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2022 Alcohol use disorder: Pharmacologic management - UpToDate

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Alcohol use disorder: Pharmacologic management

Author: Stephen R Holt, MD, MS, FACP
Section Editor: Murray B Stein, MD, MPH
Deputy Editor: Michael Friedman, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jun 2022. | This topic last updated: Mar 14, 2022.

INTRODUCTION

Alcohol use disorders are among the most prevalent of all substance use disorders worldwide. The single year
prevalence globally has been estimated to be over 100 million individuals [1]. Additionally, nearly 3 million deaths (5.3
percent of all deaths globally) have been attributed to alcohol in a single year [2].

Most clinical trials of medication efficacy for alcohol use disorder studied recently abstinent individuals with an
American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision
(DSM-IV-TR) diagnosis of alcohol dependence. Applying these findings to individuals diagnosed under the Diagnostic
and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) is imprecise, but the most closely comparable group
of individuals are those with alcohol use disorder, moderate to severe subtype (ie, individuals with four or more
symptoms within a 12-month period).

Pharmacologic treatment of alcohol use disorder has focused on altering the reinforcing effects of alcohol use.
Medication development has focused on several neurotransmitter systems that mediate reinforcement including
opioid, glutamate, gamma-aminobutyric acid, and serotonin systems.

Several medications can be used to treat alcohol use disorder, leading to reduced heavy drinking and increased days
of abstinence [3]. These outcomes likely reduce the overall risk associated with alcohol use disorder despite total
abstinence not being achieved.

This topic reviews the pharmacotherapy for treatment of alcohol use disorder. The epidemiology, pathogenesis,
clinical manifestations, assessment, and diagnosis of risky drinking and alcohol use disorder, as well as psychosocial
treatments for the disorder, are discussed separately. Other topics related to alcohol use disorder including the
management of withdrawal and nutritional issues are also reviewed separately.

● (See "Risky drinking and alcohol use disorder: Epidemiology, pathogenesis, clinical manifestations, course,
assessment, and diagnosis".)
● (See "Screening for unhealthy use of alcohol and other drugs in primary care".)
● (See "Brief intervention for unhealthy alcohol and other drug use: Efficacy, adverse effects, and administration".)
● (See "Ambulatory management of alcohol withdrawal".)
● (See "Management of moderate and severe alcohol withdrawal syndromes".)

INDICATION FOR PHARMACOTHERAPY

Medication treatment of alcohol use disorder has been shown to be effective in patients with moderate to severe
subtypes of the disorder. Medication should be prescribed in conjunction with psychosocial interventions, though it
should not be withheld if patients do not participate in or adhere to them. (See "Approach to treating alcohol use
disorder", section on 'Moderate to severe disorder'.)

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In contrast, medication treatment has not been extensively studied in patients with mild subtype of alcohol use
disorder. In these patients, we suggest initial treatment with psychosocial interventions rather than with medication.
(See "Approach to treating alcohol use disorder", section on 'Mild disorder' and "Alcohol use disorder: Psychosocial
treatment".)

An algorithm describes our approach to the pharmacologic management of alcohol use disorder ( algorithm 1).

FIRST-LINE TREATMENT

Suggested first- and second-line agents used in the treatment of alcohol use disorder can be found on the associated
table ( table 1).

Naltrexone — For most newly diagnosed patients with moderate to severe alcohol use disorder, we suggest initial
treatment with naltrexone. Naltrexone is our preferred choice due to its preferable dosing schedule and the ability to
begin treatment for alcohol use disorder while the individual is still drinking.

Naltrexone exerts its principal pharmacologic effects through blockade of the mu-opioid receptor. Endogenous
opioids modulate alcohol's reinforcing effects [4,5]. Naltrexone also modifies the hypothalamic-pituitary-adrenal axis
to suppress ethanol consumption [6].

● Contraindications – Naltrexone should be avoided in individuals using opioids or prescribed opioids for pain
management, as well as in those with acute hepatitis or hepatic failure; in such patients, the alternative first-line
treatment, acamprosate is appropriate.

● Formulations – Naltrexone can be taken orally or administered in a long-acting injectable (LAI) form. Both oral
and long-acting dosing have demonstrated efficacy compared with placebo. Comparative studies are limited and
have come to different conclusions regarding comparative efficacy [7-9].

• LAI naltrexone – For most patients treated with medication for alcohol use disorder, the decision to begin
oral versus intramuscular (IM) is based on patient preference. We typically prefer starting IM naltrexone to
ensure adherence. However, some may prefer to start with oral medication (ie, to see if side effects emerge
or liver enzymes are affected), before committing to a longer course of treatment. Depot preparations of
naltrexone may improve adherence by reducing the frequency of medication administration from daily to
monthly. However, they do require an injection visit. Some patients may adhere better to daily medication
whereas others may be willing to attend monthly visits. Additionally, a steady state of medication level is
achieved with LAI naltrexone. This may avoid peak effects that might exacerbate adverse events [10].

LAI naltrexone is given as an IM injection of 380 mg every four weeks to the gluteal area. Common adverse
events observed among individuals receiving LAI naltrexone included nausea (33 percent), fatigue (20
percent), and decreased appetite (13 percent).

The US Food and Drug Administration has reported 196 cases of serious injection site reactions from
postmarketing surveillance including induration, cellulitis, hematoma, abscess, and necrosis. Females appear
to be at higher risk for this reaction. Patients should report injection-site pain, swelling, bruising, pruritus, or
redness, and seek medical attention if symptoms are not improving after one week. Liver enzymes should be
monitored within several weeks of initiating treatment and then every six months during ongoing treatment.

LAI naltrexone appears to be superior to placebo in reducing drinking and heavy drinking among adults with
alcohol use disorder [11,12]. For example, in a meta-analysis, individuals with alcohol use disorder treated
with LAI naltrexone had fewer days of drinking per month compared with individuals receiving placebo (five
trials, n = 314; weighted mean difference -2.0, 95% CI -3.39 to -0.61) [12]. Additionally, individuals treated with
LAI naltrexone had fewer heavy drinking days per month (defined as four or more drinks/day in females; five
or more drinks/day in males) than those in placebo group (seven trials, n = 881; weighted mean difference
-1.2, 95% CI -2.1 to -0.23).
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• Oral naltrexone – Our practice is to start oral naltrexone at 50 mg per day and monitor for side effects. While
the usual dose of oral naltrexone is 50 mg/day, some trials have used up to 100 mg/day [13]; some also begin
with 25 mg daily for several days and then increase the dose to 50 mg when the medication is tolerated well.
Trials generally have included efforts such as group and individual psychotherapy [14].

Targeted (as needed) dosing may be a useful strategy for promoting adherence in young individuals who
often prefer to take medication on an as needed basis [15,16]. While we typically prescribe naltrexone for
daily use, targeted dosing may be an effective alternative or supplement to daily dosing. In one trial including
140 young adults with heavy drinking (ie, four or more heavy drinking days over the past four weeks), the use
of targeted naltrexone was found to reduce the likelihood of intoxication by nearly 23 percent versus placebo
[15].

Meta-analyses of clinical trials for alcohol dependence have found oral naltrexone to reduce alcohol
consumption compared with placebo [17,18]. As an example, a meta-analysis of 50 randomized trials with
7793 alcohol dependent participants found that compared with placebo, naltrexone reduced the risk of a
return to heavy drinking, 51 versus 61 percent (relative risk 0.83, 95% CI 0.76-0.90) and decreased total
drinking days by approximately 4 percent. Any drinking was decreased by 5 percent [17].

Side effects of oral naltrexone are nausea, headache, and dizziness, which subside with continued use.

Liver enzymes should be monitored within several weeks of initiating treatment and then every six months
during ongoing treatment. Fivefold elevation in liver enzymes occurred in 11 of 614 individuals who received
naltrexone in the COMBINE study [13]. Enzyme levels returned to baseline after discontinuation of medication
in the nine individuals who had stopped drinking and returned for follow-up. Elevations in liver enzymes are
therefore largely attributable to heavy drinking; in a large safety study (865 patients), liver enzymes did not
differ from a comparison group not taking naltrexone [19].

Acamprosate — Acamprosate is an effective alternative to naltrexone and is our first choice in patients with
contraindications to naltrexone, including those who are using opioids or prescribed opioids, or in those with
advanced liver disease. For patients who have minimal to no response to naltrexone as first line of treatment, we stop
naltrexone and treat with acamprosate as our second choice (unless contraindicated). In individuals with a partial or
insufficient response to naltrexone we augment with acamprosate; however, we do this less frequently as we are
sensitive to avoiding polypharmacy.

Acamprosate's principal antidrinking neurochemical effect has been attributed to the modulation of glutamate
neurotransmission at metabotropic-5 glutamate receptors [20].

● Contraindications – Acamprosate is contraindicated in individuals with severe renal dysfunction (creatinine

clearance ≤30 mL/min).

● Administration – We begin treatment with acamprosate when abstinence is achieved and, typically, maintain
treatment during return to use. The usual dose for acamprosate is 666 mg three times daily. However, in
individuals with moderate renal dysfunction (creatinine clearance 30 to 50 mL/min) an initial dose of 333 mg
three times daily is recommended. Additionally, in individuals with a body weight <60 kg we typically initiate
treatment at a lower dose (eg, 333 mg twice daily).

● Efficacy – Meta-analyses have shown that acamprosate is effective in maintaining abstinence in individuals with
alcohol use disorder who were recently detoxified from alcohol use [21,22]. As an example, in a meta-analysis of
18 studies including nearly 2300 individuals who were recently detoxified from alcohol use, acamprosate
increased the likelihood of continuous abstinence versus placebo at 12 months (odds ratio 1.86, 95% CI 1.49-
2.33) [22].

● Adverse effects – The most prominent adverse events of treatment with acamprosate include diarrhea,
nervousness, and fatigue. These usually subside with continued use. Because acamprosate is excreted mostly

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unchanged by the kidneys, rather than the liver, it can be used safely in alcohol-dependent individuals with liver
disease.

SPECIFIC PATIENT POPULATIONS

A number of factors such as co-occurring disease, patient motivation, and treatment goals can influence the initial
choice of medication for alcohol use disorder.

Patients with co-occurring hepatic disease — In patients with acute hepatitis, liver failure, or in patients with liver
enzymes ≥3 to 5 times normal, we suggest initial treatment with acamprosate. Naltrexone is contraindicated in these
patients.

Patients with opioid use disorder — For patients with alcohol use disorder with comorbid opioid use disorder but
without other contraindications (such as severe hepatic disease) we use naltrexone to treat both conditions after a
sufficient time has elapsed since opioid exposure (see "Medication for opioid use disorder", section on 'Naltrexone:
Opioid antagonist'). Naltrexone should be avoided in individuals currently using opioids.

Alternatively, since opioid agonists are often the medication of choice for opioid use disorder, the comorbid alcohol
use disorder can be treated with acamprosate or other medications. (See 'Patients requiring additional therapy'
below.)

Patients with clinically indicated opioid use — For patients with alcohol use disorder who are taking prescribed
opioid medication, we suggest treatment with acamprosate rather than naltrexone. Naltrexone, an opioid antagonist
cannot be given to patients needing to continue opioids (eg, for pain control or to treat opioid use disorder).

Pregnancy — The treatment of pregnant women with substance use disorder should be managed by clinicians with
specialized expertise in this area. Psychosocial treatments are prioritized as there is a paucity of data on the safety of
pharmacologic therapies for alcohol use disorder in pregnant individuals.

If abstinence is not achieved without the use of medications, the risks of continued heavy drinking likely outweigh the
possible adverse effects of medication. In weighing risks and benefits of prospective treatment, one should consider
potentially harmful effects of alcohol to the mother and to the developing fetus, with alcohol a known teratogen and
the most common cause of congenital anomaly in the United States. One small study suggested no clear association
between exposure to acamprosate with poor maternal or neonatal health outcomes [23]. Acamprosate may also be
favored because opioids may be desired around delivery. However, naltrexone has been used more widely for
substance use disorder during pregnancy.

The American Psychiatric Association guidelines for the pharmacologic treatment of patients with alcohol use
disorder, state that for pregnant or breastfeeding women with alcohol use disorder, pharmacologic treatments should
not be used unless treating acute alcohol withdrawal or a co-occurring disorder [24].

Topics related to substance use, including alcohol use during pregnancy, are reviewed separately [25,26]. (See
"Substance use during pregnancy: Screening and prenatal care" and "Alcohol intake and pregnancy".)

Patients with nonabstinence goals — We treat patients whose treatment goal is reduction of alcohol use with
naltrexone as naltrexone can be initiated while the patients is still drinking. Studies of acamprosate have generally
enrolled patients who have abstained prior to starting medication.

PATIENTS REQUIRING ADDITIONAL THERAPY

For individuals who have not responded adequately to either naltrexone or acamprosate we suggest the following
therapeutic options.

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Dose adjustments — Trials have not supported using higher doses in individuals who have not responded sufficiently
to initial therapy. Despite this, clinicians will often try a higher dose of medication if a lower dose does not reduce
drinking sufficiently. A plausible rationale for this practice is that a higher dose might compensate for missed doses.
Additionally, a higher dose may have a greater perceived effect by an individual patient. In one small study, a higher
level of beta-naltrexone correlated with less alcohol craving [27]. This may provide a rationale for using higher dose of
naltrexone (ie, 100 mg) in patients with persistent craving.

Subsequent medication trials — There are limited empirical data supporting augmenting options for suboptimal
response to initial medication in the treatment of alcohol use disorder. Our practice is generally to switch from one
medication to another in order to minimize polypharmacy. (See 'Combining medications' below.)

For patients who do not respond to naltrexone or acamprosate (or if they are contraindicated), our next choices are
disulfiram or topiramate (unless contraindicated). We choose between these based on clinical presentation. For
example, in patients who are motivated towards abstinence, and in cases where significant social support is available,
we favor treatment with disulfiram. In patients with a seizure disorder, we favor topiramate ( table 1).

Disulfiram — Clinical trials suggest that disulfiram is effective principally when taken under supervised conditions.
Disulfiram is an aversive agent that does not directly influence motivation to drink, but discourages drinking by
causing an accumulation of alcohol’s primary metabolite, acetaldehyde. This accumulation causes unpleasant effects
such as sweating, headache, dyspnea, lowered blood pressure, flushing, sympathetic overactivity, palpitations,
nausea, and vomiting [28].

● Administration – Disulfiram is initially given at 250 to 500 mg/day for one to two weeks, followed by an average
maintenance dose of 250 mg/day with a range from 125 to 500 mg based on the severity of adverse effects.

Forty-eight hours of total abstinence is needed prior to starting disulfiram. Patient education should address
"hidden" forms of ethanol (eg, tonics and mouthwashes) and also the duration of the drug's activity (up to 14
days after stopping).

Supervised dosing is not required for this medication, as highly motivated patients likely do not require this level
of oversight. Prior research, however, has suggested that patients who do have the benefit of supervised
disulfiram dosing, via strong social support, tend to fare substantially better than controls with regards to
sustained abstinence [29].

● Efficacy – Several blinded randomized controlled trials have failed to demonstrate a treatment effect for
disulfiram according to one meta-analysis [29]. However, investigators have argued that the unique deterrent
effect of disulfiram necessitates open-labeled studies to investigate its efficacy [29-31]. Meta-analysis of 17 open-
labeled studies found a medium to large treatment effect for disulfiram over controls, which included both
placebo and medication comparators (naltrexone and acamprosate) on abstinence outcomes (Hedges’ g = 0.7,
95% CI 0.46-0.93) [29]. However, the ability to draw conclusions from this analysis is limited by substantial
heterogeneity among trials in regard to patient populations, measured outcomes, and co-treatments; in
addition, several studies were judged to have possible risk of bias.

● Disulfiram reaction – Reactions to disulfiram are self-limited. However, some individuals taking disulfiram who
drink alcohol or alcohol-containing products can have a severe reaction to the combination. The severity and
duration of the reaction depends on the amount of alcohol ingested. The reaction may last for several hours or
up to a day.

Individuals may present with symptoms such as chest pain, confusion, headache, and vomiting that require
further evaluation for myocardial infarction and other etiologies. Once myocardial infarction is excluded in
patients with chest pain, treatment is primarily supportive (antiemetics for vomiting; Trendelenburg positioning
and intravenous fluids for orthostatic hypotension; diphenhydramine for flushing).

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Fomepizole has been suggested for life-threatening symptoms of acetaldehyde in patients with severe
presentations. Fomepizole (4-methylpyrazole), administered as a single intravenous 7.5 mg/kg dose, blocks
aldehyde dehydrogenase and has been shown to reverse disulfiram reactions in a small case series of patients
with nonspecific electrocardiogram changes with chest pain who are unresponsive to fluid administration and
norepinephrine [32,33].

● Contraindications – Contraindications to disulfiram include clinically significant coronary artery disease,

psychosis and known hypersensitivity to the medication or other thiuram derivatives [34,35].

● Adverse effects – Side effects of disulfiram are usually minor, including fatigue, mild drowsiness, headache, and
dermatitis. Severe adverse reactions are rare but include psychosis and hepatitis. Individuals receiving disulfiram
should be monitored for hepatotoxicity several weeks after initiating treatment and then every six months if
treatment with disulfiram continues [36].

Topiramate — Topiramate is our preferred choice of medications in patients who have a seizure disorder that would
be appropriately treated with it, and who have failed initial treatment with naltrexone or acamprosate.

Topiramate, an anticonvulsant medication with pharmacological properties including blocking of voltage-dependent

sodium channels, potentiation of gamma-aminobutyric acid mediated transmission and antagonism of glutamate
receptors, has been found to decrease alcohol use in individuals with alcohol use disorder.

● Administration – Topiramate is initiated at a dose of 25 mg daily and can be slowly titrated up to a maximum
dose of 300 mg/day, over eight weeks. A titration schedule is shown in the table ( table 2).

● Efficacy – In clinical trials, topiramate reduces alcohol consumption compared with placebo [17,37]. A meta-
analysis of seven clinical placebo-controlled trials with a total of 1125 individuals with alcohol dependence
demonstrated efficacy for topiramate with higher rates of abstinence and lower rates of heavy drinking, but
similar measure of alcohol craving [37]. The specific outcome measures used varied across studies, but overall,
the effects were judged to be small to moderate.

● Adverse effects – Adverse effects associated with topiramate include cognitive impairment (eg, word-finding
difficulties), paresthesias, weight loss, headache, fatigue, dizziness, and depression. Many of these are
intolerable to a relatively small but significant proportion of individuals. (See "Antiseizure medications:
Mechanism of action, pharmacology, and adverse effects", section on 'Topiramate'.)

Gabapentin — Gabapentin may be a reasonable option for patients who may have previously failed a first-line
option, particularly if gabapentin was used during a successful ambulatory detoxification.

Clinical trials testing the efficacy of gabapentin at various doses from 900 to 3600 mg have found mixed results in
treatment for alcohol use disorder [38-40]. In a meta-analysis of seven placebo-controlled randomized controlled
trials, gabapentin was effective only on a single drinking outcome – percent of heavy drinking days (g = 0.64, 95% CI
0.06-1.22) [41]. In one small trial, the efficacy of gabapentin in reducing heavy drinking appeared more pronounced in
those with withdrawal symptoms compared with those without [40]. (See "Ambulatory management of alcohol
withdrawal", section on 'Very mild withdrawal (CIWA-Ar <10)'.)

One important risk of gabapentin is its addictive potential.

Combining medications — Combining medications in the treatment of alcohol use disorder has not been supported
by trials. Theoretically, the combination of medications with different mechanisms of action offers the possibility of
more effective treatment for patients who do not respond adequately to an individual agent. As an example, if some
effect is achieved with naltrexone, adding acamprosate could have added effect in an individual.

However, randomized clinical trials have thus far not found medication combinations (naltrexone/acamprosate [13]
and naltrexone/sertraline [42,43]) to be more effective than the individual medications. In most cases, our practice is
to switch from agent to another rather than adding a second agent.

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Medications with limited empirical support — Other medications with few data to support their use are discussed
briefly below. Due to limited empirical support in the treatment of alcohol use disorder, we cannot recommend them
as first- or second-line agents until further studies support their efficacy.

● Nalmefene – Nalmefene, an opioid antagonist, has been found to reduce drinking in individuals with alcohol use
disorder using a targeted dosing strategy; however, the methodological rigor of the trials have been questioned
[44,45]. Nalmefene has several potential advantages over naltrexone, including absence of dose-dependent liver
toxicity, longer-acting effects, and more effective binding to central opiate receptors. Nalmefene is approved for
treatment of alcohol use disorder in the European Union. It is not available in the United States [17,46-49].

● Selective serotonin reuptake inhibitors (SSRIs) – Preliminary evidence suggests that subtypes of alcohol
dependence may respond differently to serotonergic drugs, with more favorable outcomes seen in the group
characterized by a later age of onset, less psychosocial morbidity, and low familial loading. Additionally, SSRIs
may be useful in treating individuals with depression and substance use disorder, commonly occurring
comorbidities [50-53].

● Ondansetron – This is a serotonin 5-HT3 receptor antagonist used to treat chemotherapy-induced nausea.
Ondansetron may be selectively efficacious in individuals with early-onset subtype of alcohol dependence (onset
of problem drinking prior to age 25 years) and in individuals with family history of alcohol use disorder [54-56].

● Varenicline – While an earlier study reported on the potential for varenicline to reduce alcohol consumption in
individuals with alcohol use disorder [57], this effect might be more limited [58] and in need of further validation.
Some studies suggest that varenicline treatment may be associated with reduced drinking in patients with
alcohol addiction who smoke and in patients with alcohol use disorder and depression [59,60].

● Others – Baclofen [61,62], prazosin, and doxazosin (alpha-1 antagonists) [63] also have limited data to support
their use.

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions around the world are
provided separately. (See "Society guideline links: Alcohol use disorders and withdrawal".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient
education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five
key questions a patient might have about a given condition. These articles are best for patients who want a general
overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more
sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for
patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics
to your patients. (You can also locate patient education articles on a variety of individuals by searching on “patient
info” and the keyword(s) of interest.)

● Basics topic (see "Patient education: Alcohol use — when is drinking a problem? (The Basics)")

● Beyond the Basics topic (see "Patient education: Alcohol use — when is drinking a problem? (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

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● Medication treatment of alcohol use disorder has been shown to be effective in patients with moderate to severe
subtypes of the disorder ( algorithm 1).

Medication treatment is less well studied in patients with mild alcohol use disorder. In these patients, we suggest
initial treatment with psychosocial interventions rather than with medication. (See 'Indication for
pharmacotherapy' above.)

For most patients treated with medication for moderate to severe alcohol use disorder, we suggest initial
treatment with naltrexone versus other medications available (Grade 2C). Naltrexone is preferred because of its
once daily dosing and the ability to begin treatment while the individual is still drinking (See 'First-line treatment'
above.)

Naltrexone can be taken orally or administered in long-acting injectable; the latter is injected monthly and may
improve adherence. (See 'Naltrexone' above.)

● Acamprosate is an appropriate alternative to naltrexone for initial therapy and is our first-choice treatment for
individuals who are using opioids or prescribed opioids as well as in those with advanced liver disease (See
'Acamprosate' above.)

● For patients who do not respond to naltrexone or acamprosate (or if they are contraindicated), treatment options
include disulfiram or topiramate (unless contraindicated). (See 'Subsequent medication trials' above.)

● For patients with alcohol use disorder who are pregnant, psychosocial treatments are prioritized as there is a
paucity of data on the safety of pharmacologic therapies for alcohol use disorder. (See 'Pregnancy' above.)

● Combining medications for the treatment of alcohol use disorder, has not been supported by empirical data. To
avoid polypharmacy, our practice is to switch from agent to another rather than adding a second agent. (See
'Combining medications' above.)

● Other medication options with limited data supporting their use include gabapentin, selective serotonin
reuptake inhibitors, ondansetron, and varenicline. We reserve their use for refractory cases. (See 'Medications
with limited empirical support' above.)

ACKNOWLEDGMENT

The UpToDate editorial staff acknowledges Bankole A Johnson, DSc, MD, MBChB, MPhil, FRCPsych, DFAPA, who
contributed to an earlier version of this topic review.

Use of UpToDate is subject to the Terms of Use.

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Topic 7800 Version 36.0

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GRAPHICS

Pharmacologic treatment of moderate to severe alcohol use disorder*

LAI: long-acting injectable; IM: intramuscularly; CrCl: creatinine clearance.

* This algorithm assumes management of alcohol withdrawal is not necessary or has already been
completed. Pharmacologic recommendations are for nonpregnant adults. In all individuals with
moderate to severe alcohol use disorder, we recommend psychosocial treatment in addition to
pharmacological treatment.

¶ For individuals who want medication treatment for opioid use disorder concomitant with alcohol
use disorder and in individuals who have come off of prescribed or illicit use of opioids, we typically
treat with naltrexone after a minimum washout of 7 to 10 days and in some cases up to 14 days
depending on the half-life of prior opioid used, the length of time on prior medication and its dosing
and frequency.

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Δ The decision to treat with oral versus LAI naltrexone is one of shared decision making and takes
into account patient preference, prior treatment response, and adherence to medications.

◊ Abstinence remains the primary goal of treatment of alcohol use disorder; however, reduction of
heavy drinking or of lower risk use are acceptable alternatives for those who do not quit.

§ Starting dose of acamprosate should be 333 mg orally 3 times daily in individuals with CrCl 30 to 50
mL/min. Acamprosate is contraindicated in individuals with CrCl <30 mL/min. Refer to other
UpToDate content.

¥ Refer to UpToDate clinical topic and separate table for recommended topiramate dose escalation
schedule.

‡ Gabapentin is an alternative when other agents cannot be used or in individuals with prior
response to it. Gabapentin has potential for misuse and addiction. Refer to UpToDate clinical topic,
table, and drug monograph for use and dosing.

† Disulfiram may be associated with a disulfiram reaction when taken with alcohol containing
products. 48 hours of abstinence from alcohol use is required prior to starting disulfiram. In
individuals who cannot achieve this or maintain abstinence throughout treatment with disulfiram,
we suggest treatment with topiramate as the next choice. Disulfiram is contraindicated in individuals
with significant coronary disease, or in those with known hypersensitivity to the agent. Refer to other
UpToDate content for treatment of disulfiram reaction.

** Refer to other UpToDate content for other medication options.

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First- and second-line agents used in the treatment of adults with alcohol use disorder

Titration or Dosing and

Initial daily Select adverse
  daily dose Contraindications monitoring
dose effects*
range considerations

First-line agents: For newly diagnosed patients with moderate to severe alcohol use disorder, we prefer naltrexone. In
individuals who are prescribed opioids or are using opioids or in those with hepatic failure or acute hepatitis, we use
acamprosate.

Naltrexone 380 mg IM every — Injection site Hypersensitivity to May begin

(intramuscular) 4 weeks. reaction: pain, naltrexone or treatment while
cellulitis, component of patient is still
hematoma, formulation. drinking.
induration, sterile
Current opioid use or Liver enzymes
abscess.
prescription for pain should be
Neurologic: management. monitored within
headache, several weeks of
Hepatic failure or
dizziness, sleep initiating
elevated liver
disturbance. treatment and
enzymes ≥3 to 5
then every 6
Gastrointestinal: times normal.
months during
nausea,
ongoing
decreased
treatment.
appetite,
abdominal pain.

Hepatic:
increased
transaminases.

Naltrexone 50 mg orally once Usual dosage Neurologic:

(oral) daily. Some range: 50 to 100 headache,
individuals may mg/day. dizziness, sleep
require titration disturbance.
to 100 mg once
Gastrointestinal:
daily after 1 week.
nausea,
decreased
appetite,
abdominal pain.

Hepatic:
increased
transaminases.

Acamprosate 666 mg orally 3 — Gastrointestinal: Hypersensitivity to Lower initial dose

times daily. diarrhea. acamprosate. (ie, 333 mg orally
3 times daily)
Neurologic: CrCl <30 mL/min.
recommended for
anxiety, insomnia,
individuals with
depression,
moderate kidney
dizziness.
impairment (CrCl
30 to 50 mL/min).

Lower initial dose

(ie, 333 mg 2
times daily)
recommended for
individuals
weighing <60 kg.

Second-line agents: In individuals who have not had clinically acceptable response to initial agents, we suggest the following
agents. In individuals with seizure disorder, we use topiramate.

Disulfiram Loading dose: After loading Neurologic: Severe myocardial Liver enzymes

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250 to 500 mg dose, average fatigue, disease, psychosis, should be

orally once daily maintenance headache, bitter hypersensitivity to monitored within
for 1 to 2 weeks. dose is 250 mg (garlic) taste, thiuram derivatives, several weeks of
orally once daily neuropathy. ongoing alcohol use. initiating
(range: 125 to 500 treatment and
Hepatic:
mg/day). then every 6
hepatitis.
months during
ongoing
treatment.

Topiramate 25 mg orally once Increase daily Gastrointestinal: Hypersensitivity to Lower doses (eg,
(immediate daily. dose by 25 mg abdominal pain, topiramate. 50% dose
release) per week for 4 diarrhea, nausea. reduction) and
weeks, then slower titration
Metabolic:
increase by 50 mg recommended for
weight loss.
per week to kidney
maximum dose of Neurologic: impairment (CrCl
300 mg per day dizziness, <70
as tolerated. Daily drowsiness, mL/min/1.73 m2 ).
doses >50 mg are fatigue, cognitive
administered in impairment (eg,
divided doses.¶ memory
impairment, word
finding
difficulties),
paresthesias.

Gabapentin 300 mg orally Increase daily Neurologic: Hypersensitivity to Lower doses

once daily. dose by 300 mg dizziness, gabapentin or recommended for
every 1 to 2 days drowsiness, components of kidney
as tolerated to mood changes. formulation. impairment (CrCl
target dose of <50 mL/min).
Gastrointestinal:
600 mg 3 times
nausea, diarrhea.
daily.
Risk for misuse
and addiction.

In patients with a robust response to therapy or in remission, UpToDate prefers continuation of pharmacotherapy and
psychosocial supports for one year or more. In patients who are not meeting treatment goals, we regularly reassess
treatment plan and will typically intensify psychosocial supports and consider dose adjustment, if applicable. If adequate
progress is not demonstrated within 6 months of initiating a first- or second-line agent, we consider alternative
pharmacotherapy. Refer to UpToDate topic reviews of approach to treating alcohol use disorder for additional guidance.

IM: intramuscularly; CrCl: creatinine clearance.

* This is not a complete list. For more information, refer to Lexicomp drug information included with UpToDate.

¶ Refer to topiramate dose-escalation table in UpToDate.

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Topiramate dose-escalation schedule

Week AM dose PM dose Total daily dose (mg)

1 None One 25 mg tablet 25

2 None Two 25 mg tablets 50

3 One 25 mg tablet Two 25 mg tablets 75

4 Two 25 mg tablets Two 25 mg tablets 100

5 Two 25 mg tablets One 100 mg tablet 150

6 One 100 mg tablet One 100 mg tablet 200

7 One 100 mg tablet One 100 mg tablet

250
and two 25 mg tablets

8 One 100 mg tablet

One 100 mg tablet
300
and two 25 mg tablets and two 25 mg tablets

Reprinted by permission from Springer: Addiction Medicine by Johnson BA. Copyright © 2011.

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Contributor Disclosures
Stephen R Holt, MD, MS, FACP No relevant financial relationship(s) with ineligible companies to disclose. Murray B Stein, MD,
MPH Equity Ownership/Stock Options: EpiVario [Substance use disorders and PTSD]; Oxeia Biopharmaceuticals [Traumatic brain
injury].
Consultant/Advisory Boards: Acadia Pharmaceuticals [Anxiety and traumatic stress-related disorders]; Aptinyx [Anxiety and
traumatic stress-related disorders]; atai Life Sciences [Anxiety and traumatic stress-related disorders]; Bionomics [Anxiety and
traumatic stress-related disorders]; BioXcel Therapeutics [Anxiety and traumatic stress-related disorders]; Boehringer-Ingelheim
[Anxiety and traumatic stress-related disorders]; Clexio [Anxiety and traumatic stress-related disorders]; Eisai [Anxiety and
traumatic stress-related disorders]; EmpowerPharm [Anxiety and traumatic stress-related disorders]; Engrail Therapeutics [Anxiety
and traumatic stress-related disorders]; GABA Therapeutics [Anxiety and traumatic stress-related disorders]; Jazz Pharmaceuticals
[Anxiety and traumatic stress-related disorders]; Oxeia Biopharmaceuticals [Traumatic brain injury]; Roche/Genentech [Anxiety and
traumatic stress-related disorders].
Other Financial Interest: Biological Psychiatry [Deputy Editor]; Depression and Anxiety [Editor-
in-chief].
All of the relevant financial relationships listed have been mitigated. Michael Friedman, MD No relevant financial
relationship(s) with ineligible companies to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting
through a multi-level review process, and through requirements for references to be provided to support the content.
Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.

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