Download Diagnosis and Treatment of Alcohol Withdrawal

Clinical review
Diagnosis and Treatment of Alcohol Withdrawal
Richard Tovar, MD
Abstract
• Objective: To review the diagnosis and treatment of
alcohol (ethanol) withdrawal.
• Methods: Historical overview and evidence review.
• Results: The prevalence of ethanol abuse and related medical complaints is significant, accounting for
as much as 14.3% of U.S. health care expenditures
in 1998. The detection of the ethanol withdrawal
state can be extremely challenging and can involve
the process of rapid exclusion of numerous other
similarly presenting disease states. The pathophysiology of ethanol withdrawal can be generally
viewed as the opposite of ethanol intoxication at
the central nervous system neurotransmitter level.
While the treatment of ethanol toxicity is largely
supportive, the treatment of ethanol withdrawal is
more complex but does address neurotransmitter
and neuroreceptor treatment. Benzodiazepines are
generally recommended as a first-line pharmacologic approach.
• Conclusion: Diagnosis and treatment of alcohol
withdrawal syndrome is challenging. Management
approaches continue to evolve. A
lcohol is a common drug of abuse that has significant effects on society. The total economic
costs of alcohol abuse in the United States were
estimated to be $185 billion in 1998 [1]. Diagnostic
criteria for ethanol abuse include physical dependence
symptoms (such as tolerance and withdrawal) and psychological symptoms (such as craving) [2].
Although there are descriptive reports of ethanol
withdrawal symptoms from the mid-18th century [3],
the first recorded clinical observations linking ethanol
abstinence to ethanol withdrawal were those of Victor and Adams in 1955 [4]. Isabell provided the first
documented clinical observations of delirium tremens
(DT) and ethanol-induced withdrawal seizures that
same year [5]. The prevalence of ethanol (alcohol)
withdrawal symptoms in the general population has
been estimated to be 5% [6]. Recent epidemiological
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research supports this, showing a DSM-IV alcohol
dependence prevalence rate of 3.8% [7].
Pathophysiology
An obvious prerequisite to the manifestation of ethanol
withdrawal is the establishment of ethanol dependence
and tolerance. Biochemically, ethanol exerts its effect
on the central nervous system mainly as a depressant
[8]. The resulting biochemical changes that result
from chronic use of ethanol mainly manifest themselves in the form of influence over the neurotransmitters γ-aminobutyric acid (GABA) and glutamate.
GABA is the main central nervous system (CNS)
inhibitory transmitter. GABA exerts its effect on the
CNS by increasing inhibitory tone via the chloride
channel on the nerve cell membrane [9]. Ethanol
acts as a GABA agonist, causing decreased CNS excitability. Clinically, this decreased CNS excitability
results in sedation, cognitive dysfunction, and poor
motor coordination. Furthermore, the chronic use of
ethanol results in a downregulation of GABA receptors [10]. Downregulation of receptors is a decrease
in the number of receptors on a cell membrane. The
downregulation of GABA receptors on the CNS cell
membranes from chronic ethanol use results in the
requirement of increasingly larger doses of ethanol
to achieve the same euphoric and inhibitory effect,
a phenomenon known as tolerance [11]. The downregulation of GABA receptors may also partially
explain the clinical examples of patients being awake
and functional at very high blood ethanol concentrations that would induce coma or death in nontolerant individuals [11]. With the removal of ethanol
in the chronic user, the CNS inhibition is released,
and there is an increase in CNS excitation due to
the decrease of both circulating GABA and receptor
downregulation. This CNS excitation results in the
clinical spectrum of ethanol withdrawal.
From the Medical College of Wisconsin, Milwaukee, WI.
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Alcohol Withdrawal
Table 1. DSM-IV Diagnostic Criteria for Ethanol Withdrawal
A. Cessation/reduction of ethanol use in a patient that is dependent and tolerant
B. Two or more of the following:
1. Autonomic hyperactivity
2. Increased hand tremor
3. Insomnia
4. Nausea and vomiting
5. Transient visual, tactile, or auditory illusions or hallucinations
6. Psychomotor agitation
7. Anxiety
8. Grand mal seizures
C. The symptoms in criterion B cause distress/impairment in
daily functioning
D. Criterion B symptoms are not due to another general medical condition or psychiatric disorder
Adopted from the American Psychiatric Association. Diagnostic
and statistical manual of mental disorders. Text revision. 4th ed.
Washington (DC): The Association; 2000.
A second important CNS biochemical pathway alteration involves glutamate as an excitatory neurotransmitter. Endogenous glutamate acts on the N-methyl-Daspartate (NMDA) receptors in the CNS, causing influx
of calcium into a voltage-gated and ligand-dependent
calcium channel [11]. The influx of calcium results in
cell depolarization, causing CNS stimulation. Ethanol
acts as an NDMA receptor antagonist, thereby inhibiting CNS tone below threshold; an excess of NDMA
receptor hyperactivity and production of glutamate
ensues [11]. The resultant hyperactivity in the CNS
is manifested in many ways, including catecholamine
hyperactivity. This type of receptor hyperactivity results
in the clinical picture of altered mental status, hyperthermia, hyperactive muscle activity, seizures, and other
forms of CNS excitation [11].
An effect via ethanol withdrawal on the CNS catecholamine concentrations is also observed. Initially,
acute and chronic ethanol intake results in an increase
in dopamine extracellular levels by the disinhibition
of GABA receptors [12]. This increase in dopamine
may initially account for some of the positive effects
of ethanol (euphoria) and also craving for ethanol.
The continued dopamine excess then results in increased metabolism into norepinephrine by dopamine
ß-hydroxylase. Ethanol withdrawal also affects dopa362 JCOM August 2011 Vol. 18, No. 8
minergic CNS transmission. A high plasma level of
the metabolite of dopamine, homovallinic acid, has
been observed in patients with clinical ethanol withdrawal [13]. The CNS catecholamine system is also
affected by ethanol withdrawal, not only by a increase
in dopamine but by an impairment of the action of
α-2 receptor activity (an effect that some pharmacological imidazole drugs such as dexmedetomidine
may improve). The final effect is also an excess of
CNS dopamine and norepinephrine levels, further
contributing to the clinical manifestation of ethanol
withdrawal via dysautonomic regulation.
In summary, the ingestion of ethanol on a chronic
basis results in a constellation of CNS biochemical
changes associated with dependence and tolerance.
Tolerance is partially the result of the downregulation
of GABA receptors with the upregulation of NDMA
receptors and production of excess glutamate. With
the removal or decreased concentration of ethanol, a
reversal of the above ensues, resulting in CNS excitation.
Mortality
Monte and coworkers determined a 6.6% incidence of
death in their ethanol withdrawal patient population
[14]. They determined that patients presenting with
advanced liver disease (cirrhosis), needing intubation
(especially for pneumonia), other chronic underlying
disease states, and presentation with DTs, the most
serious and potentially deadly complication of ethanol
withdrawal, had a much higher risk of dying. Among
those experiencing DTs, the mortality rate is approximately 5% [15,16].
Clinical Diagnosis
History of Abuse
A basic tenet for a patient to have the constellation of
ethanol withdrawal symptoms is that he is physically
addicted to ethanol. Therefore, the practitioner should
seek to obtain a history of ethanol abuse. In the acutely
ill patient, this determination may be challenging [17].
Further, outpatients may be unwilling to divulge the
fact that they are ethanol dependent, or may not even
consider themselves tolerant. The practitioner should
attempt to obtain the following historical data: estimation of consumption (type of alcohol consumed, volume, frequency, drinking pattern); level of dependency
(daily drinking, early in the day drinking, previous
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Clinical review
Table 2. Stratification of Ethanol Withdrawal Symptoms
Minor withdrawal
Tremor, mild anxiety, headache, diaphoresis, palpitations, anorexia, GI upset, normal mental status.
Symptoms last 24 to 48 hours.
Moderate to severe withdrawal
Seizures: Usually single, tonic-clonic, short postictal period, rare prolonged or status epilepticus.
Can occur in 10% of alcoholic patients, especially in those with no previous history of seizures
[19]. Chronic medical seizure prophylaxis is rarely recommended. Approximately 30% of patients
with ethanol withdrawal seizures will progress to DTs [20].
Alcohol hallucinosis: Visual, auditory, tactile hallucinations with intact orientation AND vital signs.
Symptoms last 24 hours up to 6 days. Chance of occurrence in heavy ethanol users is 25% [21].
Delirium tremens: Delirium, agitation, tachycardia, hypertension, fever, diaphoresis. Can begin 48
hours after abstinence and last up to 2 weeks.
Adapted from Bayard M, Mcyintyre J, Hill K, et al. Alcohol withdrawal syndrome. Am Fam Physician 2004;15:69(6):1443–50.
medical ethanol detoxification interventions, priority
of ethanol in the patient’s life); and negative outcomes
of drinking (social, financial, legal) [18].
Clinical Features
A common method by which to clinically define alcohol
withdrawal is via the DSM-IV classification (Table 1).
A scheme described by Victor and Adams in 1953
[4] stratifies patients by clinical features into mild,
moderate, and severe withdrawal categories. A modified version of this scheme is seen in Table 2.
Early and mild ethanol withdrawal symptoms can
be masked by various concomitant disease processes
including trauma or medical or underlying psychiatric
illness. Furthermore, concomitant use of cardiac or
other medications that alter vital signs can be problematic. Common examples of cardiac medications that
may “normalize” otherwise unstable vital signs include
beta and calcium channel blockers. Some common
disease states that can be clinically similar to ethanol
withdrawal are seen in Table 3. Toxins that can mimic
ethanol withdrawal are listed in Table 4 [22].
Rating Scales
The use of rating scales has been recommended
to assess the severity of ethanol withdrawal. Such
scales include the CIWA, CIWA-AD, and CIWA-Ar
developed by Sullivan and coworkers [23]. An appropriate ethanol withdrawal rating scale must possess
the following characteristics: (1) good interobserver
reliability; (2) can be applied by trained nurses, (3)
detects and quantifies the important clinical signs
and symptoms of withdrawal; (4) provides an additive
score as an index of severity; (5) can give a prognosis
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for treatment; (6) allows for serial clinical assessments; (7) assesses response to ongoing therapy. The
most commonly used scale is the revised CIWA-Ar
(Clinical Institute Withdrawal Assessment Scale for
Alcohol) (Table 5).
The CIWA-Ar can be administered at the bedside in
about 2 minutes [23]. The scale measures 10 symptoms,
with each criterion rated on a scale from 0 to 7, except
for “orientation and clouding of sensorium,” which is
rated on scale of 0 to 4. Scores of 0 to 9 indicate absent
to minimal withdrawal. Scores of 10 to 19 indicate mild
to moderate withdrawal (marked autonomic arousal);
and scores of 20 or more indicate severe withdrawal
(impending DTs). A shorter, more simplified scale for
measuring severity, the SHOT (sweating, hallucinations, orientation, and tremor) was developed by Gray
et al [24] for use in the emergency department. The
developers found the scale takes 1 minute to administer
versus 5 minutes for the CIWA-Ar [24].
Rating scale scores can be used to guide selection
of treatment setting. Many authors recommend outpatient detoxification if the CIWA-Ar score is 8 to 10
and the prerequisites seen in Table 6 are met. Some
authors recommend against using withdrawal rating
scales to determine eligibility for inpatient or outpatient treatment [31].
Pharmacotherapy
Benzodiazepines are the drug of first choice for treatment of ethanol withdrawal. The medical provider must
further consider the pharmacokinetics of each differing
benzodiazepine. Lorazepam has been recommended in
patients with liver disease and the elderly due to its lack
of pharmacologically active metabolites [32]. Lorazepam
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Table 3. Medical Disease States Similar to Ethanol
Withdrawal
Table 4. Toxins that Mimic Ethanol Withdrawal
Amphetamines
Encephalitis
Anticholinergics
Hypomagnesemia
Carbamates (pesticides)
Cocaine
Meningitis
Neuroleptic Malignant Syndrome
Lithium
Pneumonia
Organophosphates
Serotonin Syndrome
Salicylates
Thyrotoxicosis
Theophylline
Adapted from Johnson R. Alcohol and fits. Br J Addict 1985;80:227–32.
Adapted from Johnson R. Alcohol and fits. Br J Addict 1985;80:227–32.
undergoes simple glucuronidation for its in vivo deactivation. Another candidate mentioned in the ethanol literature with similar properties to lorazepam is oxazepam.
There has been interest in using other medications that
do not have the sedative and potentially addictive side
effects attributed to benzodiazepines. One commonly
recommended drug for outpatient management is carbamazepine. Malcolm and coworkers compared carbamazepine to lorazepam in patients with low to moderate
withdrawal and found similar results in the suppression
of withdrawal [33]. Other literature, including a Cochrane review, supported this view [34,35].
A less commonly used drug class used for the
treatment of both outpatient and inpatient ethanol
withdrawal is barbiturates. Most studies compare the
efficacy of barbiturates, specifically phenobarbital, to
benzodiazepines [36]. While the efficacy of treating
ethanol withdrawal with either type of GABA agonist
is logical, the concern of more pronounced hypotension and apnea with intravenous phenobarbital in the
inpatient setting has limited its use.
Other drugs have been suggested, such as valproic
acid, tiapride, baclofen, lamotrigine, topiramate, gabapentin, tiagabine, and vigabatrin. At this time, there
are limited data to recommend these therapies.
Outpatient Treatment
Management
Treatment of Minor Withdrawal
Minor withdrawal can be treated in the inpatient or
outpatient setting. One review recommends the use
of oral benzodiazepines for “days to 1 week” [31].
Classically, mild withdrawal should resolve in 24 to 48
hours. Review of the literature reveals no consensus
on the duration of outpatient benzodiazepine type or
treatment.
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The initial overall goal for outpatient medical treatment is to prevent withdrawal seizures and to treat
minor withdrawal symptoms. For the outpatient setting, Solomon and coworkers proposed a 5-day fixedschedule benzodiazepine treatment regimen [Table 7]
for those patients who qualify for outpatient ethanol
detoxification (Table 6) [37]. In their study comparing lorazepam and chlordiazepoxide, both drugs were
equally efficacious in suppression of ethanol withdrawal symptoms, especially seizures.
As in this study, most of the literature stresses the
use of a fixed pharmacologic schedule for outpatient
detoxification. There have been limited studies examining symptom-triggered outpatient therapy as
an alternative. A recent Danish study by Elholm and
coworkers examined self-administered symptom-triggered oral chlordiazepoxide use in a small number of
heavily controlled subjects and found similar overall
safety in the symptom-triggered group and the fixedschedule group [38]. At the present time, most outpatient detoxification units do not have the resources
to monitor patients in a symptom-triggered outpatient
manner. Furthermore, the safety issue of excessive use
still exists, and symptom-triggered outpatient therapy
cannot be recommended. More vigorous studies in
real-world settings should be undertaken before sending home patients with a variable amount of benzodiazepines to “treat their symptoms.” The overall
consensus is that symptom-triggered therapy is not
compatible with outpatient therapy.
There is controversy with respect to the treatment
of ethanol withdrawal seizures on an outpatient basis.
The current thought is that classic ethanol withdrawal
seizures are self-limited if the patient stops drinking
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Clinical review
Table 5. CIWA-Ar Scale (modified)
Table 6. Prerequisites for Outpatient Ethanol Withdrawal
Treatment
1. Agitation (0–7)
2. Anxiety (0–7)
Willingness to participate
3. Auditory disturbances (0–7)
4. Clouding of sensorium (0–4)
No significant comorbid medical, psychiatric, cognitive, polysubstance abuse issues
5. Headache (0–7)
6. Nausea/vomiting (0–7)
7. Paroxysmal sweats (0–7)
8. Tactile disturbances (0–7)
9. Tremor (0–7)
Reliable transportation to outpatient provider clinics
Ability to take oral medications
Absence of pregnancy
Adequate community and or family support
Adapted from reference 25–30.
10. Visual disturbances (0–7)
[39,40]. In spite of this, there is no consensus on
whether or not to offer the patient alcohol-related
seizure prophylaxis. What is certain, however, is that
using phenytoin to treat and prevent ethanol withdrawal seizures is not efficacious [41].
Inpatient Treatment
Patients with seizures, alcohol hallucinosis, or DT
require prolonged observation and/or hospital admission. Once the determination for hospitalization is
made, the ethanol withdrawal patient may be further
stratified into an ICU setting. About 5% of patients
who exhibit ethanol withdrawal will progress to DTs
[42]. Ferguson et al identified certain risk factors that
increase the chance of progression (Table 8) [16]. The
criteria listed in Table 9 have been suggested as guidelines for when to admit to the ICU [43].
Treatment of inpatient ethanol withdrawal involves
both supportive care and pharmacologic treatment with
GABA agonists. Supportive care is similar to that of
all patients who present with dehydration, electrolyte
imbalance, nausea and vomiting, and comorbid disease
[44–46].
Most patients with moderate to severe ethanol
withdrawal present with hypovolemia due to the
diuretic properties of ethanol and the lack of concurrent hydration. Hypovolemia may be associated with
disorders in serum sodium. The most concerning is
hyponatremia, which can be more commonly observed
in beer drinkers, due to the high volume of fluid [4].
Cautious restoration of a low serum sodium is warranted, with slow correction of no more than 8 to 10
mmol/L per day [47].
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Benzodiazepines are first-line inpatient pharmacotherapy [48–52] and are recommended for all types
of ethanol withdrawal including seizures, hallucinosis,
and DT. Choice among the different agents is guided
by duration of action, rapidity of onset, and cost [51].
Most clinicians use the benzodiazepine they are most
comfortable with based on the caveats with respect to
treating elderly patients and those with liver disease.
The literature for the pharmacologic treatment of
ethanol withdrawal has shifted from a fixed schedule
to a symptom-triggered approach [53–57]. Evidence
suggests that symptom-triggered therapy results in the
administration of less total medication and a shorter duration of treatment. One of the benefits of this type of
treatment may be more aggressive supportive and nursing care. An example symptom-triggered protocol by
Mayo-Smith and coworkers is seen in Table 10 [54].
The suggested protocol by Mayo-Smith and colleagues contains many caveats and exclusions, including no specific guidelines as to how much medication
to provide when symptoms are not controlled, exclusion of patients who cannot take oral medications,
and exclusion of patients that have comorbid medical,
cognitive, and psychiatric disease [53–57]. One small
study by Weaver and coworkers observed that in a
general medical inpatient population with mild to
moderate ethanol withdrawal, there was no difference
in outcome between the fixed and symptom-triggered
treatment arms [58]. It remains to be demonstrated
in other populations whether generalized guidelines
can be used. Another concern is the use of symptomtriggered therapy in patients who do not meet appropriateness criteria [59,60]. In a study by Hecksel et
al, fewer than half of the patients receiving symptomtriggered therapy met the CIWA-AR appropriateness
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Table 7. Outpatient Treatment
Table 8. Delirium Tremens Risk Factors
Day
Lorazepam
Chlordiazepoxide
Age older than 30 years
1
2 mg po TID
30 mg po TID
History of previous DTs
2
2 mg po in AM, 1 mg at
noon, 2 mg at bedtime
20 mg po TID
Chronic heavy ethanol abuse (not defined)
Concurrent significant illness
3
1 mg po TID
15 mg po TID
4
1 mg po BID
10 mg po TID
Withdrawal symptoms with a still measurable ethanol blood
level
5
1 mg po once daily
10 mg po BID
6
Stop
Stop
Presenting to the medical provider after a long period of abstinence
Adapted from reference 37.
Adapted from reference 16.
criteria for this type of therapy (ie, recentethanol use
and intact verbal communication).
monly recommended medication for benzodiazepine
resistance. Propofol and benzodiazepines exert their
effect in a similar manner, having an agonistic effect
on GABA receptors, and an antagonistic effect on
NMDA receptors. Propofol does not doe not exert its
effect on the chloride channel similar to benzodiazepine or phenobarbital [69]. Propofol may also have
an additional effect as an agonist on glutamate receptors [70]. The patient is given an initial bolus dose
of 0.5 mg/kg every 10 seconds titrated to effect, to
a total dose of 2.5 mg/kg. The continuous infusion
dose for sedation is 25–75 ug/kg/min IV, and higher
doses may result in a general anesthetic state [71]. The
most common side effects of propofol are again similar to the other commonly used sedatives, including
hypotension and respiratory depression. Hypotension
can usually be treated with crystalloid IV bolus/infusions and decreasing the drip rate. Propofol has a
3-compartment model of dissipation, allowing for
its short effect time. The first phase is that of rapid
distribution of the drug from the blood to both the
spinal and supraspinal nerve synapses for both GABA
and NDMA receptors. This effect should last less than
10 minutes for a clinical sedative effect for a bolus infusion. The second phase is that of rapid clearance of
the propofol from the blood compartment taking 30
to 50 minutes for bolus doses. The third phase is that
of slow return of the drug from the poorly perfused
non- nervous system body tissue into the blood, with
a half-life of up to 480 minutes [69].
Dexmedetomidate is a lipophilic imidazole derivative approved for use in 1999. It has a very high affinity for α2 adrenergic receptors and low affinity for
α1 receptors. Similar drugs with central α2 activity
include clonidine and tetrahydozoline, a component
Resistant Alcohol Withdrawal Syndrome
One clinical question that remains unclear is that of
“resistant alcohol withdrawal syndrome” [61–64].
This syndrome has variable definitions, the most common being lack of control of withdrawal symptoms
and/or continued abnormal vital signs in the face
of high benzodiazepine doses. It is unclear when to
resort to other pharmacological adjuncts when the
patient is not responding to conventional doses of
benzodiazepines. In the study by Hack and coworkers, the definition of resistant alcohol withdrawal was
one in which a total of 50 mg of diazepam was given
intravenously in titrated doses over 1 hour [65]. With
the caveat of the lack of a specific pharmacological
endpoint to add another sedative adjunct to benzodiazepine ethanol withdrawal resistance, numerous
medications have been proposed for treatment [66].
The most common include phenobarbital, propofol,
and dexmedetomidine. All 3 medications are given as
infusions with or without an initial bolus. All require
intensive care type monitoring, especially for sedation
causing cessation of respiratory drive.
While benzodiazepines affect the frequency of
chloride channel opening on the GABA complex, barbiturates increase the duration of the channel opening.
The recommended dose of phenobarbital is variable
and can range from commonly recommended loading
and infusion doses used in treatment of seizures to
smaller titrated doses [67,68]. One commonly recommended dose is 10–20 mg/kg IV at a maximum rate
of 1 mg/kg minute.
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Clinical review
Table 9. Indications for ICU Admission for the Treatment
of Ethanol Withdrawal
Table 10. Pharmacotherapy Regimens for Alcohol
Withdrawal
History of cardiac disease (heart failure, arrhythmia, angina,
myocardial ischemia, recent myocardial infarction)
Example symptom-triggered protocol:
Hemodynamic instability
Marked acid-base disturbances
Severe electrolyte disturbances requiring aggressive replacement
Respiratory insufficiency (hypoxia, hypercapnia, severe hypocapnia, pneumonia, COPD, asthma)
Gastrointestinal (GI) pathology (pancreatitis, GI bleeding, hepatic insufficiency, peritonitis)
Persistent hyperthermia (temperature ≥ 39ºC/103ºF). One
study observed that over half of the patients that died of DTs
had significant hyperthermia [16].
Administer CIWA-Ar and administer 1 of the following if
score is > 8 (doses are oral and should be adjusted for
parenteral use)
• Chlordiazepoxide 50–100 mg
• Diazepam 10–20 mg
• Lorazepam 2–4 mg
Repeat every hour until score is < 8, then every 4 hours
Example fixed-schedule regimens:
• Chlordiazepoxide, 4 doses of 50 mg, then 8 doses of 25 mg
• Diazepam, 4 doses of 10 mg, then 8 doses of 5 mg
• Lorazepam, 4 doses of 2 mg, then 8 doses of 1 mg
Laboratory evidence of rhabdomyolysis
Renal insufficiency with or without increased fluid requirements
Need for frequent or high doses of sedatives or an intravenous
infusion to control symptoms
Adapted from reference 43.
of over-the-counter eye drops (Visine). Clonidine
has been used in patients with concurrent opiate and
ethanol withdrawal and in patients with hypertension
in withdrawal. Dexmedetomidate’s central presynaptic
α2 agonistic effects include decreasing norepinephrine
release at the locus ceruleus, leading to non-GABA
mediated sedation [72]. The result of this type of
sedation can be a decrease in autonomic dysfunction
(tachycardia and hypertension) and anxiety. Most of
the studies on this drug are of the case report or series
variety [72,73]. The dose of dexmedetomidate is 1.0
μg/kg bolus, with a continuous infusion of 0.2–1.0
μg/kg/hr. One touted advantage to this drug is respiratory stability, along with simultaneous treatment of
co-existing opiate withdrawal. At this time, most case
series use the dexmedetomidate as an adjunct drug,
along with a benzodiazepine, to combat withdrawal.
It remains to be seen if an α agonist can be the sole
treatment agent in a GABA- and NMDA-altered alcohol withdrawal patient.
One common clinical question that is asked regards
the use of ethanol to treat ethanol withdrawal symptoms. It is thought that the most common form of
treating ethanol withdrawal is that of self treatment,
without the benefit of medical evaluation [74]. The
older medical literature has recommendations using
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both oral and intravenous ethanol to attempt gradual
withdrawal. At this time no ethanol withdrawal clinical practice guidelines recommend its use. Other authorities do not recommend the use of ethanol due the
potential of further enabling the underlying ethanol
abuse disorder with delay in rehabilitation and continued treatment with essentially a multiorgan toxin (eg,
cirrhosis, gastritis, bone marrow suppression) [75,76].
Wernicke’s Encephalopathy, Glucose, and Thiamine
It is well known that patients with chronic ethanol
abuse have a high associated incidence of thiamine
(vitamin B1) deficiency [77]. The concern is that the
antemortem diagnosis of this disease process is difficult and easily missed, possibly resulting in permanent
neurological damage (Wernicke’s encephalopathy or
Korsakoff syndrome). Therefore, the recommendation
has been to give thiamine both acutely and chronically
in an attempt to prevent this malady. Furthermore, it
is recommended that thiamine be given before glucose
in the undifferentiated confused patient, again in
order to “avoid” iatrogenic precipitation of Wernicke’s.
Therefore, several authors have recommended that the
thiamine be given first, before a carbohydrate load
(especially glucose), in order to avoid iatrogenic precipitation of Wernicke’s encephalopathy [78]. What is
clear is that prolonged use of carbohydrates (loading)
without adequate thiamine administration can either
precipitate or exacerbate Wernicke’s encephalopathy
[78]. There is no proof, or logical metabolic explanation for the acute precipitation of Wernicke’s with
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Alcohol Withdrawal
1 dose of IV glucose in the emergency setting [79].
In a metabolic sense, thiamine is taken into the cell at
a slower rate than glucose, making pretreatment with
thiamine of minimal, if any benefit [80]. Therefore
parenteral thiamine (100 mg instramuscular or IV)
can be given before or after 1 dose of IV glucose.
The older literature favored the intramuscular
use of thiamine over the IV route. The concern was
precipitation of anaphylactoid reactions [81]. The literature now supports the contention that the diluent
carrier for the thiamine, chlorbutanol, is the cause of
the majority of this type of anaphylactoid reactions
[71]. With the use of aqueous forms of thiamine, there
has been a marked decrease in these adverse reactions.
However, there are still a few case reports of IV thiamine reactions even with the more pure form [82]. A
study by Wrenn and coworkers in 1000 patients demonstrated that parental doses of up to 500 mg could be
safely tolerated [83].
Conclusion
The exact toxic and metabolic etiology of ethanol withdrawal have yet to be fully elucidated. What is known
biochemically about ethanol withdrawal enables the
clinician to combat the syndrome with available GABA
agonists, NMDA antagonists, and catecholamine antagonists. The clinical diagnosis and treatment of ethanol withdrawal, while at times obvious, can also be
very difficult, especially in the face of comorbidities.
Various rating scales have been proposed but do not
accommodate all presentations of ethanol withdrawal,
especially in those patients with comorbidities and
polysubstance withdrawal. There also remains some
controversy as to the appropriate types of pharmacotherapy for this syndrome; however it is agreed that
benzodiazepines are the first-line therapy. There are
many suggestions for adjunctive pharmacologic care,
and dexmedetomidate may represent a new efficacious
treatment opportunity. Overall, the treatment of ethanol abuse and withdrawal is constantly evolving.
Corresponding author: Richard Tovar, MD, Medical College of Wisconsin, Milwaukee, WI 53226.
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Financial disclosures: None.
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