Seminar

Alcohol use disorders

Jason P Connor, Paul S Haber, Wayne D Hall

Alcohol use disorders are common in developed countries, where alcohol is cheap, readily available, and heavily
promoted. Common, mild disorders often remit in young adulthood, but more severe disorders can become chronic
and need long-term medical and psychological management. Doctors are uniquely placed to opportunistically assess
and manage alcohol use disorders, but in practice diagnosis and treatment are often delayed. Brief behavioural
intervention is eective in primary care for hazardous drinkers and individuals with mild disorders. Brief interventions
could also encourage early entry to treatment for people with more-severe illness who are underdiagnosed and
undertreated. Sustained abstinence is the optimum outcome for severe disorder. The stigma that discourages
treatment seeking needs to be reduced, and pragmatic approaches adopted for patients who initially reject abstinence
as a goal. To engage people in one or more psychological and pharmacological treatments of equivalent eectiveness
is more important than to advocate a specic treatment. A key research priority is to improve the diagnosis and
treatment of most aected people who have comorbid mental and other drug use disorders.

Introduction
Alcohol use disorders are among the most common and
undertreated mental disorders in developed countries.1
Aected individuals have impaired control over their
alcohol consumption and continue to drink despite the
serious adverse eects on their health and the lives of
their spouses, children, family members, friends, and
workmates.
Applying Diagnostic and Statistical Manual of Mental
Disorders 5th edition (DSM-5)2 diagnostic criteria, in
201213 360% of male and 227% of female adults in
the USA met the criteria for alcohol use disorders at
some time in their lives, and 176% of men and 104% of
women did so in the past year.3 Dierences between the
sexes have narrowed because womens drinking patterns
have become similar to mens in recent birth cohorts.4
The risk of development of an alcohol use disorder
increases with the frequency of binge drinking, although
most heavy drinkers do not meet the criteria for alcohol
dependence.5
The disorders are most prevalent in young adulthood
(age 1829 years).3 Mild disorders often remit as young
adults enter the labour market, marry, and assume
responsibility for children.6 More-severe alcohol use
disorders are one of the most undertreated mental
disorders, with less than 15% of patients receiving
treatment.7 The rst episode of treatment is delayed
until the disorder is well established, typically after age
30 years.8 Doctors are uniquely placed to opportunistically assess and manage alcohol use disorders. In
this Seminar, we describe eective behavioural and
pharmacological treatments and emerging research
directions.

Alcohol-related burden of disease

Alcohol consumption is causally linked to 60 dierent
diseases. The major causes of premature death to which
it contributes are injury, alcoholic liver disease, heart
disease and stroke, cancers, and gastrointestinal disease.9
Cardiovascular benets might be gained from very low
levels of alcohol use for middle-aged men (typically age

4060 years), but these benets are most likely to be seen

in developed countries where risk of heart disease is
high. Even in these countries, the total harm caused by
alcohol use in the population far outweighs the modest
cardiovascular benets.10
Alcohol use contributes to around 4% of the global
burden of disease. This contribution is equivalent to that
of tobacco smoking because alcohol use causes more
premature deaths in young adults than does tobacco
smoking.11 This burden is greatest in developed countries,
where more people regularly drink to intoxication and
other causes of mortality are low.11 The harms caused by
alcohol are related to the average volume of alcohol
consumed and the pattern of drinking. The risk of harm
rises steeply when more than 1020 g of alcohol is
consumed per day. Episodic drinking to intoxication
greatly increases the risks of accidents, injuries, violence,
and heart disease.11
People with alcohol use disorders account for around
half of all the alcohol-related harm in developed
societies.12 The remainder arises from accidents, assaults,
and suicides in young adults, especially men, who engage
in episodic drinking to intoxication, but most of whom
do not meet the criteria for alcohol use disorders. The
harms arising from both intoxication and such disorders
need to be prevented to reduce the burden of alcoholrelated harm.5

Published Online
September 4, 2015
http://dx.doi.org/10.1016/
S0140-6736(15)00122-1
See Online/Comment
http://dx.doi.org/10.1016/
S0140-6736(15)00123-3
Centre for Youth Substance
Abuse Research (J P Connor PhD,
Prof W D Hall PhD) and
Discipline of Psychiatry
(J P Connor), The University of
Queensland, Brisbane, QLD,
Australia; Sydney Medical
School, University of Sydney,
Sydney, NSW, Australia
(Prof P S Haber MD); Drug
Health Services, Sydney Local
Health District, Sydney, NSW,
Australia (Prof P S Haber); and
Addictions Department, Kings
College London, London, UK
(Prof W D Hall)
Correspondence to:
Prof Wayne D Hall, Centre for
Youth Substance Abuse
Research, The University of
Queensland, Brisbane, QLD
4029, Australia
[email protected]

Diagnostic systems
Version 10 of the International Classication of Diseases13
distinguishes harmful use from dependence, whereas
DSM-III14 to DSM-IV-TR15 (19802013) distinguished
between alcohol abuse and alcohol dependence.
These two categories have been combined in DSM-52
into one categoryalcohol use disorderbecause of
empirical evidence that symptoms of such disorders vary
in severity along one dimension (appendix).16
According to DSM-5, at least two of 11 symptoms need
to be present for diagnosis of an alcohol use disorder.
Severity is assessed by the number of symptoms
recognised (appendix).

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See Online for appendix

Seminar

Description

Level of evidence*

Cognitive behaviour
therapy

This approach addresses cognitive, aective, and interpersonal triggers for alcohol use. It enhances drinking refusal self-ecacy skills; identies
and modies alcohol expectancies; improves problem-solving skills; and develops more eective coping strategies, including relaxation
approaches.

High2024

Motivational
enhancement
therapy

High2022
This therapy is a patient-centred approach that enhances motivation to change behaviour. It uses a collaborative therapeutic approach to assist
patients to recognise and resolve ambivalence, and develop their own reasons to reduce or abstain from drinking. Key strategies include
collaborative identication of the gap between the patients present and desired health (ie, goalstatus discrepancy), recognition of their resistance
to change, avoidance of confrontational communication, and guided assessment of the pros and cons for change.

Behavioural
therapies based on
conditioning

Cue exposure: repeated exposure to conditioned cues (eg, image or smell of alcohol, or associated emotion) can induce habituation or craving.
Exposure to cues during treatment in the absence of drinking (with or without coping skill practice) is thought to reduce habituation. It is often
combined with other cognitive therapy or skills.
Contingency management: this approach introduces a tangible reinforcer, such as money or vouchers, to increase session attendance or
abstinence. It is more suitable for inpatient and residential settings, and needs more translatable evidence.

Low;23 Moderate25,26

12-step facilitation

This approach oers continuous mutual peer support, usually in the form of self-help groups run by Alcoholics Anonymous. Participation is free of
charge. Participants need to surrender to a higher power to facilitate change. Some groups use a buddy system (a sponsor) to provide support
between group meetings.

Mixed21,22,27

*Summary based on authors narrative review of the highest level of evidence for each treatment. Individuals beliefs about their ability to refrain from drinking. Individuals expectations about the eects of
alcohol consumption.

Table 1: Non-pharmacological behavioural treatments

Ventral tegmental area

Alcohol +

Ventral
tegmental area
interneuron
Reduced GABA
transmission

Nucleus accumbens
Opioid
peptides
Glutamate
inputs
(eg, from
cortex)
Alcohol

GABA
Alcohol +

Dopamine

Dopamine

Glutamate inputs

Figure: Eects of alcohol on selected neurotransmitter systems

The ventral tegmental area is located close to the midline on the oor of the midbrain and contributes to pleasure
and reward through projections to the nucleus accumbens, which has an important role in the cognitive
processing of pleasure, reward, and reinforcement learning. Alcohol is thought to stimulate endogenous opioid
peptides and GABA receptor activity (marked by Alcohol+) in the ventral tegmental area, and inhibit release of
the excitatory neurotransmitter glutamate from nerve terminals that act on neurons in the nucleus accumbens
(marked by Alcohol). These actions enhance dopaminergic transmission. Repeated exposure to alcohol over
time leads to adaption to these eects. GABA=-aminobutyric-acid. Adapted with permission from Gilpin and
Koob,29 and from Nestler.30

Behavioural and neurobiological eects

Alcohol aects a wide range of neurotransmitter systems
in the brain that are implicated in cognition, emotion, and
motivation.17 At low doses, alcohol has rewarding, anxiolytic,
and socially facilitating eects. As the dose increases,
alcohol produces cognitive and psychomotor impairment
that increases the risks of injury, and it also disrupts
emotional regulation in ways that contribute to assaults.
The pleasurable eects of alcohol provide an
explanation for the initiation and persistence of alcohol
use and a part explanation for the development of
2

alcohol use disorders. The repeated pairing of environmental cues and rewards enhances alcohols subjective
and physiological eects via conditioning18 and social
and cognitive learning about the eects of alcohol
(ie, alcohol expectancies). Outcome expectancies (eg,
tension reduction and increased condence) and
individuals beliefs about their ability to refrain from
drinking (ie, self-ecacy) contribute to the risk of
development of alcohol use disorders.19 Individuals with
high alcohol expectancies and low self-ecacy are at
increased risk of problem drinking.19 Both factors can be
modied by cognitive behaviour therapies (table 1).28
Alcohol crosses the bloodbrain barrier and interacts
with many neurotransmitter systems rather than a
single molecular target. It increases GABA, glycine,
nicotinic acetylcholine, and serotonin activity. It also
indirectly increases dopamine, opioid, and endocannabinoid activity (gure) and inhibits glutamate
transmission. These complex eects contribute to acute
intoxication. The pleasurable eects seem to be
mediated by increased dopaminergic transmission in
the mesolimbic reward system.
The clinical features of alcohol dependence include
tolerance and withdrawal. With repeated dosing, neurotransmitter responses are reduced, and increased doses
of alcohol are needed to produce the same eect. Abrupt
cessation produces rebound eects that are experienced
as withdrawal symptoms. Each of the neurotransmitter
systems aected by alcohol has been targeted with some
success by pharmacological treatments. An increased
understanding of the neurobiology holds promise to
translate into improved targeted drug treatments for
alcohol dependence.

Risk factors for alcohol use disorders

Patients and their families need to understand that
alcohol use disorders are not merely a result of an
individual moral failing but arise from the combined

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Seminar

eects of many personal, social, and biological factors.

The prevalence of alcohol use disorders in the
population is increased in cultures that encourage
adults to drink to intoxication. These cultures typically
make alcohol readily available at low cost, allow use in
everyday settings, and create a social milieu in which
drinking to intoxication is socially approved and
promoted by ubiquitous alcohol advertisements.31 Early
initiation and hazardous alcohol consumption in
adolescence predict a raised risk of development of
alcohol use disorders in adulthood.32 Other risk factors
include a family history of alcohol dependence, low
parental monitoring and poor family support, childhood
conduct and mood disorders, low self-control and
impulsivity, and positive alcohol expectancies.33 Peer
alcohol use is one of the strongest predictors of
adolescent alcohol use.33 People with a family history of
early-onset alcohol use disorders in several male and
female rst-degree relatives are at high risk of
development of such disorders.34 This pattern shows the
combined eects of increased genetic risk and a
childhood environment in which parents model heavy
drinking.
Twin studies estimated that 5070% of the risk of
alcohol use disorders is attributable to additive genetic
factors.35 The strongest genetic association is with a
genotype that reduces the risk. Alcohol dehydrogenase
and the mitochondrial form of aldehyde dehydrogenase
(ALDH2) are liver enzymes that metabolise alcohol.
The ALDH2 genotype is expressed by two primary
alleles known as ALDH2*1 and ALDH2*2. Carriers of
ALDH2*2 (ie, those with a single copy of the allele)
have impaired alcohol metabolism. If they drink
alcohol, they usually have facial ushing, sweating,
tachycardia, nausea, vomiting, and headache, which
protect against development of alcohol use disorders.36
This polymorphism is carried by roughly 23% of all
Asian populations (range 153%) but is rare in
Europeans.36
Risk alleles have been identied that modestly increase
the risk of alcohol use disorders.37 These alleles aect
neurotransmitter responses to alcohol in the dopaminergic, opioidergic, GABAergic, serotonergic, cholinergic, and glutamatergic systems. These gene variations
each contribute less than 1% of the genetic risk for
alcohol use disorders.38 The hope is that the remaining
contributors to genetic risk will be identied39 by higherpowered genome-wide association studies that examine
the dierences between cases and controls across large
numbers of single-nucleotide polymorphisms.

Clinical presentation, signs, and symptoms in

primary care
Drinkers often underestimate their alcohol consumption40 because standard drink units are usually
poorly understood and vary between 8 g in the UK and
1975 g in Japan.41 Recommended low-risk alcohol

consumption values also vary between countries, but

typical ranges are 2040 g per day (<200 g per week) for
men and 1030 g per day (<140 g per week) for women.
With the variations in glass size and average pours,
these values roughly equate to two to three drinks (eg,
glasses of wine, shots of whisky) per day for men and
one to two drinks per day for women. These values
approximate Rehm and colleagues42 estimated lifetime
risk thresholds for alcohol-related mortality from
chronic illness (two drinks per day) and acute injury
(three to four drinks per day). Medical and other health
professionals should be familiar with national safe
drinking guidelines and the alcohol content of widely
consumed beverages. Age of onset and duration of
alcohol use, pattern of use, and circumstances of any
periods of abstinence should be assessed.
Roughly half of individuals with alcohol use disorders
remain undiagnosed if doctors rely only on their clinical
judgment.43 Structured questions about alcohol use and
brief questionnaires such as CAGE,44 the Michigan
Alcohol Screening Test,45 and Alcohol Use Disorders
Identication Test (AUDIT)46 can identify patients who
need further assessment. The ten-item WHO AUDIT46
is useful in detection of problem drinking in a range of
clinically and culturally diverse populations (sensitivity
and specicity typically 8090%).47,48 It takes less than
2 min to complete and is easily scored. Scores of 8 or
higher suggest hazardous drinking, and scores of 16 or
higher suggest probable alcohol dependence. A brief
version of the AUDIT (AUDIT C), consisting of the rst
three questions (how often is alcohol consumed, how
many alcoholic drinks are typically drunk in a day, and
how often are six or more drinks consumed), has similar
psychometric properties to the full scale. A cuto score
of 3 has been suggested for hazardous drinking and
4 for possible alcohol use disorder.47

Management
Patients are most likely to be diagnosed and managed in
a medical settingeg, when they are treated in hospital
for an alcohol-related injury, or gastrointestinal or liver
disease. The adverse eects of their alcohol use might be
discovered in the course of other treatmenteg, preparation for surgery or via abnormal blood tests.
A patient seeking treatment for an alcohol use disorder
is less common.
Clinical assessment should obtain a detailed history
of alcohol use, the symptoms of alcohol use disorder
(panel), and the details of the last drinking session.
The use of other substances, including tobacco and
prescription drugs, should be assessed. Patients should
be asked about any harm to their physical and mental
health, social situation, including interpersonal and
forensic issues, and their work. Their insight into the
contribution of alcohol to their health problem and
their motivation to change their drinking habits should
be assessed. Inquiries should be made about any

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Seminar

Diagnostic investigations

Panel: Common features to identify on physical

examination
Mental state: intoxication or withdrawal, delirium,
depression, anxiety, psychosis, motivation, insight
Neurological: cognitive decline, cerebellar degeneration,
peripheral neuropathy, proximal myopathy
Cardiovascular: hypertension, cardiomyopathy, atrial
brillation (so-called holiday heart)
Gastrointestinal: malnutrition, liver disease, pancreatic
disease
Respiratory: aspiration pneumonitis, pneumonia,
tuberculosis, tobacco-related disorders
Endocrine: pseudo-Cushings syndrome, hypogonadism

Monitor
Identify
abstinence high-risk
drinking

Time to
normalise

Usefulness for
detection of high-risk
drinking
Sensitivity Specicity

Routinely available tests

Alcohol concentration in breath or blood

Yes

No

Hours

Low

-glutamyl transferase

No

Yes

4 weeks

Low

High
Moderate

Mean corpuscular volume of red blood cells No

Yes

3 months

Low

Moderate

Aspartate aminotransferase

No

Yes

4 weeks

Low

Low

Carbohydrate-decient transferrin

No

Yes

4 weeks

Moderate

High

Ethyl glucuronide and ethyl sulphate

Yes

No

2 days

High

High

Phosphatidyl ethanol

No

Yes

4 weeks

High

High

Tests done in specialised laboratories*

*May be costly.

Table 2: Common biological markers

previous treatment for alcohol use disorders, its

outcome, and any mental health symptoms, diagnoses,
or treatment.
Physical examination should begin by assessment of
symptoms of intoxication and withdrawal. Intoxication
manifests in slurred speech, ataxia, and inappropriate
aect. Alcohol value should be measured in the blood or
breath. The earliest signs of withdrawal are restlessness,
tachycardia, and a ne action tremor.
A neurological examination should look for signs of
Wernickes encephalopathy or acute intracranial lesion.
The classic triad of confusion, ataxia, and nystagmus
suggests Wernickes encephalopathy, but most cases will
have only one or two signs.49,50 Tests should be done for
upper motor neuron signs, particularly lateralising signs,
such as pupillary asymmetry, that suggest an intracranial
lesion. Orientation, short-term memory, mental state,
insight, and motivation should be assessed, as should
common cerebellar signs such as nystagmus and ataxia.
A general medical examination should identify other
physical signs of alcohol use disorders (panel) and exclude
unrelated disorders. In particular, alcohol is an underrecognised leading reversible cause of hypertension.51,52
4

Standard blood tests, including liver tests and mean

corpuscular volume of red blood cells (MCV), are often
abnormal in people with alcohol use disorders, but these
tests have low sensitivity and specicity.53,54 -glutamyl
transpeptidase (gGT) is the most widely used marker but
is of little value because of poor sensitivity and specicity
(table 2): gGT can detect only about one in ve cases of
heavy drinking.53 Its predictive value is greatest in
overweight (body-mass index [BMI] >25 kg/m) men
older than 40 years.5557 It is rarely helpful in detection of
heavy drinking in young lean women (age <20 years).58
The most common cause of high gGT is an increased
BMI.55 Other causes of liver disease and some drugs
reduce the specicity of gGT as a marker of alcohol use
disorders. Uric acid, triglycerides, MCV, and liver
enzymes are commonly raised but are not specic to
alcohol use disorders. The presence of several
abnormalities is uncommon but suggestive of alcohol
use disorders.
Biomarkers for alcohol use that are more sensitive and
specic than standard clinical assays exist, but they are
not widely used because of their high cost and limited
availability. These biomarkers include carbohydratedecient transferrin, ethyl glucuronide, ethyl sulphate,
phosphatidyl ethanol, and fatty acid ethyl esters (table 2).54
Once a disorder is recognised, full blood count and
biochemical, glucose, and liver tests are important in
assessment of medical complications. Alcohol use
disorders are associated with nutritional disorders, but
vitamin testing is costly and not routinely recommended.
Imaging studies (eg, in the brain and liver) should be
done only when clinically indicated.

Acute management
A heavy drinker who cannot be roused should be admitted
to hospital to prevent fatal aspiration. Airway protection,
hydration, management of seizures, and monitoring of
blood glucose and ketoacidosis might be necessary.
Individuals with alcohol intoxication who show aggressive
behaviour might need intramuscular sedation in the
emergency department.59 Supportive care protects
unconscious patients from injury. Patients should be
monitored for withdrawal as intoxication resolves.
Withdrawal can be managed in the community,
primary care, specialist services, or hospital, according to
its severity and the availability of services. The most
widely used withdrawal assessment scale is the clinical
institute withdrawal assessment for alcohol (revised
version; CIWA-Ar).60 It is sensitive, reproducible, and can
be used with minimum training, but a high score can
show intercurrent illnesses rather than alcohol withdrawal. No withdrawal scale has been validated in the
inpatient setting, in which comorbidity is prevalent.
Rating scores should be checked carefully before treatment is modied. Serious comorbidity is probably better
managed without use of a scale.

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Seminar

The most widely used drugs for management of alcohol

withdrawal are benzodiazepines.61 These drugs can be
given by xed (eg, day 1: 20 mg four times; day 2: 10 mg
four times; day 3: 10 mg twice; day 4: 5 mg twice; day 5:
5 mg up to twice if needed; day 6: cease), symptomtriggered, or front-loading regimens. High doses are
generally needed in the rst 24 h. They are then tapered
over the next few days and cease within 57 days of initial
treatment. Symptom-triggered dosing needs monitoring
of withdrawal severity according to the CIWA-Ar, dose
adjustment when needed, and close nursing care. Fixed
dosing is most practical in less well monitored settings,
including home detoxication.
Inpatients with comorbidities could be most safely
managed by xed dosing with daily clinical review. Front
loading via hourly dosing of 1020 mg diazepam is
appropriate for those with severe withdrawal symptoms. It
is ceased once the patient settles. Risks of benzodiazepines
include oversedation and benzodiazepine dependence. In
jaundiced patients with liver failure, oxazepam is preferred
to diazepam because it has a short half-life and no active
metabolites.61 Sedation is hazardous in patients with head
injury or respiratory failure, and should be done only with
specialist oversight in high-dependency units.
Potentially fatal complications of alcohol withdrawal
include seizures and delirium. Withdrawal delirium (ie,
delirium tremens) occurs in roughly 5% of patients. Few
controlled trials to direct management or dosing
regimens have been done.60 Delirium is probably best
managed with intravenous benzodiazepines and antipsychotic drugs in an inpatient or intensive-care unit
setting. Other agents trialled to treat withdrawal include
baclofen, gabapentin, carbamazepine, and valproic acid.
The few studies of these drugs have had mixed ndings.
Until better evidence is obtained, these drugs should not
be used in routine clinical practice.61
Many patients do not need sedation; they do well
with reassurance in a safe, alcohol-free environment.
Supportive care should monitor and manage dehydration,
electrolyte disorders, and infections, and monitor
complications. The risk of relapse to alcohol use after
withdrawal exceeds 90%, so further treatment is needed
to reduce this risk.62
Wernicke-Korsako syndrome is a devastating neurological complication of alcohol use disorders that can
produce lifelong disability or death. Symptoms such as
confusion, ataxia, or nystagmus often emerge during
alcohol withdrawal. The evidence base to guide treatment
of the syndrome is poor,63 and no randomised controlled
trials have been done in the past decade. Guidelines64,65
are related to clinical experience, pathophysiology where
known, and the ease of thiamine supplementation.
Prophylactic parenteral thiamine should be given in
every case. The rst parenteral dose of thiamine should
be given in the emergency department without delay.
Present practice is to give thiamine before any dextrose,
although a recent review66 reported little evidence that

intravenous dextrose precipitates the syndrome. For

prophylaxis, a parenteral dose of 200 mg per day is
recommended. For treatment of suspected or established
Wernicke-Korsako syndrome, the recommended dose
is 500 mg given intravenously three times per day for
23 days.49 Further treatment is guided by response. Oral
thiamine treatment should be continued until sustained
abstinence is achieved, and indenitely if the person
continues to drink.

Dierential diagnosis
In epidemiological surveys, half of all individuals with a
lifetime history of alcohol use disorders have at least one
other mental health disorder.67 Treatment studies typically
exclude patients with concurrent psychiatric diagnoses,
making it dicult to advise how to manage the most
common forms of comorbidity, such as anxiety and mood
(so-called internalising) disorders.68 A comprehensive
psychiatric assessment is essential to identify the primary
disorder or disorders (psychiatric or alcohol use disorder)
for treatment planning. Engagement of patients in
treatment is crucial, and motivational strategies might
assist (table 1).69,70 Mood symptoms typically reduce with
abstinence,71,72 but treatment might be needed for mood
and anxiety disorders that do not remit.73
Research into how to best manage patients with
comorbid alcohol use disorders and other mental disorders,74,75 or drug and alcohol use disorders, is scarce.69,7680
A research priority is to do high-quality treatment trials
of patients with alcohol use disorders who have the most
common forms of psychiatric comorbidity.
Most individuals also have another substance use
disorder. At least half are tobacco smokers81 and a third
have another drug use disorder.67 Alcohol and tobacco
potentiate the risk for head and neck cancers.82 People
using more than one substance have poorer mental
health than do those using only one substance.83 Alcohol
and benzodiazepine use is often overlooked.84 Patients
who also use more than one substance have poor
outcomes from behavioural treatment.25
Heavy drinkers who are prescribed CNS depressants
and opioids need to be carefully monitored.85,86
Dependence on both alcohol and opioid is dangerous.
Most fatal and non-fatal opioid overdoses occur in combination with use of alcohol or benzodiazepine, or both,87
often as a result of respiratory depression.85,88 Whether
detoxication is needed for individuals with dependence
on other substances needs to be established; if so,
evidence-based approaches should be used.89
Alcoholic liver disease is the most common serious
medical complication of alcohol use disorders. Almost
50% of the worldwide burden of liver disease has been
attributed to alcohol consumption.90 The risk of
alcoholic liver disease is highest in overweight (BMI
>2530 kg/m) and obese (BMI >30 kg/m) individuals,
in women, and in those with a family history of
alcoholic liver disease, hereditary haemochromatosis,

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Seminar

and chronic viral hepatitis B and C. Patients presenting

with alcoholic liver disease usually have less severe
alcohol use disorder91 and have consumed less alcohol
than those without such disease.57
Alcoholic liver disease is recognised by clinical
hepatomegaly or abnormal ultrasound. The liver tests are
abnormal and, in most cases, have dominant gGT concentrations and higher concentrations of aspartic acid
aminotransferase than alanine aminotransferase. Treatment options are few. Abstinence is essential in all but
trivial cases of alcoholic liver disease and improves
survival.92 Few treatment trials have been done for people
presenting with alcoholic liver disease, but one trial has
shown baclofen to be safe and eective.93

Brief behavioural interventions

Brief interventions are recommended for all patients
who are drinking hazardously. They usually last
520 min and typically include one to three sessions.94,95
They provide information and advice on safe levels of
consumption and might include motivational interviewing (table 1).96 More frequent, brief interventions
are usually more eective than one extended session.94,95
Brief interventions are moderately eective and can
reduce problem drinking in primary-care patients94 and
inpatients;95 more-intensive interventions in emergency
departments97 and sexual health services can also
do so.98 Studies have been predominantly done in
middle-aged male drinkers. Variations in the content
and intensity of brief interventions create uncertainty
over how they work,99 and more research is needed to
assess their benets.
Screening and brief interventions could encourage
people with alcohol use disorders to receive treatment
early. Patients scoring 07 in the AUDIT in primary
care100 should be given basic alcohol education, those
scoring 815 given straightforward advice on reduction
of hazardous drinking, those scoring 1619 given
straightforward advice in addition to brief counselling
and continued monitoring, and those scoring
2040 referred for specialist assessment.

Relapse prevention

For more on the SMART

recovery model see http://www.
smartrecovery.org

Follow-up studies of untreated patients show average

abstinence of 21% for up to 1 year.101 Most patients reduce
their frequency of heavy drinking because of illness,
adverse social eects, or the urging of family members.102
After formal treatment, meta-analyses nd abstinence
ranging from 25%103 to 43%,104 dependent on treatment
intensity and length of follow-up.
Behavioural treatments improve outcomes (table 1).20,104
These approaches dier in rationale but seem to be
similarly eective.20,21,105 In practice, dierent behavioural
approaches are often combined. Motivational interviewing is most widely used to engage patients in
treatment so that cognitive and behavioural approaches
can modify dysfunctional cognitions and address skill

decits.106 Treatment can take place on an individual or a

group basis. Engagement of spouses of people with
alcohol use disorders in joint therapy is eective.107
12-step facilitation is the most widely recognised group
intervention.106
Dierent pharmacotherapies for relapse prevention are
similarly eective.108 Three drugs have been approved by
the equivalent of the US Food and Drug Administration
(eg, Therapeutic Goods Administration in Australia) to
treat alcohol use disorders by maintenance of abstinence:
naltrexone, acamprosate, and disulram (table 3).
Naltrexone and acamprosate have similar ecacy
(number needed to treat 912).109 Meta-analyses show
that acamprosate is probably more eective in
maintenance of abstinence,109111 whereas naltrexone is
best at prevention of heavy drinking.109,110 The combination
of acamprosate and naltrexone resulted in fewer relapses
than did single agents in some studies115,116 but not in the
largest study done so far.117 No robust data for optimum
length of pharmacotherapy exist because the average
duration of treatment trials is 6 months for acamprosate
and 3 months for naltrexone.109
Two recent meta-analyses113,114 found disulram eective
only when dosing was supervised, and little evidence of
longer-term eectiveness exists.109 Disulram might be
suitable only for highly motivated, supervised patients
who will also do well with other pharmacotherapies that
have fewer adverse eects and contraindications.
Nalmefene has been approved by the European
Medicines Agency to reduce alcohol use rather than
achieve abstinence (table 3). It is taken when the patient
feels at risk of drinking.118 In one large multisite outpatient
trial, nalmefene signicantly reduced heavy drinking
days and daily consumption in patients who continued to
drink.119 Its use has a clinical and public health
justication. It helps heavy drinkers to reduce their
average consumption. It is also a cost-eective way to
reduce the population burden of alcohol-related disease.120
The available evidence does not provide clear recommendations about which drug or psychosocial intervention
is best for which patients. Therefore, best practice is for
physicians to encourage their patients to choose from
available treatments that have proved safe and eective.
Alcoholics Anonymous is a widely used intervention
for alcohol use disorders. Evidence for its eectiveness
is mixed (table 1). Many patients nd the social support
provided by 12-step self-help groups useful in
maintenance of abstinence, especially if they have no
other social support. Those who have chosen abstinence
as a goal should be encouraged to attend these meetings.
The SMART recovery model is an alternative self-help
approach for individuals who reject the religious aspects
of the 12-step approach.
Alcohol use disorders are highly stigmatised,121,122 and
many people with them do not seek treatment for this
reason.7 Less stigmatising attitudes could be encouraged
by a diagnostic approach that emphasises a continuum

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Seminar

Proposed mechanism

Approved
treatment goal

Abstinence
Naltrexone (oral) -opioid antagonist; blocks
endogenous opioid rewards and
reduces alcohol-cue-conditioned
reinforcement signals

Typical dose*

Adverse reactions

Level of evidence

50100 mg per day orally

Nausea, vomiting, headache,

dizziness, fatigue, anxiety,
insomnia, tiredness, and
joint or muscle pain

High109,110

380 mg gluteal
intramuscular injection
monthly

Same as above, in addition to Moderate; reduces

heavy drinking days
risk of site infection or
but does not promote
reactions
abstinence109

Naltrexone
(intramuscular
injection)

Abstinence
-opioid antagonist; blocks
endogenous opioid rewards and
reduces alcohol-cue-conditioned
reinforcement signals

Acamprosate

Uncertain; glutamate system

modulator. Normalises
dysregulation of N-methyl-Daspartate-mediated glutamergic
neurotransmission in chronic
alcohol use and might act
through calcium

Abstinence

High109,111,112
666 mg three times per day Gastrointestinal upset,
especially diarrhoea, pruritus,
orally; reduce dose if
rash, and altered libido
weight <65 kg or if renal
function is impaired

Disulram

Aldehyde dehydrogenase
inhibitor; alcohol use results in
acetaldehyde accumulation,
leading to nausea, ushing,
sweating, and tachycardia

Abstinence

200 mg per day orally; dose Drowsiness, metallic taste,

skin rash, headache,
may be reduced or
peripheral neuropathy,
increased as needed
neuritis, polyneuritis, optic
neuritis, mood change,
impotence, seizure, and
hepatotoxicity

Nalmefene

Structurally similar to
naltrexone; antagonistic at
-opioid and -opioid receptors
and partly agonistic at the
-opioid receptors

Reduced drinking
(Europe only)

18 mg per day orally on

days of increased risk of
drinking (as-needed),
preferably 12 h before
likelihood of drinking

Dizziness, headache,
insomnia, nausea, and
vomiting

Mixed for supervised

dosing;
low for unsupervised
dosing109,113,114

Moderate109

*Based on typical doses across studies.109 Duration of studies was typically 3 months for naltrexone and 6 months for acamprosate.109 Disulram studies up to 12 months.113
Summary based on authors narrative review of the highest level of evidence studies for each treatment.

Table 3: Approved pharmacological treatments

of symptoms rather than a dichotomous diagnostic

category.123 If so, the adoption of a severity continuum in
DSM-5 could increase treatment engagement.
A crucial aspect is to engage patients in any evidencebased treatment.124 The similar eectiveness of
behavioural21,105 and pharmacological approaches suggests
that patients should be given a choice of clinically
indicated treatments.109 Patient-centred care and shared
decision making also help to destigmatise alcohol use
disorders and engage patients in treatment.124
Another important aspect is to increase patients
motivation to address their drinking habits, resolve their
ambivalence about alcohol use, set realistic goals, and
engage in decision making.125 Patients with more-severe
disorders (eg, high levels of dependence, high craving,
end-organ damage, and severe social disruption) should
be encouraged to add drug treatment to their existing
treatment.124 Further eld testing will examine whether
the DSM-5 severity index (appendix) could guide health
professionals and patients in their choice of the type and
intensity of treatment.
Sustained abstinence is the optimum outcome for most
patients with an alcohol use disorder. Risk of relapse
reduces considerably after 1014 weeks of abstinence.126
Abstinence is recommended for those with more-severe
alcohol use disorders, end-organ damage, and severe
social disruption. The treatment goal will aect

pharmacotherapy choice. Meta-analyses109112 suggest that

acamprosate and disulram might be better suited to
abstinence-oriented treatment, whereas naltrexone and
nalmefene might be better choices when reduced or
controlled drinking is the goal.
Few patients with severe alcohol use disorders can
return to moderate drinking,6,103 but many initially reject
abstinence as a goal, which is often a barrier to their
engagement in treatment.127 A pragmatic approach is to
clinically engage with patients who insist on controlled
or reduced-risk drinking as the goal of treatment. This
approach enables a therapeutic relationship to develop
and leaves open the future modication of treatment
goaleg, the failure to achieve control over drinking
could suggest the need for abstinence.128
Patients who are unresponsive to treatment in primary
care and as outpatients might need structured residential
treatment in a therapeutic community or rehabilitation
programme. These patients usually have more-severe
alcohol use disorders, little social support for abstinence,
and unstable living conditions. In populations with drug
and alcohol abuse, little evidence exists that dierent types
of residential services have dierent outcomes.129 Cost and
unavailability of facilities might restrict use of this option.
Online treatment and telephone-based helplines130
have recently been trialled to increase treatment access
for problem drinkers who are reluctant to seek traditional

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Seminar

Search strategy and selection criteria

We searched the Cochrane Library and PubMed for relevant
high-quality studies (eg, systematic reviews, meta-analyses,
cohort studies, and population surveys) published in
English. We mainly focused on publications from
Jan 1, 2009, to Dec 31, 2014, but included commonly
referenced and highly regarded older publications. Search
terms used were alcoholism, alcohol use disorders, and
alcohol dependence with epidemiology, treatment,
disease burden, criteria, aetiology, risk, genetics,
pharmacotherapy, pharmacogenetics, and
comorbidity. We also searched the reference lists of articles
identied by this search strategy and included any papers
that we judged relevant.

treatment. These treatments vary in content and delivery.

Randomised controlled trials of internet-based treatment
in college populations show large variations in response
rates and retention.130,131 In alcohol-dependent populations, little evidence is currently available for
telephone-based interventions130 or internet-based interventions.131 This rapidly developing area of research
could, in future, deliver more eective online treatments
for alcohol use disorders.
Public health policies are a cost-eective way to reduce
the substantial population health burden that is
attributable to alcohol intoxicationeg, policies that
make alcohol more expensive by increase in taxation, and
less accessible by restrictions on the sale and promotion
of alcohol.10,33,132,133 These policies are also eective in
reduction of the prevalence of alcohol use disorders.31

Unresolved research questions

Preclinical and early clinical studies have investigated
new drugs to treat alcohol use disorders. These drugs
include selective antagonists (and agonists) of opioid,
cannabinoid, nicotinic, neuropeptide, and dopaminergic
receptors, and agents that modulate glutamate activity,
glycine activity, the hypothalamicpituitaryadrenal axis,
and -aminobutyric-acid systems.134,135 On the basis of our
review, drugs that have shown more consistent results
but have not yet been approved for use include topiramate,
gabapentin, baclofen, and varenicline (appendix).
Genetic factors could determine the eects of drugs
and guide treatment selection, but the data are not
suciently robust to justify routine clinical use of genetic
tests. The Asn40Asp polymorphism of the opioid
receptor, mu 1 (OPRM1) gene has been linked to
eectiveness of naltrexone treatment in some but not all
studies.136 The rs2832407 polymorphism in the GRIK1
gene, which encodes the kainate glutamate receptor
subunit, could aect the eectiveness of topiramate
treatment.137 High-quality replications are needed.
Research into health services is needed to better
identify and treat the most common and remediable
8

forms of psychiatric comorbidity in patients with alcohol

use disordersnamely, anxiety and mood disorders. We
need much better evidence to decide when treatment is
needed for these psychiatric comorbidities and how best
to integrate such treatment into the treatment of alcohol
use disorders.

Conclusions
Alcohol use disorders contribute substantially to the
burden of disease in many developed countries. Mild
forms often remit without treatment, but the more severe
forms are underdiagnosed and undertreated. The
diagnosis and treatment of more-severe illness need to be
improvedeg, doctors could screen patients in high-risk
settings, reduce stigma, and engage patients earlier in
eective psychological and pharmacological treatments.
Ideally, patients should be oered a choice of behavioural
or pharmacological treatments, or a combination of both.
A pragmatic approach should be adopted towards patients
who initially reject abstinence as a treatment goal.
Contributors
JPC, PSH, and WDH designed the content of the Seminar, conducted
literature searches, drafted the Seminar and revised its content.
Declaration of interests
JPC is supported by a National Health and Medical Research Council of
Australia Career Development Fellowship (1031909). PSH is a member
of the International Advisory Committee for Lundbeck (nalmefene) and
holds no shares or any nancial interests. He has previously been a
consultant for Alphapharm (acamprosate). WDH declares no
competing interests.
Acknowledgments
We thank Sarah Yeates for her assistance in conducting literature
searches and compiling a detailed bibliography, and Megan Weier for
her assistance in formatting the paper for publication. Gerald Feeney
provided helpful comments during preparation of this Seminar.
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