Transcript Pharmacotherapy of Alcohol Dependence

Pharmacotherapy of
Alcohol Dependence
Department of Surgery Grand Rounds
St. Luke’s and Roosevelt Hospitals
New York, Wednesday, September 7, 2005
Petros Levounis, M.D.
Director, The Addiction Institute of New York
Chief, Division of Addiction Psychiatry at
St. Luke’s and Roosevelt Hospitals
www.AddictionInstituteNY.org
4 HANDOUTS
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2.
3.
4.
Mayo-Smith, M.F. (2003). Management of
Alcohol Intoxication and Withdrawal. In A.
W. Graham, T. K. Shultz, M. F. Mayo-Smith,
R. K. Ries, & B. B. Wilford (Eds.), Principles
of Addiction Medicine (3rd ed., pp. 621-631).
Chevy Chase, Maryland: American Society of
Addiction Medicine.
Fundamentals of Addiction Medicine
Addiction Institute Brochure
These slides
OUTLINE
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2.
3.
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6.
Introduction
Alcohol Intoxication
Alcohol Withdrawal
Relapse Prevention
Co-Occurring Disorders
New Directions
1
INTRODUCTION
Epidemiology
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207 million
18 million
8 million
2 million
1.2 million
.6 million
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US Population
Alcohol Use Disorders (9%)
Alcohol Dependence (45%)
Ever treated (24%)
Ever seen an M.D. (60%)
Ever given meds (50%)
Grant BF et al. Arch Gen Psychiatry. 2004;61:807-816.
http://imshealth.com
Neurotransmitter
Systems
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GABA
Glutamate
Opioid
Dopamine
Serotonin
→
→
→
→
→
CNS Inhibition
CNS Excitation
Euphoria/Reward
Addiction
Impulsivity
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ALCOHOL
INTOXICATION
Characteristics
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0-100 mg/dL
100-200 mg/dL
200-300 mg/dL
300-400 mg/dL
400-600 mg/dL
600-800 mg/dL
Well-being
Incoordination
Ataxia
Stage I Anesthesia
Coma
Death
Pharmacotherapy
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Use IV thiamine and glucose
Do not use ipecac, activated
charcoal, caffeine, amphetamines,
or flumazenil.
Treatment is supportive.
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ALCOHOL
WITHDRAWAL
Characteristics 1
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Following the last drink:
– 6 to 24 hours:
– 24 to 48 hours:
– 48 to 96 hours:
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Autonomic Hyperactivity
Seizures
Delirium tremens
“Kindling effect” for seizures.
Older patients are at higher risk of DTs.
Typically mild, occasionally severe, rarely
fatal.
Characteristics 2
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Autonomic Hyperactivity with:
– Reduced GABA activity and
– Enhanced glutamate activity.
Characteristics 3
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Early signs of withdrawal:
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Tachycardia
Blood pressure elevation
Sweating
Hyperthermia
Tremor (6 to 8 cycles per second)
Assessment
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Clinical Institute Withdrawal
Assessment for Alcohol (revised).
Mayo-Smith MF. JAMA. 1997;278:144-51.
CIWA-Ar Categories
[ Range of Scores: 0-7* ]
Neuropsych.
Symptoms
Perceptual
Disturbances
CLOUDED
SENSORIUM
Physical
Symptoms
NAUSEA/
VOMITING
ANXIETY
HEADACHE
VISUAL
AGITATION
TREMORS
TACTILE
SWEATS
* except 0-4 for
sensorium
Adapted from www.asam.org
AUDITORY
Practice Guidelines
CIWA-Ar
SCORE
<9
Mild
Withdrawal
9 - 15
Moderate
Withdrawal
> 15
Severe
Withdrawal
No
Medications
Supportive
Treatment
PRN
Medications
Outpatient Sympt.
Treatment
Standing
Medications
Inpatient Medical
Treatment
Adapted from Mayo-Smith MF. JAMA. 1997;278:144-51.
Pharmacotherapy 1
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Long-acting benzodiazepines (e.g.,
chlordiazepoxide) are the
treatment of choice.
Short-acting benzodiazepines (e.g.,
lorazepam) are preferred in liver
damage and the elderly.
Anticonvulsants are being studied.
Holbrook AM et al. Can Med Assoc J. 1999;160:649-55. Bonnet U et al. J Clin
Psychopharmacol. 2003;23:514-9.
Pharmacotherapy 2
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For symptom triggered medication,
administer every hour when CIWAAr >= 9:
– Chlordiazepoxide
– Lorazepam
– Diazepam
Mayo-Smith MF. JAMA. 1997;278:144-51.
50 to 100 mg
2 to 4 mg
10 to 20 mg
Pharmacotherapy 3
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For standing po chlordiazepoxide:
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Day
Day
Day
Day
1:
2:
3:
4:
50
50
25
25
Garbutt JC et al. JAMA. 1999;281:1318-25.
mg
mg
mg
mg
Q
Q
Q
Q
4
6
4
6
hours
hours
hours
hours
Pharmacotherapy 4
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For delirium tremens:
– 2 to 4 mg IV lorazepam followed by
– 1 to 2 mg IV lorazepam every 5
minutes until patient is calm.
– Taper slowly over 4 to 5 days.
Adopted from Garbutt JC et al. JAMA. 1999;281:1318-25.
Pharmacotherapy 5
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In general, for severe
withdrawal:
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Titrate to light sedation.
Have flumazenil ready.
Calculate daily dose.
Decrease dose by 25% daily.
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RELAPSE
PREVENTION
DISULFIRAM
Introduced in 1954
Mechanism of Action
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Alcohol → Acetaldehyde → Acetate
Disulfiram irreversibly binds to
acetaldehyde dehydrogenase
inhibiting the metabolism of
acetaldehyde to acetate.
Acetaldehyde accumulates
resulting in a violent reaction
(nausea, vomiting, flushing).
Efficacy
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Double-blind, placebo-control
study design is not helpful as both
the medication and the placebo
pills may (or may not) result in
fear of drinking.
Most studies are negative, but
disulfiram may be helpful in highly
structured settings.
Fuller RK et al. JAMA. 1986;256:1449-55.
Dosing and Safety
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250-500 mg daily.
Medication costs approximately
$40 a month.
Some liver toxicity; liver function
should monitored.
Inhibits hepatic microsomal
enzymes and increases drug levels.
Physician’s Desk Reference. 59th ed. Pp 2442-3.
NALTREXONE
Introduced in 1995
Mechanism of Action
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Reduces positive reinforcement
(reward craving).
The patient does not experience
the full euphorogenic/reinforcing
effect of alcohol.
Prevents a slip from becoming a
full-blown relapse.
Efficacy
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Effective in reducing relapse to
heavy drinking ( >4 in men, >3
drinks/day in women).
The Srisurapanont (2005) metaanalysis found efficacy up to 12
weeks but not after 12 weeks.
Medication compliance may be a
limiting factor in treatment.
Mason BJ. Eur Neuropsychopharmacol. 2003;13:469-475. Srisurapanont M & Jarusuraisin N.
Cochrane Database Syst Rev 2005.
Dosing and Safety
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50 mg daily.
Medication costs $103 a month.
Liver toxicity; liver function should
monitored closely.
Otherwise safe and well-tolerated.
No significant drug-drug
interactions.
http://ncadi.samhsa.gov/govpubs/BKD268/28c.aspx
ACAMPROSATE
Introduced in 2005
Mechanism of Action
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Reduces negative reinforcement
(abstinence craving).
Neuroadaptation and upregulation
of the glutamate system in
alcoholism.
Acamprosate interferes with the
glutamatergic system.
Efficacy
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Effective in improving abstinence.
The Mann et al (2004) metaanalysis found a 50% improvement
in 6-month abstinence (36%
acamprosate vs. 23% placebo).
Three times a day dosing may
compromise compliance.
Sass et al. Arch Gen Psychiatry. 1996;53:673-680. Mann K et al. Alcohol Clin Exp Res.
2004;28:51-63.
Dosing and Safety
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666 mg three times a day.
Medication costs $110 a month.
Excreted by the kidneys - No liver
metabolism.
Mild diarrhea (16% acamprosate
vs. 10% placebo).
No drug-drug interactions.
Physician’s Desk Reference. 59th ed. Pp 3428-30.
5
CO-OCCURRING
DISORDERS
In General
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Co-occurring alcohol dependence
and other psychiatric disorder(s)
typically require treatment for both
(all).
Treating patients under one roof
improves both addiction and
mental health outcomes.
Mariani JJ, Levin FR. Harvard Rev Psychiatry. 2004;12:351-66. Kranzler HR, Jaffe JH. In:
Graham TK et al, eds. Principles of Addition Medicine. 3rd ed. Chevy Chase, MD: American
Society of Addition Medicine. 2003:701-19.
Depression
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Antidepressants typically improve
depressive symptoms.
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However, they have limited impact
on alcohol use.
Nunez EV, Levin FR. JAMA. 2004;291:1887-96.
Antidepressants’ Effect
on Depression
From Nunez EV, Levin FR. JAMA. 2004;291:1893.
Antidepressants’ Effect
on Substance Use
From Nunez EV, Levin FR. JAMA. 2004;291:1893.
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NEW DIRECTIONS
New Delivery Systems
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Long-acting naltrexone injection:
100 μm diameter microspheres
composed of naltrexone and PLG
polymeric matrix.
Nausea, headache, and fatigue are
the prominent adverse effects.
FDA decision expected in late ‘05.
http://www.fda.gov
Please note: This agent is not approved by the FDA for use in alcohol dependence.
Injectable Naltrexone
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50%
40%
30%
20%
10%
0%
(n=624)
Placebo
Naltrexone 190 mg
Naltrexone 380 mg
Adapted from Garbutt et al. JAMA. 2005;293:1622.
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Heavy drinking days
rates during a 24
week treatment trial
with injectable
naltrexone 190 mg
and 380 mg
Qmonth.
Injectable naltrexone
reduced the rate of
heavy drinking by
25% (P=.02).
New Combinations
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Acamprosate and naltrexone have
different mechanisms of action
and may work synergistically.
The COMBINE trial (n=1,375; 11
sites) will assess the medication
combination and two behavioral
interventions for a total of 9
possible treatment formulations.
COMBINE Study Research Group. Alcohol Clin Exp Res. 2003;27:1123-1131.
Naltrexone/Acamprosate
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60%
50%
40%
30%
20%
10%
0%
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(n=160)
Placebo
Acamprosate
Naltrexone
Combination
Abstinence rates
during a 12-week
treatment trial with
naltrexone 50 mg
QD and acamprosate
666 mg TID.
The combination of
the two medications
helped alcoholics
stay abstinent
(P=0.002) better than
each drug alone.
Adapted from Kiefer F et al. Arch Gen Psychiatry. 2003;60:96.
New Pharmacological
Agents
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Anticonvulsants
– Topiramate
– Carbamazepine
– Valproic Acid
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GABA agonist
– Baclofen
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Selective Serotonin Reuptake Inhibitors
Serotonin (5-HT3) antagonist
– Ondansetron
Please note: These agents are not approved by the FDA for use in alcohol dependence.
Where you can find us
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You can request an addiction
consultation by contacting:
– Galen Cooper, Ph.D., x38409/pgr 35864 at
Roosevelt, or
– Raisa Montalvo, M.A., x31743/pgr 39046 at
St. Luke’s.
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Our website:
www.AddictionInstituteNY.org
Our 24-hour-line: 212-523-6491