Pyruvate is converted to lactate, rather than
glucose, through gluconeogenesis
50% glucose (50 mL) by IV push
CNS, central nervous system; IV, intravenous.
For many alcohol-dependent individuals with significant physical dependence, a
cluster of withdrawal symptoms known as “alcohol withdrawal syndrome” (AWS)
may occur on cessation or reduction of alcohol consumption. Depending directly on
the degree of physical dependence, AWS can range from creating significant
discomfort to mild tremor to alcohol withdrawal-related delirium, hallucinosis,
seizures, and potentially death.
155,156 A gamma-glutamyl transferase (GGT) of 992
units/Lin combination with the patient’s medical history suggests that J.M. is a heavy
drinker. Although J.M.’s AST, ALT, and total bilirubin are elevated, his direct
(unconjugated) bilirubin is within normal limits, suggesting a problem with bilirubin
excretion as would be consistent with viral hepatitis or cirrhosis.
Patients may present with AWS in a variety of settings, because alcohol-dependent
patients may be unrecognized and experience withdrawal after inpatient hospital
admission for unrelated medical reasons. For example, a sample from a primary care
practice indicated that 15% of patients presented with at-risk drinking patterns or
identified alcohol-related problems.
157 Surgical patients should be screened
preoperatively for possible alcohol dependence, to prevent and adequately treat
AWS-related complications during and after surgery.
Diagnosis requires cessation or reduction in alcohol use that has been heavy and
prolonged, and two or more of the following symptoms developing within several
hours to a few days after the cessation: autonomic hyperactivity, hand tremor,
insomnia, nausea or vomiting, transient hallucinations or illusions (tactile, visual, or
auditory), psychomotor agitation, anxiety, and generalized tonic–clonic seizures.
These symptoms must cause significant distress or impairment of important areas of
functioning, and not be caused by a general medical condition or another mental
disorder. Withdrawal-related seizure is considered a more severe manifestation of
withdrawal, as is alcohol withdrawal delirium (AWD), or delirium tremens as it is
traditionally called. AWD is estimated to have a mortality rate of approximately 5%
of patients who go into alcohol withdrawal.
159 Recognized predictors for AWS
complications include the duration of alcohol consumption, total number of prior
detoxifications from alcohol, and previous withdrawal-related seizures and episodes
CASE 90-10, QUESTION 2: How could the severity of J.M.’s withdrawal symptoms be quantitatively
Of currently used instruments available for measuring the degree of withdrawal in
an alcohol-dependent patient, the most commonly used is the revised Clinical
Institute Withdrawal Assessment (CIWA-Ar).
161 Additionally the Sedation-Agitation
Scale (SAS) could be used to assess agitation.
assessment of withdrawal. The CIWA-Ar provides a final score with a maximum of
67 points assessing the extent of headache, nausea, tremors, agitation, paresthesia,
sweats, audio and visual disturbances, and lack of awareness of time or location.
pharmacologic support. A rating of 9 to 15 is associated with moderate withdrawal
and may require some pharmacotherapy. A rating more than 15 corresponds to severe
withdrawal, with an increased risk of seizures and AWD. Providers should also
consider concomitant illnesses and medications when interpreting CIWA-Ar scores
because individual items in the scale are not specific to AWS, and likewise some
manifestations of withdrawal may be blunted. The SAS can be used in combination
with the CIWA-Ar to evaluate the level of agitation and consciousness of a patient,
and be linked to administer benzodiazepines on a symptom-triggered regimen when a
patient becomes agitated (for scores >4 on a 7-point scale).
CASE 90-10, QUESTION 3: What drugs are demonstrated to be the most clinically effective for alcohol
withdrawal, particularly in a patient such as J.M. with evidence of cirrhosis?
Benzodiazepines modulate anxiolysis by stimulating GABAA receptors and, in doing
so, substitute pharmacologically for alcohol.
163 They are considered the drugs of
choice for alcohol withdrawal,
long-acting benzodiazepines (e.g.,
chlordiazepoxide and diazepam) and short-acting agents (e.g., lorazepam and
oxazepam) represent the most efficacious pharmacotherapies for the treatment of
157 They are effective in preventing both first seizures and
subsequent seizures during alcohol withdrawal.
165 Longer-acting benzodiazepines
may provide for easier weaning because they gradually self-taper on metabolism and
excretion; this allows for less fluctuation in plasma drug levels.
benzodiazepines also cause fewer rebound effects and withdrawal seizures on
discontinuation. Shorter-acting agents (e.g., lorazepam or oxazepam), which undergo
phase II hepatic metabolism to inactive metabolites, require more frequent dosing but
may be more appropriate for alcoholics with liver disease and the elderly.
When used appropriately, all benzodiazepines appear equally effective in
ameliorating the signs and symptoms of alcohol withdrawal; however, the choice of a
benzodiazepine is dependent on factors such as pharmacokinetic properties, dosage
formulation, presence of liver impairment, and ease of dosage titration.
Suggested Treatment Strategies for Alcohol Withdrawal Syndrome
Protocol Clinical Rationale Drug
days regardless of the severity
generally used in severe alcohol
Chlordiazepoxide 25 to 100 mg orally
that less medication is used to
Chlordiazepoxide 50–100 mg Less abuse potential
Diazepam 10–20 mg Long duration of
Lorazepam 2–4 mg Shorter duration of
In patients with benzodiazepine
Carbamazepine Taper from 600–800
Adrenergic hyperactivity Clonidine 0.1 mg PO BID as
Adrenergic hyperactivity β-Blockers:
IM, intramuscular; IV, intravenous; PO, oral; TID, 3 times daily.
Source: Guirguis AB, Kenna GA. Treatment considerations for alcohol withdrawal syndrome. US Pharm.
Two strategies for dosing benzodiazepines in AWS include fixed-schedule and
symptom-triggered regimens. Fixed-schedule regimens involve a set dose and
interval for the agent chosen, which is to be tapered off at specific times, usually
starting on the second day of treatment. Symptom-triggered regimens depend on the
use of a rating scale of withdrawal severity, such as the CIWA-Ar previously noted,
which is repeated at set intervals. Medication is only administered if the scoring
from the scale is above a predetermined threshold value for treatment. In this way,
the risk of undermedicating or overmedicating patients may be minimized, because
the degree of withdrawal symptoms guides dosing. Several studies confirm that
symptom-triggered regimens compared with fixed-dose regimens appear to result in a
shorter duration of necessary therapy and less medication administered in total
The treatment challenge associated with individuals who are in alcohol
withdrawal with a comorbid medical illness is illustrated by the case of a patient
with AWS who has coronary artery disease. Such a patient may be more aggressively
treated for withdrawal-related hypertension and thus treated with a β-blocker or
clonidine. The result of such adjuvant treatment may be a reduced sensitivity of the
CIWA-Ar owing to a masking of the patient’s autonomic manifestations of
withdrawal. This could then lead to a higher likelihood of undermedicating the
patient for withdrawal and may put the patient at higher risk for severe sequelae from
withdrawal. Because of these exclusion criteria, the symptom-triggered approach has
not been tested in such populations or those with histories of severe withdrawal
including seizures or delirium. Therefore, traditional fixed-dose regimens are
recommended in these populations.
168 An effective approach is most likely to
consider combining these two dosing strategies. For example, a low-risk patient (no
history of AWS or AWD, the patient consumes low weekly amounts of alcohol and
has no signs or symptoms of early AWS) receives a symptom-triggered regimen (e.g.,
lorazepam 1 mg every hour as needed). Alternatively, a high-risk patient (history of
AWS, AWD, or withdrawal seizures, consumes large daily amounts of alcohol, has
signs or symptoms of early AWS) receives fixed-dose lorazepam or diazepam with a
tapering dose schedule and as needed benzodiazepine administration for uncontrolled
alcohol withdrawal signs or symptoms. Importantly, phenobarbital, dexmedetomidine
and propofol are useful adjuncts to benzodiazepines if an inpatient has severe
CONTRAINDICATIONS, WARNINGS, AND INTERACTIONS
Elderly patients, those with hepatic or renal insufficiency, and those with medical
(e.g., diabetes, cirrhosis) or other psychiatric illnesses (e.g., dementia) require close
-adrenergic agonists, some signs of withdrawal
such as hypertension, tachycardia, and tremor may not be apparent.
Patients with a history of severe withdrawal symptoms, withdrawal seizures, or
delirium tremens; multiple previous detoxifications; concomitant psychiatric or
medical illness; recent high levels of alcohol consumption; pregnancy; and lack of a
reliable support network should be considered for inpatient treatment regardless of
the severity of their symptoms.
Lorazepam is the only benzodiazepine with predictable intramuscular absorption
(if intramuscular administration is necessary). Rarely, it is necessary to use
extremely high dosages of benzodiazepines to control the symptoms of alcohol
withdrawal. Controlled studies comparing the advantages and disadvantages of the
various benzodiazepines in alcohol detoxification have not been performed, and no
evidence exists to definitively support the use of lorazepam as the first-line agent in
In most patients with mild to moderate withdrawal symptoms, outpatient
detoxification is safe and effective, and costs less than inpatient treatment. If
outpatient treatment is chosen, the patient and support person(s) should be instructed
on how to take the prescribed medication, its side effects, the expected withdrawal
symptoms, and what to do if symptoms worsen. Small quantities of the withdrawal
medication, especially benzodiazepines, should be prescribed at each visit. Because
close monitoring is not available in outpatient treatment, a fixed-schedule regimen
Given J.M.’s elevated liver enzymes, a reasonable approach would be to start
with lorazepam. Shorter-acting agents, such as lorazepam, which do not undergo
extensive hepatic metabolism, are more appropriate for patients with evidence of
CASE 90-10, QUESTION 4: What adjunctive therapeutic support might be considered for J.M.?
The hydration, electrolyte (especially potassium and magnesium), and nutritional
status of patients should be assessed at presentation. Support with IV fluids may be
necessary in those patients with excessive losses through vomiting, sweating, and
170 Thiamine and multivitamins as well as folate 1mg should be
routinely administered to patients in alcohol withdrawal. If IV fluids are given, to
prevent precipitation of Wernicke encephalopathy thiamine administration should
160 Alcohol-dependent patients are deficient of thiamine and
have a higher risk for developing Wernicke encephalopathy.
triad of acute mental confusion, ataxia, and ophthalmoplegia. Korsakoff amnestic
syndrome is a late neuropsychiatric manifestation of Wernicke encephalopathy with
memory loss and confabulation; hence, the condition is referred to as Wernicke–
Korsakoff syndrome. It is most often seen in chronic alcohol use disorder patients,
but it can also be seen in disorders associated with malnutrition, e.g., long-term
hemodialysis or patients with acquired immunodeficiency syndrome (AIDS).
Thiamine deficiency results in a decrease in cerebral glucose utilization. The body
usually stores about 3 weeks of thiamine with daily requirements of about 1.5 mg.
Rapid correction of brain thiamine deficiency can occur with high plasma
concentrations of thiamine, achieved by parenteral supplementation only because
absorption of the oral thiamine by the GI tract is minimal (<5%), even with massive
171 Patients should receive at least 200-500mg TID IV for 3 days to
prevent the neuropsychiatric effects of thiamine deficiency.
Several adjunctive medications, aside from the sedative-hypnotics, may serve
ancillary roles in the therapy of AWS. Their selection should be based on treating
specific symptoms associated with the syndrome. For instance, β-blockers
-adrenergic agonists (e.g., clonidine
dexmedetomidine if in an ICU) can be used for moderate to severe hypertension or
other autonomic manifestations. α2
-adrenergic agonists are preferred because it
reduces NE outflow from the nerve and addresses all hyperadrenergic effects instead
of just effecting the β receptors with a β-blocker, and delirium seems to be more
common with the β-blocker use.
168,169 Antipsychotics (e.g., haloperidol, quetiapine)
can be used for managing hallucinations and severe agitation, but care must be used
because these drugs can reduce the seizure threshold.
Sodium, 132 mEq/L AST, 30 units/L
Potassium, 3.3 mEq/L ALT, 35 units/L
, 22.6 mEq/mL Uric acid, 9.1 mg/dL
Chloride, 109 mEq/L Calcium, 8.7 mg/dL
BUN, 14 mg/dL Magnesium, 1.7 mg/dL
Creatinine, 1.0 mg/dL Albumin, 4.0 g/dL
Glucose, 123 mg/dL Cholesterol, 255 mg/dL
Total bilirubin, 0.3 mg/dL CK, 78 units/L
Direct bilirubin, 0.1 mg/dL GGT, 30 units/L
Is disulfiram an appropriate agent to consider for R.M.?
In order to assess alcohol use disorder treatments an accurate medical history,
including laboratory test results. In addition, several instruments are available to
screen and delineate the extent of a patient’s alcohol use. Ultimately, time and
purpose for use are always major factors when deciding which instrument to use. The
simplest screen to assess risk of alcohol abuse is to ask the patient, during the past
year on how many occasions have you had five or more drinks (for a man) or four or
more drinks (for a woman) at one time?
177 An affirmative answer would suggest that
further follow-up of the patient’s alcohol use history is needed. A second tool called
the C-A-G-E consists of four questions: (1) Have you ever felt you should cut down
on your drinking?; (2) Have people annoyed you by criticizing your drinking?; (3)
Have you ever felt bad or guilty about your drinking?; and (4) Have you ever felt you
needed a drink first thing in the morning to steady your nerves or get rid of a
hangover (eye opener)? Positive responses to two questions suggest an alcohol
178 The Alcohol Use Disorders Identification Test (AUDIT),
which was developed by the World Health Organization, has also been shown to be
effective in screening individuals and distinguishing problem drinkers from others.
The pharmacologic treatments of alcohol dependence focus on relapse prevention
once detoxification is complete and the patient has achieved a few days of
abstinence. Treatment is intended to be an adjunct to psychosocial treatments and not
180 To date, disulfiram, acamprosate, and naltrexone tablet and injection
have been FDA-approved for the treatment of alcohol dependence. In addition,
several other drugs have shown varying degrees of success such as quetiapine,
180–202 Yet much is still unknown about the long-term rates of
abstinence, how long these drugs should be used once patients are in treatment, the
optimal doses, and whether the drugs are more effective in men or women or for
which specific subpopulations.
Useful Screens for Assessing Alcohol Problems
The C-A-G-E Screening Questions (CAGE)
Have you ever felt you should cut down on your drinking?
Have other people annoyed you by criticizing your drinking?
Have you ever felt guilty about drinking?
Methods for Determining Recent Alcohol Consumption
Gamma-glutamyl transferase (GGT)
Carbohydrate-deficient transferrin (CDT)
Disulfiram is an irreversible acetaldehyde dehydrogenase inhibitor that blocks
alcohol metabolism, leading to an accumulation of acetaldehyde. Disulfiram
reinforces an individual’s desire to stop drinking by providing a disincentive
associated with increased acetaldehyde levels, resulting in headache, palpitations,
hypotension, flushing, nausea, and vomiting when patients consume alcohol. The
primary predictor of success with disulfiram is the patient’s commitment to total
abstinence from alcohol. Although anecdotal reports of success are common, clinical
evidence suggests disulfiram appears to be most effective for alcoholics who are
involved in special high-risk situations (e.g., weddings, graduations) and is
particularly effective when administration is supervised.
Controlled clinical trials of disulfiram have clearly shown efficacy, yet this has
not been a consistent finding.
180 Double-blind, placebo-controlled studies using
disulfiram are difficult because the psychological deterrent to use alcohol is
experienced by both treatment groups and those who relapse will be unblinded when
they experience the pharmacologic interaction.
In the most rigorous clinical trial conducted in a population of veterans, no
significant difference in abstinence rates was demonstrated between patients taking
placebo or 1 mg or 250 mg of disulfiram.
181 Patients randomly assigned to receive
250 mg of disulfiram daily drank less frequently (significantly fewer drinking days
per year), however. Patients who were middle-aged and had social stability were
more likely to benefit from disulfiram. In another trial in which administration was
supervised, patients receiving disulfiram drank less alcohol and less frequently;
however, on randomization, patients were unblinded to their drug.
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