Alcohol Withdrawal Dynamed

...
/ Medications / Thiamine and other supplementation
[+]Updated 2017 Jan 17 02:16 PM (ET)

Topic Editors
Daniel A. Ostrovsky, MD
Daniel C. Vinson, MD, MSPH
Recommendations Editor Esther Jolanda van Zuuren, MD
Deputy Editor Brian C. Weiner, MD, MS, FACP, AGAF
Overview and Recommendations

Background
Alcohol withdrawal syndrome refers to a progression of signs and symptoms that occur following the reduction or cessation of
alcohol intake after heavy and prolonged use.
Symptoms typically occur in 4 clinical stages, but not all patients will experience all stages or progress sequentially through them:
minor withdrawal symptoms - stage 1
6-12 hours after stopping alcohol
tremors, insomnia, irritability, mild agitation, anorexia, nausea, vomiting, tension, anxiety, sweating, restlessness
alcoholic hallucinosis - stage 2
12-24 hours after stopping alcohol
hallucinations (auditory, visual, or tactile) may occur
withdrawal seizures - stage 3

24-48 hours after stopping alcohol, although may begin as early as 2 hours after stopping alcohol
usually tonic-clonic seizures
alcohol withdrawal delirium (delirium tremens) - stage 4

usually occurs 3-7 days after stopping alcohol but can occur at any time up to 14 days
hallucinations (usually visual), disorientation, tachycardia, hypertension, agitation, diaphoresis, low-grade fever
Consider prophylactic treatment in inpatients admitted for reasons other than alcohol withdrawal (and are without withdrawal
symptoms) and have history of either:
withdrawal seizures or delirium tremens
prolonged, heavy alcohol consumption
Evaluation
Diagnose alcohol withdrawal if stopping or decreasing heavy and prolonged alcohol use leads to typical symptoms in the absence of
an alternative diagnosis.
Evaluate for reasons leading to sudden reduction or cessation of alcohol intake, such as precipitating illness.
Testing may include blood alcohol level, complete blood count, electrolyte levels, liver function tests, coagulation tests, urine and/or
serum drug screen, and in selected patients lumbar puncture and neuroimaging for assessment of possible head trauma or other
anatomic abnormalities of the central nervous system.
Differential diagnosis is extensive, and one or more conditions may mimic or be associated with alcohol withdrawal.
... /Consider
Medications / Thiamine and other supplementation
using a tool such as the Clinical Institute Withdrawal Assessment-Alcohol, revised (CIWA-Ar) or another structured
instrument to assess the initial severity of withdrawal and to monitor treatment.
Management
Management involves alleviating symptoms and correcting metabolic abnormalities.
Consider outpatient treatment for patients with mild-to-moderate symptoms who are not at high risk for delirium tremens or
withdrawal seizures.
Admit all other patients for observation and treatment.
Administer thiamine (Strong recommendation), folic acid, and consider giving a multivitamin to patients with alcohol withdrawal.
Consider hydration, nutritional support, and electrolyte replacement as part of the supportive care.
Consider treatment with a benzodiazepine if CIWA-Ar score > 8-10.
Regimen options in the inpatient setting include symptom-triggered dosing, fixed-tapering dosing, or a loading-dose regimen. The
symptom-triggered dosing is generally preferred in institutions capable of close patient monitoring.
Regimen options in the outpatient setting include fixed schedule or symptom-triggered schedule.
Other medications may be used in certain situations:

Anticonvulsants may be considered to treat seizures in patients with mild-to-moderate withdrawal.
Consider using barbiturates or propofol if large doses of benzodiazepines fail to control agitation in patients with delirium tremens
(Weak recommendation).
Medications to consider in addition to benzodiazepine agent:
Consider using an adjunctive alpha2-adrenergic agonist or a beta blocker in patients with persistent cardiac adrenergic
symptoms despite the treatment of dehydration and electrolyte imbalances (Weak recommendation).
Consider adjunctive antipsychotics if agitation, disturbed thinking, or perceptual disturbances are not adequately controlled
(Weak recommendation).
See Alcohol use disorder to address patient's alcohol consumption.
Related Summaries
Alcohol use disorder
Wernicke encephalopathy
General Information
Description
acute syndrome of adverse central nervous system, autonomic, and cognitive effects occurring after cessation or reduction of heavy,
prolonged (≥ 2 weeks) alcohol use(2, 3, 5)
Definitions
alcohol withdrawal syndrome consists of ≥ 2 of the following criteria after cessation or reduction of heavy or prolonged use of alcohol
autonomic hyperactivity
hand tremor
insomnia
nausea or vomiting
transient hallucinations or illusions
psychomotor agitation
anxiety
generalized tonic-clonic seizures
Reference - N Engl J Med 2014 Nov 27;371(22):2109 full-text, commentary can be found in N Engl J Med 2015 Feb 5;372(6):580
delirium tremens (also called alcohol withdrawal delirium) consists of the following in patients with alcohol withdrawal syndrome
decreased attention or awareness
disturbances in memory, orientation, language, visuospatial ability, or perception
disturbance is a change from normal level and fluctuates in severity throughout the day
no evidence of coma or other evolving neurocognitive disorders
... / Medications / Thiamine and other supplementation
Epidemiology
Who is most affected
patients with alcohol dependence who are deprived of alcohol, as during hospitalization(2, 5)
elderly patients are at risk for more rapidly severe alcohol withdrawal syndrome, due to relatively higher alcohol blood concentrations
from lower total body water, increasingly permeable blood-brain barrier, and increased comorbidities and medications(5)
Incidence/Prevalence
overall incidence of alcohol withdrawal symptoms not established
reported rates of alcohol withdrawal syndrome in intensive care units ranges from < 1% in all patients to > 60% among highly
selected patients with alcohol dependence (Intensive Care Med 2013 Jan;39(1):16)
estimated 8% of hospitalized patients will have signs of alcohol withdrawal due to lack of alcohol in inpatient setting(4)
Associated conditions
Wernicke encephalopathy - chronic thiamine deficiency leading to classic triad of confusion, ataxia, and ophthalmoplegia(1, 2, 4, 5)
may result from chronic alcohol use, which depletes magnesium and thiamine, and leads to cell damage in mammillary body,
thalamus, and hippocampal area
can progress to permanent amnesia condition of Korsakoff syndrome
thiamine supplementation is recommended in all patients with acute withdrawal to prevent Wernicke encephalopathy
Etiology and Pathogenesis

Causes
homeostatic readjustment of central nervous system after abrupt reduction or cessation of prolonged alcohol use(2)
Pathogenesis
excitatory state results from abrupt removal or reduction of alcohol(2, 4)
prolonged use of alcohol causes adaptation of neuroreceptors in 2 different pathways
Effect of Prolonged Alcohol Use on Central Nervous System:
Acute Effect of Alcohol Resultant Adaptive Response to Removal of

Change From Prolonged Alcohol
Alcohol Use
Enhances inhibitory effect of Down-regulation of GABA Decreased ability to inhibit

GABA receptors overactivation of GABA
receptors
Abbreviations: GABA, gamma-amino butyric acid; NMDA, N-methyl-D-aspartate.

... / Medications / Thiamine
Acute Effect and other supplementation
of Alcohol Resultant Adaptive Response to Removal of
Change From Prolonged Alcohol
Alcohol Use
Decreases excitation by acting Up-regulation of glutamate to In absence of alcohol, up-

as antagonist to NMDA maintain homeostatic level of regulation of NMDA pathway
receptors excitation leads to overactivation NMDA
receptors
Abbreviations: GABA, gamma-amino butyric acid; NMDA, N-methyl-D-aspartate.
overactivation leads to
autonomic symptoms including tachycardia, tremors, sweating
neuropsychiatric symptoms including delirium or seizure
during acute withdrawal, dopamine levels are also increased, which is thought to lead to hallucinations and autonomic hyperarousal(2,
4, 5)
more severe withdrawal and seizures may be due to "kindling" effect(4, 5)

patients with alcohol dependence may have multiple episodes of untreated alcohol withdrawal syndrome
repeated alcohol withdrawal syndrome leads to progressive sensitivity and excitability of central nervous system
kindling may lead to higher risk of seizure and delirium tremens in alcohol withdrawal syndrome
hypothesis supported by association of past alcohol withdrawal syndrome to risk for more severe alcohol withdrawal syndrome
episode
History and Physical

History
Chief concern (CC)
most common symptoms are(2, 3, 5)

tremor, restlessness, paroxysmal sweating, tachycardia, fever, nausea, vomiting, tremulousness
agitation, insomnia, nightmares, irritability, seizures, transient visual, tactile, or auditory hallucinations
if untreated, withdrawal may progress to delirium tremens with symptoms/signs including(3)

disorientation, impaired attention or consciousness, and visual and/or auditory hallucinations
hyperthermia, excessive sweating, tachypnea, and/or tachycardia
History of present illness (HPI)
assess pattern of alcohol use(2, 3, 4, 5)

time since reduction or cessation of alcohol and symptom onset
estimated quantity and frequency of consumption
kind of drink typically consumed
drinking pattern (such as daily, weekly, or early in the day)
previous episodes of alcohol withdrawal
4 generally recognized stages used for reference of expected progression, but stages are not clinically reliable due to potential for
patients(4, 5)
not progressing through them sequentially
presenting with overlapping symptoms from varying stages
approximate stages are(2, 3, 4, 5)
stage 1 - minor symptoms which may occur even in presence of elevated blood alcohol levels
occurs 6-12 hours after last drink
may consist of tremors, anxiety, gastrointestinal upset, anorexia, nausea, excessive sweating (diaphoresis), palpitations,
tachycardia, hypertension and other supplementation
reported to resolve within 24-48 hours if withdrawal does not progress or is treated
stage 2
may consist of hyperactivity, insomnia, and visual, tactile, or auditory hallucinations, which generally resolve within 48 hours
stage 3 - 3% to 5% of patients progress to this stage
occurs 12-48 hours after last drink (though seizures have been reported as soon as 2 hours after last drink)
similar to stage 2 but with tonic-clonic seizures; seizures typically singular or recur only few times, and spontaneously
resolve
stage 4 - reported in 33% of untreated patients in stage 3

occurs 3-5 days after last drink; symptoms may last up to 7 days
consists of delirium tremens with disorientation, agitation, hyperactivity, hallucinations, excessive sweating, hypertension,
and tachycardia
Medication history
ask about prior benzodiazepine use (reported risk factor for severe withdrawal)(4)
ask about medications with overdose symptoms similar to delirium tremens, including
lithium
atropine
tricyclic antidepressants
Reference - Ind Psychiatry J 2013 Jul;22(2):100 full-text
Past medical history (PMH)
ask about risk factors of more severe withdrawal, including(1, 2, 4)

current acute illness or chronic condition
history of alcohol withdrawal
history of neurological illness with presence of brain lesions
ask about liver or kidney disease(1)
Social history (SH)
ask about other substance use problems(5)
Physical
General physical
common signs include(2)

tremors in body or hands
elevated blood pressure
tachycardia
elevated body temperature
excessive sweating
dilated pupils
look for signs of(1, 4)

malnutrition
decompensated liver disease
dehydration (increases risk of severe withdrawal)
suspect Wernicke encephalopathy if classic triad present; triad includes(1, 2)

ataxia
confusion
ophthalmoplegia
assess for complicating medical conditions
arrhythmias
heart failure
coronary artery disease
gastrointestinal bleeding
infections
liver disease
nervous system impairment
pancreatitis
Reference - Am Fam Physician 2004 Mar 15;69(6):1443 full-text
Diagnosis
Making the diagnosis
diagnosis made clinically in patient with history of heavy and regular alcohol intake and onset of symptoms (listed below) after
cessation of alcohol intake(2)
symptoms typically begin around 6 hours after cessation/reduction
alcohol withdrawal syndrome is unlikely if onset of symptoms is ≥ 1 week after alcohol reduction or cessation
Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) diagnosis requires the following criteria after exclusion of
other medical or substance-associated causes(4, 5)
history of reduction or cessation of heavy and prolonged alcohol use
≥ 2 of following must be present within a few hours to a few days after alcohol reduction/cessation, and cause clinically significant
distress or impairment
autonomic hyperactivity (sweating or tachycardia > 100 beats/minute)
increased hand tremor
insomnia
nausea or vomiting
transient hallucinations (visual, tactile, or auditory) or illusions
psychomotor agitation
anxiety
generalized tonic-clonic seizures
criteria for delirium tremens (also called alcohol withdrawal delirium) consists of the following in patients with alcohol withdrawal
syndrome
decreased attention or awareness
disturbances in memory, orientation, language, visuospatial ability, or perception
disturbance is a change from normal level and fluctuates in severity throughout the day
no evidence of coma or other evolving neurocognitive disorders
assess all patients in acute withdrawal for severity both initially and periodically to guide treatment decisions and assess for
progression of medical or neurological illness(2, 4)
Differential diagnosis
alcohol-induced psychotic disorder
rare complication of long-term alcohol abuse that may occur during or after episode of heavy drinking
consists primarily of auditory hallucinations, and may also have delusions or mood disturbances, all occurring in clear state of
consciousness (unlike delirium tremens)
Reference - Metab Brain Dis 2014 Jun;29(2):231 and Ind Psychiatry J 2012 Jul;21(2):155 full-text
withdrawal and delirium tremens can appear similar to

infections such as
encephalitis/meningitis, symptoms/signs can include presence of fever, seizures, meningeal signs, focal neurologic deficits,
and abnormalities on imaging or cerebrospinal fluid test
pneumonia, signs include presence of fever, cough, and low arterial blood oxygen saturation
sepsis in adults
hepatic encephalopathy, in addition to history of jaundice, hematemesis, or melena, symptoms/signs include

sleep-wake reversal with daytime drowsiness and nighttime agitation
jaundice, ascites, parotid enlargement, or other signs of liver disease
asterixis
overdoses of medications including anticholinergics, lithium, selective serotonin reuptake inhibitors (SSRIs), or other
antidepressants
amphetamine abuse
cocaine abuse
benzodiazepine withdrawal
opiate withdrawal
thyrotoxicosis (hyperthyroidism), signs include thyromegaly or exophthalmos
psychosis, symptoms include long-standing duration of delusions or hallucinations without disorientation
hypoglycemia
diagnoses associated with hypoactive delirium rather than hyperactive delirium typical of delirium tremens
hyponatremia, signs include dehydration and uremia
head injury, symptoms/signs include bradycardia, pinpoint pupils, focal neurologic deficits, and ear or nose bleed
Reference - (2), Ind Psychiatry J 2013 Jul;22(2):100 full-text, Am Fam Physician 2004 Mar 15;69(6):1443 full-text
other causes of seizures include

epilepsy, metabolic imbalances, central nervous system infections, focal neurologic lesions, systemic conditions affecting central
nervous system, certain medications, illicit substance or toxin ingestion
see Seizure in adults - Causes of seizure other than epilepsy section for additional information
Testing overview
Clinical Institute Withdrawal Assessment – Alcohol, revised (CIWA-Ar) recommended by many organizations to assess initial severity
and monitor treatment
in patients with suspected alcohol withdrawal, testing includes(5)
basic blood chemistry panel
complete blood cell count - thrombocytopenia or hyperhomocysteinemia may help discern risk for developing severe withdrawal,
including delirium tremens, in inpatients with alcohol withdrawal syndrome (level 2 [mid-level] evidence)
alcohol and toxicology screen when clinically indicated
in patients with confirmed alcohol withdrawal, testing includes(4, 5)

liver and kidney function tests
blood alcohol level
toxicology studies
electrolyte monitoring including magnesium and phosphate
in patients with seizure or delirium, perform tests to exclude other causes and monitor clinical status
Blood tests
magnesium, thiamine, and electrolyte deficiencies common in patients with alcohol withdrawal(2, 4)
testing for inpatients includes(1, 2, 4, 5)
complete blood count to assess for anemia
serum glucose to assess for hypoglycemia
serum electrolytes including magnesium to detect deficiencies or abnormalities for differential diagnosis and treatment
considerations
liver and kidney function tests to assess for disease and for possible medication considerations
blood alcohol level, as withdrawal symptoms in presence of elevated blood alcohol level may suggest impending severe withdrawal
toxicology studies to assess for nonalcohol substance use
see also Alcoholic hepatitis - Testing for testing for liver disease
Imaging studies
consider imaging if concern for head injury or seizures present ((2), Ind Psychiatry J 2013 Jul;22(2):100 full-text)
Cerebrospinal fluid (CSF) analysis

consider lumbar puncture to assess for encephalitis or meningitis if suggestive symptoms such as fever, seizures, meningeal signs, or
focal neurologic deficits are present (Ind Psychiatry J 2013 Jul;22(2):100 full-text)
Other diagnostic testing

Severity assessment tools
tools recommended for severity assessment
Clinical Institute Withdrawal Assessment – Alcohol, revised (CIWA-Ar) recommended by many organizations to assess initial
severity and monitor treatment(2, 3, 4, 5)
10-question tool to assess severity of alcohol withdrawal in order to
make initial treatment decision (inpatient vs. outpatient)
guide symptom-triggered treatment regimen
scoring clinical dimensions

rates 10 symptom dimensions on 0-4 or 0-7 Likert scales (total score range 0-67)
clinical dimensions include nausea and vomiting, tremor, paroxysmal sweats, anxiety, agitation, tactile disturbances, auditory
disturbances, visual disturbances, headache/fullness in head, and orientation and sensorium clouding
generally used severity rating by score(2, 3, 4)

score ≤ 8 considered absent or very mild withdrawal
9-14 considered mild withdrawal
15-20 considered moderate withdrawal, or impending severe withdrawal
≥ 20 considered severe withdrawal
patients with scores < 10 do not typically need additional medication
see DynaMed calculator for interactive CIWA-Ar Clinical Institute Withdrawal Assessment for Alcohol Scale
Short Alcohol Withdrawal Scale(3)

self-completed 10-item scale
10 dimensions rated from 0 (not present) to 3 (severe)
scoring
< 12 points considered mild withdrawal
≥ 12 points considered moderate-to-severe withdrawal
Glasgow Modified Alcohol Withdrawal Scale (GMAWS) is a 5-item tool to designed to assess and monitor alcohol withdrawal in acute
settings, and to guide symptom-triggered dosing of benzodiazepines; see Monitoring treatment section for details
Risk factors for severe withdrawal

in addition to assessing baseline severity and risk, National Institute for Health and Clinical Excellence (NICE) recommends assessing
risk to self or others (includes unplanned withdrawal, suicidality, and neglect)(1)
assess risk of severe withdrawal
factors reported to be associated with more severe withdrawal (including seizures or delirium tremens [DT]) include(1, 2, 4, 5)
increasing time since last drink
history of delirium tremens or alcohol withdrawal seizure
moderate-to-severe baseline symptoms (CIWA-Ar score > 10)
prior benzodiazepine use
dehydration
electrolyte disturbance (hyponatremia or hypokalemia)
elevated aspartate aminotransferase (AST) and gamma-glutamyl transpeptidase (GGT)
presence of structural brain lesions
prior outcomes of past alcohol withdrawal syndrome may be associated with risk of developing DT, severe withdrawal, or seizure in
patients with acute alcohol withdrawal (level 2 [mid-level] evidence)
based on systematic review of observation studies limited by clinical and statistical heterogeneity
systematic review of 17 observational studies evaluating clinical and medical factors and incident of severe alcohol withdrawal
syndrome (SAWS), DT, and seizure in patients with acute alcohol withdrawal
SAWS definitions were heterogeneous across studies, most relied on cutoff scores from symptom scales
development of DT
DT associated with history of prior DT in analysis of 6 studies with 1,637 patients (odds ratio [OR] 2.58, 95% CI 1.41-4.7), results
limited by heterogeneity
factors not associated with incident DT included
demographic and comorbid variables of age, male sex, acute medical illness, liver disease, or pancreatic disease
substance use disorder variables including history of withdrawal seizure, prior inpatient alcohol detoxifications, history of
prior alcohol withdrawal syndrome, duration of alcohol use disorder, or daily intake of alcohol
severe alcohol withdrawal syndrome

SAWS associated with history of prior delirium tremens in analysis of 6 studies with 1,637 patients (OR 2.58, 95% CI 1.41-4.7),
results limited by heterogeneity
factors not associated with SAWS included
demographic and comorbid variables of age, male sex, acute medical illness, liver disease, or pancreatic disease
substance use disorder variables of history of withdrawal seizure, prior inpatient alcohol detoxifications, history of prior
alcohol withdrawal syndrome, duration of alcohol use disorder, daily intake of alcohol, or age at alcohol use disorder onset
alcohol withdrawal seizure

seizure associated with history of prior alcohol withdrawal seizure in analysis of 2 studies with 1,143 patients (OR 2.8, 95% CI
1.09-7.19), results limited by heterogeneity
factors not associated with seizure included
demographic and comorbid variables of age or liver disease
substance use disorder variables including history of delirium tremens, prior inpatient alcohol detoxifications, duration of
alcohol use disorder, or daily intake of alcohol
Reference - Alcohol Clin Exp Res 2014 Oct;38(10):2664 full-text, commentary can be found in Alcohol Clin Exp Res 2015
Feb;39(2):390
laboratory tests that can help determine risk of severe withdrawal

lower initial platelet count and lower initial potassium levels may be associated with risk of developing delirium tremens, severe
withdrawal, or seizure in patients with acute alcohol withdrawal (level 2 [mid-level] evidence)
based on systematic review of observational studies limited by clinical and statistical heterogeneity
systematic review of 17 observational studies evaluating clinical and medical factors and incident of SAWS, delirium tremens,
and seizure in patients with acute alcohol withdrawal
SAWS definitions were heterogeneous across studies, most relied on cutoff scores from symptom scales
development of delirium tremens (DT)
factors associated with DT included
lower initial platelet count in analysis of 4 studies with 1,527 patients (mean difference [MD] -45.64 mm3, p = 0.003),
results limited by heterogeneity
lower initial potassium level in analysis of 4 studies with 1,525 patients (MD -0.26 mEq/L, p = 0.006), results limited by
heterogeneity
factors not associated with incident DT included initial alanine transaminase (ALT), AST, GGT, sodium, systolic or diastolic
blood pressure, heart rate, white blood cell count, mean corpuscular volume, or creatinine
severe alcohol withdrawal syndrome
factors associated with SAWS included
lower initial platelet count in analysis of 4 studies with 1,527 patients (MD -45.64 × 103/mcL, p = 0.003), results limited by
heterogeneity
lower initial potassium level in analysis of 4 studies with 1,525 patients (MD -0.26 mEq/L, p = 0.006), results limited by
heterogeneity
higher initial ALT in analysis of 5 studies with 939 patients (MD 20.97 units/L, p = 0.04), results limited by heterogeneity
factors not associated with SAWS included initial AST, GGT, sodium, blood alcohol level, systolic or diastolic blood pressure,
heart rate, white blood cell count, mean corpuscular volume, or creatinine
alcohol withdrawal seizure

factors associated with seizure included
lower initial platelet count in analysis of 2 studies with 1,160 patients (MD -59.91 × 103/mcL, p = 0.01), results limited by
heterogeneity
lower initial potassium level in analysis of 2 studies with 1,160 patients (MD -0.2 mEq/L, p = 0.0001)
higher initial GGT in analysis of 2 studies with 1,160 patients (MD 202.56 units/L, p = 0.05)
factors not associated with seizure included initial blood alcohol level, systolic or diastolic blood pressure, or heart rate
Reference - Alcohol Clin Exp Res 2014 Oct;38(10):2664 full-text, commentary can be found in Alcohol Clin Exp Res 2015
Feb;39(2):390
thrombocytopenia or hyperhomocysteinemia may help discern risk for developing severe withdrawal, including delirium tremens,
in inpatients with alcohol withdrawal syndrome (level 2 [mid-level] evidence)
based on 2 retrospective cohort studies
normal platelet count may help rule out development of delirium tremens and seizures in patients with alcohol withdrawal
syndrome (level 2 [mid-level] evidence)
based on retrospective cohort study
334 patients ≥ 20 years old admitted for alcohol dependence and withdrawal
delirium tremens in 3%, seizures in 2% (none had co-occurrences)
patients with delirium tremens had increased rate of thrombocytopenia, lower systolic blood pressure and serum potassium,
and higher levels of liver function tests (p < 0.05)
patients with seizures had lower blood platelet count and increased rate of thrombocytopenia (defined as < 150 × 109
platelets/L) (p < 0.05)
thrombocytopenia predicted development of delirium tremens with
sensitivity 70%
specificity 69%
positive predictive value 6%
negative predictive value 99%
thrombocytopenia predicted development of seizures with

sensitivity 75%
specificity 69%
positive predictive value 6%
negative predictive value 99%
Reference - Alcohol Alcohol 2009 Jul-Aug;44(4):382
hyperhomocysteinemia and thrombocytopenia each might help predict development of delirium tremens in patients admitted
for alcohol withdrawal seizures (level 2 [mid-level] evidence)
97 patients (84.5% male) admitted to emergency department with acute seizure precipitated by alcohol withdrawal were
followed for at least 48 hours
35.1% developed delirium tremens
hyperhomocysteinemia and thrombocytopenia each significantly predicted delirium tremens development (p < 0.0001 for
each)
for prediction of delirium tremens
hyperhomocysteinemia with cutoff of 14.5 mg/dL had
sensitivity 81.5%
specificity 67.3%
2.5 positive likelihood ratio and 0.28 negative likelihood ratio
thrombocytopenia with cutoff of 137 × 103/mcL had

sensitivity 72.7%
specificity 69.8%
2.4 positive likelihood ratio and 0.39 negative likelihood ratio
Reference - Am J Emerg Med 2015 May;33(5):701
Seizure or delirium testing
testing in patients with alcohol withdrawal seizure includes(2)

detailed neurological and medical exam
blood tests to assess for other causes of seizure
brain imaging
evaluation in patients with delirium tremens(2)

continuously monitor vital signs
perform detailed neurological and medical exam
obtain tests to rule out common causes of delirium including
hypoglycemia
electrolyte imbalance
head injury leading to subdural hemorrhage
septicemia
kidney or liver failure
Treatment
Treatment overview
treatment goals include minimizing symptoms, preventing complications, and facilitating continued abstinence from alcohol(3)
consider using the Clinical Institute Withdrawal Assessment – Alcohol, revised (CIWA-Ar) or a similar assessment scale for
establishing baseline severity and monitoring symptoms throughout treatment
identify risk for severe withdrawal or complications
patients with mild-to-moderate symptoms may be treated as outpatients with similar 6-month outcomes (level 2 [mid-level]
evidence)
indications for inpatient management include
severe alcohol withdrawal symptoms or CIWA score ≥ 15-20
autonomic overactivity and signs of withdrawal in presence of high blood alcohol content (suggests possible impending severe
withdrawal)
high risk or presence of delirium tremens and/or high risk or presence of withdrawal seizure
urine drug screen positive for other substances
serious psychiatric condition such as suicidal ideation or psychosis
poorly controlled chronic medical conditions
consider intensive care in patients with
CIWA score ≥ 20
hallucinations
need for sedation and intensive monitoring
respiratory failure
hemodynamic instability
comorbid conditions such as trauma, gastrointestinal bleeding, ingestion and/or intoxication of other substances, significant
fluid and/or electrolyte disorder, sepsis, or organ failure
medications typically suggested if CIWA-Ar score > 8-10 and tapered and discontinued once when CIWA-Ar < 8-10
... /benzodiazepines
Medicationsare/ first-line
Thiamine and other supplementation
treatment in most patients with alcohol withdrawal syndrome
benzodiazepines may reduce alcohol withdrawal symptoms, seizures, and recurrent seizures (level 2 [mid-level] evidence)
different benzodiazepines reported to be similarly effective (level 2 [mid-level] evidence), so consider patient characteristics and
drug metabolism when selecting benzodiazepine agent
for inpatient treatment
regimen options include symptom-triggered dosing, fixed tapering dosing, or loading dose regimen
symptom-triggered dosing generally preferred in institutions capable of close monitoring
fixed-tapering dose may be useful in patients with history of delirium tremens or in patients where symptoms are not easily
assessed
symptom-triggered and fixed-dosing of benzodiazepines appear equally effective for improving withdrawal symptoms overall,
but symptom-triggered schedule may be associated with greater improvement in symptoms at 48 hours (level 2 [mid-level]
evidence)
loading protocol with long-acting benzodiazepine might reduce symptoms of alcohol withdrawal more rapidly than symptom-
triggered use of short-acting benzodiazepine in inpatient setting (level 2 [mid-level] evidence)
for delirium tremens
use sedative hypnotic drugs (benzodiazepine therapy being most commonly used) for delirium tremens (ASAM Grade A)
pentobarbital and propofol can be considered if large doses of benzodiazepines fail to control agitation in patients with
delirium tremens (ASAM Grade C)
goal is to achieve calm, and then light somnolence (ASAM Grade C)
for alcohol withdrawal seizures, higher doses of benzodiazepines may be required
for outpatient treatment

fixed schedule or symptom-triggered schedule may be considered
National Institute for Health and Clinical Excellence (NICE) recommends fixed schedule for outpatient withdrawal management
symptom-triggered self-medication and fixed-schedule self-medication in outpatient alcohol treatment unit associated with
similar medication consumption and risk of relapse in patients with mild-to-moderate alcohol withdrawal symptoms (level 2
[mid-level] evidence)
anticonvulsants not suggested in acutely ill medical patients or patients with delirium tremens, but may have a role in patients with
mild-to-moderate withdrawal
anticonvulsants such as carbamazepine, gabapentin, and pregabalin appear at least as effective as lorazepam for reducing
withdrawal symptoms (with studies mainly done in the outpatient setting), but insufficient evidence regarding anticonvulsants for
reducing alcohol withdrawal seizures (level 2 [mid-level] evidence)
adjunctive medications
benzodiazepine augmentation with adrenergic medications such as dexmedetomidine or clonidine may be useful in patients with
autonomic symptoms of tachycardia, tremor, and hypertension
beta blockers may be considered in combination with benzodiazepines in patients with persistent hypertension or tachycardia
(ASAM Grade C) but not routinely recommended in all patients with delirium tremens
antipsychotic medications not recommended as monotherapy (ASAM Grade A) but may be considered as adjunct to
benzodiazepine for agitation or cognitive disturbance (ASAM Grade C)
supportive care consists of ensuring quiet environment with reduced stimulation, as well as
hydration
nutritional support
electrolyte abnormality correction
supplements including
folic acid 1 mg/day to prevent macrocytic anemia
thiamine to prevent or treat Wernicke-Korsakoff syndrome (thiamine 100 mg/day for ≥ 3 days IV or intramuscularly
recommended for patients with delirium tremens [ASAM Grade C])
multivitamin IV and magnesium replacement in patients with severe alcohol withdrawal
after successful treatment of alcohol withdrawal syndrome, refer all patients to long-term treatment program to maintain abstinence
from alcohol
a visit from a recovering alcoholic may reduce problem drinking in hospitalized patients with alcohol problems (level 2 [mid-level]
evidence)
integrated medical and substance abuse treatment appears to improve abstinence rates in patients with substance abuse related
medical conditions (level 2 [mid-level] evidence)
see Alcohol use disorder
Treatment setting
presence of seizure or delirium tremens considered severe withdrawal even if Clinical Institute Withdrawal Assessment – Alcohol,
revised (CIWA-Ar) score does not correlate(2, 4)
outpatient management
most patients with mild-to-moderate symptoms (CIWA ≤ 15-20) can receive outpatient detoxification with daily assessment(2, 3, 5)
consider outpatient management if(4)
mild-to-moderate symptoms present
no significant concurrent drug use
minimal alcohol craving
all patients should be seen daily until symptoms subside(3)

National Institute for Health and Clinical Excellence (NICE) guideline recommendations for outpatient management of alcohol
withdrawal
in outpatients with alcohol dependence, advise to avoid sudden alcohol reductions and provide contact information for support
services
fixed-dose regimen recommended for outpatient withdrawal management
Reference - NICE guidance on alcohol use disorders (NICE 2011 Feb:CG115 PDF) and Royal College of Physicians concise
guidance(1)
inpatient management
indications for inpatient management(1, 2, 3, 4)
severe alcohol withdrawal symptoms or CIWA score ≥ 15-20
autonomic overactivity and signs of withdrawal in presence of high blood alcohol content (suggests possible impending severe
withdrawal)
high risk or presence of delirium tremens
high risk or presence of withdrawal seizure
long-term intake of large amounts of alcohol
abnormal laboratory results, such as elevated aspartate aminotransferase (AST)
acute illness
urine drug screen positive for other substances
poorly controlled chronic medical conditions such as diabetes or heart failure
serious psychiatric condition such as suicidal ideation or psychosis
higher risk patients who
are < 16 years old
are frail
have cognitive impairment, learning difficulties, or multiple comorbidities
lack social support
supportive care for inpatients consists of(2, 4)

quiet room, low lighting, and minimal stimulation
monitoring dehydration and if present, managing with IV fluids
access to immediate IV if seizures or delirium tremens
provision of adequate sedation and nutrition
restraints if necessary to prevent injuries if severe agitation present
treatment of electrolyte or glucose deficiencies
thiamine supplementation to prevent Wernicke encephalopathy in all patients
consider intensive care unit admission in patients with(4, 5)

CIWA score ≥ 20
hallucinations
need for sedation and intensive monitoring
respiratory failure
hemodynamic instability
comorbid conditions such as trauma, gastrointestinal bleeding, ingestion and/or intoxication of other substances, significant
fluid and/or electrolyte disorder, sepsis, or organ failure
outpatient detoxification and inpatient detoxification associated with similar rates of self-reported abstinence and use of
alcoholism-treatment services at 6 months in patients with mild-to-moderate alcohol withdrawal syndrome (level 2 [mid-level]
evidence)
based on randomized trial with baseline differences
164 male veterans of low socioeconomic status with mild-to-moderate alcohol withdrawal syndrome randomized to 1 of 2 groups
outpatient detoxification including daily clinic visits (except on weekends), medical and psychiatric evaluations, oral oxazepam
(adjusted each day depending on progress), and brief counseling
inpatient detoxification including stay in closed ward of medical center, medical and psychiatric evaluations, oral oxazepam
(adjusted each day depending on progress), and initiation of rehabilitation treatment (including group counseling, discharge
planning, and social therapy)
inpatients had increased severity of alcoholism, alcohol withdrawal syndrome, and medical problems at baseline
successful detoxification defined as meeting each of following criteria
reduction in Selected Severity Assessment scores to ≤ 6 (assessment includes ratings of 11 physical and behavioral symptoms
with score of 0-8 assigned to each symptom)
self-report of nonuse of ethanol
negative breath analysis for ≥ 3 consecutive days
reduction in dose of oxazepam to ≤ 30 mg during preceding 24 hours
comparing outpatient detoxification vs. inpatient detoxification

mean duration of treatment 6.5 days vs. 9.2 days (p < 0.05)
successful detoxification completed in 72% vs. 95% (p < 0.0001)
no significant differences in self-reported alcohol-related problems (abstinence and nonintoxication), medical problems, or use
of other alcoholism-treatment services at 6 months
inpatient therapy associated with increased cost
Reference - N Engl J Med 1989 Feb 9;320(6):358
Fluid and electrolytes

closely monitor and correct fluid and electrolyte abnormalities in patients with alcohol withdrawal(4, 5)
Medications
Medication overview
currently there is no standard for medication dosing, administration, or assessment protocols in patients with alcohol withdrawal(3, 4,
5)
patients with Clinical Institute Withdrawal Assessment – Alcohol, revised (CIWA-Ar) score ≥ 8-10 or Short Alcohol Withdrawal Scale
(SAWS) score ≥ 12 typically receive medication
medication can be tapered and discontinued when CIWA-Ar < 8-10 or SAWS score < 12
in patients with CIWA-Ar score < 8 or mild withdrawal symptoms and without risk factors for severe withdrawal(2)
medication generally not needed
management can include supportive care and monitoring for 36 hours
benzodiazepines are preferred treatment(2, 4, 5)

commonly used agents are chlordiazepoxide, diazepam, lorazepam, oxazepam
agents reported to have similar efficacy, so choice should be individualized to patient with consideration of half-life of drug,
comorbid disease, and monitoring plans
IV benzodiazepines recommended for patients with seizure or delirium tremens due to rapid onset of drug
other agents include

anticonvulsants may have a role in patients with mild-to-moderate withdrawal
pentobarbital and propofol can be considered if large doses of benzodiazepines fail to control agitation in patients with delirium
tremens (ASAM Grade C)
medications to consider in addition to benzodiazepine agent
adjunctive alpha2-adrenergic agonist or beta blocker may be considered in patients with persistent cardiac adrenergic
symptoms despite treatment of dehydration and electrolyte imbalances
adjunctive antipsychotics may be considered if agitation, disturbed thinking, or perceptual disturbances not adequately
controlled (ASAM Grade C)
supplements include
folic acid 1 mg/day to prevent macrocytic anemia
considering multivitamin IV and magnesium replacement in patients with severe alcohol withdrawal
prophylactic thiamine is recommended for all patients with acute alcohol withdrawal
Benzodiazepines
Benzodiazepine overview
benzodiazepines are first-line treatment in most patients with alcohol withdrawal(1, 2, 3, 5)
common agents and equivalent doses(3, 5)
chlordiazepoxide (longer acting [up to several days]) 25 mg
diazepam (long acting) 5 mg
lorazepam (intermediate acting [several hours]) 1 mg
oxazepam (intermediate acting) 15 mg
shorter-acting benzodiazepines, such as lorazepam, should be tapered gradually before being discontinued(2)
adverse events
common adverse events include sedation, fatigue, respiratory depression, retrograde amnesia, ataxia, dependence, and abuse(3)
delirium may result from benzodiazepine toxicity(4)
contraindications include(3)
hypersensitivity to class or ingredient
concomitant alcohol consumption (may lead to respiratory depression and death)
for hospitalized patients

regimen options include symptom-triggered dosing, fixed tapering dosing, or loading dose regimen
American Society of Addiction Medicine (ASAM) recommends sedative hypnotic drugs (benzodiazepine therapy being most
commonly used) for delirium tremens (ASAM Grade A)(6)
agents with rapid onset (for example, diazepam) control agitation more quickly
long-acting agents (such as diazepam) may lead to fewer breakthrough and rebound symptoms
short-acting agents may have lower risk of oversedation in patients at higher risk (such as elderly patients and patients with
liver disease) (ASAM Level III)
short-acting agents need to be tapered gradually to prevent rebound symptoms and benzodiazepine withdrawal seizures
use of benzodiazepines intramuscularly not recommended because of difficulty in absorption (ASAM Grade C); lorazepam may
be an exception as it is absorbed well intramuscularly
dosing goal of medication is to achieve and maintain light somnolence (ASAM Grade C)
Royal College of Physicians (RCOP) and National Institute for Health and Clinical Excellence (NICE) recommend(1)
for patients requiring medications without delirium tremens
consider benzodiazepine (chlordiazepoxide and diazepam are most commonly used) or carbamazepine
clomethiazole is alternative, but should be used with caution
offering oral lorazepam as first-line treatment in patients with delirium tremens

if symptoms persist or oral medication is declined, giving parental lorazepam, haloperidol, or olanzapine
considering quick-acting benzodiazepine (such as lorazepam) in patients with alcohol withdrawal seizures, to reduce likelihood
of additional seizures
if staff is trained in monitoring withdrawal symptoms and resources for frequent assessments present, pharmacotherapy
dosing should be individualized in symptom-triggered manner
factors to consider for individualizing treatment
severity of alcohol dependence (including amount of past alcohol intake)
severity of acute withdrawal
comorbidities
considerations for patients with history of withdrawal seizure (in current withdrawal or prior)(2)
administer prophylactic lorazepam 2 mg IV or intramuscularly
lorazepam reported to reduce risk of second seizure, so is preferred over diazepam
higher doses of benzodiazepines may be required (diazepam equivalents of 20-60 mg; see equivalent doses below)
inpatient monitoring for 36-48 hours suggested
in outpatient setting(1, 3)
fixed schedule or symptom-triggered schedule may be considered
National Institute for Health and Clinical Excellence (NICE) recommends fixed schedule for outpatient withdrawal management
loading dose schedule not recommended in outpatient setting
benzodiazepines reported to be similarly effective, so consider patient characteristics and drug metabolism when selecting
benzodiazepine agent(2, 4, 5)
Considerations in Special Populations:
Patient Benzodiazepines to Rationale Alternatives

Characteristic Avoid
Severe liver disease Chlordiazepoxide and Prolonged effects due Lorazepam or

diazepam to slower oxidative oxazepam
metabolism in these
patients
End-stage renal Diazepam or Potential propylene Chlordiazepoxide or

disease or acute lorazepam glycol accumulation oxazepam
kidney injury with parenteral
administration;
decreased protein
binding and impaired
elimination
Elderly patients Chlordiazepoxide and Prolonged effects due Lorazepam or

diazepam to slower oxidative oxazepam
metabolism
Patients with severe Chlordiazepoxide and Risk of medical Lorazepam or

lung disease and other diazepam consequences oxazepam
patients with risk of following sedation
serious medical
consequences
following sedation
Benzodiazepine regimen options

Inpatient settings
benzodiazepine regimens in inpatient setting
symptom-triggered dosing(1, 2, 3, 5)
drug administration based on assessment symptom severity at set intervals
requires training in use of scales such as CIWA-Ar
generally preferred in institutions capable of close monitoring due to reported efficacy in
using less medication overall
shortening treatment duration
potentially reducing risk of over- or under-medication
example of symptom-triggered regimen by CIWA-Ar score in inpatients

CIWA-Ar score < 8
no medication necessary
reassess CIWA-Ar and vital signs every 2 hours, then redose
CIWA-Ar score 8-10

chlordiazepoxide 25-50 mg orally
lorazepam 1-2 mg orally or IV
reassess CIWA-Ar and vital signs every 2 hours, then redose
CIWA-Ar score 11-15

reassess CIWA-Ar and vital signs every 1-2 hours, then redose
CIWA-Ar score 16-19
reassess CIWA-Ar and vital signs every 1-2 hours, then redose
CIWA-Ar score > 20 - evaluate for transfer to intensive care unit (ICU)
CIWA-Ar score < 8 for 3 consecutive assessments
reassess or redose every 4 hours; if score remains < 8 for 3 more consecutive checks, reassess or redose every 8 hours
if score < 8 for 48 hours, discontinue monitoring
example of symptom-triggered regimen by Glasgow Modified Alcohol Withdrawal Scale (GMAWS) scoring in inpatients
score 0 - repeat scoring in 2 hours; discontinue scoring after 4 consecutive scores of 0, unless it has been < 48 hours after
last drink
score 1-3 points
give diazepam 10 mg
repeat scoring in 2 hours
score 4-8 points

give diazepam 20 mg
repeated scoring in 1 hour
score 9-10
give diazepam 20 mg
repeat scoring in 1 hour; consult with clinician (if nurse)
Reference - Nurs Times 2012 Jun 26-Jul 2;108(26):15
fixed tapering dose(2, 3, 4, 5)

fixed dosing at regular intervals regardless of symptom severity
initial dose based on initial symptom severity and time since last drink
may be useful in patients
with history of delirium tremens
patients in whom symptoms are not easily assessed due to
lack of clinician training
comorbid illness or current medications that may affect CIWA-Ar measurements
patients require monitoring for

breakthrough symptoms, which require additional medication
symptoms of benzodiazepine toxicity, which require dose adjustments
example of fixed dose regimen in inpatient setting
day 1 - chlordiazepoxide 50-100 mg 4 times daily
day 2-3 - chlordiazepoxide 25-50 mg 4 times daily, with tapering dependent on patient response
loading dose regimen(2, 4)

uses higher doses of long-acting agents to reduce risk of seizures and delirium
rationale is to limit intensive medication and monitoring in early withdrawal, resulting in shorter regimen overall
typical regimens
diazepam 10-20 mg orally every 1-2 hours
chlordiazepoxide 100 mg orally every 1-2 hours
symptom severity and clinical status including signs of benzodiazepine toxicity assessed before each dose
medication is stopped once patient reaches adequate sedation (after about 3 doses)
dosing regimens for patients with delirium tremens(6)

goal is to achieve and then maintain light somnolence (ASAM Grade C)
example of diazepam regimen
diazepam 5 mg IV (2.5 mg/minute), if initial dose not effective, repeat dose in 5-10 minutes
if second dose unsatisfactory, administer diazepam 10 mg IV twice, with doses separated by 5-10 minutes
if unsatisfactory response, administer diazepam 20 mg IV every 5-10 minutes until sedation is achieved
use diazepam 5-20 mg/hour as needed to maintain light somnolence
examples of lorazepam regimen options

lorazepam 1-4 mg IV every 5-15 minutes
lorazepam 1-40 mg intramuscularly every 30-60 minutes
regimens administered until calm achieved, and then every hour as needed to maintain light somnolence
Outpatient settings
benzodiazepine regimens in outpatient settings
fixed tapering dose(1, 2, 3, 5)

fixed dosing at regular intervals regardless of symptom severity
initial dose based on initial symptom severity and time since last drink
NICE recommends fixed schedule for outpatient withdrawal management
may be useful in patients outpatients, or patients in whom symptoms are not easily assessed due to
lack of clinician training
comorbid illness or current medications that may affect CIWA-Ar measurements
patients require monitoring for
breakthrough symptoms, which require additional medication
symptoms of benzodiazepine toxicity, which require dose adjustments
example of fixed-schedule benzodiazepine regimen for outpatients

day 1
diazepam 10 mg orally every 6 hours
chlordiazepoxide 25-50 mg orally every 6 hours
lorazepam 2 mg orally every 8 hours
day 2
day 3
day 4
diazepam 10 mg orally at bedtime
chlordiazepoxide 25-50 mg orally at bedtime
day 5
diazepam 10 mg orally at bedtime
chlordiazepoxide 25-50 mg orally at bedtime
lorazepam 1 mg orally at bedtime
symptom-triggered dose(3)
drug administration based on assessment symptom severity at set intervals
in outpatient settings, requires patient and caregiver to reliably rate symptoms, and may not be appropriate in all patients
when CIWA-Ar score < 10 or SAWS score < 12, medication is tapered and discontinued
examples of oral symptom-triggered regimens for outpatients with CIWA-Ar > 9 or SAWS score ≥ 12
day 1
day 2
day 3
day 4
day 5
loading dose schedule not recommended in outpatient setting(3)
Comparative efficacy of dose regimens

symptom-triggered vs. fixed-dose
use of CIWA-Ar generally recommended to determine dose for symptom-triggered dosing(1, 5)

see benzodiazepine regimen options for examples of symptom-triggered and fixed-dose regimens
symptom-triggered and fixed-dosing of benzodiazepines appear equally effective for improving withdrawal symptoms overall,
but symptom-triggered schedule may be associated with greater improvement in symptoms at 48 hours (level 2 [mid-level]
evidence)
based on Cochrane review of trials with methodologic limitations
systematic review of 64 randomized trials comparing benzodiazepines with placebo, other benzodiazepines, anticonvulsants, or
nonanticonvulsants in 4,309 inpatients and outpatients with alcohol withdrawal symptoms
48 trials had inadequate or unclear sequence generation, and 51 trials had unclear or inadequate allocation concealment
3 trials compared symptom-triggered to fixed-schedule dosing in 262 patients; seizure and delirium outcomes had low event
rates in all comparisons
benzodiazepine agents included flunitrazepam, oxazepam, and chlordiazepoxide
comparing symptom-triggered to fixed-schedule benzodiazepine dosing, symptom-triggered dosing associated with
reduced symptom severity by CIWA-Ar score at 48 hours in 1 trial with 44 patients (mean difference in reduction -5.7 points,
95% CI -11 to -0.38)
no significant differences in
resolution of symptoms by CIWA-Ar score at end of treatment in analysis of 2 studies with 161 patients
alcohol withdrawal seizure in analysis of 1 study with 117 patients
delirium tremens in analysis of 2 studies with 218 patients
dropout rates in analysis of 2 studies with 154 patients
Reference - Cochrane Database Syst Rev 2010 Mar 17;(3):CD005063
symptom-triggered dosing may reduce medication consumption with similar reduction in alcohol withdrawal symptoms
compared to fixed-schedule dosing in adults with alcohol dependence and medical comorbidity in general hospital ward (level 2
based on quasi-randomized trial
183 adults with alcohol dependence admitted to general hospital ward for medical comorbidity were assigned by nursing unit to
symptom-triggered vs. fixed-schedule dosing of lorazepam
symptom-triggered group received lorazepam doses based on Revised CIWA-Ar scale
fixed-schedule group received scheduled lorazepam doses with tapering over 4 days
protocol errors (administration of inappropriate lorazepam dose) occurred in 17.6% with symptom-triggered dosing vs. 7.6%
with fixed-schedule dosing (p = 0.042)
symptom-triggered dosing associated with significantly reduced use of lorazepam
no significant difference in reduction in mean CIWA-Ar scores during first 2 days
Reference - J Addict Dis 2006;25(2):17
symptom-triggered self-medication and fixed-schedule self-medication in outpatient alcohol treatment unit associated with
similar medication consumption and risk of relapse in patients with mild-to-moderate alcohol withdrawal symptoms (level 2
based on randomized trial with baseline differences
163 adults with alcohol dependence and mild-to-moderate alcohol withdrawal symptoms were randomized to symptom-
triggered self-medication vs. fixed-schedule self-medication and followed for 1 year
in symptom-triggered group
patients with SAWS score ≥ 12 at baseline were prescribed chlordiazepoxide (up to 300 mg/day) for 10 days
patients with SAWS score < 12 at baseline were prescribed chlordiazepoxide (up to 120 mg/day) for 10 days
in fixed-schedule group
patients with SAWS score ≥ 12 at baseline were prescribed chlordiazepoxide 200 mg/day as starting dose with 25
mg/day dose tapering
patients with SAWS score < 12 at baseline were prescribed chlordiazepoxide 80 mg/day as starting dose with 10 mg/day
dose tapering
all patients were treated in outpatient setting in specialized alcohol treatment unit
more patients in symptom-triggered group lived alone at baseline
SAWS includes 10 patient-rated symptoms with each item scored on 4-point scale for severity over past 24 hours (0 being no
symptoms and 3 being severe symptoms)
time to SAWS score < 12
time to SAWS score < 6
median cumulated dose of chlordiazepoxide
relapse rates
well-being
treatment satisfaction
Reference - Alcohol Alcohol 2011 May-Jun;46(3):318 full-text

symptom-triggered alcohol withdrawal protocol associated with reduced postoperative complications (level 2 [mid-level]
... / Medications
evidence) / Thiamine and other supplementation
based on cohort of 26 postoperative patients with head and neck cancer and alcohol withdrawal syndrome enrolled in a
symptom-triggered protocol compared to 14 patients treated without the protocol
protocol associated with reduced alcohol withdrawal syndrome intensive care admissions, delirium, and violence compared to
patients treated before the protocol
no significant difference in medication use between groups
Reference - Arch Otolaryngol Head Neck Surg 2008 Aug;134(8):865 full-text
loading dose vs. symptom-triggered

loading protocol with long-acting benzodiazepine might reduce symptoms of alcohol withdrawal more rapidly than symptom-
triggered use of short-acting benzodiazepine in inpatient setting (level 2 [mid-level] evidence)
based on small randomized trial without statistical significance
51 patients admitted to medical center with alcohol withdrawal syndrome were randomized to loading protocol vs. symptom-
triggered protocol
loading protocol included
on day 1, diazepam 20 mg orally every 2 hours for 3 doses (for parenteral treatment, diazepam 10 mg IV every 1 hour for
6 doses), holding for excessive sedation
additional diazepam 10 mg orally or IV administered every 2 hours as needed for residual withdrawal symptoms, holding
for excessive sedation
symptom-triggered protocol included lorazepam 1-2 mg orally or IV administered every 2 hours as needed for active
withdrawal symptoms, holding for excessive sedation
primary outcome was change in CIWA-Ar scale score
comparing loading protocol vs. symptom-triggered protocol
free of withdrawal symptoms within 72 hours of admission in 69.6% vs. 41.7% (p = 0.08)
mean decrease in CIWA-Ar score was 2.3 points/day vs. 1.5 points/day (not significant)
total benzodiazepine usage was 103.8 mg vs. 92.4 mg (not significant)
mean decrease in systolic blood pressure was 2.3 mm Hg vs. 2.7 mm Hg (not significant)
no significant differences in heart rate, diastolic blood pressure, or respiratory rate

Reference - Gen Hosp Psychiatry 2012 Nov-Dec;34(6):611
Benzodiazepine efficacy
benzodiazepines appear to reduce alcohol withdrawal symptoms, seizures, and recurrent seizures
benzodiazepines may reduce alcohol withdrawal seizures (level 2 [mid-level] evidence)
systematic review of 64 randomized trials comparing benzodiazepines with placebo, other benzodiazepines, anticonvulsants, or
nonanticonvulsants in 4,309 patients with alcohol withdrawal symptoms
comparing benzodiazepines vs. placebo
benzodiazepines reduced seizures (relative risk 0.16, 95% CI 0.04-0.69, NNT 13-41 assuming seizures in 8% of controls) in
analysis of 3 trials with 324 patients
nonsignificant increase in adverse effects (relative risk 3.28, 95% CI 0.31-34.52) in analysis of 2 trials with 71 patients
no significant differences in seizures comparing benzodiazepines to

any other drug in analysis of 12 trials with 1,228 patients
anticonvulsants in analysis of 7 trials with 523 patients
severe, life-threatening adverse events were rare (single cases in 1-2 trials)
benzodiazepines may reduce acute alcohol withdrawal symptoms (level 2 [mid-level] evidence)
based on systematic review without assessment of allocation concealment
systematic review of 11 trials of benzodiazepines vs. placebo or active control with 1,286 patients
therapeutic success defined as reduction in CIWA-Ar scores ≤ 10
benzodiazepines superior to placebo in therapeutic success in 2 days (odds ratio 3.28, 95% CI 1.3-8.28) in analysis of 3 trials
with 162 patients
review found no evidence that benzodiazepines were superior to other drugs in terms of efficacy (9 trials with heterogeneity) or
adverse effects (3 trials with 148 patients)
authors conclude that benzodiazepines remain drugs of choice for acute alcohol withdrawal
Reference - CMAJ 1999;160(5):649 PDF
lorazepam 2 mg IV may reduce risk of recurrent seizures (level 2 [mid-level] evidence)

based on randomized trial with allocation concealment not stated
186 emergency department patients with alcohol withdrawal seizure randomized to lorazepam 2 mg vs. placebo IV and
observed for 6 hours
comparing lorazepam vs. placebo
second seizure within 6 hours in 3% vs. 24% (p < 0.001, NNT 5)
admission to hospital in 29% vs. 42% (p = 0.02, NNT 8)
of patients discharged from emergency department, 1.4% vs. 14% returned to emergency department within 48 hours with
second seizure
DynaMed commentary – follow-up emergency presentation was determined by retrospective examination of records from
ambulance service used by 85% of patients for their first emergency department visit and may not have accurately captured
all recurrent seizures
Reference - N Engl J Med 1999 Mar 25;340(12):915 full-text, commentary can be found in N Engl J Med 1999 Aug 19;341(8):609
Benzodiazepine selection
different benzodiazepines appear to have similar safety and efficacy for treatment of alcohol withdrawal (level 2 [mid-level]
evidence)
systematic review of 64 randomized trials comparing benzodiazepines with placebo, other benzodiazepines, anticonvulsants or
nonanticonvulsants in 4,309 patients with alcohol withdrawal symptoms
in direct comparison trials of different benzodiazepines
4 trials reported alcohol withdrawal seizures
4 trials reported delirium tremens
3 trials reported alcohol withdrawal symptom score at 48 hours
3 trials reported alcohol withdrawal symptom score at end of treatment
7 trials reported adverse events
6 trials reported severe, life-threatening adverse events
11 trials reported dropouts
sample sizes in each of these comparison trials ranged from 20 patients to 100 patients
none of these trials found statistically significant differences
propylene glycol toxicity reported in 1 case related to high doses of IV diazepam

propylene glycol is a solvent used for IV diazepam and is metabolized to lactic acid
Reference - N Engl J Med 2000 Sep 14;343(11):815
Anticonvulsants
Overview
recommendations and suggestions
anticonvulsants not suggested in acutely ill medical patients(5)

may have a role in patients with mild to moderate withdrawal(4)
NICE recommends considering carbamazepine as initial treatment in patients with acute alcohol withdrawal without delirium
tremens(1)
phenytoin does not prevent seizures, and is not recommended by NICE guidance to treat alcohol withdrawal seizures(1, 3, 4)
common oral agents with typical single dose(3)

carbamazepine 600-800 mg
gabapentin 300-600 mg
oxcarbazepine 450-900 mg
valproic acid 1,000-1,200 mg
common adverse events include dizziness, ataxia, diplopia, nausea, and vomiting(3)
hypersensitivity to class or ingredient
hypersensitivity to tricyclic antidepressants
monoamine oxidase inhibitor use within past 14 days
hepatic porphyria
reported advantages of anticonvulsant regimen as alternative to benzodiazepine(2)

some might decrease risk of seizure
decreased alcohol craving
less risk of sedation compared to benzodiazepines
no potential for abuse
Anticonvulsant efficacy
evidence comparing different drug classes for reducing seizures in patients with alcohol withdrawal is limited; only drug class with
significant evidence for reducing seizures is benzodiazepines (level 2 [mid-level] evidence)
carbamazepine
NICE guideline recommends considering carbamazepine for acute alcohol withdrawal in patients without delirium tremens(1)
carbamazepine appears at least as effective as benzodiazepine for reducing withdrawal symptoms, but insufficient evidence
regarding anticonvulsants for reducing alcohol withdrawal seizures (level 2 [mid-level] evidence)
based on Cochrane review with limited evidence
systematic review of 56 randomized trials comparing anticonvulsants (not including benzodiazepines) vs. other drugs or
placebo in 4,076 patients with alcohol withdrawal symptoms
anticonvulsants had lower rates of seizures and side effects compared with other drugs but these findings were not statistically
significant
other drugs studied were primarily benzodiazepines
no significant differences in any outcomes comparing anticonvulsants vs. placebo
comparing anticonvulsants to active treatment
only statistically significant finding was improvement in CIWA-Ar score with carbamazepine compared with benzodiazepine
in analysis of 3 trials with 260 patients (mean difference in decrease -1.04, 95% CI -1.89 to -0.2)
no significant difference in any other comparisons
no significant differences comparing different anticonvulsants

gabapentin
gabapentin appears at least as effective as lorazepam for reducing alcohol withdrawal symptoms and may reduce early return to
drinking (level 2 [mid-level] evidence)
based on randomized trial without intention-to-treat analysis
100 outpatients with alcohol withdrawal and CIWA-Ar score ≥ 10 were randomized to 1 of 3 treatments for 4 days
gabapentin 300 mg 3 times daily for 3 days, then 300 mg twice daily for 1 day
gabapentin 400 mg 3 times daily for 3 days, then 400 mg twice daily for 1 day
lorazepam 2 mg 3 times daily for 3 days, then 2 mg twice daily for 1 day
74% of patients completed 4 days of treatment

CIWA-Ar scores decreased over time in all groups; gabapentin 400 mg was statistically superior (p = 0.009) but clinically similar
to lorazepam
gabapentin 400 mg associated with lower rates of drinking on day 2 and day 6 (p = 0.0002, NNT 4-5)
Reference - Alcohol Clin Exp Res 2009 Sep;33(9):1582
gabapentin may be as effective as chlordiazepoxide for reducing alcohol withdrawal symptoms in outpatients (level 2 [mid-level]
evidence)
based on small randomized trial with high loss to follow up
26 patients with alcohol withdrawal (meeting Diagnostic and Statistical Manual of Mental Disorder [DSM-IV] criteria) not
requiring hospitalization were randomized to gabapentin vs. chlordiazepoxide for 6 days
gabapentin dosing 1,200 mg orally for 3 days then 900 mg, 600 mg, and 300 mg orally for 1 day each
chlordiazepoxide dosing 100 mg orally for 3 days then 75 mg, 50 mg, and 25 mg orally for 1 day each
35% of patients were lost to follow-up and were excluded from analysis
gabapentin associated with less sleepiness on days 5-7 (p = 0.04)
no significant differences in alcohol craving or alcohol withdrawal symptoms
Reference - Ann Pharmacother 2013 Jul-Aug;47(7-8):961
pregabalin, lorazepam, and tiapride appear similarly effective for preventing withdrawal symptoms, but tiapride may be less
effective for maintaining abstinence (level 2 [mid-level] evidence)
based on investigator-blinded randomized trial with high dropout rate
111 patients aged 18-75 years with alcohol dependence, alcohol consumption > 80 g during previous 24 hours, and CIWA-Ar score
≥ 10 were randomized to 1 of 3 treatments for 14 days
pregabalin up to 450 mg/day
lorazepam up to 10 mg/day
tiapride up to 800 mg/day
doses score-guided to achieve minimum withdrawal symptomatology
patients were in outpatient setting with medication administered by principal investigator from 8 AM to 4 PM and by family
member from 4 PM to 8 AM
52% completed trial
abstinence at day 14 in 62.2% with pregabalin vs. 56.8% in lorazepam vs. 37.8% with tiapride (p = 0.04 between groups)
all treatments associated with similar reduction in scores from baseline (all p < 0.001)
withdrawal
obsessive and compulsive drinking
craving
psychiatric symptoms
quality of life
Reference - Addiction 2010 Feb;105(2):288
Adrenergic medications
Adrenergic overview
consider adjunctive antihypertensive agent in patients with persistent cardiac adrenergic symptoms despite treatment of dehydration
and electrolyte imbalances(5)
clonidine or beta blockers are not recommended as monotherapy, but may be adjunctive to benzodiazepine agent(2)
antihypertensive agents can reduce adrenergic symptoms, but will not prevent seizures(3)
Alpha2-adrenergic agonists
Clonidine
clonidine (lacks United States FDA approval for use in alcohol withdrawal syndrome)
consider adjunctive clonidine in patients with
significant increase in blood pressure or nearing hypertensive urgency (pressure > 180/120 mm Hg)(5)
other autonomic symptoms such as tachycardia or tremor(4)
clonidine does not prevent seizure or delirium and is not recommended as monotherapy or to treat general withdrawal symptoms(4,
5)
suggested oral dosing(5)

0.1 mg orally hourly up to 3 times until systolic blood pressure < 140 mm Hg and diastolic pressure < 90 mm Hg
for stabilized patients, maximum dose is 2.4 mg/day
suggested IV dosing of adjunctive clonidine in surgical or critical care patients

as prophylactic dose in surgical ICU settings, clonidine 0.15 mg bolus (range 0.075-0.3 mg) then infusion of 0.83 mcg/kg/hour
(range 0.07-3.39 mcg/kg/hour)
as treatment dose in surgical ICU settings, clonidine 0.3 mg bolus (range 0.15-1.2 mg) then infusion of 0.88 mcg/kg/hour (range
0.14-4.69 mcg/kg/hour)
Reference - Anesth Analg 1999 Apr;88(4):946 full-text
common adverse events include hypotension, dry mouth, dizziness, constipation, and sedation(3)
contraindications include hypersensitivity to drug class or ingredient(3)
Dexmedetomidine
dexmedetomidine
augmentation of benzodiazepine with dexmedetomidine may be useful in patients(4)

autonomic symptoms of tachycardia, tremor, and hypertension not controlled with a benzodiazepine alone
with treatment-resistant withdrawal
infusion rate < 0.7 mcg/kg/hour reported sufficient (no current standard dose)
intubation not required, and patient will be easily aroused, allowing for regular assessments
adverse events include bradycardia and hypotension
dexmedetomidine is alpha-2 agonist that decreases release of norepinephrine thereby decreasing sympathetic overdrive
dexmedetomidine does not prevent seizures or delirium and should not be used as monotherapy
addition of dexmedetomidine to diazepam may reduce benzodiazepine use and improve sedation outcomes in patients with
alcohol withdrawal in intensive care (level 2 [mid-level] evidence)
based on randomized trial without placebo control
72 patients with alcohol withdrawal in ICU receiving symptom-triggered diazepam 10 mg bolus as needed were randomized to
receive addition of dexmedetomidine vs. receiving diazepam alone
dexmedetomidine was initiated at 0.2-1.4 mcg/kg/hour and titrated up until patient achieved target sedation range (-2 to 0 score
on Richmond Agitation Sedation Scale [RASS])
5 patients were excluded from analysis due to refractory symptoms requiring additional sedative agents
comparing addition of dexmedetomidine vs. usual care, dexmedetomidine associated with
reduced diazepam use at 24 hours (median 20 mg vs. 40 mg, p < 0.001)
reduced overall diazepam use during ICU stay (median 60 mg vs. 90 mg, p < 0.001)
improved sedation outcomes including
greater proportion of time spent in target sedation range (median 90% vs. 64.5%, p < 0.001)
decreased proportion of time of insufficient sedation (7.75% vs. 15%, p < 0.001)
decreased proportion of time of oversedation (2% vs. 15%, p < 0.001)
fewer rescue sedation boluses in 24 hours (median 1.25 vs. 4, p = 0.004)
better nurse-assessed communication ability (p < 0.001)

decreased haloperidol initiation (2 patients vs. 10 patients, p = 0.02)
nonsignificant decrease in length of ICU stay (median 50 hours vs. 70 hours, p = 0.06)
increased bradycardia (10 patients vs. 2 patients, p = 0.03)
no significant difference in patients excluded from analysis due to persistent symptoms
no serious adverse events occurred in either group, including need for mechanical ventilation
Reference - Ann Intensive Care 2015 Dec;5(1):33 full-text
dexmedetomidine might not affect duration of hospital stay, but may reduce lorazepam dose requirement at 24 hours (level 2
based on small randomized trial
24 patients with Clinical Institute Withdrawal Assessment score ≥ 15 despite lorazepam IV ≥ 16 mg over 4-hour period were
randomized to dexmedetomidine IV (1.2 mcg/kg/hour vs. 0.4 mcg/kg/hour) vs. placebo for up to 5 days
mean reduction in lorazepam dose requirement at 24 hours after study drug compared to 24 hours before study drug
45 mg with dexmedetomidine 1.2 mcg/kg/hour (p = 0.1 vs. placebo)
62 mg with dexmedetomidine 0.4 mcg/kg/hour (p = 0.067 vs. placebo)
8 mg with placebo
no significant difference between either dexmedetomidine group vs. placebo for lorazepam dose requirement at 7 days or
duration of stay in hospital or and
ICU other supplementation
decrease in heart rate > 20 beats/minute in
7 patients (88%) with dexmedetomidine 1.2 mcg/kg/hour (p = 0.04 vs. placebo)
3 patients (38%) with dexmedetomidine 0.4 mcg/kg/hour (not significant vs. placebo)
2 patients (25%) with placebo
Reference - Crit Care Med 2014 May;42(5):1131

dexmedetomidine reported to reduce benzodiazepine dose, symptom severity, tachycardia, and systolic hypertension in patients
with refractory alcohol withdrawal in intensive care (level 3 [lacking direct] evidence)
based on case series
23 patients with refractory alcohol withdrawal in intensive care received adjunctive dexmedetomidine and were assessed for
clinical status change at 24 hours
compared to 24 hours before augmentation, at 24 hours dexmedetomidine associated with reduced
benzodiazepine dosing in 17 patients (p < 0.001)
heart rate in 17 patients (no p value reported)
systolic blood pressure in 17 patients (p = 0.002)
symptom severity score in 11 patients (mean 21% score reduction, p = 0.015)
1 patient had two 9-second asystolic pauses on telemetry and had dexmedetomidine discontinued
Reference - Ann Intensive Care 2012 May 23;2(1):12 full-text
review of adjunctive dexmedetomidine in the management of severe acute alcohol withdrawal syndrome can be found in Am J
Drug Alcohol Abuse 2015;41(5):382
Beta blockers
beta blockers may be considered in combination with benzodiazepines in patients with persistent hypertension or tachycardia (ASAM
Grade C) but not routinely recommended in all patients with delirium tremens(6)
no evidence they improve clinical outcomes
propranolol may worsen delirium (ASAM Level V)
consider beta blockers only in patients with symptomatic tachycardia or as adjunct to hypertension management(5)
atenolol commonly used; typical single doses are(3)
50 mg if pulse 50-79 beats/minute
100 mg if pulse ≥ 80 beats/minute
common adverse events include bradycardia, hypotension, fatigue, dizziness, cold extremities, and depression(3)
hypersensitivity to drug class or ingredient
second- or third-degree atrioventricular block
uncompensated heart failure
cardiogenic shock
sick sinus syndrome without implantable cardioverter-defibrillator
untreated pheochromocytoma
Antipsychotic medications
neuroleptics not recommended as monotherapy for alcohol withdrawal or delirium tremens due to increased risk of seizures (ASAM
Grade A)(6)
neuroleptics have higher mortality, more complications, and longer duration of delirium compared to sedative-hypnotics in controlled
trials(6)
consider neuroleptics in conjunction with benzodiazepines if agitation, disturbed thinking, or perceptual disturbances not adequately
controlled (ASAM Grade C)(6)
consider haloperidol as adjunctive therapy for agitation(4, 5, 6)
suggested dosing
0.5-5 mg IV every 0.5-2 hours
maximum doses are 0.5 mg/kg/day or 35 mg/day
0.5-5 mg orally every 4 hours as needed for agitation is another option
cautions include
lower seizure threshold
extrapyramidal effects
increased risk of arrhythmias due to QTc prolongation
prior to haloperidol administration, perform baseline electrocardiogram and electrolyte panel
if ≥ 2 risk factors for QTc prolongation, avoiding haloperidol suggested; risk factors include
female gender
myocardial infarction diagnosis
septic shock
left ventricular dysfunction
use of other QTc prolonging drugs
age > 68 years
baseline QTc ≥ 450 milliseconds
hypokalemia
perform daily electrocardiograms in patients receiving haloperidol
haloperidol may be associated with fewer hallucinations and cardiac complications than clonidine as adjunct to benzodiazepine in
postoperative trauma patients with alcohol dependence (level 2 [mid-level] evidence)
based on randomized trial with allocation concealment not stated and without intention-to-treat analysis
180 multiple-injured alcohol-dependent patients in ICUs after operative management randomized to 1 of 3 treatments with need for
medication based on CIWA-Ar score
flunitrazepam plus clonidine
chlormethiazole plus haloperidol
flunitrazepam plus haloperidol
4 patients (7%) in flunitrazepam/clonidine group excluded from further analysis due to hallucinations, no hallucinations reported in
either haloperidol group (no p value reported)
159 patients analyzed
flunitrazepam/clonidine associated with increased risk for cardiac complications (p = 0.0047)
chlormethiazole/haloperidol associated with prolonged mechanical ventilation (p = 0.032) and increased risk for pneumonia (p =
0.041)
no significant differences in mortality, sepsis, upper respiratory tract infections, bleeding, or days in intensive care unit
Reference - Crit Care Med 1996 Mar;24(3):414
DynaMed commentary – trial does not establish need for second drug
haloperidol and clonidine may have similar rates of severe alcohol withdrawal syndrome when used as adjunct to benzodiazepine in
postoperative tumor resection patients with alcohol dependence (level 2 [mid-level] evidence)
based on randomized trial without blinding of patients and without intention-to-treat analysis
220 patients (mean age 53 years) with alcohol dependence admitted to ICU after tumor resection for carcinoma of upper digestive
tract were randomized to 1 of 4 groups
flunitrazepam plus clonidine
chlormethiazole plus haloperidol
flunitrazepam plus haloperidol
ethanol
all patients had daily ethanol intake > 60 g at baseline

23 patients (10%) were excluded for various reasons, 197 patients (90%) analyzed
incidence of alcohol withdrawal syndrome
severe alcohol withdrawal syndrome (CIWA-Ar score > 20)
major intercurrent complication rate (pneumonia requiring mechanical ventilation, sepsis, cardiac complications, bleeding
disorders, and death)
duration of ICU stay
chlormethiazole plus haloperidol associated with increased risk of tracheobronchitis (p = 0.0023)
incidence of hallucinations was low in all groups (0%-4%, or 0-2 patients per group), but 5 patients were excluded from analysis due
to persistent hallucinations andhaloperidol
requiring other supplementation
Reference - Br J Anaesth 1995 Dec;75(6):734
neuroleptics alone may increase mortality and duration of delirium compared to sedative-hypnotics (benzodiazepines or
barbiturates) in patients with delirium tremens (level 2 [mid-level] evidence)
based on systematic review without assessment of trial quality
systematic review of 9 prospective controlled trials of treatments for delirium tremens
no placebo-controlled trials of sedative-hypnotic agents found
compared to sedative-hypnotics, neuroleptics associated with
increased mortality (relative risk 6.6, 95% CI 1.2-34.7) in analysis of 5 trials with 386 patients
longer duration of delirium in 2 of 4 trials, no significant difference in delirium in 2 trials
Reference - Arch Intern Med 2004 Jul 12;164(13):1405, correction can be found in Arch Intern Med 2004 Oct 11;164(18):2068,
commentary can be found in ACP J Club 2005 Jan, Arch Intern Med 2005 Feb 14;165(3):346, Arch Intern Med 2005 Mar
14;165(5):586
Thiamine and other supplementation

no evidence found evaluating multivitamins, folic acid, or other specific vitamins (except thiamine and magnesium) in patients with
alcohol withdrawal
consider folic acid 1 mg/day to prevent megaloblastic or macrocytic anemia(3, 4, 5)
thiamine
prophylactic thiamine is recommended for all patients with acute alcohol withdrawal(1, 2, 3, 5)
thiamine options
orally in patients in acute alcohol withdrawal, with or at risk of malnourishment, with decompensated liver disease, or before
and during planned medically assisted detoxification
parenterally followed by orally in patients who are seen in the emergency department or admitted to the hospital with an
acute injury or illness and have either of the following
are malnourished or at risk for malnourishment
have decompensated liver disease
parenterally in patients with suspected Wernicke encephalopathy, especially if they are about to receive glucose IV, as
glucose alone may precipitate Wernicke in thiamine-deficient patients
in United Kingdom, each Pabrinex carton of 5 ml ampoules for injection contains 250 mg of thiamine along with other
vitamins and nutrients
suggested dosing for thiamine varies from 100 mg/day to > 500 mg/day for 3-5 days, depending on clinical status
British Association for Psychopharmacology (BAP) guidelines recommended dosing for thiamine in alcohol-related brain
disorder (based on uncontrolled trials)
oral thiamine > 300 mg/day during detoxification in healthy uncomplicated alcohol-dependent or heavy drinkers
250 mg intramuscularly or IV once daily for 3-5 days (or until no further improvement) in patients at high risk for Wernicke
encephalopathy (such as malnourished or unwell patients)
> 500 mg/day intramuscularly or IV for 3-5 days, then 250 mg intramuscularly or IV once daily for 3-5 days if suspected or
established Wernicke encephalopathy
Reference - BAP updated evidence-based guideline on pharmacological management of substance abuse, harmful use,
addiction, and comorbidity (J Psychopharmacol 2012 Jul;26(7):899 full-text)
other suggested regimens

thiamine 100 mg/day for ≥ 3 days IV or intramuscularly recommended for patients with delirium tremens to prevent or
treat Wernicke-Korsakoff syndrome (ASAM Grade C)(6)
for patients without Wernicke encephalopathy, 100 mg/day orally(2, 3)
for patients with severe alcohol withdrawal or poor diet or signs of malnutrition, 250 mg/day IV for 3-5 consecutive
days(2)
with decompensated liver disease or evidence of malnutrition, give ≥ 1 dose prophylactic thiamine intravenously (NICE
guidance on alcohol use disorders [NICE 2011 Feb:CG115 PDF] and Royal College of Physicians concise guidance(1))
see also Wernicke encephalopathy
efficacy
thiamine 200 mg once daily for 2 days reported to improve working memory performance in patients with alcohol
dependence, but dose-response relationship not established (level 3 [lacking direct] evidence)
based on randomized trial without clinical outcomes and with high dropout rate
169 patients (mean age 42 years) admitted to alcohol detoxification unit were randomized to 1 of 5 thiamine doses (5 mg vs.
20 mg vs. 50 mg vs. 100 mg vs. 200 mg) intramuscularly once daily for 2 consecutive days and then tested with attention
task 3 days later
at baseline all patients were free from acute Wernicke encephalopathy (defined as ataxia, eye movement abnormalities, and
reduced consciousness)
primary outcome included assessment of delayed alternation measured by recording number of trials needed to reach
learning criterion (correctly identifying coin location 12 consecutive times on a test with a recurring pattern)
62 patients (37%) were excluded from analyses
43 patients were excluded because they did not complete study
19 patients were excluded to account for baseline differences observed after high patient dropout
mean number of trials needed to reach learning criterion (estimated from graph)
50 with thiamine 5 mg
32 with thiamine 200 mg (p = 0.031 compared to mean of other 4 doses)
normal values and clinically important difference in number of trials needed to reach learning criterion not reported
Reference - Alcohol Clin Exp Res 2001 Jan;25(1):112
Cochrane review evaluating thiamine for prevention and treatment of Wernicke-Korsakoff syndrome found only 1 additional
unpublished trial with 8 patients (Cochrane Database Syst Rev 2013 Jul 1;(7):CD004033)
thiamine 300 mg/day reported to reduce risk for cognitive deficit during alcohol withdrawal in alcohol-dependent men (level 3
[lacking direct] evidence)
based on controlled trial published in German
45 alcohol-dependent men had 2 weeks of withdrawal treatment in psychiatric clinic
23 given thiamine 300 mg/day, 22 had hospital diet alone with no vitamin substitution
thiamine decreased percentage of weak test performances (details and clinical relevance not reported in abstract), but no
significant difference in mean test performances
Reference - Nervenarzt 1989 Oct;60(10):633 [German]
giving thiamine before glucose (when practical) has been recommended to avoid Wernicke encephalopathy in thiamine-
deficient patients
all case reports of Wernicke encephalopathy have been with patients with prolonged glucose administration and continued
thiamine deficiency
glucose administration should not be delayed in acute situations and thiamine should still be supplemented but not
necessarily before glucose
Reference - JAMA 1998 Feb 25;279(8):583
magnesium supplementation
consider multivitamin IV and magnesium replacement in patients with severe alcohol withdrawal(2, 4)
magnesium not suggested in acutely ill medical patients if magnesium levels are normal(5)
ASAM recommendations
in patients with delirium tremens (ASAM Grade C)(6)

provide magnesium if hypomagnesemic
consider including magnesium in IV fluids if renal function normal and levels are monitored
magnesium may not reduce symptoms of acute alcohol withdrawal (level 2 [mid-level] evidence)
based on Cochrane review with limited evidence
systematic review of 4 randomized trials comparing magnesium vs. placebo in 317 hospitalized adults with or at risk of acute
alcohol withdrawal
all trials had unclear allocation concealment and/or unclear blinding
delirium tremens, grand mal seizures, and other alcohol withdrawal symptoms in 1 trial with 100 adults
grip strength in analysis of 3 trials with 226 adults
no clinically important differences in adverse events reported, but meta-analysis precluded by insufficient reporting of data on
serious adverse events
serious adverse events related to magnesium may include central nervous system depression, arrhythmias, heart block,
hypotension, respiratory tract paralysis, coagulopathies, and hyporeflexia
Reference - Cochrane Database Syst Rev 2013 Jun 5;(6):CD008358
Other medications
Barbiturates
barbiturates not recommended for outpatient treatment(3)
pentobarbital can be considered if large doses of benzodiazepines fail to control agitation in patients with delirium tremens (ASAM
Grade C)(6)
augmentation of benzodiazepine with phenobarbital may be useful in patients with treatment-resistant withdrawal(4)
close monitoring recommended
intubation and mechanical ventilation may be required
phenobarbital for severe alcohol withdrawal (defined as elevated CIWA score and symptoms refractory to benzodiazepines)
mechanism of action is potentiating synaptic inhibition of GABAA receptor
doses ranging from 65 to 260 mg IV in either weight-based or fixed-dosing have been reported in literature
onset and duration of action
phenobarbital IV action onset is about 5 minutes, with maximal effect at 30 minutes
duration of action reported to be approximately 4-10 hours
Reference - Ann Pharmacother 2016 May;50(5):389

addition of barbiturate to lorazepam may reduce need for ICU admission, and barbiturate monotherapy might be as effective as
benzodiazepines alone in patients with alcohol withdrawal (level 2 [mid-level] evidence)
based on systematic review with incomplete reporting of quality assessment
systematic review of 7 studies (3 randomized controlled trials, 1 nonrandomized controlled trial, and 3 retrospective cohort
studies) comparing barbiturates vs. benzodiazepines for management of acute alcohol withdrawal
barbiturates included pentobarbital intramuscularly (1 randomized controlled trial), barbital 500 mg orally (1 controlled trial), and
phenobarbital IV (2 randomized controlled trials and 3 retrospective cohorts)
3 trials involved patients with severe alcohol withdrawal (ICU admission and/or presence of delirium tremens)
comparing addition of barbiturate to lorazepam vs. addition of placebo in 1 randomized controlled trial with 102 patients with
alcohol withdrawal, augmentative barbiturates associated with
reduced rate of ICU admissions (8% vs. 25%, p < 0.05) and reduced use of continuous lorazepam infusion (4% vs. 31%, p < 0.05)
no significant difference in intensive care or hospital length of stay, use of other medications, or adverse events
no significant difference in outcomes comparing barbiturates vs. benzodiazepines

in duration and severity of episodes comparing pentobarbitol intramuscular vs. chlordiazepoxide intramuscular vs.
perphenazine intramuscular vs. paraldehyde orally for 10 days in 1 trial with 188 patients with delirium tremens
in discharge CIWA scores, emergency department length of stay, hospital admission rate, and 48-hour follow-up CIWA scores
comparing phenobarbital IV vs. combination of lorazepam IV followed by chlordiazepoxide orally in 1 trial with 44 patients with
alcohol withdrawal syndrome
in symptom reduction in patients experiencing grade 1 (tremor only) or grade 2 (tremor and hallucinations) delirium tremens,
barbiturates associated with reduced grade 3 (tremor, hallucinations, and disorientation) delirium tremens in 1 controlled trial
comparing barbital orally vs. diazepam intramuscular with 91 patients with acute alcohol withdrawal syndrome
Reference - J Crit Care 2016 Apr;32:101
Gamma-hydroxybutyrate (GHB) (Sodium oxybate)

GHB
also called 4-hydroxybutanoic acid or sodium oxybate
may indirectly activate GABAA receptors to suppress symptoms of alcohol withdrawal
illegal in many countries; regulated drug in Canada, Europe, and United States due to abuse potential
used in Austria and Italy (brand name Alcover) at 50-100 mg/kg/day in 3 divided doses to treat acute alcohol withdrawal and for
long-term detoxification
sodium oxybate (Xyrem) in United States indicated for narcolepsy
common adverse events include vertigo, drowsiness, diarrhea, gastric upset(4)
GHB 50 mg/kg/day might reduce alcohol withdrawal symptoms and help maintain abstinence (level 2 [mid-level] evidence)
based on Cochrane review of limited evidence
systematic review of 13 randomized trials comparing GHB vs. other active treatment or placebo for treatment of withdrawal
syndrome and prevention of relapse with 648 patients
11 trials conducted in Italy
GHB 50 mg associated with improved withdrawal symptom scores compared to placebo at 1 hour to 7 hours in 1 trial with 23
patients
comparing GHB 50 mg vs. placebo at 3 months in 1 trial with 71 patients
abstinence in 30.6% vs. 5.7% (p = 0.022, NNT 4)
relapse to heavy drinking in 27.8% vs. 77.1% (p = 0.0032, NNT 2)
mean craving score 3.1 vs. 7.6 (p < 0.0001)
comparing GHB to diazepam

GHB 50 mg associated with significant reductions in CIWA-Ar subscale scores for tremor, paroxysmal sweats, anxiety, and
agitation in analysis of 2 trials with 90 patients
GHB associated with nonsignificant reduction in overall CIWA-Ar scores at 18-21 days in 1 trial with 48 patients
no significant differences in CIWA-Ar scores comparing GHB 50 mg or 100 mg to clomethiazole in 1 small trial
no significant differences in abstinence at 12 months comparing GHB to
naltrexone in 1 trial with 55 patients
disulfiram in 1 trial with 59 patients
Reference - Cochrane Database Syst Rev 2010 Feb 17;(2):CD006266

sodium oxybate appears as effective and safe as oxazepam for alcohol withdrawal syndrome in outpatients with uncomplicated
withdrawal (level 1 [likely reliable] evidence)
based on randomized trial
126 outpatients with uncomplicated alcohol withdrawal (without history of delirium or seizure) randomized to sodium oxybate 175
mg/mL vs. oxazepam 15 or 30 mg/day each 3 times daily for 10 days
all patients also received placebo to conceal treatment condition (sodium oxybate group also received placebo tablet, while
oxazepam group also received placebo suspension)
doses were tapered throughout course of treatment
uncomplicated alcohol withdrawal defined as no history of delirium tremens or withdrawal seizure in prior alcohol withdrawal
episodes
mean CIWA-Ar score was 18.35
follow-up was 10 days post treatment
both groups had significant CIWA-Ar score reduction from baseline (p < 0.0001 each)
comparing sodium oxybate vs. oxazepam no significant differences in
reduction of CIWA-Ar scores from baseline (-15.62 vs. -16.27, not significant)
reduction of sweating, tremor, and anxiety scores
maintaining abstinence throughout follow-up with alcohol breath test measurement (90.2% vs. 84.6%, not significant)
intensity and frequency of craving for study medication
adverse events (≥ 1 events in 31.1% vs. 26.2%, not significant)
drug compliance (96.34% vs. 94.67%, not significant)
1 patient in sodium oxybate group developed delirium tremens, and 1 patient in oxazepam group developed severe dermatitis
Reference - GATE 1 trial (CNS Drugs 2014 Aug;28(8):743)
Psychotropic analgesic nitrous oxide

psychotropic analgesic nitrous oxide may reduce alcohol withdrawal symptoms more than benzodiazepines (level 2 [mid-level]
evidence)
based on Cochrane review of trials with methodological limitations
systematic review of 5 randomized trials of psychotropic analgesic nitrous oxide for alcohol withdrawal in 212 patients with
alcohol dependence
psychotropic analgesic nitrous oxide is therapy combining subanesthetic doses of nitrous oxide with ≥ 30% oxygen producing
concentrations ranging from 15% to 70% nitrous oxide
trial limitations included lack of allocation concealment and small sample sizes
comparing analgesic nitrous oxide vs. benzodiazepine
symptom score reductions > 50% on modified Gross scale in 91% vs. 68% (p = 0.04, NNT 5) in 1 trial with 51 patients
weighted mean difference of 3.7 points on State-Trait Anxiety Inventory favoring nitrous oxide at 1 hour after intervention (not
significant) in 2 trials with 47 patients
weighted mean difference of 2.4 points on Beck Depression Inventory favoring nitrous oxide at 1 hour after intervention (not
significant) in 2 trials with 47 patients
mean difference of 8.71 points on the Quick Neurological Screening Test for psychomotor functioning favoring nitrous oxide at
1 hour after intervention (p = 0.0006) in 1 trial with 31 patients
Reference - Cochrane Database Syst Rev 2007 Apr 18;(2):CD005190 (review updated 2008 Aug 11)
Clomethiazole (chlormethiazole)
Royal College of Physicians (RCOP) concise guidance of NICE guideline recommendations(1)
consider offering clomethiazole as alternative to benzodiazepine or carbamazepine for acute alcohol withdrawal in inpatient
setting
using clomethiazole with caution, only in inpatient settings, and as directed by summary of product characteristics
chlormethiazole (clomethiazole) may produce bronchial hypersection and respiratory depression requiring mechanical ventilation
(Anesth Analg 1999 Apr;88(4):946 full-text)
IV chlormethiazole dosing for surgical or critical care patients

DynaMed commentary – some of these drugs are unavailable or unavailable in IV formulations in some countries
prophylactic dose
in surgical ward setting is chlormethiazole 0.25-1 g IV every 6 hours
in surgical ICU setting is chlormethiazole 150 mg bolus (range 25-500 mg) then infusion of 2.5 mg/kg/hour (range 0.6-8.9
mg/kg/hour)
treatment doses
in surgical ICU settings is chlormethiazole 375 mg bolus (range 45-500 mg) then infusion of 8.2 mg/kg/hour (range 1.5-12
mg/kg/hour)
contraindicated if CIWA-Ar score > 15
Reference - Anesth Analg 1999 Apr;88(4):946 full-text
Baclofen
baclofen has limited evidence to evaluate for alcohol withdrawal syndrome
based on Cochrane review
systematic review of 2 randomized trials evaluating baclofen in 81 adults with alcohol withdrawal syndrome
baclofen significantly reduced dependence on high-dose lorazepam but had no significant difference in alcohol withdrawal
symptoms vs. placebo in 1 trial with 44 adults, but results limited by high dropout rate (< 80% analyzed)
no significant difference in alcohol withdrawal symptoms comparing baclofen vs. diazepam in 1 trial with 37 adults
Reference - Cochrane Database Syst Rev 2015 Apr 3;(4):CD008502
Ethyl alcohol
ethyl alcohol not recommended (ASAM Grade C)(6)
Phenothiazines
phenothiazines not recommended for outpatient treatment(3)
Propofol
propofol can be considered if large doses of benzodiazepines fail to control agitation in patients with delirium tremens (ASAM Grade
C)(6)
augmentation of benzodiazepine with propofol may be useful in patients with treatment-resistant withdrawal(4)
intubation and mechanical ventilation required
doses are approximately 0.3-1.25 mg/kg (20%-50% less than those for anesthesia)
monitor for bradycardia and hypotension
augmentative propofol may be associated with increased time to symptom resolution, and increased duration of mechanical
ventilation, intensive care, and hospital stay in patients with treatment-resistant alcohol withdrawal (level 2 [mid-level] evidence)
66 patients with treatment-resistant alcohol withdrawal were assessed for clinical outcomes
treatment-resistant withdrawal defined as requiring ≥ 40 mg diazepam (or equivalent) in 1 hour
33 patients received benzodiazepines alone (usual care), and 33 patients received adjunctive propofol
all patients receiving propofol had invasive mechanical ventilation (42.4% of usual care group had mechanical ventilation) and
propofol group had significantly more males (93.9% compared to 69.7% in usual care group [p = 0.01])
comparing adjunctive propofol vs. usual care, addition of propofol associated with increased
time to withdrawal resolution (mean 7 days vs. 5 days, p = 0.025)
duration of mechanical ventilation (mean 7 days vs. 2.5 days, p = 0.017)
duration of stay in
intensive care (mean 10 days vs. 4 days, p < 0.001)
hospital (mean 16.2 days vs. 6.7 days, p < 0.001)
nosocomial pneumonia (12% vs. 1%, p = 0.001)
Reference - Drug Alcohol Depend 2015 Sep 1;154:296

DynaMed commentary – this study may suggest that propofol use is more common in more severely ill patients, rather than being
the causative agent of longer hospital stay
Comparative efficacy
evidence comparing different drug classes for reducing seizures in patients with alcohol withdrawal is limited; only drug class with
significant evidence for reducing seizures is benzodiazepines (level 2 [mid-level] evidence)
based on Cochrane overview with heterogeneity and trials with methodologic limitations
systematic review of 5 Cochrane reviews with 114 randomized trials evaluating effectiveness and safety of pharmacological
interventions in 7,333 patients with alcohol withdrawal
CD005063 evaluating benzodiazepines included 64 trials with 4,309 patients
CD005190 evaluating psychotropic analgesic nitrous oxide included 5 trials with 212 patients
CD006266 evaluating gamma-hydroxybutyrate included 13 trials with 648 patients
CD008502 evaluated baclofen vs. diazepam in 1 trial with 37 patients
CD005064 evaluating anticonvulsants (excluding benzodiazepines) included 56 trials with 4,076 patients
only 3% of trials were considered high quality

benzodiazepines associated with reduced seizures compared to placebo (relative risk [RR] 0.16, 95% CI 0.04-0.69) in analysis of 3
trials with 324 patients; no other drug classes significantly reduced seizures compared to placebo
in comparisons for seizures
benzodiazepines associated with reduced seizures compared to antipsychotics (RR 0.24, 95% CI 0.07-0.88) in analysis of 4
trials with 633 patients
no significant differences in comparisons of
benzodiazepines vs. anticonvulsants in analysis of 6 trials with 479 patients
anticonvulsants vs. placebo in analysis of 10 trials with 1,108 patients
anticonvulsants vs. antipsychotics in analysis of 4 trials with 266 patients
benzodiazepines among themselves
no significant differences in adverse events or dropouts in most comparative analyses, but most analyses had small numbers of
trials
Reference - Cochrane Database Syst Rev 2011 Jun 15;(6):CD008537
Other management
Resistant alcohol withdrawal
resistant alcohol withdrawal(4)
defined as not achieving sedation with diazepam > 200 mg or lorazepam 40 mg during first 3-4 hours of treatment
management options
progressively larger benzodiazepine IV bolus doses
continuous infusion of benzodiazepine
augmentation of benzodiazepine with rescue medications including phenobarbital, propofol, or dexmedetomidine
if adjunctive rescue medication used, intubation and mechanical ventilation may be required
Addressing alcohol use

after successful treatment of alcohol withdrawal, refer all patients to long-term treatment program to maintain abstinence from
alcohol(3)
referral recommended after
symptoms are minimal and no medication required
patient has not had alcohol in ≥ 3 days
indications for referral to addiction specialist or inpatient treatment program
inadequate response to benzodiazepine therapy
missing an appointment
resumption of drinking
a visit from a recovering alcoholic may reduce problem drinking in hospitalized patients with alcohol problems (level 2 [mid-level]
evidence)
based on nonrandomized trial
314 patients hospitalized with alcohol-related injuries randomized to 1 of 3 treatments
peer intervention (physician message plus 30- to 60-minute visit with a recovering alcoholic)
brief intervention (5- to15-minute physician-delivered message)
usual care
abstinence rates 6 months after hospital discharge
64% with peer intervention (p = 0.006, NNT 4 vs. usual care)
51% with brief intervention (p = 0.006, NNT 7 vs. usual care)
36% with usual care
Reference - J Fam Pract 2001 May;50(5):447
integrated medical- and substance-abuse treatment appears to improve abstinence rates at 6 months in patients with substance-
abuse related medical conditions (level 2 [mid-level] evidence)
based on subgroup analysis of randomized trial
592 patients with alcohol or other substance abuse randomized to integrated care vs. usual care
integrated care consisted of integrated primary healthcare and addiction treatment program
usual care consisted of separate primary care and substance-abuse treatment
both programs were group based for 8 weeks followed by 10 months of optional aftercare
no significant difference in overall abstinence rates (68% vs. 63%, p = 0.18)
no significant difference in subgroup without substance abuse related medical conditions (66% vs. 73%, p = 0.23)
subgroup of 341 patients with substance abuse related medical conditions more likely to be abstinent with integrated care (69% vs.
55%, p = 0.006, NNT 8)
findings significant both for patients with medical conditions and psychiatric conditions
Reference - JAMA 2001 Oct 10;286(14):1715 full-text, editorial can be found in JAMA 2001 Oct 10;286(14):1764
narrative systematic review of studies evaluating patient and program factors associated with transition from detoxification to alcohol
use disorder treatment can be found in J Subst Abuse Treat 2015 May;52:31
see also Alcohol use disorder
Monitoring treatment
clinically assess all patients periodically to monitor for emergence of medical or neurological illness not present at admission(2)
outpatients should be monitored daily until symptoms decrease and medication dosage reduced(3)
at each visit, assess
blood pressure and pulse
Clinical Institute Withdrawal Assessment – Alcohol, revised (CIWA-Ar)
check alcohol breath analysis at random intervals (if available)
monitor symptoms with validated tool such as CIWA-Ar recommended(2, 4)

reported limitation of CIWA-Ar is reliance on patient response, which may be difficult to interpret in severely agitated patients
other scales with less reliance on patient response include(4)
Alcohol Withdrawal Syndrome Scale
Richmond Agitation-Sedation Scale - used for patients admitted to intensive care and sedated, can be found online at RASS PDF
Glasgow Modified Alcohol Withdrawal Scale (GMAWS) was designed to assess and monitor alcohol withdrawal in acute settings,
and to guide symptom-triggered dosing of benzodiazepines
Clinical Institute Withdrawal Assessment – Alcohol, revised (CIWA-Ar) recommended to assess initial severity and monitor
treatment (1, 2, 3, 5)
10-question tool to assess severity of alcohol withdrawal in order to
help make initial treatment decision in addition to history and physical (inpatient vs. outpatient)
guide symptom-triggered treatment regimen
scoring clinical dimensions

rates 10 symptom dimensions on 0-4 or 0-7 scales (total score range 0-67)
clinical dimensions include nausea and vomiting, tremor, paroxysmal sweats, anxiety, agitation, tactile disturbances, auditory
disturbances, visual disturbances, headache/fullness in head, and orientation and sensorium clouding
severity rating by score

score ≤ 8 considered absent or very mild withdrawal
9-14 considered mild withdrawal
15-20 considered moderate withdrawal
≥ 20 considered severe withdrawal
see DynaMed calculator for CIWA-Ar Clinical Institute Withdrawal Assessment for Alcohol Scale or above for CIWA-Ar
questionnaire
timing of monitoring(4)
in patients with CIWA-Ar score > 8-10, conduct hourly assessments to guide symptom-triggered dosing
in patients with CIWA-Ar score ≤ 8-10, assessment is typically every 8 hours
Glasgow Modified Alcohol Withdrawal Scale (GMAWS)

can not be used if patient is intoxicated, use only if patient had last drink ≥ 8 hours ago
consists of 5-items scored 0-10
GMAWS Tool*:
Item Scoring
Tremor No tremor - 0 points

Tremor on movement - 1 point
Tremor at rest - 2 points
*For use in patients with last drink ≥ 8 hours ago

Item and other supplementation Scoring
Sweating No sweat visible - 0 points

Moist - 1 point
Drenching sweats - 2 points
Hallucination Not present - 0 points

Dissuadable hallucinations - 1 point
Non-dissuadable hallucinations - 2 points
Orientation Orientated - 0 points

Vague, detached - 1 point
Disorientated, no contact - 2 points
Agitation Calm - 0 points

Anxious - 1 point
Panicky - 2 points
*For use in patients with last drink ≥ 8 hours ago
scoring for symptom-triggered regimens in inpatients

score 0 - repeat scoring in 2 hours; discontinue scoring after 4 consecutive scores of 0, unless it has been < 48 hours after last
drink
score 1-3 points
give diazepam 10 mg
repeat scoring in 2 hours
score 4-8 points

give diazepam 20 mg
repeated scoring in 1 hour
score 9-10
give diazepam 20 mg
repeat scoring in 1 hour; consult with clinician (if nurse)

Glasgow Modified Alcohol Withdrawal Scale (GMAWS) reported to have moderate internal consistency and GMAWS protocol
reported to be rated as "good or better" and "easy to use" by majority of staff respondents in cohort study of 221 patients
hospitalized with acute alcohol withdrawal syndrome (QJM 2012 Jul;105(7):649, commentary can be found in QJM 2012
Oct;105(10):1033)
Complications and Prognosis

Complications
cardiac arrhythmia may result from electrolyte imbalances(5)
delirium tremens (DT) may occur about 3-5 days after last drink if alcohol withdrawal untreated(2, 3, 4, 5)
about 5%-15% reported mortality rate
presentation
includes disorientation with hallucinations (usually visual) which are distressing but not dangerous, plus severe agitation,
tremor, hyperactivity, hallucinations, excessive sweating, exacerbated autonomic symptoms including hypertension, tachycardia,
tachypnea
associated with and
disrupted fluid other
status, supplementation
electrolyte abnormalities, hypovolemia, and deficiencies in potassium, magnesium, and
phosphate
associated electrolyte abnormalities may increase risk for cardiac arrhythmias and seizures
symptoms may last up to 7 days

reported in
about 33% of untreated patients in stage 3
about 5% of patients hospitalized for alcohol withdrawal
risk factors for DT include
sustained heavy drinking
age > 30 years
increasing days since last alcohol use
prior episode of DT or seizures
concurrent illness
presence of withdrawal symptoms with high blood alcohol level
tonic-clonic seizures(2, 3, 4)
reported 3%-5% of patients develop seizures 12-48 hours after last drink
seizures typically singular or recur only few times, and spontaneously resolve
protracted withdrawal syndrome reported in some patients after acute period of alcohol withdrawal
defined as symptoms of withdrawal persisting or recurring beyond acute period of withdrawal
symptoms may linger after acute period
symptoms may clear for 1-2 months after acute period and then recur
reported symptoms of protracted alcohol withdrawal include anxiety, hostility, irritability, depression, labile mood, fatigue, insomnia,
difficulties concentrating and thinking, reduced interest in sex, and unexplained physical complaints particularly of pain
hypothesized to result from persistence of central nervous system adaptive changes to chronic substance use
Reference - Substance Abuse and Mental Health Services Administration (SAMHSA) Protracted Withdrawal 2010 PDF
Prognosis
stages of progression
4 generally recognized stages used for reference of expected progression, but stages are not clinically reliable due to potential of
patients(4)
not progressing through them sequentially
presenting with overlapping symptoms from varying stages
approximate stages are(2, 3, 4)

stage 1 - minor symptoms which may occur even in presence of elevated blood alcohol levels
may consist of tremors, anxiety, gastrointestinal upset, anorexia, nausea, excessive sweating (diaphoresis), palpitations,
tachycardia, hypertension
reported to resolve within 24-48 hours if withdrawal does not progress or is treated
stage 2
may consist of hyperactivity, insomnia, and hallucinations (visual, tactile, or auditory)
stage 3 - 3% to 5% of patients progress to this stage

similar to stage 2 but with tonic-clonic seizures; seizures typically singular or recur only few times, and spontaneously
resolve
stage 4 - reported in 33% of untreated patients in stage 3

occurs 3-5 days after last drink; symptoms may last up to 7 days
consists of delirium tremens with disorientation, agitation, hyperactivity, hallucinations, excessive sweating, hypertension,
and tachycardia
reported mortality rate about 5%-15% if untreated
increased serum potassium levels may be associated with increased risk of mortality in psychiatric inpatients with delirium tremens
(level 2 [mid-level] evidence)
based on retrospective cohort study with nested case control analysis
190 psychiatric inpatients (mean age 51 years) with delirium tremens in Serbia between 2002 and 2011 were assessed for medical
record data and clinical outcomes
14 patients who died were matched for age, sex, and year of hospitalization with 28 controls who had survived
in overall analysis, lethal outcome associated with
increased age (p = 0.037)
higher serum potassium level (p < 0.001); all patients had potassium levels within normal range (mean 4.5 mmol/L in cases and
mean 3.87 mmol/L in all survivors)
in nested case-control analysis

higher serum potassium level was associated with increased mortality (adjusted odds ratio 40.52, 95% CI 1.2 to > 1,000, p =
0.004)
no other variable (including age) was significantly associated with increased mortality
Reference - Ann Gen Psychiatry 2013 Dec 2;12(1):39 full-text

DynaMed commentary – The results of this study may appear to conflict with reports of hypokalemia's association with alcohol
withdrawal, but the authors note that since hypokalemia is an adaptive mechanism to account for the sudden lack of ethanol in the
blood, increased potassium may signal an inappropriate response to withdrawal.
Prevention and Screening

Prevention
consider prophylactic treatment in inpatients admitted for reasons other than alcohol withdrawal (and are without withdrawal
symptoms) and have history of either(4)
withdrawal seizures or delirium tremens
prolonged, heavy alcohol consumption
typical prophylactic treatment of hospitalized patients at risk of withdrawal consists of(4)

chlordiazepoxide 50-100 mg every 6 hours for 1 day
reduce to 25-50 mg every 6 hours for 2 additional days
frequent assessments, and switch to typical treatment regimen if withdrawal symptoms develop
ethanol IV has been reported as withdrawal prophylaxis in patients with alcohol dependence admitted to intensive care for other
medical reason(4, 5)
ethanol increases risk of toxic complications and drug interactions, so is not widely used or recommended
IV ethanol appears no more effective than diazepam for prevention of alcohol withdrawal in intensive care unit (level 2 [mid-level]
evidence)
based on small randomized trial
50 patients with history of chronic daily alcohol consumption ≥ 5 beverage equivalents daily admitted to intensive care unit with
trauma were randomized to IV ethanol infusion vs. scheduled-dose diazepam for 4 days
ethanol associated with more patients deviating from "calm and cooperative" score during treatment (p = 0.02) (mostly
attributed to under sedation)
ethanol associated with 1 patient failing treatment (not significant)
Reference - J Trauma 2008 Jan;64(1):99
see Alcohol use disorder for additional information on interventions to reduce problem drinking
Screening
AUDIT-PC score at admission may help identify hospital inpatients who will develop alcohol withdrawal syndrome (level 2 [mid-level]
evidence)
based on diagnostic case-control study
223 medical or surgical inpatients who developed alcohol withdrawal syndrome (AWS) during hospital stay and 466 matched
... / Medications / without
inpatient controls Thiamine andscreened
AWS were otherfor
supplementation
alcohol use disorder with Alcohol Use Disorders Identification Test - [Piccinelli]
Consumption (AUDIT-PC) at admission
AUDIT-PC consists of 5 Likert items (score range 0-19) from alcohol use disorders identification test (AUDIT) to screen for
hazardous alcohol use in outpatient primary care
increasing AUDIT-PC score at admission associated with incident AWS (odds ratio 1.68, 95% CI 1.55-1.82 per point increase)
for distinguishing patients with incident AWS from control, AUDIT-PC
with cutoff score ≥ 3 had sensitivity 93.3% and specificity 84.3%
with cutoff score ≥ 4 had sensitivity 91% and specificity 89.7%
with cutoff score ≥ 5 had sensitivity 83% and specificity 94.9%
Reference - J Gen Intern Med 2014 Jan;29(1):34 full-text, editorial can be found in J Gen Intern Med 2014 Jan;29(1):7
AUDIT screen identifies hospital patients who develop clinically significant alcohol withdrawal symptoms (level 2 [mid-level]
evidence)
based on prospective cohort study
874 patients admitted to acute medical ward screened with AUDIT
98 (11%) screened positive for alcohol use disorder
17 (2%) had clinically significant alcohol withdrawal symptoms
AUDIT score ≥ 8 had 100% sensitivity, 90.5% specificity, 17.3% positive predictive value, and 100% negative predictive value
AUDIT score ≥ 8 PLUS at least 2 abnormal blood tests (out of gamma-glutamyltransferase [GGT], aspartate aminotransferase
[AST], alanine aminotransferase [ALT], and mean corpuscular volume [MCV]) had 94% sensitivity, 97.3% specificity, 47% positive
predictive value, and 99.9% negative predictive value
Reference - Alcohol Alcohol 2005 Nov-Dec;40(6):515 full-text
see Alcohol use disorder for additional information
Guidelines and Resources

Guidelines
United States guidelines
American Academy of Pediatrics (AAP) clinical report on binge drinking can be found in Pediatrics 2015 Sep;136(3):e718
American Society of Addiction Medicine (ASAM)

guideline on management of delirium tremens can be found in Arch Intern Med 2004 Jul 12;164(13):1405, correction can be found
in Arch Intern Med 2004 Oct 11;164(18):2068, commentary can be found in Arch Intern Med 2005 Feb 14;165(3):346, ACP J Club
2005 Jan-Feb;142(1):4, or in Arch Intern Med 2005 Mar 14;165(5):586
guideline on pharmacological management of alcohol withdrawal can be found in JAMA 1997 Jul 9;278(2):144
United Kingdom guidelines

Royal College of Physicians (RCOP) guideline on assessment and management of alcohol dependence and withdrawal in acute
hospital can be found in Clin Med 2012 Jun;12(3):266, produced with National Institute for Health and Care Excellence (NICE)
National Institute for Health and Care Excellence (NICE) guidance on

alcohol use disorders: physical complications can be found at NICE 2010 Jun:CG100 PDF, addendum can be found at NICE 2017
Apr:CG100.1
diagnosis, assessment, and management of harmful drinking and alcohol dependence can be found at NICE 2011 Feb:CG115 PDF,
summary can be found in BMJ 2011 Feb 23;342:d700
nalmefene for reducing alcohol consumption in people with alcohol dependence can be found at NICE 2014 Nov:TA325 PDF
British Association for Psychopharmacology (BAP) updated evidence-based guideline on pharmacological management of substance
abuse, harmful use, addiction, and comorbidity can be found in J Psychopharmacol 2012 Jul;26(7):899
European guidelines
S3 Leitlinie Screening, Diagnose und Behandlung alkoholbezogener Störungen finden Sie unter AWMF 2016 PDF [Deutsch]
European Federation of Neurological Societies (EFNS) guideline on alcohol-related seizures can be found at EFNS 2010 Sep PDF
Australian and New Zealand guidelines

Queensland Health Primary Clinical Care Manual: mental health and substance misuse can be found at Queensland 2016 PDF
New South Wales (NSW) Ministry of Health clinical practice guidelines on drug and alcohol withdrawal can be found at NSW 2008 Jul
4 PDF
New South Wales (NSW) Ministry of Health guideline on management of patients with acute severe behavioral disturbance in
emergency departments can be found at NSW 2015 Aug 10 PDF
Review articles
literature review of clinical management of alcohol withdrawal can be found in Ind Psychiatry J 2013 Jul;22(2):100 full-text
literature review of treatment of severe alcohol withdrawal can be found in Ann Pharmacother 2016 May;50(5):389
Applied Evidence review can be found in J Fam Pract 2004 Jul;53(7):545, commentary regarding baclofen can be found in J Fam Pract
2005 Jan;54(1):24
review of recognition and management of delirium tremens can be found in N Engl J Med 2014 Nov 27;371(22):2109
review of pharmacological strategies for detoxification from substances including alcohol can be found in Br J Clin Pharmacol 2014
Feb;77(2):302 full-text
review of alpha2-adrenorecepter agonists in treatment of withdrawal syndromes can be found in J Med Toxicol 2014
Dec;10(4):369 full-text
review of management of drug and alcohol withdrawal can be found in N Engl J Med 2003 May 1;348(18):1786, commentary can be
found in N Engl J Med 2003 Jul 24;349(4):405
review of ambulatory detoxification of patients with alcohol dependence can be found in Am Fam Physician 2005 Feb 1;71(3):495
review of alcohol abuse in the critically ill patient can be found in Lancet 2006 Dec 23;368(9554):2231
review of common problems in patients recovering from chemical dependency can be found in Am Fam Physician 2003 Nov
15;68(10):1971
case report of patient with delirium tremens receiving emergency exploratory laparotomy for perforated viscus can be found in Indian
J Anaesth 2012 Mar;56(2):189 full-text
MEDLINE search
to search MEDLINE for (Alcohol withdrawal syndrome) with targeted search (Clinical Queries), click therapy, diagnosis, or prognosis
Patient Information
handout from American Academy of Family Physicians or in Spanish
handout from Harm Reduction for Alcohol
handout on alcohol detoxification from Patient UK PDF
ICD-9/ICD-10 Codes
ICD-9 codes
291 alcoholic psychoses
291.0 alcohol withdrawal delirium
291.1 alcohol amnestic syndrome
291.2 other alcoholic dementia
291.3 alcohol withdrawal hallucinosis
291.8 other specified alcoholic psychosis
291.81 alcohol withdrawal
291.82 alcohol induced sleep disorders
291.89 other alcoholic psychosis
291.9 unspecified alcoholic psychosis
ICD-10 codes
F10 mental and behavioural disorders due to use of alcohol
F10.0 mental and behavioural disorders due to use of alcohol with acute intoxication
F10.1 mental and behavioural disorders due to use of alcohol with harmful use
F10.2 mental and behavioural disorders due to use of alcohol with dependence syndrome
F10.3 mental and behavioural disorders due to use of alcohol with withdrawal state
F10.4 mental and behavioural disorders due to use of alcohol with withdrawal state delirium
F10.5 mental and behavioural disorders due to use of alcohol with psychotic disorder
F10.6 mental and behavioural disorders due to use of alcohol with amnesic disorder
F10.7 mental and behavioural disorders due to use of alcohol with residual and late-onset psychotic disorder
P96.1 neonatal withdrawal symptoms from maternal use of drugs of addiction
References
General references used
1. Stewart S, Swain S; National Institute for Health and Clinical Excellence (NICE), Royal College of Physicians, London. Assessment
and management of alcohol dependence and withdrawal in the acute hospital: concise guidance. Clin Med. 2012 Jun;12(3):266-71
2. Sachdeva A, Choudhary M, Chandra M. Alcohol Withdrawal Syndrome: Benzodiazepines and Beyond. J Clin Diagn Res. 2015
Sep;9(9):VE01-VE07 full-text
3. Muncie HL Jr, Yasinian Y, Oge' L. Outpatient management of alcohol withdrawal syndrome. Am Fam Physician. 2013 Nov
1;88(9):589-95 full-text
4. Perry EC. Inpatient management of acute alcohol withdrawal syndrome. CNS Drugs. 2014 May;28(5):401-10
5. Gortney JS, Raub JN, Patel P, Kokoska L, Hannawa M, Argyris A. Alcohol withdrawal syndrome in medical patients. Cleve Clin J Med.
2016 Jan;83(1):67-79 full-text
6. Mayo-Smith MF, Beecher LH, Fischer TL, et al; Working Group on the Management of Alcohol Withdrawal Delirium, Practice
Guidelines Committee, American Society of Addiction Medicine. Management of alcohol withdrawal delirium. An evidence-based
practice guideline. Arch Intern Med. 2004 Jul 12;164(13):1405-12
Recommendation grading systems used

American Society of Addiction Medicine (ASAM) guideline grading system
grades of recommendation
Grade A – supported by level I studies or by meta-analysis in which lower limit of confidence interval for effect of treatment
exceeds minimally clinically significant benefit
Grade B – supported by level II studies or by meta-analysis in which estimate of treatment effect exceeds minimally clinically
significant benefit but lower limit of confidence interval does not
Grade C – supported by data other than prospective controlled trials, including secondary analysis of level I or level II studies
levels of evidence
Level I – randomized trials with low false-positive and low false-negative errors
Level II – randomized trials with high false-positive and high false-negative errors
Level III – nonrandomized, concurrent cohort comparisons
Level IV – nonrandomized, historical cohort comparisons
Level V – case series without controls
Reference - ASAM guideline on management of alcohol withdrawal delirium (Arch Intern Med 2004 Jul 12;164(13):1405 full-text)
Synthesized Recommendation Grading System for DynaMed Plus

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clinical decision-making (see 7-Step Evidence-Based Methodology).
Guideline recommendations summarized in the body of a DynaMed topic are provided with the recommendation grading system used
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In DynaMed Plus (DMP), we synthesize the current evidence, current guidelines from leading authorities, and clinical expertise to
provide recommendations to support clinical decision-making in the Overview & Recommendations section.
We use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) to classify synthesized
recommendations as Strong or Weak.
Strong recommendations are used when, based on the available evidence, clinicians (without conflicts of interest) consistently
have a high degree of confidence that the desirable consequences (health benefits, decreased costs and burdens) outweigh the
undesirable consequences (harms, costs, burdens).
Weak recommendations are used when, based on the available evidence, clinicians believe that desirable and undesirable
consequences are finely balanced, or appreciable uncertainty exists about the magnitude of expected consequences (benefits and
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DynaMed Plus (DMP) synthesized recommendations (in the Overview & Recommendations section) are determined with a systematic
... /methodology:
Medications / Thiamine and other supplementation
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Panel members will make Strong recommendations if and only if there is consistent agreement in a high confidence in the
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Special acknowledgements
Daniel A. Ostrovsky, MD (Assistant Professor of Medicine and Pediatrics, Duke University School of Medicine; North Carolina, United
States)
Dr. Ostrovsky has declared that he has no financial conflicts of interest.
Daniel C. Vinson, MD, MSPH (Professor of Family and Community Medicine, University of Missouri; Missouri, United States)
Esther Jolanda van Zuuren, MD (Head of Allergy, Dermatology, and Venereology, Leiden University Medical Centre; Netherlands; Editor,
Cochrane Skin Group)
Brian C. Weiner, MD, MS, FACP, AGAF (Deputy Editor of Gastroenterology; Medical Director, Manalapan Surgery Center; New Jersey,
United States)
Dr. Weiner declares relevant financial relationships with Marlboro Medical Devices, LLC and Forest Labs (Consultant).
The American College of Physicians (Marjorie Lazoff, MD, FACP; ACP Deputy Editor, Clinical Decision
Resource) provided and
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How to cite
National Library of Medicine, or "Vancouver style" (International Committee of Medical Journal Editors):
DynaMed Plus [Internet]. Ipswich (MA): EBSCO Information Services. 1995 - . Record No. 114807, Alcohol withdrawal syndrome;
[updated 2016 Apr 29, cited place cited date here]; [about 29 screens]. Available from http://www.dynamed.com/login.aspx?
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/ Medications / Thiamine and other supplementation

[+]Updated 2017 Jan 17 02:16 PM (ET)

Recommendations Editor Esther Jolanda van Zuuren, MD

Deputy Editor Brian C. Weiner, MD, MS, FACP, AGAF

Overview and Recommendations

withdrawal seizures - stage 3

alcohol withdrawal delirium (delirium tremens) - stage 4

Other medications may be used in certain situations:

See Alcohol use disorder to address patient's alcohol consumption.

Etiology and Pathogenesis

Effect of Prolonged Alcohol Use on Central Nervous System:

Acute Effect of Alcohol Resultant Adaptive Response to Removal of

Enhances inhibitory effect of Down-regulation of GABA Decreased ability to inhibit

Abbreviations: GABA, gamma-amino butyric acid; NMDA, N-methyl-D-aspartate.

Decreases excitation by acting Up-regulation of glutamate to In absence of alcohol, up-

Abbreviations: GABA, gamma-amino butyric acid; NMDA, N-methyl-D-aspartate.

more severe withdrawal and seizures may be due to "kindling" effect(4, 5)

History and Physical

most common symptoms are(2, 3, 5)

if untreated, withdrawal may progress to delirium tremens with symptoms/signs including(3)

History of present illness (HPI)

assess pattern of alcohol use(2, 3, 4, 5)

stage 4 - reported in 33% of untreated patients in stage 3

Past medical history (PMH)

ask about risk factors of more severe withdrawal, including(1, 2, 4)

ask about liver or kidney disease(1)

Social history (SH)

ask about other substance use problems(5)

common signs include(2)

look for signs of(1, 4)

suspect Wernicke encephalopathy if classic triad present; triad includes(1, 2)

withdrawal and delirium tremens can appear similar to

hepatic encephalopathy, in addition to history of jaundice, hematemesis, or melena, symptoms/signs include

other causes of seizures include

in patients with conﬁrmed alcohol withdrawal, testing includes(4, 5)

Cerebrospinal ﬂuid (CSF) analysis

Other diagnostic testing

scoring clinical dimensions

generally used severity rating by score(2, 3, 4)

Short Alcohol Withdrawal Scale(3)

Risk factors for severe withdrawal

severe alcohol withdrawal syndrome

alcohol withdrawal seizure

laboratory tests that can help determine risk of severe withdrawal

alcohol withdrawal seizure

thrombocytopenia predicted development of seizures with

thrombocytopenia with cutoff of 137 × 103/mcL had

Reference - Am J Emerg Med 2015 May;33(5):701

Seizure or delirium testing

testing in patients with alcohol withdrawal seizure includes(2)

evaluation in patients with delirium tremens(2)

for alcohol withdrawal seizures, higher doses of benzodiazepines may be required

for outpatient treatment

all patients should be seen daily until symptoms subside(3)

supportive care for inpatients consists of(2, 4)

consider intensive care unit admission in patients with(4, 5)

comparing outpatient detoxiﬁcation vs. inpatient detoxiﬁcation

Fluid and electrolytes

benzodiazepines are preferred treatment(2, 4, 5)

other agents include

for hospitalized patients

offering oral lorazepam as ﬁrst-line treatment in patients with delirium tremens