephens
cussion with a senior coauthor (R.W.K.). et al17 found rehospitalization rates of 10.2%
(13 of 128) preintervention and 11.4% (13
of 114) postintervention (P¼.75). In a sub-
Data Synthesis and Analyses group analysis of those counseled about
Owing to small sample size and heterogeneity naltrexone use in the postintervention group,
of the included studies, we performed a qual- rehospitalization rates decreased from 26.2%
itative narrative synthesis of results. Risk of (11 of 42) to 2.8% (2 of 72) (P<.001).
bias in all included studies was assessed using
the Cochrane-validated ROBINS-I assessment Thirty-Day All-Cause ED Visits
tool,14 which is specifically designed for Thirty-day ED revisits were examined in 2
assessing the risk of bias in nonrandomized studies. Wei et al16 found that 18.8% of pa-
trials (Supplemental Appendix 2, available on- tients (12 of 39) eligible for naltrexone before
line at http://www.mcpiqojournal.org). intervention had an ED revisit within 30 days.
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 MAYO CLINIC PROCEEDINGS: INNOVATIONS, QUALITY & OUTCOMES

Identification
2078 records identified through 24 additional records identified
database searching through other sources

1118 records after duplicates removed

Screening

1118 records screened 1078 records excluded

40 full-text articles assessed 37 full-text articles excluded,

Eligibility

for eligibility with reasons

2 studies included in
qualitative synthesis
Included

0 studies included in
quantitative synthesis
(meta-analysis)

FIGURE. PRISMA 2009 flow diagram. From PLoS Med.15

This figure decreased to 6.1% (3 of 16) post- rehospitalization rates in those prescribed
intervention (P ¼ .056). Stephens et al17 naltrexone. Both studies used oral naltrexone,
found 25.8% (33 of 128) vs 19.3% (22 of and results may not be applicable to the use of
114) of patients (P ¼ .23) after intervention the long-acting intramuscular formulation.
had an ED revisit. In a subgroup analysis, pa- Barriers to initiation identified in the studies
tients who received counseling about included general relative contraindications or
naltrexone before discharge were noted to contraindications such as current opioid use,
have a lower odds ratio of ED revisit (odds ra- opioid use disorder, or severe liver dysfunc-
tio, 0.21; 95% CI, 0.07 to 0.60). tion. However, a lack of knowledge among
prescribers needs to be addressed, and simple
interventions were found to increase prescrib-
DISCUSSION
ing rates in these 2 studies. This lack of knowl-
Summary of Evidence edge could be as simple as providers having a
The objective of this study was to review the poor understanding of drug mechanism, indi-
published literature on naltrexone initiated in cations, or side effects due to a lack of familia-
the inpatient setting for the management of tiry with the drug.
AUDs. Two small pre-post intervention trials Ultimately, this systematic review reveals a
showed some promise with regard to paucity of evidence regarding naltrexone initi-
increasing naltrexone prescription rates with ation in the inpatient medical setting. Given
appropriate provider education and a trend to- the dearth of information published on the
ward lower 30-day readmission rates and topic, it begs the question as to whether there

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NALTREXONE INITIATION IN THE INPATIENT SETTING

time and resources as well as a multidisci-

TABLE. Assessed Risk of Bias in Evaluated
plinary approach.16
Studies
Although there are factors to predict read-
Stephens Wei
mission,4 clinical management received by
Bias et al17 et al16
most patients largely remains the same regard-
Bias due to confounding Serious Serious less of risk stratification. The use of a multidis-
Bias in selection Serious Serious ciplinary approach may allow for the creation
Bias in the classification of Moderate Moderate of protocols that can direct care toward the
interventions most vulnerable patients. One such protocol
Bias due to deviations from Low Low is the initiation of naltrexone or other MAT
intended interventions at discharge. However, as evident by our sys-
Bias due to missing data Serious Serious tematic review, there remains a lack of evi-
Bias in the measurement of Serious Serious dence to equip hospitalists with the
outcomes confidence to do so. Nonetheless, this remains
Bias in the selection of the Serious Serious an important research topic given the safety
overall result and efficacy of MAT.22,23
Overall bias Serious Serious Medical teams frequently interact with pa-
tients diagnosed with AUD and therefore play
an important role in establishing initial steps
are shortcomings in the standards of care for to treatment, which may promote abstinence
patients with AUD. Although it has been pre- from drinking and subsequent reductions in
viously described that MAT of AUD is under- hospitalizations. Prescribing MAT along with
prescribed,18 the reasons for this are likely referral to substance abuse counselors, psychi-
multifaceted. Patients suffering from substance atrists, and chemical dependency treatment
use disorder represent a clinically challenging centers may be effectively integrated into pa-
population, whose care is complicated by tient care when approached in a standardized
ambivalence to engage in treatment as well manner. Limited evidence supports protocoli-
as low adherence, loss to follow-up, and low zation or enhancements through the elec-
levels of insurance. This cohort also frequently tronic medical record to increase prescribing
experiences multiple comorbidities, especially and to reduce 30-day rehospitalization
psychiatric illnesses, and management of rates.24 Naltrexone may be a promising way
AUDs can fall to the wayside as acute crises to help break the readmission cycle in patients
take priority in the inpatient setting.19,20 Un- with AUD who are interested in taking medi-
fortunately, it is also likely that the social cation. Additionally, it is important to
stigma associated with AUD, a lack of under- consider the patient’s comorbidities and goals
standing of AUD as a treatable condition, of case when discussing initiation of
and a lack of clinician familiarity with pharma- naltrexone, as it has shown the most benefit
cotherapy for AUD are contributing factors in in reducing heavy drinking days as opposed
the low treatment rates observed. to abstinence and may not be the best MAT
In the clinical setting, referrals for addic- choice for all patients. More research is
tion medicine or chemical dependency treat- needed to further investigate the utility of pre-
ment are often provided, yet patients are scribing naltrexone upon discharge and its ef-
often lost to follow-up and may begin drinking fect on outcomes such as readmission rate,
shortly after discharge, only to be readmitted relapse rate, and successful follow-up for
with a similar clinical picture. Given the op- chemical dependency treatment.
portunity to make substantial interventions
in the hospital setting, more research is needed Limitations
to determine whether the initiation of MAT Given the paucity of literature on this topic,
before discharge is of benefit. Indeed, there combined with the high degree of heterogene-
are ample data to suggest that hospitalized pa- ity between the studies chosen, we are unable
tients are more motivated to change their to draw meaningful conclusions about the ef-
behavior, creating an opportunity for a “teach- ficacy of inpatient naltrexone initiation. Our
able moment,”7,21 yet this will require both findings highlight a need for further
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 MAYO CLINIC PROCEEDINGS: INNOVATIONS, QUALITY & OUTCOMES

investigation into this topic, ideally in the form ORCID

of an RCT assessing outcomes related to read- Robert W. Kirchoff: https://orcid.org/0000-0001-9369-
2242; Jack McHugh: https://orcid.org/0000-0002-7507-
mission rates, relapse rates, and rates of suc-
232X; Matej Markota: https://orcid.org/0000-0002-
cessful referral for chemical dependency 0437-5497; Thomas Kingsley: https://orcid.org/0000-
treatment. Furthermore, our decision to focus 0002-6212-8988; Jonathan Leung: https://orcid.org/
only on studies involving inpatient medical 0000-0003-3836-9375; Rahul Chaudhary: https://orci-
admissions does create a notable limitation of d.org/0000-0002-3276-385X
available studies for review. We acknowledge
the high prevalence of psychiatric comorbid-
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