DOI: 10.7860/JCDR/2015/13407.

6538
Review Article

Alcohol Withdrawal Syndrome:

Psychiatry Section

Benzodiazepines and Beyond

Ankur Sachdeva1, Mona Choudhary2, Mina Chandra3

ABSTRACT
Alcohol dependence is an increasing and pervasive problem. Alcohol withdrawal symptoms are a part of alcohol dependence syndrome
and are commonly encountered in general hospital settings, in most of the departments. Alcohol withdrawal syndrome ranges from mild
to severe. The severe complicated alcohol withdrawal may present with hallucinations, seizures or delirium tremens. Benzodiazepines
have the largest and the best evidence base in the treatment of alcohol withdrawal, and are considered the gold standard. Others, such
as anticonvulsants, barbiturates, adrenergic drugs, and GABA agonists have been tried and have evidence. Supportive care and use of
vitamins is essential in the management. Symptom triggered regime is favoured over fixed tapering dose regime, although monitoring
through scales is cumbersome. This article aims to review the evidence base for appropriate clinical management of the alcohol withdrawal
syndrome. We searched Pubmed for articles published in English on ‘Alcohol withdrawal syndrome’ in humans during the last 10 years.
A total of 1182 articles came up. Articles not relevant to clinical utility and management were excluded based on the titles and abstract
available. Full text articles, meta-analyses, systematic reviews and randomized controlled trials were obtained from this list and were
considered for review.

Keywords: Alcohol detoxification, Management, Pharmacotherapy, Thiamine

Introduction
Alcohol use is a pervasive problem that is taking an increasing
toll on the world’s population. The World Development Report
[1] found that the alcohol related disorders affects 5-10% of the
world’s population each year and accounted for 2% of the global
burden of disease. Globally alcohol consumption has increased in
recent decades, with most of the increase in developing countries.
Increase is more in countries where use of alcohol is traditionally less
on population level and methods of prevention, control or treatment
are not easily available. ICMR bulletin estimated 62 million alcoholics
in India which is as big as that of the population of France [2].
Heavy drinkers suddenly decreasing their alcohol consumption or
abstaining completely may experience alcohol withdrawal (AW).
Symptoms and signs of AW include mild to moderate tremors,
irritability, anxiety, or agitation, among others. The most severe
manifestations of withdrawal include delirium tremens, hallucinations,
and seizures. These happen due to alcohol-induced imbalances in
the brain which result in excessive neuronal activity if the alcohol is [Table/Fig-1]: Flowchart of article selection

withheld [3].
The aim of the present paper was to review the evidence base for important social, interpersonal and legal implications. Dependence
the history, diagnosis and management of the alcohol withdrawal on alcohol is associated with both physiological symptoms such
syndrome (AWS), with a focus on role of benzodiazepines in as tolerance and withdrawal, and behavioural symptoms such as
AWS. This review informs readers about pathophysiology of AWS, impaired control over drinking [4]. It usually manifests when an
historical aspects, diagnosis and medications to be used for treating alcohol dependent individual develops withdrawal symptoms after
alcohol withdrawal, their dosing strategies to be used and different stopping alcohol, either due to family pressure, self-motivation, or
regimes of benzodiazepines. We searched Pubmed and MEDLINE difficulty in procuring alcohol.
database as detailed in the flowchart. After reading the abstract of Alcohol dependence is one of the most common psychiatric
these articles those relevant to clinical utility and management were disorders, second only to major depression [5]. Data from the
shortlisted. The full text of the shortlisted articles were retrieved National Co-morbidity Survey and the NIMH Epidemiologic
and read in full by the authors [Table/Fig-1]. Cross-references from Catchment Program revealed that approximately 14% of the
selected studies were searched and further relevant articles were general population has a lifetime history of alcohol dependence. A
considered for inclusion. The data was synthesized and the relevant recent National Household Survey of Drug Use in India [6] recorded
findings are discussed below. alcohol use in only 21% of adult males. However, this figure cannot
Alcohol dependence syndrome: Concept and prevalence Alcohol be expected to mirror accurately the wide variation that exists in a
abuse and dependence pose a major health problem world­wide with large and complex country such as India. The prevalence of current

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use of alcohol ranged from 7% in the state of Gujarat (officially under usually start around 6 hours of alcohol cessation. When the onset
Prohibition) to 75% in Arunachal Pradesh. of withdrawal like symptoms or delirium is after 1 week of complete
cessation of alcohol, the diagnosis of AWS becomes untenable,
The Alcohol Withdrawal Syndrome regardless of the amount and severity of alcohol dependence. For
The Alcohol withdrawal Syndrome (AWS) is one of the most establishing a diagnosis of AWS, following conditions need to be
common presentations of Alcohol Dependence Syndrome. AWS is fulfilled [17,18]:
a cluster of symptoms which occurs in alcohol-dependent people 1. A clear evidence of recent cessation or reduction of alcohol
after cessation or reduction in heavy or prolonged alcohol use. after previous high dose regular use.
The clinical presentation varies from mild to severe and the onset
2. Symptoms of alcohol withdrawal seen cannot be accounted
of symptoms typically occurs a few hours after the last alcohol
for by any medical or another mental disorder.
intake. The most common manifestations are tremor, restlessness,
insomnia, nightmares, paroxysmal sweats, tachycardia, fever, 3. Significant distress or decline in functioning in socio-
nausea, vomiting, seizures, hallucinations (auditory, visual, and occupational or other important areas due to the withdrawal
tactile), increased agitation, and tremulousness. A minority of symptoms.
patients develop very severe alcohol withdrawal syndrome, The common AWS noted in patients presenting to clinics are
including delirium tremens. These symptoms involve disturbances anxiety, tremors of body and hands, elevated blood pressure,
in a wide range of neurotransmitter circuits that are implicated in tachycardia, insomnia, elevated body temperature, sweating,
alcohol pathway and reflect a homeostatic readjustment of the hallucinations, dilated pupils nausea, disorientation, irritability,
central nervous system [7-9]. headache and grand mal seizure [17]. However, the signs and
symptoms of AWS vary over time and may cause confusion. A
Pathophysiology time based presentation of AWS symptoms is described in [Table/
Historically, several mechanisms have been suggested to play a role Fig-2] [19,20]. The patient’s condition must be reviewed from time
in the development and etiology of AWS. Initially, the researchers to time for the appearance of signs of medical or neurological
thought that withdrawal might be caused by the nutritional illness which may not have been evident at admission but may
deficiencies [10,11]. Some of the complications of withdrawal develop subsequently.
(e.g., seizures) were thought to result directly from alcohol use or
intoxication [12]. Although alcohol dependent persons exhibit many Time of Appearance after
metabolic and nutritional disturbances, overwhelming laboratory Cessation of Alcohol Use Symptoms

and clinical evidence presently indicates that the constellation of 6 to 12 hours Minor withdrawal symptoms: insomnia, tremors,
anxiety, gastrointestinal upset, headache,
signs and symptoms known as AWS are caused by interruption diaphoresis, palpitations, anorexia, nausea,
of the constant exposure of the Central Nervous System (CNS) to tachycardia, hypertension
alcohol itself. 12 to 24 hours Alcoholic hallucinosis: visual, auditory, or tactile
Long-term alcohol consumption affects brain receptors, which hallucinations

undergo adaptive change in an attempt to maintain normal function. 24 to 48 hours Withdrawal seizures: generalized tonic-clonic
seizures
Some key changes involve decrease in both brain gamma-amino
butyric acid (GABA) levels and GABA-receptor sensitivity [13,14] 48 to 72 hours Alcohol withdrawal delirium (delirium tremens):
hallucinations (predominately visual), disorientation,
and activation of glutamate systems [15], which leads to nervous agitation, diaphoresis
system hyperactivity in the absence of alcohol. Alcohol potentiates
[Table/Fig-2]: Symptoms of Alcohol Withdrawal Syndrome
GABA’s inhibitory effects on efferent neurons, thereby suppressing
neuronal activity. With chronic alcohol exposure, GABA receptors Objective assessment of severity of alcohol withdrawal may be
become less responsive and higher alcohol concentrations are done through scale based measurements. One of the reliable scales
required to achieve the same level of suppression, which is termed in common clinical practices is the Clinical Institutes Withdrawal
‘tolerance’. Assessment - Alcohol Revised (CIWA-Ar) scale [21]. It is used to
Alcohol also acts on N-methyl-D-aspartate (NMDA) receptor as an measure the severity of alcohol withdrawal in a patient diagnosed
antagonist, thereby decreasing the CNS excitatory tone. Therefore, to have AWS. The CIWA-Ar is a 10-item scale used to quantify
chronic use of alcohol leads to an up regulation of glutamate to the severity of alcohol withdrawal. It can also be used to monitor
maintain CNS homeostasis. Even when alcohol is no longer present withdrawal and medicate accordingly. The CIWA-Ar has high inter-
in this adapted system, the GABA receptors remain less responsive; rater reliability (r > 0.8) and constructs validity. Scoring is done for
leading to an imbalance in favour of excitatory neurotransmission each item by the clinician using a Likert-type scale (0–7 in most
as the CNS excitation mediated by glutamate is left unopposed cases) and maximum possible total score is 67. The evaluation is
[3]. This CNS excitation is clinically observed as symptoms of easy and takes less than two minutes. However, the scale is not a
alcohol withdrawal in the form of autonomic over activity such as diagnostic tool [22]. It has also been found useful in Indian setting
tachycardia, tremors, sweating and neuropsychiatric complications [23]. Scores of 0-8 indicate absent to minimal withdrawal, scores
such as delirium and seizures. of 9-15 indicate moderate withdrawal and scores of 16 or more
Dopamine is another neurotransmitter that is involved in alcohol indicate severe withdrawal (impending DT) [24].
withdrawal states. During alcohol use and the increase in the
dopamine levels in CNS contribute to the autonomic hyper arousal Pharmacotherapy for Alcohol
and hallucinations. Withdrawal seizures are also thought to result Withdrawal
from a lowering of seizure threshold due to kindling [16]. Over the years, the treatment for alcohol detoxification has evolved
from the use of gradual weaning schedule of alcohol itself to the use
Diagnosis of Alcohol Withdrawal Syndrome of benzodiazepines and the newer miscellaneous drugs. Prompt
The alcohol withdrawal syndrome is diagnosed after a proper pharmacological treatment is indicated in all cases of AWS, as non-
history and a thorough clinical examination. The diagnosis requires treatment or under treatment can be fatal [25,26]. Benzodiazepines
adequate history of the amount and frequency of alcohol intake, are safe, effective and the preferred treatment for AWS. The
the temporal relation between cessation/reduction of alcohol intake best-studied benzodiazepines for AW treatment are diazepam,
and the onset of withdrawal symptoms. Withdrawal symptoms chlordiazepoxide, and lorazepam [24,27].

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www.jcdr.net Ankur Sachdeva et al., Comprehensive Management Alcohol Withdrawal Syndrome

Goals of Detoxification supplementation helps to prevent Wernicke’s encephalopathy (WE)

Three goals of drug and alcohol detoxification as described by the and should be given orally or intramuscularly to all the patients.
American Society of Addiction Medicine (ASAM) are as follows [28]: Adequate nutrition must be ensured with balanced nutrients.
1. “To provide a safe withdrawal from the drug(s) of dependence
and enable the patient to become drug-free”. Cost of Management
The choice of treatment setting for alcohol detoxification has
2. “To provide a withdrawal that is humane and thus protects the
important cost implications. Hayashida and colleagues (1989) found
patient’s dignity”.
outpatient alcohol detoxification to be considerably less costly
3. “To prepare the patient for on-going treatment of his or her than inpatient treatment ($175 to $388 versus $3,319 to $3,665,
dependence on alcohol or other drugs.” respectively) [35]. To some extent, the higher cost of inpatient
treatment reflects the occurrence of more severe symptoms of AW
Setting For Detoxification as well as more co-occurring medical problems among hospitalized
Before the 1980’s, AWS was generally treated in an inpatient setting. patients compared to ambulatory patients.
Today, most detoxifications take place on an outpatient basis. A
review by Abbott et al., in 1995 suggested that fewer than 20% Drugs Used For Detoxification
of patients undergoing AWS detoxification required admission to
an inpatient unit. Most importantly no reports of serious medical 1. Historical: Detoxification with Alcohol
complications among AWS outpatients were found in this review Alcohol was itself used as a detoxifying agent through ‘gradual
except that one patient suffered a seizure after the start of weaning’ that commanded support in the 18th and early 19th centuries
detoxification [29]. However, Myrick and Anton (1998) suggested [36]. By the mid-19th century, the Temperance movement strongly
that the inpatient detoxification provided the safest setting for influenced the way habitual drunkenness is conceptualized and
the treatment of AW, because it ensured that patients would be had widened its focus to condemnation of all alcoholic beverages.
carefully monitored and appropriately supported. Compared with This made it difficult to advocate ‘gradual weaning’ as a justifiable
outpatient facilities, inpatient clinic may provide better continuity intervention. A literature search (Medline, Cochrane, EmBase,
of care for patients who begin treatment while in the hospital. In Psycinfo and DARE) found just two recent reports concerning the
addition, inpatient detoxification separates the patient from alcohol- use of alcohol for alcohol detoxification [37,38], although there are
related social and environmental stimuli that might increase the risk reports in other medical specialties [39].
of relapse [30]. Richard Saitz suggested that Alcohol should not be used to
Despite the lack of research-based criteria, certain factors suggest treat withdrawal for several reasons [3]. First, using alcohol as a
that a patient should receive inpatient treatment. These factors treatment would promote its acceptability to the alcoholic. Second,
include a history of significant alcohol withdrawal symptoms, high alcohol has known toxic effects (e.g., impairing the function of the
levels of recent drinking, a history of withdrawal seizures or DTs liver, pancreas, and bone marrow) that are not shared by the safer
(Delirium Tremens), and the co-occurrence of a serious medical or benzodiazepines. Third, in one clinical study, alcohol was inferior to
psychiatric illness [31,32]. Predictors of severe alcohol withdrawal the benzodiazepine, chlordiazepoxide [38].
(Withdrawal Seizure or Delirium Tremens) should be taken into
account and are listed in [Table/Fig-3] [33,34]. Out-patient treatment 2.  Benzodiazepines
can be offered to patients who don’t have these risk factors and this Benzodiazepines (BZD) are the mainstay of treatment in alcohol
decision relies on the withdrawal signs. Pharmacotherapy may not withdrawal. Benzodiazepines are safe, effective and the preferred
be needed in all cases of mild alcohol withdrawal syndrome. These treatment for AWS. Benzodiazepines are cross-tolerant with
patients can be managed by supportive care and observation for alcohol and modulate anxiolysis by stimulating GABA-A receptors
up to 36 hours, after which they are unlikely to develop withdrawal [24]. During withdrawal from one agent, the other may serve as
symptoms. a substitute. They are proven to reduce withdrawal severity and
incidence of both seizures and delirium tremens (DT) [40-42].
1. Older age The ideal drug for alcohol withdrawal should have a rapid onset and
2. Past history of DT or alcohol withdrawal seizure a long duration of action, a wide margin of safety, a metabolism not
3. Severe withdrawal symptoms at initial assessment dependent on liver function, and absence of abuse potential [43].
4. Co-morbid medical or surgical illness Various BZDs offer many of these advantages. BZDs have been
found effective in: 1) preventing agitation and alcohol withdrawal
5. Presence of dehydration
seizures; 2) preventing delirium tremens; and 3) as cross-tolerant
6. Electrolyte disturbances (hyponatremia or hypokalemia)
agents with ethanol. BZDs, owing to their wide margin of safety
7. Deranged liver enzymes and low potential to produce physical dependence and tolerance
8. The presence of structural brain lesions in short-course therapy, are therefore very, effective in the treatment
[Table/Fig-3]: Predictors of severe alcohol withdrawal (withdrawal seizure or of alcohol-withdrawal syndrome. They are the drugs of choice for
Delirium Tremens) alcohol withdrawal [44].
Holbrook et al., did a meta-analysis of benefit of BZD in the treatment
General Principles of Supportive Care
of acute alcohol withdrawal through randomized controlled trials in
It is essential to provide comfort and relaxation for patients pre­
MEDLINE and the Cochrane Controlled Trials Registry [45]. They
senting for alcohol detoxification. They should preferably be kept in
found that BZD were superior to placebo (common odds ratio {OR}
a room which is quiet and has minimal stimulation and low lighting.
3.28, 95% confidence interval {CI} 1.30–8.28). Data on comparisons
Dehydration is an important component of AWS and should be
between benzodiazepines and other drugs, including α-blockers,
given emergency check up. There should be immediate intravenous
carbamazepine and clonidine could not be pooled, but none of
access for all patients with seizures or DT. If dehydrated, intra
them was found to be superior to benzodiazepines. Another meta-
venous fluids should be started. Adequate sedation should be
analysis concluded that BZD reduce withdrawal severity, reduce
provided to calm the patient as early as possible. Restraints should
incidence of delirium and seizures [24]. Hence, Benzodiazepines are
be avoided, however, may be used as required in order to prevent
suitable agents for alcohol withdrawal. The choice among different
injuries due to agitation or violence. Electrolyte imbalances must
agents should be guided by rapidity of onset, duration of action
be promptly corrected after investigations. Vitamin B1 (Thiamine)

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and also the cost. Clonidine, beta-blockers, carbamazepine, and Mayo-Smith and Saitz and O’Malley formulated a treatment regimen
neuroleptics are not recommended as monotherapy though may in accordance with CIWA–Ar score severity [24,51]. According
be used as adjunct. to these authors, patients with mild withdrawal symptoms (i.e.,
CIWA–Ar scores of 8 or less) and no increased risk for seizures
•  Choice of Benzodiazepine can be managed without specific pharmacotherapy. Successful
All subclasses of benzodiazepines appear to be equally effective in non-pharmacological treatments include frequent reassurance and
treating AWS [24]. Therefore, choosing a benzodiazepine depends monitoring by treatment staff in a quiet, calm environment. Patients
on selection of preferred pharmacokinetic properties in relation to the who experience more severe withdrawal (CIWA-Ar scores ≥ 8)
patient being treated. The most commonly used benzodiazepines should get pharmacotherapy to manage their symptoms and lower
for alcohol detoxification are chlordiazepoxide, diazepam (long the risk of seizures and DT’s.
acting) and lorazepam, oxazepam (short/intermediate acting).
Saitz et al., suggested that long acting agents like diazepam and •  Efficacy of fixed tapering dose regimens over
chlordiazepoxide which have greater half-life (i.e., for up to several symptom triggered regimens
days) can provide a smooth course of treatment without the risk of A few International studies tried to compare the different regimens
rebound symptoms (e.g. Seizures) that occur late during withdrawal of benzodiazepines used for alcohol detoxification but there is a
as blood levels are reasonably uniform across the course of the paucity of Indian literature comparing the fixed tapering dose and
day [3]. However, a disadvantage of these two drugs is that the the symptom triggered regimens of benzodiazepines inspite of
dependence on demethylation and hydroxylation metabolic alcohol abuse being such a huge public health problem.
pathways, the long half-lives, and the presence of active metabolites Reoux and Miller in their retrospective analysis using treatment charts
make it likely that drug accumulation will occur in patients with liver of patients hospitalized for uncomplicated alcohol withdrawal found
disease. The benzodiazepine equivalents for 5 mg diazepam are 25 that patients detoxified using a CIWA-Ar based protocol received
mg chlordiazepoxide, 1 mg lorazepam and 15 mg oxazepam. significantly fewer chlordiazepoxide milligram equivalents over
Short-acting (i.e., for several hours) benzodiazepines like lorazepam shorter durations than patients managed by other detoxification
should be used in patients with severe liver dysfunction and in patients methods [52].
who are at high risk of experiencing serious medical consequences The advantage of the STR lies in the fact that detoxification
following sedation, such as people with severe lung disease or elderly is monitored through a standardized scale that results in
patients as it has no active metabolites and its metabolism is not administration of less benzodiazepines for a significantly shorter
much affected in liver. Short-acting benzodiazepines probably are duration thereby reducing the cost to the patient as well as to
efficacious as well but are associated with a greater risk of rebound the hospital. Day et al., concluded that STR is acceptable to
symptoms. To prevent recurrence of withdrawal symptoms, these both patients and staff and is potentially a useful technique for
agents must be given in gradually decreasing doses/tapering doses busy acute psychiatric wards [53]. Cassidy et al., reported that
before they can be discontinued. symptom-triggered approach reduced cumulative benzodiazepine
dose and length of stay in an emergency department set up [54].
•  Regimens for alcohol detoxification Similarly, other studies have also shown that STR reduces the
Three regimens for alcohol detoxification using benzodiazepines are benzodiazepine doses and duration of detoxification. Studies
most commonly followed [26], have been conducted on oxazepam [47], chlordiazepoxide [46]
1. Fixed tapering dose regimen (FTDR) – fixed doses of and chlormethiazole [55].
benzodiazepines are administered at scheduled intervals Jaeger T et al., conducted a retrospective analysis to assess
regardless of symptom severity. The initial doses are decided the effectiveness usual care for AWS vs. the symptom-triggered
based upon the presenting severity of withdrawal and the time therapy in patients admitted to the general medical services. They
since last intake. This is best suited for out‑patient setting concluded that STR is an effective treatment for AWS in medical
where close monitoring is not possible [24]. Consequently, inpatients. Although it did not result in shorter duration of treatment,
a fixed-dose regimen may be preferred in admitted patients the STR was associated with a decreased occurrence of delirium
if CIWA-Ar scores cannot be accurately performed (i.e. lack tremens, the most severe and life-threatening complication of
of training, outpatient care setting, co-morbid medical or AWS [25].
psychiatric illnesses or use of medications that may affect An Indian study comparing the STR and FTDR of lorazepam for
CIWA-Ar measurements) [24]. alcohol detoxification in 63 indoor patients found that STR resulted
2. Symptom triggered regimen (STR) – benzodiazepines are in shorter duration of treatment and lower total doses of medication.
administered according to the withdrawal symptoms as This double blind randomized controlled trial found STR to be as
assessed by withdrawal rating scales e.g. CIWA- AR. The safe as the fixed tapering dose [56].
ratings are done at a fixed schedule and drug doses are The review suggests that benzodiazepines are the preferred drugs
administered as per withdrawal severity. It needs training in for alcohol detoxification and all the benzodiazepines have proved
applying scales and trained personnel. A symptom-triggered similar efficacy for detoxification.
regimen is preferred in most cases of AWS because it results
in the administration of less total medication and shorter 3.  Anticonvulsant drugs
duration of treatment [46,47]. This regimen may also reduce BZD’s are the drugs of choice for AWS in most of the treatment
the risk of under medicating or over medicating a patient since settings; however, anti-convulsant drugs may represent suitable
dosing is based upon withdrawal symptoms [48]. The efficacy alternatives. There are several potential advantages to using anti-
of symptom-triggered regimens, however, depends on the convulsant drugs. Use of an anti-convulsant drug decreases the
validity of patient assessment. probability of a patient experiencing a withdrawal seizure, thereby
3. Loading dose regimen (LDR) - These regimens use long acting reducing the complications of AWS. Anti-convulsant drugs also
benzodiazepines to reduce the risk of complications such as reduce craving. Anti-convulsant drugs have been shown to block
seizures and delirium. An oral loading dose of 20 mg diazepam kindling in brain cells. Anti-convulsant drugs do not appear to have
given every 2 hours was found useful in treating alcohol abuse potential. Anti-convulsant drugs have been effectively used
withdrawal. The withdrawal severity and the clinical condition to treat mood disorders, which share some symptoms with AWS,
needs to be monitored before each dose [49,50]. including depression, irritability, and anxiety. The propensity of anti-
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convulsant drugs to cause sedation is much less as compared to are GABA-B pathways (agonist). Addolorato et al., reported a case
BZD’s [30]. series with five patients in which a single 10-mg dose of Baclofen
Carbamazepine has been shown to be superior in ameliorating resulted in relief of severe withdrawal symptoms [68]. In a preliminary
global psychological distress and reducing aggression and anxiety RCT by the first author in 2002, Baclofen also reduced craving in
compared to oxazepam [57]. Carbamazepine was also reported alcohol-dependent patients [69]. A study found that the efficacy of
to be an effective alternative to benzodiazepines in the treatment Baclofen in treatment of uncomplicated AWS was comparable to
of alcohol withdrawal syndrome in patients with mild to moderate that of the “gold standard” diazepam, with significantly decreased
symptoms [58]. Carbamazepine also appeared to decrease the CIWA-Ar scores [70].
craving for alcohol after withdrawal. Carbamazepine was found
superior to benzodiazepines in prevention of rebound withdrawal 7. Newer Drugs
symptoms and reducing post-treatment alcohol consumption, Most of the recently tried drugs in AWS are being used only as
especially in patients who had multiple repeated withdrawals adjuncts to BZDs. N-methyl-d-aspartate antagonist ketamine
[59]. Carbamazepine use, however, has been limited due to its appears to reduce BZD requirements and is well tolerated at low
interaction with multiple medications that undergo hepatic oxidative doses [71]. However, there are not enough published data. Still,
metabolism, making it less useful in older patients and patients with it is a promising new agent. Levetiracetam has also been tried
medical co-morbidities [60]. Also, carbamazepine has not been but with negative results [72]. It did not significantly reduce the
evaluated for treating delirium tremens. benzodiazepine requirements of patients with AWS. A review found
that sodium oxybate, sodium salt of γ-hydroxybutyric acid, is a useful
Reoux et al., and Malcolm et al., concluded that Valproic acid
option for the treatment of alcohol withdrawal syndrome [73]. The
significantly affects the course of alcohol withdrawal and reduces
salt is approved in Italy and Austria for the same. Dexmedetomidine
the need for treatment with a benzodiazepine [61,62]. These two
is a drug which acts on the noradrenergic system and is currently
double-blind, randomized studies showed that patients treated with
used in the US in the treatment of AWS in emergency set up. It may
Valproic acid for 4 to 7 days dropped out less frequently, had less
reduce the need for BZD and is a promising and effective adjuvant
severe withdrawal symptoms including fewer seizures, and required
treatment for AWS [74].
less oxazepam than patients receiving either carbamazepine or
placebo. Although effective, Valproic acid use may be limited by
side effects—somnolence, gastrointestinal disturbances, confusion, •  Alcohol withdrawal syndrome with alcohol withdrawal
and tremor—which are similar to alcohol withdrawal symptoms, seizures and/or delirium
making assessment of improvement difficult. The occurrence of seizures during the AWS is indicative of severe
alcohol withdrawal, although the CIWA-Ar score may not correlate.
Gabapentin, which has structural similarity to GABA, is shown to
All patients with AWS, with seizures in the current withdrawal
be effective in the treatment of alcohol withdrawal [63,64]. Its low
period or past history of withdrawal seizure should be given
toxicity makes it a promising agent. Gabapentin was as effective
prophylactic intravenous/intramuscular injection of 2mg lorazepam
as lorazepam in a randomized, double blind controlled study on 46
[75]. Lorazepam is considered more effective than diazepam in
in-patients with alcohol withdrawal in the treatment of acute mild
to moderate AWS [65]. Vigabatrin, an anticonvulsant agent, which preventing seizure recurrence as lorazepam has consistent plasma
irreversibly blocks GABA transaminase, showed improvement in level distribution unlike diazepam. These patients may require high
withdrawal symptoms after only three days of treatment and is a doses of benzodiazepine (diazepam equivalents of about 20-60
promising agent for detoxification [66]. mg) to prevent further seizures and to prevent the development
of DT [51]. Patients with AW seizures should be ideally admitted
4.  Adrenergic medications and monitored for at least 36-48 h to watch for further seizures
Adrenergic medicines (centrally acting alpha-2 agonists like clonidine; or DT [76]. Detailed neurological and medical examination, blood
and antagonist like propranolol), which alter the function of adrenergic investigations and brain imaging are required and should be done,
receptors, are thought to significantly improve symptoms of AWS, especially to rule out alternative causes.
especially autonomic symptoms, by reducing elevated pulse and Alcohol withdrawal delirium DT is a medical emergency and
blood pressure [51]. There is no evidence that these medications requires indoor treatment and monitoring. Detailed neurological
prevent or treat delirium or seizures. Adrenergic medications are and medical examination along with blood investigations should
of value largely as adjuncts to BZD’s in the management of AWS. be done in all patients to rule out other common causes of
These medications also may be useful in outpatient settings, where delirium such as hypoglycemia, electrolyte imbalance, and head
the abuse liability of BZD’s by patients is difficult to monitor or
injury leading to subdural hemorrhage, septicemia and renal/liver
prevent and where AWS symptoms are generally less severe than
failures. Brain imaging may be undertaken in suspected cases of
among inpatient populations [67].
neurological insult. The goal of management is to achieve a calm
and awake state. The goal is best achieved through judicious
5.  Barbiturates
use of BZDs. Intravenous or intramuscular lorazepam should
Barbiturates such as phenobarbitone act via GABA pathways.
be preferred and administered at frequent intervals with close
Barbiturates are cross tolerance to alcohol and can ease withdrawal
monitoring. Lorazepam is more suitable in patients with hepatic
symptoms significantly. However, controlled studies have not
provided sufficient data to demonstrate that these agents can disease, in the elderly where there is risk of over sedation and
prevent seizures or DT’s. Furthermore, barbiturates have a narrow respiratory depression with diazepam. Initial doses of 10 mg
therapeutic index, that is, the difference between the minimum equivalents of diazepam are given intravenously/intramuscularly
doses required for a therapeutic effect and the dose at which the and can be repeated every 15-30 minutes [51,77]. Some experts
agents become toxic is small, as compared to BZDs and are not in even advice and advocate use of loading doses of diazepam
common practice [3]. for management of DT. However, it is purely based on clinical
experience as no clinical trials have been conducted in patients
6.  Baclofen with DT. When light somnolence is achieved and the patient is
The advances in knowledge of neurobiology and neurochemistry relaxed, management may be shifted to oral/injectable symptom
have prompted the use of drugs in the treatment of alcohol withdrawal monitored schedule. Vitals monitoring is extremely important and
that act through "t GABA pathways", such as the Baclofen, which should be done regularly.

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•  Adjunctive Supplements Survey. United Nations Office on Drugs and Crime, Regional Office for South Asia
and Ministry of Social Justice and Empowerment, Government of India, New
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PARTICULARS OF CONTRIBUTORS:
1. Assistant Professor, Department of Psychiatry, ESIC Medical College and Hospital, Faridabad, Haryana, India.
2. Senior Resident, Department of Psychiatry and Drug De-addiction, Post Graduate Institute of Medical Education and Research,
Dr Ram Manohar Lohia Hospital, New Delhi, India.
3. Chief Medical Officer (NFSG), Department of Psychiatry and Drug De-addiction, Post Graduate Institute of Medical Education and Research,
Dr Ram Manohar Lohia Hospital, New Delhi, India.

NAME, ADDRESS, E-MAIL ID OF THE CORRESPONDING AUTHOR:

Dr. Mona Choudhary,
Senior Resident, Department of Psychiatry and Drug De-addiction, Post Graduate Institute of Medical Education and Research, Date of Submission: Feb 08, 2015
Dr Ram Manohar Lohia Hospital, Park Street, New Delhi-110001, India.
Date of Peer Review: Jun 08, 2015
E-mail: [email protected]
Date of Acceptance: Jul 03, 2015
Financial OR OTHER COMPETING INTERESTS: None. Date of Publishing: Sep 01, 2015

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