Specialist presentation 3 25 alcohol withdrawal

Alcohol Withdrawal
Scott Hansen MD
Virginia Mason Medical Center
Hospital Psychiatry Consultation Service

© 2014 Virginia Mason Medical Center
High-Risk Drinking, Alcohol Use Disorder Rises Significantly Over Past Decade
Between 2001-2002 and 2012-2013, the number of U.S. adults who engaged in regular high-risk drinking increased by almost 30%, and the number of
people meeting criteria for alcohol use disorder (AUD) grew by 49.4%, according to a report published today in JAMA Psychiatry.
“Increases in all of these outcomes were greatest among women, older adults, racial/ethnic minorities, and individuals with lower educational level and
family income,” Bridget F. Grant, Ph.D., of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and colleagues wrote.
Grant and colleagues compared information collected during face-to-face interviews from two nationally representative surveys of U.S. adults: NIAAA’s
2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) and the 2012-2013 NESARC-III. Survey participants were asked
identical questions regarding 12-month alcohol consumption and how often they engaged in high-risk drinking (four or more standard drinks containing
alcohol [for example 12 oz. beer or 5 oz. wine] on any given day for women; five or more standard drinks for men); for this study, high-risk drinking was
defined as exceeding the daily drinking limits at least weekly. Participants were considered to have a DSM-IV AUD diagnosis if they met criteria for alcohol
dependence or abuse in the past 12 months.
The study sample included 43,093 participants in the NESARC and 36,309 participants in the NESARC III. Between 2001-2002 and 2012-2013, alcohol use
in the United States increased from 65.4% to 72.7% (11.2% increase), high-risk drinking increased from 9.7% to 12.6% (29.2% increase), and the
prevalence of DSM-IV AUD increased from 8.5% to 12.7% (49.4% increase).
“While the prevalence of AUD among both 12-month alcohol users and 12-month high-risk drinkers increased, the prevalence of AUD among high-risk
drinkers (46.5% in 2001-2002 and 54.5% in 2012-2013) was much greater than the prevalence of AUD among 12-month users (12.9% in 2001-2002 and
17.5% in 2012- 2013), highlighting the critical role of high-risk drinking in the increase in AUD between 2001-2002 and 2012-2013,” the authors wrote.
In a related editorial, Marc A. Schuckit, M.D., a professor of psychiatry at the University of California, San Diego, described the costs associated with
alcohol-related problems and noted that the populations that appear to be at greatest risk may also be least likely to have access to care.
The article “makes a compelling case that the United States is facing a crisis with alcohol use, one that is currently costly and about to get worse,” he
wrote. It is also a reminder that “the chilling increases in opioid-related deaths reflect a broader issue regarding additional substance-related problems.”
The findings “highlight the urgency of educating the public, policymakers, and health care professionals about high-risk drinking and AUD, destigmatizing
these conditions, and encouraging those who cannot reduce their alcohol consumption on their own, despite substantial harm to themselves and others, to
seek treatment,” Grant and colleagues wrote.
For related information, see the Psychiatric News article “Why Treat Alcohol Use Disorders in Primary Care?” and the AJP article “Vulnerability for Alcohol
Use Disorder and Rate of Alcohol Consumption.”
Risky Alcohol Intake on the Rise — Especially in Women, Minorities, Seniors
By Kelly Young
Edited by Susan Sadoughi, MD
The prevalence of high-risk drinking and alcohol use disorder increased sharply over a decade, constituting a public health crisis, a JAMA Psychiatry study
concludes.
Two surveys taken in 2001–2002 and 2012–2013 asked 80,000 U.S. adults about their alcohol use.
2

Our Strategic PlanOur Strategic Plan
© 2012 Virginia Mason Medical Center

© 2012 Virginia Mason Medical Center© 2014 Virginia Mason Medical Center
Humility…
Factors in understanding best practices for treatment of alcohol
withdrawal:
•decades of research / practice experience contributes to knowledge
base
•gems and fables sorted from old literature
•emerging data
•something may be better or worse, more of less important than
portrayed…

DSM IV-TR: Alcohol Abuse
A) A maladaptive pattern of drinking, leading to clinically significant impairment or
distress, as manifested by at least one of the following occurring within a 12-month
period:
•Recurrent use of alcohol resulting in a failure to fulfill major role obligations at work,
school, or home (e.g., repeated absences or poor work performance related to alcohol
use; alcohol-related absences, suspensions, or expulsions from school; neglect of
children or household)
•Recurrent alcohol use in situations in which it is physically hazardous (e.g., driving an
automobile or operating a machine when impaired by alcohol use)
•Recurrent alcohol-related legal problems (e.g., arrests for alcohol-related disorderly
conduct)
•Continued alcohol use despite having persistent or recurrent social or interpersonal
problems caused or exacerbated by the effects of alcohol (e.g., arguments with spouse
about consequences of intoxication).
(B) Never met criteria for alcohol dependence.

DSM IV-TR: Alcohol Dependence
A) A maladaptive pattern of drinking, leading to clinically significant impairment or distress, as
manifested by three or more of the following occurring at any time in the same 12-month
period:
•Need for markedly increased amounts of alcohol to achieve intoxication or desired effect; or
markedly diminished effect with continued use of the same amount of alcohol
•The characteristic withdrawal syndrome for alcohol; or drinking (or using a closely related
substance) to relieve or avoid withdrawal symptoms
•Drinking in larger amounts or over a longer period than intended.
•Persistent desire or one or more unsuccessful efforts to cut down or control drinking
•Important social, occupational, or recreational activities given up or reduced because of
drinking
•A great deal of time spent in activities necessary to obtain, to use, or to recover from the
effects of drinking
•Continued drinking despite knowledge of having a persistent or recurrent physical or
psychological problem that is likely to be caused or exacerbated by drinking.
(B) No duration criterion separately specified, but several dependence criteria must occur
repeatedly as specified by duration qualifiers associated with criteria (e.g., “persistent,”
“continued”).

DSM V: Alcohol Use Disorder
A. A problematic pattern of alcohol use leading to clinically significant impairment or
distress, as manifested by at least two of the following, occurring within a 12-month
period.
1.Alcohol is often taken in larger amounts or over a longer period than was intended
2.There is a persistent desire or unsuccessful efforts to cut down or control alcohol use.
3.A great deal of time is spent in activities necessary to obtain alcohol, use alcohol, or
recover from its effects.
4.Craving, or a strong desire or urge to use alcohol.
5.Recurrent alcohol use resulting in a failure to fulfill major role obligations at work, school
or home.
6.Continued alcohol use despite having persistent or recurrent social or interpersonal
problems caused or exacerbated by the effects of alcohol.
7.Important social, occupational, or recreational activates are given up or reduced
because of alcohol use.
8.Recurrent alcohol use in situations in which it is physically hazardous.
9.Alcohol use is continued despite knowledge of having a persistent or recurring physical
or psychological problem that is likely to have been caused or exacerbated by alcohol.

DSM V: Alcohol Use Disorder
10. Tolerance as defined by either of the following:
a. A need for markedly increased amounts of alcohol to achieve intoxication or desired effect
b. A markedly diminished effect with continued use of the same amount of alcohol
11. Withdrawal as manifested by either 2 of a-h, or i:
a. Autonomic hyperactivity (e.g. sweating or pulse rate >100 bpm)
b. Increased hand tremor
c. Insomnia
d. Nausea or vomiting
e. Transient visual, tactile or auditory hallucinations or illusions
f. Psychomotor agitation
g. Anxiety
h. Generalized tonic-clonic seizures
OR
i. Alcohol (or a closely related substance such as benzodiazepine) is taken to relieve or avoid withdrawal
symptoms.
Specify:
a. early (3-13 mo) v. sustained (>12 mo) remission
b. in a controlled environment
c. Mild (2-3 sx), Moderate (4-5 sx), Severe (6 or more sx)

Epidemiology
National Epidemiologic Survey on Alcohol and Related Conditions.
 Hasin et al. Arch Gen Psychiatry. 2007.
 Face-to-face interviews with a representative US adult sample
(N = 43093).
 Alcohol abuse Prevalence
 lifetime = 17.8%
 12-month = 4.7%
 Alcohol dependence Prevalence
 lifetime = 12.5% and
 12-month = 3.8%
 Current alcohol abuse was more prevalent among men, Caucasians,
younger and unmarried individuals.
 Alcohol dependence was more prevalent among men, Caucasians,
Native Americans, younger and unmarried adults, and those with lower
incomes.

Epidemiology
National Epidemiologic Survey on Alcohol and Related Conditions. Cont.
 Only 24.1% of those with alcohol dependence were ever treated, slightly
less than the treatment rate found 10 years earlier.
 Strong associations found between alcohol use disorders and other
substance use disorders.
 Strong association between alcohol dependence as well as other
behavioral health conditions including mood, anxiety, and personality
disorders
2008 National Survey on Drug Use and Health
 Substance Abuse and Mental Health Services Administration. (2009).
HHS Publication No. SMA 09-4434.
 51.6 % of Americans aged 12 or older reported being current drinkers of
alcohol. More than 23.3 % participated in binge drinking (>5 drinks in
setting) in the 30 days prior to the survey. 6.9 % reported heavy
drinking (>5 episodes in 30 days).

Pathophysiology
Alcohol acts:
 as an antagonist at N-methyl-D-aspartate (NMDA) receptors acutely reducing excitatory glutaminergic
transmission. Chronic use causes receptor up-regulation to maintain glutamate sensitivity and
homeostatic Ca flux causing which is needed for neuroexcitation.
 as a facilitator at gamma-amino-butyric-acid (GABA) receptors causing Cl ion flux which inhibits
action potentials. GABA receptor complex becomes less sensitive.
 dysregulation of dopamine synthesis and metabolism. Specifically GABA mediated afferents to the
nucleus accumbens are dysregulated which increases dopamine levels (pleasure, craving,
reinforcement)
 desensitization of alpha-2 receptors
 enhanced extracellular dopamine beta hydroxylase mediated metabolism increases norepinephrine
 acute alcohol use simultaneously enhances inhibitory tone (via modulation of GABA) and inhibits
excitatory tone (via modulation of excitatory amino acid - i.e. glutamate - activity).
 chronic alcohol use changes receptor numbers and sensitivity, when this occurs users tend to use
alcohol to preserve the sense of neurophysiological homeostasis.
Abrupt cessation unmasks the adaptive responses to chronic alcohol use
resulting in central nervous system hyperactivity
 Duration and amount of continuous alcohol use is directly correlated with severity of withdrawal.
 Vulnerability to withdrawal is related to the abruptness of cessation of prolonged, sustained alcohol
intake. Previous withdrawals may worsen NE transmission dysregulation increasing vulnerability.
 Withdrawal usually does not occur in the general population because most people drink in an episodic
fashion that does not lead to the sustained high blood concentrations of alcohol necessary to develop
tolerance and withdrawal. (Sir William Osler!)

Pathophysiology

Alcohol Withdrawal Diagnostic Criteria
(DSM IV-TR = DSM V)
A. Cessation of (or reduction in) alcohol use that has been heavy and prolonged
B. Two (or more) of the following developing within several hours to a few days after criterion A
1. Autonomic hyperactivity (eg, sweating or pulse rate >100/min)
2. Increased hand tremor
3. Insomnia
4. Nausea or vomiting
5. Transient visual, tactile, or auditory hallucinations or illusions
6. Psychomotor agitation
7. Anxiety
8. Grand mal seizures
C. The symptoms in criterion B cause clinically significant distress or impairment in social,
occupational, or other important areas of functioning
D. The symptoms are not due to a general medical condition and are not accounted for by another
mental disorder
Specify if with perceptual disturbances. This specifier may be noted in the rare instance when
hallucinations with intact reality testing or auditory, visual, or tactile illusions occur in the absence of a
delirium. Intact reality testing means that the person knows that the hallucinations are induced by the
substance and do not represent external reality. When hallucinations occur in the absence of intact
reality testing, a diagnosis of substance-induced psychomotor disorder, with hallucinations, should be
considered.

Assess: risk for physiologic dependence
and withdrawal potential
• Alcohol history: amounts (clarify), duration, frequency, high amount and effect,
number drinking days/week, eye opener, CAGE questions, environment (controlled,
risk conveying), collateral history
 CAGE is attempt to Cut down? others Annoyed? Guilty about use? have an Eye
opener?
 Score > 2 shows sensitivity 91%, specificity 77% for the identification of alcohol
dependence
• Prior episodes of alcohol withdrawal syndrome requiring detoxification, including
seizures or delirium (consider kindling theory shown in multiple decades of research)
• Recognized severity on presentation (CIWA-Ar Score >10, tremor, diaphoresis,
hyperactivity, hallucinations etc)
• Advanced age
• Acute or chronic comorbid conditions, including alcoholic liver disease, co-
intoxications, polysubstance dependence, trauma, infections, sepsis
• Detectable blood alcohol level on admission
• Abnormal liver function (serum aspartate aminotransferase activity >80 U/L)
• Prior benzodiazepine use
• Male sex
adapted from Box 1, Carlson. Crit Care Clin. 2012

PAWSS 2014

The Conundrum, as articulated by Maldonado, et al. 2014.
In medically ill, hospitalized subjects (i.e., not a specialized detoxification or substance abuse unit),
most cases of AWS are relatively mild and require only symptomatic management (e.g., mild anxiety,
agitation, tremors, nervousness, irritability, insomnia, GI symptoms). Most patients with AUD
experience only uncomplicated or mild withdrawal symptoms. In most cases, the symptoms of mild
alcohol withdrawal do not require medical intervention and usually disappear within 2-7 days of the
last drink.
Furthermore, the incidence of AWS, among alcohol-dependent subjects admitted to a general medical
hospital severe enough to require pharmacological treatment, is between 5 and 20%.
The unnecessary prophylaxis or treatment of patients feared to be at risk of AWS or experiencing
AWS may lead to a number of unintended consequences including excessive sedation, falls,
respiratory depression, propylene glycol toxicity, and disinhibition. Delirium may be a significant
potential complication of treatment of presumptive alcohol withdrawal.
Yet, when complicated (i.e., moderate to severe) AWS does occur, it increases in-hospital morbidity
and mortality, prolongs hospital stays, inflates costs, increases the burden on nursing and medical
staff, and further worsens cognitive functioning among subjects experiencing withdrawal.

Hospital Based Alcohol Withdrawal Interventions
Many areas of controversy, conflicting/inadequate evidence.
Treatment decisions often influenced by training and local practice cultures.
Distinguish the phase of withdrawal AND targets for treatment: i.e.
 prevent severe withdrawal
 maintain physical comfort and ability to engage in medical care
 prevent or stop seizures
 decrease agitation/aggression
 decrease patient distress
 improve cognitive status
 manage duration of inpatient course
 manage benzodiazepine dosing in a patient motivated to receive medication AND at risk for
severe withdrawal complications

Withdrawal Course Table: UpToDate, 2013.
Syndrome Clinical findings
Onset after last
drink
Minor withdrawal
Tremulousness, mild
anxiety, headache,
diaphoresis, palpitations,
anorexia, GI upset;
Normal mental status
6 to 36 hours
Seizures
Single or brief flurry of
generalized, tonic-clonic
seizures, short post-ictal
period; Status epilepticus
rare
6 to 48 hours
Alcoholic hallucinosis
Visual, auditory, and/or
tactile hallucinations with
intact orientation and
normal vital signs
12 to 48 hours
Delirium tremens
Delirium, agitation,
tachycardia,
hypertension, fever,
diaphoresis
48 to 96 hours

Alcohol Withdrawal Hallucinosis
• Occurs between hours 12-48
• Visual phenomena > auditory or tactile
• Vital signs usually normal
• NOT associated with a symptoms of delirium (i.e. confusion, inattention,
disorientation)
• Delusional elaborations arise from the hallucinatory experience, and do not
precede them or arise in their absence
• 10-20% may experience a chronic hallucinosis state, independent of further
alcohol intake

Alcohol Withdrawal Seizures
• Onset commonly 6-48 hours after last alcohol intake, but may be as little as
2 hours after last consumption
• Withdrawal seizures may occur with or without significant preceding
autonomic excitation
• Generalized, tonic-clonic type most common, however reported that up to
24% of alcohol related seizures can be partial (focal) seizures
• Pearl: BAL does NOT need to be zero (i.e. an individual with longstanding
maintenance of a BAL at 250 has increased seizure risk prior to BAL falling
to zero)
• Patients with preexisting seizure disorders are at increased risk
• To distinguish from DT’s, note that alcohol related seizures usually onset
with a clear sensorium

Alcohol Withdrawal Seizures
• There is some controversy in defining the risk of progression to status
epilepticus. Progression itself may be a distracting description as patients
presenting with status epilepticus may have alcohol withdrawal etiology.
• Some authors assert that status epilepticus is rare in ETOH withdrawal
seizures (8% in one estimate)
• However case series evaluating incidence of status epilepticus itself have
found that 15-24% may be linked to alcohol withdrawal. Ongoing seizure
activity should prompt investigation of structural or infectious etiologies.
 Some authors suggest that patients' presenting with first or focal
seizures receive standard seizure evaluation even if in setting of ETOH
withdrawal. One case series showed 17-21% of patients with alcohol
related seizures have structural lesions including hematomas, tumors,
or vascular abnormalities.
• While often self limited, 1/3 of patients who experience alcohol withdrawal
seizures may progress to delirium tremens in the absence of adequate
treatment.

Alcohol Withdrawal Treatment
with Anticonvulsants
• Benzodiazepines are shown to be effective in prevention and
treatment of alcohol withdrawal related seizures.
• Use of anticonvulsants for 1) symptom reduction and 2) seizure prevention
is an area of controversy
• Differential effects of anti-convulsants upon primary alcohol related seizure
occurrence and preventing recurrent alcohol withdrawal seizures are not clear.

Alcohol Withdrawal Treatment
with Anticonvulsants
• Phenytoin has appeared to have low utility in alcohol withdrawal seizures and minimal
benefit to withdrawal syndrome symptoms when formally studied.
• Carbamazepine and possibly Valproate may have utility for withdrawal symptoms.
• Carbamazepine is used in for alcohol withdrawal syndrome more commonly in
Europe than North America, however evidence showing greater efficacy and safety
than standard benzodiazepine treatments is lacking. Carbamazepine may prevent
withdrawal seizures and reduce the “kindling effect” which increases symptom
severity.
 A 2010 Cochrane Database Systematic Review, “Anticonvulsants for Alcohol Withdrawal”
found very little benefit for anticonvulsants compared to benzodiazepines, other agents or
placebo in domains including: alcohol withdrawal seizures, alcohol withdrawal delirium,
safety, life threatening adverse events. When statistical significance in comparison between
carbamazepine and benzodiazepines was reached, carbamazepine was favored only for
alcohol withdrawal symptoms rated with CIWA-Ar score at the end of treatment.
• Gabapentin special mention:
 Some findings of less craving, anxiety, sedation compared to lorazepam
 Decreased probability of drinking during or after withdrawal compared to lorazepam
 Gabapentin 400 mg TID + “rescue” medication
 Limitations: poor data on seizure prophylaxis, used in outpatient cohorts

Delirium Tremens
• Typically appears as a hyperactive delirium with psychotic features.
Symptoms often include tachycardia, hypertension, fever, diaphoresis,
disorientation, hallucinations, and agitation.
• Commonly occurring after 5-15 years of previous heavy alcohol use.
• DTs have a historically high mortality rate (death in >1/3 of patients in early
1900s), now recognized to be up to 5%. Identify this state as an emergency
requiring vigilant management to prevent death.
 Mechanism of death includes: infection, cardiac arrhythmia associated
with electrolyte abnormalities, ketoacidosis, rhabdomyolysis,
hyperpyrexia/dehydration syndrome, HTN associated harms.
Respiratory alkalosis from hyperventilation with cerebral blood flow
reduction has been recognized.
 Other alcohol related mortality not necessarily via a DT pathway include
acute GI bleeding, hepatitis, and pancreatitis.
• Duration may be up to 7 days.

Treatment: Benzodiazepines
General Principles:
 There is not clear evidence that one benzodiazepine is superior to others for alcohol
withdrawal. HOWEVER considering the pharmacologic profile and goals of care with an
individual patient can and should inform benzodiazepines medication choice, timing,
monitoring, route, and duration of therapy. (i.e. elderly, liver disease, reliable reporter of
symptoms vs. medication motivated, seizure occurrence, risk of AMA d/c, need for IM or IV
route etc. May even consider the effect of the first choice agent when spread across a
population over time.)
 Doses when used in refractory withdrawal and delirium tremens can be very high (i.e. case
report of 2640 mg IV diazepam in a 34 yo patient over 48 hrs). Lorazepam close to 100
mg/24 hr dosing.
Lorazepam
 T1/2 12-14 hours, duration of effect 6-8 hours (sedation, amnesia effects, etc)
 Onset: 5 minutes via IV
 Phase II metabolism via conjugation/glucuronidation which remains intact in hepatic failure
 Propylene glycol (solvent vehicle) accumulation is a rare but identified adverse effect of IV
lorazepam and IV diazepam (but not midazolam). Risk includes lactic acidosis,
hyperosmolarity, and renal failure, thus should consider the cumulative effect of IV delivery

Chlordiazepoxide
 T1/2 10-48 hours, with metabolites recognized to have activity up to 95 hours, multiple
dosing results in accumulation of the drug and its active metabolites producing a
cumulative clinical effect
 Onset: time to peak 30 to 120 minutes
 Phase I metabolism requires circulatory delivery and active hepatic enzyme function
Diazepam
 T1/2: 0.8 – 2.2 days, multiple active metabolites have 100+ hour duration
 Onset: 30 minutes with peak effect by 80 minutes, 15 minutes via IV
 Phase I metabolism requires circulatory delivery and active hepatic enzyme function
 Variability with diazepam elimination has been noted in research with significantly increased
time shown with increased age, body fat, and hepatic failure
 Protocol for first dosing response popular with some clinicians: diazepam IV 5 to 10 mg
every 5 to 10 minutes until symptom control attained

• Benzodiazepines are shown to have an unequivocal beneficial effect on
reducing symptoms of alcohol withdrawal and seizures when compared to
placebo
• It cannot be definitively stated that any particular benzodiazepine treats
alcohol withdrawal better than any other member of its medication class
 “Comparing benzodiazepines versus other drugs, there is a trend in favor of
benzodiazepines for seizure and delirium control, severe life threatening side effect,
dropouts, dropouts due to side effects and patient's global assessment score.” and
“Comparing different benzodiazepines among themselves, results never reached statistical
significance but chlordiazepoxide performed better.” Cochrane Database Syst Rev. 2010.
Benzodiazepines for alcohol withdrawal. Amato et al.
• The decision regarding which benzodiazepine to utilize should be based on
various factors such as time to peak effect, efficacy, and duration of action.
 Some authors have suggested that the factors above favor diazepam. However diazepam’s
long T1/2 and factors which cause variability in its metabolism suggest caution in
populations of elderly or medically complex patients.
 Some studies have recognized that diazepam’s effect upon status epilepticus (15-30
minutes) may be shorter lived than lorazepam (3-6 hours)

Fixed schedule vs. symptom triggered benzodiazepine dosing vs. combination therapy is
a source of significant controversy.
 The Cochrane Collaboration 2010, Benzodiazepines for Alcohol Withdrawal notes caution
when extrapolating from single studies but notes 1 study with reduced CIWA-Ar scores at a
fixed endpoint when symptom triggered (not fixed schedule) dosing is used.
 Other authors have suggested reduced total benzodiazepine dosing and reduced lengths of
stay with symptom triggered dosing as opposed to fixed schedule dosing.
 CIWA-Ar (Clinical Institute Withdrawal Assessment for Alcohol Scale, Revised) is a very
commonly used tool.
HOWEVER
Some criticisms of CIWA usage include:
 Objective vital sign measures not part of the scale
 No validation in critical care settings
 Validation concern in the setting of co-morbid pain, seizure history or occurrence,
medical/surgical co-morbidity, or concurrent use of other sedating medications
 Medication dosing is significantly shaped by variability in the RN-patient interaction

Patients deemed to be at high risk for withdrawal may benefit from fixed dosing and symptom
triggered dosing. The fixed dosing scheduled can be conceived as encompassing multiple 24 hour
periods with active adjustment (greater or reduced amounts in subsequent) depending on symptoms
and prn usage expected. (DO ENCOURAGE CONSIDERING FIXED DOSE SCHEDULES AS A
TAPER…)
For instance:
1. Chlordiazepoxide 50 mg q4 hr for 6 doses, then
5. Chlordiazepoxide 25 mg q12 hr for 3 doses, then stop
OR
1. Lorazepam 2 mg q4 hr x6 doses, then
5. Lorazepam 1 mg q8 hrs x4 doses then stop

Alpha-2 Agonist Mechanism and Alcohol
Withdrawal Syndrome
Alpha-2 mechanism rationale
 Presynaptic binding (at the locus ceruleus) in the setting of noradrenergic stimulation can
reduce norepinephrine release and provide sedative/anxiolytic effects, and reduction in
pulse and blood pressure via a non-GABAergic mechanism.
 Adjunctive use of clonidine has shown reduction in alcohol withdrawal symptoms when
combined with benzodiazepine therapy.
Dexmedetomidine:
 Alpha-2 agonist with much 8x greater alpha-2 receptor affinity compared to clonidine
 Not FDA approved for alcohol withdrawal related symptoms of refractory withdrawal though
has been utilized in this fashion at VMMC in the CCU setting.
 Case series and direct clinical experience suggest that this is a safe and effective treatment
for alcohol withdrawal syndrome symptoms
 Recent trial data has NOT consistently shown whole course benzodiazepine accumulative
dose differential, or cost differential between benzo vs. benzo + dexmed (2014 update)
 Cost is a factor in the scope of this medication’s research and clinical use at VM and
nationally
 Use of dexmedetomidine early in a withdrawal course should be concurrent with adequate
benzodiazepine dosing as this medication does not have anticonvulsant activity
 Practically, this medication is used in patients with significant agitation despite high dose
benzodiazepine use.

Treatment of Delirium Tremens and
Refractory Symptoms
Propofol
 Presumed GABA receptor agonism (neuroinhibitory) and NMDA receptor antagonism
(reduced glutamatergic excitation)
 Rapid onset. Short T1/2 with initial response to sedation in minutes and further elimination
at 4-7 hrs. Monitor for rapidly emerging alcohol withdrawal symptoms when propofol
discontinued.
 Use expands vulnerability to adverse events from intubation and airway management
 Possible enhanced susceptibility to pancreatitis (i.e. propofol + underlying liver vulnerability
from ETOH) is not clear
Phenobarbital
 Similar action to benzodiazepines (increases GABA receptor responsiveness to binding)
 Risk of increased respiratory depression compared to benzodiazepines.
 Long T1/2 (80-120 hours) makes titration of effective dose targeting symptoms which also
allows progression of patient function difficult

Treatment of Delirium Tremens and
Refractory Symptoms
Antipsychotics
 Concern regarding use of these medications in alcohol withdrawal are well founded.
 Hesitancy regarding use dates to 1960’s when comparison trials showed promazine and
chlorpromazine with higher rates of seizure, progression to delirium, and death when
compared to agents such as chlordiazepoxide and paraldehyde
 Dopamine blocking mechanism does not target understood GABA and NMDA receptor
mechanism of alcohol withdrawal sxs
 Seizure threshold is lowered with use of antipsychotic medications, which creates particular
risk if used in the early alcohol hallucinosis phase when seizure risk has not fallen.
 Arrhythmia risk which accompanies antipsychotic medications may be increased in alcohol
withdrawal patients who are more likely to have fluid balance and electrolyte abnormalities
 There is some publication support for use such as Archives of Internal Medicine Practice
Guideline 2004: “Neuroleptic agents may be considered for use in conjunction with
benzodiazepines when agitation, perceptual disturbance, or disturbed thinking are not
adequately controlled by benzodiazepine therapy.”

Practical Benzodiazepine
Management Ideas
 Monitor trajectory on day 3-4 for length of stay considerations.
 Consider AMA discharge potential when considering medication choice and
dosing
 Conceptualizing the ‘seizure window’ as closed at 48 hours may be wrong
when extended by GABA agonist replacement dosing. Thus want to be
cautious about abrupt or steep change in dosing curve when considering
discontinuation

Wernicke’s Encephalopathy
 Thiamine is a cofactor for multiple key enzymes important in energy metabolism
 Thiamine requirement depends on metabolic rate with increased demand at
times of during increased glucose
 Classic triad:
 Encephalopathy (disorientation, inattentiveness, indifference)
 Oculomotor dysfunction (nystagmus, lateral rectus palsy, and conjugate gaze palsies)
 Ataxia (likely caused by combination of polyneuropathy, cerebellar involvement, and vestibular
dysfunction)
 3/3 symptoms recognized only in about 1/3 of WE patients – LEADS TO POOR RECOGNITION
 Caine criteria, 2/4 needed: dietary deficiency, ocular motor abnormalities, cerebellar dysfunction,
AMS or mild memory impairment. Index of suspicion is most important element.
 No labs are diagnostic. Brain imaging shows findings at the aqueduct, third
ventricle, medial thalamus, and mamillary bodies. Mamillary body volume
reduction is relatively sensitive (80%) in ETOH dependent populations with
classic symptoms
 Failure to treat may lead to coma and death

Wernicke’s Encephalopathy
Treatment:
Suggested: 500 mg IV thiamine TID x2d, then 500 mg qd x5d, then 100 mg qd
(guidelines vary)
Thiamine noted to have unreliable GI absorption
Prevention: 100 mg qd
Thiamine before Glucose (any carbohydrate load) dictum: Concern that
depletion secondary to metabolic demand spike would precipitate neurologic
symptoms
 Some controversy about CNS availability of thiamine v. glucose and actual evidence for this
phenomena
Other recognized vitamin deficiencies in alcohol withdrawal: B complex
vitamins, vitamin C, folic acid, zinc and magnesium

Korsakoff’s Syndrome
 Marked deficits in anterograde and some retrograde memory, apathy, intact
sensorium, and relative preservation of long-term memory and other
cognitive skills
 Attention and social behavior relatively preserved
 No insight into illness
 Considered a late manifestation of WE
 Prognosis: very poor with recovery very uncommon

Withdrawal Symptoms Not Responding to Initial
Benzodiazepine Administration
 Increase benzodiazepine dosing
 Use benzodiazepine in scheduled fashion or longer T1/2
 Clonidine
 Dexmedetomidine
 Haldol
 Propofol
 Anticonvulsants (VPA, carbamazepine, gabapentin)
 Treatment setting (CCU v. floor)
 Generate expectations for duration
 Consider other etiologies

Post-Hospital Pharmacologic Treatment of Alcohol
Dependence
 Disulfiram: inhibits aldehyde dehydrogenase and causes acetaldehyde accumulation
when alcohol is consumed. This causes a syndrome of headache, flushing, sweating,
sympathetic activity, nausea, vomiting, low blood pressure and dyspnea.
Cardiovascular co-morbidity is a contraindication to use.
 Acamprosate: Glutamate neurotransmission modulator with poor randomized-control
trial performance for duration of abstinence or days of heavy drinking.
 Naltrexone: Available in both PO and IM depot formulations. Antagonist at the mu-
opioid receptor which blocks the endogenous opioid mediated reinforcing effects of
alcohol consumption. Has shown benefit to increase in abstinent days and reduction
in days of heavy alcohol consumption.
 All pharmacology options should only be considered in the setting of:
 ongoing, clearly established medical monitoring for safety and effectiveness
and
 psychosocial support planning to enhance success

Appropriate Psychosocial Inpatient Intervention for
an Alcohol Dependent Patient: MI
ANY staff member (medicine service, social worker, behavioral health team)
can utilize motivational interviewing principles to guide interactions with
patient with substance use disorders.
– MI is engagement in which attempt is made to evoke within the patient the motivation to
make steps toward behavior change.
Organizing themes in Motivational Interviewing
•COLLABERATION: Patient’s personal perspective provides the context.
•EVOCATION: The goal of the interview is definitely eliciting the patient’s
viewpoint, and only maybe imparting wisdom, insight, or the clinicians view of
the reality.
•AUTONOMY: Responsibility for change is left completely with the patient.
•ROLL WITH RESISTANCE: Reluctance and ambivalence are not opposed, but
are acknowledged to be natural and understandable. Response to resistance
is reframing.

Directive Pneumonic to facilitate MI
DARN: Desire, Ability, Reason, Need
D: “Why would you want to make a change?”
A: “How could you do things in order to find success?”
R: “What are the three best reasons to change?”
N: “On a scale from 0 to 10, where 0 is not at all important and 10 is
most important, how much do you want to make this change?” When
told a number, you could then ask, “Why are you at that number and
not 10?”

Appropriate Psychosocial Inpatient Medical/Surgical
Course Intervention for an Alcohol Dependent Patient
Consider available resources with the patient, social work staff, or behavioral
health team
Be aware of complexity in determination of next steps
 Nomenclature is important: “Detox” is a time limited inpatient medical procedure
designed for medically facilitated cessation of alcohol (i.e. 3-5 days)
 Further substance treatment episodes include many types of care: outpatient,
day treatment, partial hospitalization, hospitalization, residential.
 Potential next steps in care may differ in cost, availability, duration of
commitment, insurance or 3rd
party payer coverage, patient willingness, and
preauthorization requirement.
 Medical necessity criteria and utilization review commonly govern resource
availability to any individual. These factors, in addition to service availability, can
be a obstacle to immediate program placement via transfer from VMMC.
 PLAY A DIRECT ROLE IN SEEING THAT CONSIDERATION OF FURTHER
ADDRESS OF ALCOHOL DEPENDCE OCCURS

References
 Emerg Med Clin North Am. 2011. Alcohol-related seizures. McMicken D, Liss JL
 Neurology. 1993. Status epilepticus at an urban public hospital in the 1980s. Lowenstein DH,
Alldredge BK
 Epilepsia. 1993. Status epilepticus related to alcohol abuse. Alldredge BK, Lowenstein DH
 The Journal of Emergency Medicine. 2006. Alcohol Related Seizures. Rathleve et al.
 The Annals of Pharmacotherapy. 2011. The Role of a2-Agonists in the Treatment of Acute
Alcohol Withdrawal. Muzyk et al.
 J Anesth. 2012. Use of dexmedetomidine for the treatment of alcohol withdrawal syndrome in
critically ill patients: a retrospective case series. DeMuro et al.
 Annals of Intensive Care. 2012. Dexmedetomidine as adjunct treatment for severe alcohol
withdrawal in the ICU. Rayner et al.
 The Manual of Psychiatric Care for the Medically Ill. 2005. Wyszynski and Wyszynski.
 Uptodate.com. 3/28/2013 revision. Management of moderate and severe alcohol withdrawal
syndromes. Hoffman et al.
 Alcohol Clin Exp Res. 2009. A double blind trial of gabapentin vs. lorazepam in the treatment of
alcohol withdrawal.
 Archives of Internal Medicine. 2004. Management of Alcohol Withdrawal Delirium. An Evidence-
Based Practice Guideline.

References
 Cochrane Database Syst Rev. 2010. Anticonvulsants for alcohol withdrawal. Minozzi et al.
 Cochrane Database Syst Rev. 2010. Benzodiazepines for alcohol withdrawal. Amato et al.
 J Intensive Care Med. 2005. Management of delirium tremens. DeBellis et al.
 Am J Addict. 2013. The role of diazepam loading for the treatment of alcohol withdrawal
syndrome in hospitalized patients. Muzyk et al.
 Intensive Care Med. 2013. Alcohol Withdrawal and delirium tremens in the critically ill: a
systematic review and commentary. Awissi et al.
 Prim Care Companion J Clin Psychiatry. 2010. Current Approaches to the Recognition and
Treatment of Alcohol Withdrawal and Delirium Tremens. Stern et al.
 Alcohol and Alcoholism. 2011. Carbamazepine and Valproate as Adjuncts in the Treatment of
Alcohol Withdrawal Syndrome: A Retrospective Cohort Study.
 Lancet. 1982. Comparison of questionnaire and laboratory tests in the detection of excessive
drinking and alcoholism.
 Alcohol. 2014. The “Prediction of Alcohol Withdrawal Severity Scale” (PAWSS): Systematic
literature review and pilot study of a new scale for the prediction of complicated alcohol withdrawal
syndrome
 http://www.alcohol.gov.au/internet/alcohol/publishing.nsf/ accessed 9/11/2014
 PubMed.gov search term: dexmedetomidine for alcohol withdrawal

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