Received: 28 February 2021 Accepted: 6 July 2021

DOI: 10.1111/add.15647

CLINICAL MANAGEMENT OF WITHDRAWAL

Clinical management of the alcohol withdrawal syndrome

Ed Day1 | Chris Daly2

1
Addiction Psychiatry, Institute for Mental Abstract
Health, School of Psychology, University of
Birmingham, Edgbaston, Birmingham, UK Up to half of individuals with a history of long-term, heavy alcohol consumption will
2
Addiction Psychiatry, Greater Manchester experience the alcohol withdrawal syndrome (AWS) when consumption is significantly
Mental Health FT, Chapman Barker Unit,
decreased or stopped. In its most severe form, AWS can be life-threatening. Medically
Prestwich Hospital, Manchester, UK
assisted withdrawal (MAW) often forms the first part of a treatment pathway. This
Correspondence clinical review discusses key elements of the clinical management of MAW, necessary
Ed Day, Clinical Reader in Addiction
Psychiatry, Institute for Mental Health, School adjustments for pregnancy and older adults, likely outcome of an episode of MAW,
of Psychology, University of Birmingham, factors that might prevent completion of the MAW process and ways of overcoming
52 Pritchatts Road, Edgbaston, Birmingham
B15 2TT, UK. barriers to ongoing treatment of alcohol use disorder. The review also discusses the use
Email: [email protected] of benzodiazepines in MAW. Although there is clear evidence for their use, benzodiaze-
pines have been associated with abuse liability, blunting of cognition, interactions with
depressant drugs, craving, delirium, dementia and disrupted sleep patterns. Because
glutamatergic activation and glutamate receptor upregulation contribute to alcohol
withdrawal, anti-glutamatergic strategies for MAW and other potential treatment
innovations are also considered.

KEYWORDS
Alcohol, benzodiazepine, delirium tremens, detoxification, pharmacological, psychosocial, seizure,
treatment, withdrawal

I N T R O D U CT I O N T H E CH A R A C T E R I S T I C S O F A L C O H O L
DE P E N D E N C E A N D W I T H D R A W A L S T A T E S
The intended audience of this narrative review is primarily clinicians
working in specialist addiction treatment settings, with a focus on Symptoms of withdrawal and their physiological counterpart tolerance
planned medically assisted alcohol withdrawal (MAW) as a part of a make up two of the 11 features of Diagnostic and Statistical Manual
longer treatment journey. Although consideration will be given to of Mental Disorders Fifth edition (DSM-5) alcohol use disorder (AUD)
the management of unplanned withdrawal in hospital settings, [11]. Up to 50% of individuals with a history of long-term, heavy alco-
severe complications of the alcohol withdrawal syndrome (AWS) hol consumption will experience the AWS (see Table 1) to some
such as seizures and delirium tremens are medical emergencies and degree when alcohol use is reduced or stopped [7,12]. Symptoms and
detailed reviews of treatment regimens are available elsewhere signs usually appear within 8 to 24 hours of a drop in blood alcohol
[1–8]. Both authors have been part of the Public Health England levels caused by initiation of abstinence or a significant reduction in
expert group to develop the United Kingdom’s (UK) first national consumption [13]. Transient visual, auditory or tactile hallucinations
treatment guidelines for alcohol use disorders, which in turn was occur in 2% to 8% of individuals [14]. In many cases the symptoms
supported by evidence from the UK National Institute for Health resolve without treatment, but in some they can progress to a more
and Care Excellence (NICE) guidance [9,10]. This was supplemented serious, potentially life-threatening condition. Approximately 10% of
by a Web of Science review using the key words ‘alcohol’, ‘with- symptomatic individuals experience withdrawal-related seizures [15]
drawal’ and ‘management’. and if left untreated up to one-third of patients in hospital with severe

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited and is not used for commercial purposes.
© 2021 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.

804 wileyonlinelibrary.com/journal/add Addiction. 2022;117:804–814.

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MANAGEMENT OF ALCOHOL WITHDRAWAL 805

TABLE 1 DSM-5 diagnostic criteria for alcohol withdrawal [11].

All 4 criteria must be present to diagnose alcohol withdrawal
A. Cessation of (or reduction in) alcohol use that has been heavy and prolonged
B. Two (or more) of the following, developing within several hours to a few days after cessation of (or reduction in) alcohol use described in criterion A:
1. autonomic hyperactivity (e.g. sweating or pulse rate greater than 100 b.p.m)
2. increased hand tremor
3. insomnia
4. nausea or vomiting
5. transient visual, tactile or auditory hallucinations or illusions
6. psychomotor agitation
7. anxiety
8. generalized tonic–clonic seizures
C. The signs and symptoms in criterion B cause clinically significant distress or impairment in social, occupational or other important areas of functioning
D. The signs or symptoms are not attributable to another medical condition and are not better explained by another medical disorder, including
intoxication, or withdrawal from another substance

Alcohol withdrawal seizure

Typically the generalized tonic–clonic type, characterized by rhythmic, yet jerking movement, especially of the limbs

Delirium
The DSM-5 criteria for delirium are:
A. A disturbance in attention (i.e. reduced ability to direct, focus, sustain and shift attention) and awareness (reduced orientation to the environment)
B. The disturbance develops over a short period of time (usually hours to a few days), represents a change from baseline attention and awareness, and
tends to fluctuate in severity during the course of day
C. An additional disturbance in cognition (e.g. memory deficit, disorientation, language visuospatial ability or perception)
D. The disturbances in criteria A and C are not better explained by another pre-existing, established, or evolving neurocognitive disorder and do not
occur in the context of severely reduced level of arousal, such as coma
E. There is evidence from the history, physical examination, or laboratory findings that the disturbance is a direct physiological consequence of another
medical condition, substance intoxication or withdrawal (i.e. because of a drug of abuse or to a medication), or exposure to a toxin, or is because of
multiple aetiologies

withdrawal symptoms will progress to delirium (known as delirium of the GABA system [19]. Epileptiform activity is rarely detected in
tremens) [16], although delirium tremens may also occur without pre- the electroencephalogram (EEG) after alcohol withdrawal seizures,
ceding seizures. possibly because of a different trigger zone than is normal in the
context of epilepsy. Alcohol withdrawal also produces an increase
in the neurotransmitter dopamine, which in turn contributes to
PATHOPHYSIOLOGY the clinical manifestations of autonomic hyperarousal and hallucina-
tions [20].
Alcohol acts as a central nervous system depressant by rapidly Historically, a slow reduction in alcohol consumption to absti-
increasing the release of γ-aminobutyric acid (GABA) in the brain, nence was the only method available to reduce the discomfort and
with prominent effects on GABA-type A (GABAA) receptors [17]. harms of the AWS and mild cases may only require supportive care
At the same time it inhibits postsynaptic N-methyl-d-aspartate [15]. However, planned and early intervention with medication
(NMDA) glutamate receptor activity [18]. An extended period of reduces the likelihood of severe complications. Pharmacological stim-
alcohol use at higher levels produces a downregulation of GABAA ulation of the ligand-gated GABAA receptor produces membrane
receptors, and a corresponding upregulation of NMDA receptors hyperpolarization by enhancing chloride ion influx, resulting in a global
and the glutamatergic system. An abrupt drop in blood levels of slowing of neurotransmission, anxiolysis, sedation and anticonvulsant
alcohol unmasks glutamate-mediated excitation, and the resulting activity. Agents that target the GABAA receptor can, therefore, be
autonomic overactivity produces delirium. Seizure activity is driven used to support ‘detoxification’ (e.g. benzodiazepines, barbiturates
largely in the brainstem by removal of the tonic inhibitory effect and propofol).
 13600443, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/add.15647 by Cochrane Mexico, Wiley Online Library on [01/09/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
806 DAY AND DALY

OBJECTIVES OF CLINICAL MANAGEMENT on objective measurement of withdrawal symptoms, at least daily

O F A L C O H O L WI T H D R A W A L structured monitoring of the patient’s progress and linkage with con-
tinuing psychosocial care after completion of detoxification’ [25]. The
Detoxification or MAW is a part of an overall treatment pathway, review of 20 studies found benzodiazepines were the primary medica-
and failure to consider ongoing treatment for the newly abstinent tion prescribed, and that community detoxification was safe with high
drinker often leads to relapse. The goals of the MAW episode are completion rates. When compared to inpatient treatment, MAW in
to safely achieve physical withdrawal from alcohol, prevent (or treat) the community had better drinking outcomes, good acceptability and
severe withdrawal phenomena such as seizures or delirium tremens, was 10 to 23 times cheaper [25].
and optimise physical and mental health. Knowledge of the usual
level of drinking and the time of the last alcoholic drink helps to
gauge the extent and severity of the AWS. Patients may under- Hospital
report their consumption (quantity and/or frequency), and so valida-
tion by other reliable sources is helpful. It is also important to A planned episode of MAW for alcohol and/or other drugs in a spe-
enquire about the outcome of past attempts to stop and the use of cialist inpatient setting should be prioritised in the following circum-
other psychoactive substances. A history of delirium tremens (likeli- stances [25,26]:
hood ratio [LR] = 2.9, 95% CI = 1.7–5.2) and baseline systolic blood
pressure 140 mmHg or higher (LR = 1.7, 95% CI = 1.3–2.3) are 1. previous history of severe AWS, especially with delirium tremens
associated with an increased likelihood of delirium tremens or with- and withdrawal seizures;
drawal seizure [13]. The Prediction of Alcohol Withdrawal Severity 2. current presentation of severe withdrawal, especially with high
Scale (PAWSS, Supporting information Data S1) [21] is useful in breathalyser alcohol reading;
predicting a severe AWS (LR = 174, 95% CI = 43–696) when scor- 3. co-morbid physical health problems (e.g. significant liver disease
ing 4 or more and LR = 0.07 (95% CI = 0.02–0.26, when scoring [cirrhosis, alcoholic hepatitis], epilepsy, cardiac disease, or mobility
3 or less) (see Supporting information Data S1). The use of a issues because of cerebellar damage, severe myopathy or
breathalyser is also important in considering when to commence neuropathy);
MAW and identifying high-risk withdrawal. However, the clinician 4. pregnancy;
should be directed by emergent withdrawal symptoms rather than 5. co-morbid mental health problems (e.g. cognitive impairment
waiting for the breath alcohol concentration (BrAC) to return to zero including dementia, Wernicke-Korsakoff syndrome, psychosis,
before commencing MAW. bipolar disorder, personality disorder, and/or high suicide risk);
6. complex social circumstances (e.g. homelessness, domestic vio-
lence or safeguarding concerns); and
B ES T P R A CT I CE T O A CH I E V E EF F E C TI V E 7. frequent previous unsuccessful community MAW episodes, espe-
C LI N I C A L M A N A G E M E N T O F W I T H D RA W A L cially with evidence of increasing severity of AWS.

Setting There is also emerging evidence for the benefit of providing timely
MAW following admission to hospital with a presentation of alcohol-
Non-residential/community (‘home’ or ‘ambulatory’) related physical or mental health problems [27]. Literature exists to
guide clinicians working in intensive care units who are managing
MAW can be undertaken at home, in outpatient clinics, day hospitals cases with severe withdrawal and other physical comorbidity [2,4,8].
or specialist residential settings, with the intensity of supervision Healthcare professionals treating people during MAW should be
matching the severity of the AUD and the likely medical risks associ- skilled in the assessment and monitoring of withdrawal symptoms and
ated with withdrawal [22]. A community setting is the default position signs [9], follow local protocols and use validated assessment tools to
in most UK specialist alcohol treatment services unless the criteria for support the process (e.g. CIWA-Ar, see below).
inpatient admission (below) are met. Such an approach can lead to
cost-savings [23], although there is some randomized controlled trial
(RCT) evidence that patients assigned to inpatient detoxification are Timeframe
more likely to complete than a group receiving the same MAW in an
outpatient setting [24]. MAW in inpatient or outpatient settings is usually completed within
MAW in a community setting usually involves daily monitoring of 3 to 10 days depending on complexity and the emergence of severe
the signs and symptoms of the AWS by a specialist nurse, with the withdrawal symptoms. The crucial period for the development of
medication prescribed by a general practitioner (GP) or a specialist delirium tremens and seizures is the first 48 to 72 hours after cessa-
service [25]. A recent review of community MAW for alcohol depen- tion or significant reduction in alcohol consumption and careful moni-
dence concluded that such programs are characterised by ‘clearly toring and active treatment is important during this period. The
defined eligibility criteria, non-ambiguous medication protocols based treatment duration will depend on individual factors (severity of AWS,
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MANAGEMENT OF ALCOHOL WITHDRAWAL 807

physical and mental health), treatment factors (fixed dose or preferred in patients with a history of delirium tremens, repeated sei-
symptom-triggered MAW) and setting (acute hospital, mental health zures or seizures in a previous MAW episode, and those requiring
unit or specialist detoxification unit). additional detoxification from benzodiazepines. Shorter acting benzo-
diazepines with a different metabolism pathway (e.g. oxazepam or lor-
azepam) may be preferred in those with known or suspected liver
Pre-detoxification preparation function impairment. Lorazepam is recommended (in addition to
diazepam) in the treatment of delirium tremens, but can also be used
Patients with high use of inpatient alcohol withdrawal services are a in patients with significant liver disease, including those in which it
small, but costly population with poor follow-on rates to subsequent has taken over 24 hours for the blood alcohol concentration (BAC) to
treatment [28] and may benefit from targeted services to address fall below zero. Clomethiazole should be reserved for inpatient
their complex clinical and social needs [29,30]. MAW should be settings [9,31].
embedded within a wider treatment program that supports lifestyle Because reducing glutamate overactivity is thought to be
changes to increase the likelihood of long-term alternations in drink- important in reducing the risk of brain toxicity during withdrawal,
ing behaviour [31]. Retrospective reviews of hospital records show alternatives to benzodiazepines such as carbamazepine may be con-
that a history of previous withdrawal episodes is associated with sidered. NICE has recommended using carbamazepine or benzodiaze-
more severe and medically complicated withdrawal [32]. Kindling is pines [9], but a Cochrane review acknowledging potential benefits
a phenomenon whereby the repeated administration of weak electri- found ‘insufficient evidence in favour of anticonvulsants for treat-
cal or chemical stimuli, which initially cause no overt behavioural ment of alcohol withdrawal’ [46]. Reviews of prescribing practice in
response, result in the appearance of a behavioural effect such as a the United Kingdom suggest that benzodiazepines are overwhelm-
seizure [33]. Both clinical and experimental evidence support the ingly preferred [47].
existence of such a kindling mechanism, whereby AWS severity pro-
gressively increases with each episode [34,35]. One model suggests
that limbic system hyperirritability accompanying each withdrawal Fixed-dose versus symptom-triggered regimens
episode kindles increasingly widespread subcortical structures, lead-
ing to a progression from tremor to seizures and delirium tremens A fixed-dose regimen uses a predetermined dosing schedule with a
over time. slowly reducing daily dose. As shown in Table 2 (and Supporting
Human studies also show that repeated withdrawal episodes are information Data S1), such regimens may be guided by an initial
associated with cognitive impairments, as well as changes in affect, assessment of the severity of dependence [49] and supplemented
increased craving and impairment in behavioural control [36]. The with ‘as needed’ doses to titrate to effect. Fully ‘symptom-triggered’
risks and benefits of undertaking MAW should therefore be assessed, regimens can produce rapid symptom control with reduced total ben-
and the chances of longer-term success optimized through prepara- zodiazepine dose (Fig. 1). A trained observer assesses the withdrawal
tion and aftercare planning [37,38]. This may involve developing par- symptoms using a standardized scale at fixed regular intervals, and a
tial control over drinking as an interim step toward abstinence, predetermined dose of benzodiazepine is administered when a pre-
combined with individual and social lifestyle changes before MAW. set score is obtained. The most commonly recommended scale is the
Both brief (3-hour) motivation-oriented therapy [39] and a psycho- revised Clinical Institute Withdrawal Assessment for Alcohol
educational intervention related to stress and trauma [40] have shown (CIWA-Ar) [50]. It has 10 items producing a total score between
potential in increasing the likelihood of completing MAW when 0 (no withdrawal) and 67 (severe withdrawal and delirium tremens)
compared with treatment as usual, but require definitive evaluation. [50]. Scores <8 represent mild AWS not requiring medication, 8 to
Treatment with benzodiazepines is not likely to produce sufficient 15 represent moderate AWS and >15 represents severe AWS and an
attenuation of the hyperglutamatergic state produced by withdrawal, increased risk of seizures and/or delirium.
and acamprosate is known to reduce glutamate in the brain [41,42]. A systematic review [51] found moderate strength evidence for
Adding acamprosate to benzodiazepines does not appear to reduce symptom-triggered therapy reducing the duration of MAW and total
withdrawal symptoms, but may support a longer period of post- benzodiazepine dose. However, this mainly applies to lower risk
withdrawal abstinence [43]. patients in specialized settings, and it is less clear that the process is
useful in general hospital settings. There is insufficient evidence to
support symptom-triggered therapy producing better outcomes in
Medication of choice terms of mortality, seizure control or delirium in any setting [51]. NICE
guidance recommends a fixed-dose regimen for community-based
The pharmacological management of alcohol withdrawal has been withdrawal [26], a fixed-dose regimen with ‘as needed’ medication in
systematically reviewed on behalf of the UK NICE [26,44], the specialist services and a ‘symptom-triggered’ regimen within a general
Cochrane collaboration [45,46], and the British Association for Psy- medical inpatient setting [9].
chopharmacology [31]. The evidence base is strongest for long acting In the acute hospital, the patient with AWS often has co-morbid
benzodiazepines such as chlordiazepoxide [31,44]. Diazepam may be conditions and nursing staff may be regularly diverted by other
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808 DAY AND DALY

TABLE 2 Sample fixed dose regimens of chlordiazepoxide, titrated to effect.

Indicative daily alcohol consumption 15–25 units 30–49 units 50–60 units

Severity of alcohol dependence Moderate SADQ score 15–29 Severe SADQ score 30–39 Very severe SADQ score 40–60
a
Day 1 (starting dose) 15 mg qid 25 mg qid 30 mg qid 40 mg qid 50 mg qidb
Day 2 10 mg qid 20 mg qid 25 mg qid 35 mg qida 45 mg qidb
Day 3 10 mg tid 15 mg qid 20 mg qid 30 mg qid 40 mg qida
Day 4 5 mg tid 10 mg qid 15 mg qid 25 mg qid 35 mg qida
Day 5 5 mg bid 10 mg tid 10 mg qid 20 mg qid 30 mg qid
Day 6 5 mg qhs 5 mg tid 10 mg tid 15 mg qid 25 mg qid
Day 7 5 mg bid 5 mg tid 10 mg qid 20 mg qid
Day 8 5 mg qhs 5 mg bid 10 mg tid 15 mg qid
Day 9 5 mg qhs 5 mg tid 10 mg qid
Day 10 5 mg bid 10 mg tid
Day 11 5 mg qhs 5 mg tid
Day 12 5 mg bid
Day 13 5 mg qhs

Taken from NICE Guidelines 100 and 115 [48]. SADQ = Severity of Alcohol Dependence Questionnaire.
a
Doses of chlordiazepoxide in excess of 30 mg qid should be prescribed only in severe alcohol dependence and the response to treatment should be
monitored regularly and closely.
b
Doses of chlordiazepoxide in excess of 40 mg qid should be prescribed only in very severe alcohol dependence. Such doses are rarely necessary in
women and children and never in older people or in cases of liver impairment.
Administer Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) and breathalyser on admission
If breathalyser reading elevated (i.e. >Breath Alcohol Content (BrAC) 87 mcg% or Blood Alcohol Content (BAC) 200 mg/100 mL) repeat in 1 hour and
monitor CIWA-Ar
If CIWA-Ar >10 at second reading give chlordiazepoxide 20 mg PRN and commence chlordiazepoxide 25 mg qds regime (or higher if appropriate)
NB: The BAC is for guidance only. Some patients will need to start chlordiazepoxide with BAC >200 mg % if withdrawal symptoms are severe.
Continue CIWA-Ar readings hourly for first 24–48 hours:
CIWA-Ar scores >10 should trigger as needed (PRN) prescribing of chlordiazepoxide 20 mg on each occasion
If >5 doses of PRN required in 48 hours this should prompt a review of the withdrawal regime
All regimes to be reviewed at 48 hours, adjusting upward (or downward if over sedated) as necessary. The doses should be a reflection of the frequency of
PRN medication dispensed and physical assessment of the patient.
The British National Formulary recommends a maximum dose of chlordiazpoxide of 250 mg/day, but this can be exceeded if titrating to effect (i.e. mild
sedation) using regular (minimum every 4 hours) assessment with CIWA-Ar. The lowest dose needed to achieve the effect should always be used, and the
dose reduced and stopped as soon as possible.

severely ill patients. CIWA-Ar involves a mixture of subjective and severe tremor, hallucinations (auditory, olfactory and classically visual)
objective items and has not been validated for use in severely ill and confusion, alongside associated paranoid delusions, agitation,
patients (who may be unconscious). In this setting symptom-triggered insomnia, tachycardia, hyperthermia, hypertension, and tachypnoea. It
MAW may be unreliable, encouraging use in cases with non-alcohol- is estimated that 3% to 5% of patients hospitalised with AWS meet
related delirium where benzodiazepines have made the problem the criteria for delirium [8]. Risk factors significantly correlated with
worse [52]. A review of 18 AWS rating scales found a lack of agree- the development of alcohol withdrawal delirium include current infec-
ment about what constituted the most important markers of with- tious disease, tachycardia (heart rate above 120 b.p.m at admission),
drawal, with 30 separate signs and symptoms used [53]. Several signs of alcohol withdrawal with a BAC of more than 1 g/L of body
hospital-based rating scales have been incorporated into a complete fluid, a history of epileptic seizures, and a history of delirium [55].
symptom-triggered package of care (e.g. Glasgow Modified Alcohol Electrolyte abnormalities, for example, low levels of potassium and/or
Withdrawal Scale [54], Minnesota Detoxification Scale (MINDS) [2]), magnesium, low platelet count, and cardiac, respiratory or gastrointes-
although at present these lack multi-centre RCT evaluation. tinal disease also predict delirium during alcohol withdrawal [8]. Death
occurs in up to 4% of hospitalized patients with delirium tremens, and
hyperthermia, persistent tachycardia and the use of physical restraints
Delirium tremens predict mortality [56].
The onset of delirium tremens can be prevented by prompt
Delirium tremens usually emerges after 2 to 3 days of withdrawal and initiation of treatment, alongside identification and management of
should be treated as a medical emergency. It is characterised by co-morbid medical problems [57]. Key treatment goals are to control
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MANAGEMENT OF ALCOHOL WITHDRAWAL 809

F I G U R E 1 A sample symptom-triggered medically assisted withdrawal process using Clinical Institute Withdrawal Assessment for Alcohol
(CIWA-Ar). Stop process when CIWA-Ar consistently <10 for 12 hours. Oxazepam (30 mg orally) may be used in cases of liver impairment (raised
International Normalised Ratio (INR) or reduced albumin)

agitation, reduce the risk of seizures and decrease the risk of injury patient is already taking an anticonvulsant medication this should be
and death [8]. Management of established delirium tremens should continued and the blood levels monitored. Lorazepam (1-4 mg intra-
involve nursing in a well-lit, quiet room with reorientation chart and muscularly) has been shown to prevent a second seizure in the
infrequent nursing changes. A fluid balance chart is essential to same withdrawal episode and should be used in preference to
ensure intake of at least 3 L/day, but avoiding over hydration, and starting anticonvulsants [9].
vital signs should be measured every 15 to 30 minutes until the
patient is stable. Other emerging causes of confusion such as infec-
tion must be monitored, alongside daily blood tests for urea and Wernicke’s encephalopathy
electrolytes, blood glucose and full blood count. Electrolyte imbal-
ances such as hypokalaemia and hypomagnesemia should be Wernicke’s encephalopathy (WE) is an abrupt onset confusional state
corrected. A review of treatment regimens recommends diazepam characterised by impairment in consciousness, ophthalmoplegia and
10 to 20 mg intravenously or orally every 1 to 4 hours as needed ataxia. Cases are often missed and a high index of suspicion should be
for 5 days or until delirium settles [8]. Parenteral administration of maintained [58], with every patient with delirium tremens treated as if
lorazepam may be required to produce light sedation (1–4 mg they have incipient WE [57]. It is caused by a deficit in vitamin B1 (thi-
6-hourly intramuscularly), and prominent psychotic symptoms amine) brought on by poor diet and the negative impact of alcohol on
treated with haloperidol 1 to 5 mg oral 8-hourly (Supporting its intestinal absorption [59] and is more common in people with co-
information Data S1). existing malnutrition and poor physical health. Because the biologi-
cally active form of thiamine (thiamine pyrophosphate) is an essential
coenzyme in biochemical pathways in the brain, thiamine must be
Seizures given before (or concomitantly with) intravenous administration of
glucose to prevent the precipitation of WE in thiamine-deficient
Grand mal epileptiform seizures can occur 12 to 48 hours after ces- individuals [60].
sation or significant reduction in consumption. They are more likely Although the pathophysiology of WE is reasonably clear and the
in individuals with previous history of withdrawal seizures or epi- role of thiamine in treating patients with WE is well established [61],
lepsy and in severe dependence can occur even if the breathalyser recommendations about dosage and duration of treatment are
reading has not reached zero. There may be multiple seizures, but acknowledged to be arbitrary [58]. The British Association for
rarely status epilepticus. Consideration should be given to correcting Psychopharmacology guidelines recommend that WE requires imme-
low magnesium levels and other electrolyte disturbance. Benzodiaz- diate treatment with 2 pairs of Pabrinex ampoules (equivalent
epines prevent de novo seizures, and although anticonvulsants are 500 mg thiamine) every 8 hours by intravenous infusion for 3 days,
equally efficacious there is no advantage in combining the two [31]. followed by 1 pair of Pabrinex ampoules (250 mg thiamine) once
If the risk of seizures is known to be high, diazepam may be the daily intramuscularly for 3 to 5 days or until clinical improvement
first choice medication with doses as high as 40 mg 6-hourly. If the ceases. Patients with significant weight loss, poor diet, signs of
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810 DAY AND DALY

malnutrition, memory disturbance, previous history of WE or a P O S T - D E T O X I F I CA T I O N P R O G N O S I S

suspicion of Korsakoff psychosis represent an ‘at-risk’ group that
may benefit from prophylaxis with 1 pair of Pabrinex ampoules Failure to complete MAW can be a barrier to ongoing treatment [70],
intramuscularly for 3–5 days. Lower risk groups require only oral reducing confidence in achieving long-term abstinent recovery. Sys-
thiamine (50 mg every 6 hours) [31]. tematic reviews of both community and residential MAW report com-
pletion rates of 45% to 100% [25,71]. In specialist residential settings
increased odds of completing MAW are associated with: greater
SPECIAL CONSIDERATIONS length of time in education; stable accommodation; referral from pro-
fessional agencies; and absence of co-existing drug use or psychiatric
Neuropsychological impairment conditions [72]. Programs that address barriers to completion such as
previous trauma achieve better outcomes [73]. A return to alcohol
People with alcohol dependence often show mild to moderate consumption is the norm for people with severe AUD who complete
neuropsychological impairment. Memory, executive function and MAW, with more than half having their first drink within 2 weeks [74]
visuospatial ability may be affected, with general intelligence, declara- and 85% of patients eventually relapsing [75]. Impairment in the pre-
tive memory, language skills and motor and perceptual abilities less frontal cortex associated with repeated episodes of withdrawal may
impaired [62]. Withdrawal from alcohol has been associated with impair conflict resolution and increase sensitivity to stress, both of
cognitive impairments, which in turn are associated with an increased which can contribute to relapse. Withdrawal may also exacerbate
risk of relapse [63]. Although there is evidence of cognitive recovery craving, further increasing the likelihood of relapse [37].
in IQ, verbal skills and recent memory following 7 to 14 days of
abstinence, sustained impairments in problem-solving visuospatial
ability and perceptual motor skills have been found after 28 days, with Transition to treatment
some deficits lasting beyond a year of abstinence [64].
Although MAW is an opportunity to link patients to specialist treat-
ment or mutual aid groups, this does not happen for the majority. In a
Pregnancy national United States (US) data set, 66% of MAW episodes were
completed, but only 11% of discharges were followed by transfer to
MAW can be undertaken at any stage in pregnancy [65], although ongoing treatment [71]. One UK service reported 60% of patients
AWS may lead to placental abruption, preterm delivery and foetal dis- completing a planned MAW engaging in ongoing aftercare [76],
tress or death [66]. An inpatient setting is therefore recommended, improving to 82% through the use of an abstinence preparation group
with frequent monitoring of the mother and of foetal movements and [38]. People are more likely to access further treatment if they are
heart rate [67]. Benzodiazepine use during pregnancy does not educated, white and have previously attended addiction treatment
increase the risk of major foetal malformations, and chlordiazepoxide [71]. Building positive perceptions about ongoing treatment through a
and diazepam appear to be safer than clonazepam, alprazolam and specific treatment plan promotes greater post-MAW treatment
lorazepam [68]. However, benzodiazepines in the third trimester have uptake [77]. Patients with little mutual-help experience benefit from a
been associated with floppy baby syndrome, failure to feed, and motivational intervention as part of the referral method [78,79], and
temperature dysregulation. Some clinicians recommend lorazepam as including more mutual-help components is associated with higher
the preferred benzodiazepine in the third trimester, because its short rates of treatment entry or mutual-help group attendance within
onset and offset of action reduces neonatal benzodiazepine with- 7 days of MAW completion [80]. In short-term, standalone inpatient
drawal [67]. MAW, providing a staff escort to attend the assessment for the next
stage of treatment and an incentive for attending are associated with
an increased likelihood of completing intake procedures [81]. The pro-
Older adults vision of individual counselling that extends beyond the MAW period
[82] and use of peer-led interventions have been associated with
Instruments such as PAWSS can be helpful to screen for those increased rates of 12-step meeting attendance in the longer term
requiring MAW [69]. A hospital setting is required for older adults in [83]. Brief family treatment has also been shown to facilitate ongoing
poor general health with multiple co-morbidities, dementia or a treatment post-detoxification [84]
requirement for constant one-to-one monitoring. Benzodiazepines
with a longer half-life (diazepam, chlordiazepoxide) can produce over-
sedation, and so consider reducing the dose or using shorter-acting Post-MAW treatment
benzodiazepines such as oxazepam or lorazepam. Careful monitoring
with an objective scale (e.g. CIWA-Ar) may help to prevent falls or A plan for ongoing relapse prevention including medication, psychoso-
respiratory depression. There is evidence to support the use of cial and mutual-aid components should be built into the MAW pro-
thiamine, magnesium, multivitamins and supportive care [69]. gram [26,31]. Greater time spent in addiction treatment and mutual
 13600443, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/add.15647 by Cochrane Mexico, Wiley Online Library on [01/09/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
MANAGEMENT OF ALCOHOL WITHDRAWAL 811

aid groups post-detoxification is associated with sustained abstinence relapse during early abstinence, include baclofen, some anticonvul-
[85,86]. Receiving any treatment within the first month after MAW is sants (e.g. topiramate) and gamma-hydroxybutyric acid (GHB or
also associated with significantly less chance of readmission [87]. Sim- sodium oxybate), but evidence of benefit is inconclusive. Baclofen is a
ple, telephone-based contact can be used to monitor treatment and GABA-B receptor agonist approved to reduce spasticity associated
mutual aid group participation [88], and telehealth interventions have with neurological disorders and is relatively safe with medical
the potential to deter repeated MAW episodes and improve out- co-morbidity. However, in a meta-analysis of 14 RCTs baclofen
comes [89]. Computerized cognitive bias modification training during showed no statistically significant superiority over placebo [99], and it
MAW helps to prevent relapse during the high-risk early period remains an experimental option.
following discharge from treatment [90].
Psychosocial treatments are the mainstay of ongoing care and DECLARATION OF INTERESTS
have small, but significant relapse prevention effects [91,92]. Excellent None.
reviews of relapse prevention medication are available [93]. Naltrex-
one and acamprosate reduce relapse rates by 5% to 8% up to 1 year
ORCID
after treatment [94] and both are offered as first-line treatment post-
Ed Day https://orcid.org/0000-0002-7106-7013
MAW in the United Kingdom [26]. There are no specific contraindica-
tions for their use in patients with comorbid psychiatric conditions
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[95]. Acamprosate has the better evidence for supporting abstinence
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