Alcohol:
Research to Practice
Gail D’Onofrio MD, MS
Section of Emergency Medicine
Yale University School of Medicine
Case Study
Mr. Smith is a 35 year old white male
who presents with a new onset
seizure this morning. He has no
known past medical history, and
takes no regular medications. He
does not have a primary care
physician
Initial Management
History
 Physical Exam
 Laboratory tests
 Diagnostic Imaging

GABA
GABAA Receptor
glutamate
ClNMDA NO
receptor Ca++
ClGlycine
Receptor
CNS
Neuron
Ca+
+
VOCCL,N
Alcohol Dependence
3 or more of these criteria in a 12-month period:
1. Tolerance
2. Withdrawal
3. More or longer consumption than intended
4. Cannot cut down or control alcohol use
5. A great deal of time getting, using, recovering
6. Activities given up or reduced
7. Use despite knowledge of health problem
(3-7) Loss of control/preoccupation
American Psychiatric Association DSM IV, 1994
Alcohol-Related Seizures

Adult onset seizures occurring in the
setting of chronic alcohol dependence
Historical perspective

Hippocrates 400 B.C. - first description

Isbell 1955 - first experimental study

Victor and Brausch 1967 - landmark
study
Alcohol-Related Seizures Withdrawal

Recurrent detoxifications and prior seizure
are risk factors
 Occur 24-48 hrs after abstinence or
decreased intake
 Often occur prior to autonomic hyperactivity
 Generalized, single or a few over a short time
– < 3% status epilepticus
– 79% < 3
– 86% recurrent seizure within 6 hrs
Victor and Brausch. Epilepsia 1967;8:1,
Differential diagnosis

Structural brain lesions
Stroke & traumatic brain injury.
Susceptibility due to cerebral atrophy
and head trauma

Toxic-metabolic disorders
Alkalosis, hypomagnesemia,
hypoglycemia & illicit drug use
Differential diagnosis

Alcohol withdrawal – underestimated as
a cause of generalized seizures

Idiopathic generalized epilepsy - poor
seizure control in alcohol dependence

Sleep deprivation & medication
compliance
Pathogenesis

Biochemical effects of alcohol on CNS

Kindling - increased susceptibility and
severity of recurrent withdrawal
episodes.

Brown 1988 – no. of prior detoxifications
a risk factor
Exacerbation of idiopathic generalized epilepsy
Other predisposing
factors causing acute
symptomatic seizures,
e.g., associated drug
abuse
Alcohol
Epilepsy related to
other risk factors
associated with chronic
alcohol abuse, e.g.
traumatic brain injury
Alcohol-withdrawal seizures Alcohol-intoxication seizures
Diagnostic evaluation

Screening for alcohol dependence

Laboratory testing –rarely changes
management.

Earnest 1988 - head CT indicated for all
patients with new-onset alcohol-related
seizures

Sand 2002 – EEGs on all patients
Seizure Recurrence
• 186 subjects with
alcohol withdrawal
seizures
• RCT, double blinded
• 2 mg of lorazepam IV
• Also decreased
hospital admission
50
40
30
24
20
% with
2nd
seizure
10
3
0
lorazepam
D'Onofrio G et al. N Engl J Med
1999;340:915-919.
Treatment of Alcohol
Withdrawal
Alcohol Withdrawal (DSM-IV)
• Cessation or reduction in alcohol use that has been heavy/prolonged
• Two or more of the following, developing in hours-days, causing
distress or impairment, not due to other condition
– Autonomic hyperactivity (sweating, tachycardia)
– Increased hand tremor
– Insomnia
– Nausea or vomiting
– Transient tactile, visual or auditory hallucinations or illusions
– Psychomotor agitation
– Anxiety
– Grand mal seizures
Detoxification: Inpatient versus Outpatient with
mild/moderate alcohol withdrawal (RCT)
OUTpt (N=87) INpt (N=77)
Completing treatment (%)*
72
95
Abstinence (1 month)(%)**
No Intoxication (1 month)(%)*
66
76
81
88
Abstinence (6 months)(%)
No Intoxication (6 mo)(%)
48
59
46
51
Days of treatment (mean)*
Cost ($)*
4.5
175-388
No difference in Addiction Severity Scores
9.2
3319-3665
*p<.001, **p<0.03.
Hayashida et al. NEJM 1989;320:358
Pharmacologic Therapies for
Alcohol Withdrawal
Treatment Phase and
Drug Class
Alcohol Withdrawal
Benzodiazepines
diazepam (10-20 mg)
chlordiazepoxide (50-100 mg)
lorazepam (2-4 mg every 1-2 hr
until symptoms subside
[e.g., CIWA-Ar score
<8] for 24 hr*)
Examples
Chlordiazepoxide*
Diazepam*
Oxazepam*
Lorazepam and
others
Mechanism & Effects
Decrease hyperautonomic
state by facilitating inhibitory yaminobutyric acid receptor for
transmission, which is downregulated by long term
exposure to alcohol
Sedation
* Drug has a Food and Drug Administration-approved indication for this use in the US
O’Connor P, et al. NEJM 1998;338;9;592-602
Pharmacological Therapies for
Alcohol Withdrawal
Treatment Phase and Drug Class
Alcohol Withdrawal
Examples
Effects
Beta-blockers
Atenolol
Propranolol
Improvement in
vital signs;
reduction in craving
Alpha-agonists
Clonidine
Antiepileptics
Carbamazepine
Decreased
withdrawal
symptoms
Decreased severity
of withdrawal;
prevention of
seizures
O’Connor P, et al. NEJM 1998;338;9;592-602
CIWA-Ar
CIWA-Ar denotes:
Clinical Institute Withdrawal Assessment for Alcohol, revised. The
scale assesses 10 domains (nausea or vomiting; anxiety; tremor;
sweating; auditory, visual, and tactile disturbances; headache;
agitation; and clouding of sensorium) and assigns 0 to 7 points for
each item except for the last item, which is assigned 0 to 4 points,
with a total possible score of 67. This scale has been validated as
a measure to assess the severity of alcohol withdrawal. Higher
scores indicate a higher risk of complications; patients receiving
scores of 8 or more should be treated.*
*Mayo-Smith MF. JAMA 1997;278:144-51.
Symptom-triggered Therapy
101 adults with no past seizures
hospitalized for alcohol withdrawal
 Placebo or Chlordiazepoxide 50 mg
qid X4 then 25 mg qid X8 (doubleblind)
 ALL: Chlordiazepoxide 25-100 mg q
1 hour as needed (objective scale:
CIWA-Ar)

Saitz R et al JAMA 1994;272:519-23
Decreased Duration of Treatment
Saitz R et al JAMA 1994;272:519-23
ASAM Practice Guidelines
Treatment approaches
• Monitor q 4-8 hrs until symptoms improved
• Symptom-triggered (q 1 when CIWA>8)
• Chlordiazepoxide 50-100 mg
• Diazepam 10-20 mg
• Lorazepam 2-4 mg
• Fixed schedule (q 6 for 4/8 doses + PRN)
• Chlordiazepoxide 50 mg/25 mg
• Diazepam 10 mg/5 mg
• Lorazepam 2 mg/1 mg
Mayo-Smith and ASAM working group JAMA 1997;278:144-51
Saitz and O’Malley Med Clin N A 1997;81:881-907
Treatment of Alcohol Dependence
Detoxification is NOT treatment
 Behavioral Counseling
– Motivational
– Cognitive-behavioral (Cue exposure,
contingency management, coping skills
– 12 step
– Psychotherapy

Pharmacotherapy
Treatment Does Work

2/3rds of patients (1-year) reduce:
– Consequences of alcohol consumption
(injury job loss)
– Amount of consumption by > 50%

1/3 of patients treated are either abstinent or
drink moderately without consequences
Miller WR, Walters ST, Bennett ME. How effective is alcoholism
treatment in the US? J Stud Alcohol 2001;62:211-20
Success Rates for Addictive
Disorders
Disorder
Success Rate
(%)*
Alcoholism
50 (40-70)
Opioid Dependence
60 (50-80)
Cocaine Dependence
55 (50-60)
Nicotine Dependence
30 (20-40)
* Follow-up 6 mo. Data are median (range)
O, Brien C; McLellan A. Lancet 1996;347;237-40
Compliance and Relapse in
Selected Chronic Medical Disorders
Compliance and
Relapse
IDDM (Insulin-dependent
diabetes mellitus)
Medication Regimen
Diet and Foot Care
Relapse*
<50%
<30%
30-50%
Hypertension+
Medication Regimen
Diet
Relapse*
<30%
<30%
50-60%
Asthma
Medication Regimen
Relapse*
<30%
60-80%
*Retreatment within
12 mo by physician at
emergency room or
hospital; +Requiring
medication
O, Brien C; McLellan A. Lancet 1996;347;237-40
Self Help/Mutual Help
Alcoholics Anonymous (AA)

Provides support at no charge
 Veteran study shows higher frequency of
abstinence at 12 months than those
programs with CBT (26% vs 19%)

Participation in AA associated with higher
rates of abstinence 7 months after inpt tx
compared with no participation.
Quimette PC, et al. Twelve-step and cognitive-behavioral treatment for substance abuse: a
comparison of treatment effectiveness. J Consult Clin Psychol 1997;65:230-40.
Montgomery HA et al. Does AA involvement predict treatment outcomes? J Subst Abuse Treat
1995;12:241-6.
AA
1. We admitted we were powerless over alcohol - that our lives had
become unmanageable.
2. Came to believe that a Power greater than ourselves could restore
us to sanity.
3. Made a decision to turn our will and our lives over to the care of God
as we understood Him.
4. Made a searching and fearless moral inventory of ourselves.
5. Admitted to God, to ourselves and to another human being the exact
nature of our wrongs.
6. Were entirely ready to have God remove all these defects of
character.
AA (continued)
7. Humbly asked Him to remove our shortcomings.
8. Made a list of all persons we had harmed, and became willing to make
amends to them all.
9. Made direct amends to such people wherever possible, except when to do
so would injure them or others.
10. Continued to take personal inventory, + when we were wrong promptly
admitted it.
11. Sought through prayer and meditation to improve our conscious contact
with God as we understood Him, praying only for knowledge of His will for
us and the power to carry that out.
12. Having had a spiritual awakening as the result of these steps, we tried to
carry this message to alcoholics and to practice these principles in all our
affairs.
Behavioral Therapy
Project MATCH





Subjects recruited after inpatient treatment or
outpatient treatment
Randomized to MET, CBT or 12-step facilitation,
over 12-week period
Little difference in outcomes by type of Treatment
Aftercare after inpatient stay: 12-month
continuous abstinence 35%, 40% relapsed to 3
consecutive heavy drinking days
Outpatients, 19% abstained, and 46% relapsed
Project MATCH Research Group.
J Stud Alcohol 1997;58:7-29
Pharmacotherapy
Pharmacologic Therapies for
Alcohol Prevention Relapse
Treatment Phase and
Drug Class
Prevention of Relapse
Examples
Alcohol sensitizers
Disulfiram*
Opioid antagonists
Naltrexone*
Homotaurine derivatives
Acamprosate
Effects
Decreased alcohol use
among those who relapse
Increased abstinence,
decreased # of drinking
days
Increased abstinence
* Drug has a Food and Drug Administration-approved indication for this use in the US
O’Connor P, et al. NEJM 1998;338;9;592-602
Medications for Treatment of Alcohol
Dependence to Prevent Relapse
Medication
DISULFIRAM
Antabuse (Initial
dose, 250 mg
daily; therapeutic
dose, 500 mg
daily)
Presumed Mechanism
of Action
Blocks acetaldehyde
dehydrogenase; blockade
allows acetaldehyde to
accumulate with alcohol
consumption, causing
unpleasant symptoms (e.g.,
flushing, headache, vomiting,
dyspnea, confusion)
Side Effects
Idiosyncratic fulminant
hepatitis, neuropathy (at
doses >500mg), psychosis,
and symptoms that generally
resolve on discontinuation of
drug (headache,
drowsiness, fatigue, rash,
pruritus, dermatitis, garlicky
taste in mouth)
Contraindications: wait 24
hours after drinking, elderly,
varices, confusion, HTN Rx
Saitz R NEJM 2005;352;6;596-607
Disulfiram
Multicenter RCT, 12-month F/u of N=605
 DS 250mg, 1 mg, or none
 No difference in abstinence
 More abstinence in those adherent to DS
(43% vs. 8%,p<0.001)
 Fewer drinking days in the 162 assigned
to DS, adhered, and completed F/u,
compared to other groups (p=0.05)

Fuller RK JAMA 1986;256:1449
Disulfiram

Daily or just prior to risky situation
– Duration of action: 4-7 days, up to 14

Monitor LFTS (2 wks, 3,6 Mo, 1yr), avoid
alcohol in OTC meds, interacts with
warfarin, INH and anticonvulsants
 Contraindications
– alcohol within 24 hours
– Elderly, pregnancy, varices, confusion,
seizures, heart disease, anti-HTN therapy, (ie.
anti-adrenergics
Medications for Treatment of Alcohol
Dependence to Prevent Relapse
Medication
Presumed Mechanism
of Action
Side Effects
NALTREXONE
ReVia (initial dose
12.5 mg daily or
25 mg daily;
therapeutic dose
50 mg daily)
Acts as an opiate agonist; decreases
heavy drinking by blocking endogenous
opioids, a process that attenuates
craving and the reinforcing effects of
alcohol
Nausea, headache, dizziness,
nervousness, fatigue,
insomnia, vomiting, anxiety,
somnolence, dry mouth,
dyspepsia, elevated liverenzyme levels (dose-related),
difficult pain management
Contraindicated: opiate
dependence, pregnancy, liver
disease
ACAMPROSATE
Campral (666 mg 3
times a day)
Increases abstinence by stabilizing
activity in the glutamate system, which
is affected by long-term heavy
consumption
Diarrhea
Contraindications: Renal
insufficiency
Saitz R NEJM 2005;352;6;596-607
Naltrexone

A meta-analysis showed that in RCTs
of a short duration (< 3 months)
– decreased the risk of a return to heavy
drinking from 48% to 37%
– Decreased drinking days by 4.5%
– Proportion of patients who were abstinent
was higher with naltrexone than placebo
(35% vs. 30%); borderline significance
Carmen B et al. Addiction 2004:99:811-28
Naltrexone






Can be prescribed in the context of
psychosocial treatments for those with
alcohol dependence, not drinking. Last drink
5-30 days ago, LFTs < 3x normal, no opiates
Less drinking, less relapse
12.5 mg →25mg →50mg over first few days
Med Alert bracelet, stop 3 days pre-op
Monitor LFTs, drinking and SEs monthly
? Duration of treatment
Back to Our Patient
Treatment of ARS
 Brief Intervention: Goal is to link with
specialized treatment center for
initial detoxification
 Referral to primary care
 Long term treatment through
behavioral and/or pharmacotherapy

Thanks
Richard Saitz MD, MPH
 Niels Rathlev, MD

Boston University School of Medicine