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National Institute on Alcohol Abuse and Alcoholism

Alcohol Use, Abuse, and Dependence
Ting-Kai Li, M.D.
Director National Institute on Alcohol Abuse and Alcoholism National Institutes of Health U.S. Department of Health and Human Services

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National Institute on Alcohol Abuse and Alcoholism

Ting-Kai Li, M.D. Director
National Institute on Alcohol Abuse and Alcoholism

http://www.niaaa.nih.gov/AboutNIAAA/DirectorsCorner/default.htm

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National Institute on Alcohol Abuse and Alcoholism

National Institute on Alcohol Abuse and Alcoholism Mission
● increase the understanding of how alcohol use impacts normal and abnormal biological functions and behavior across the lifespan ● improve the diagnosis, prevention, and treatment of alcoholism and other alcohol-related disorders ● enhance quality health care
http://pubs.niaaa.nih.gov/publications/StrategicPlan/NIAAASTRATEGICPLAN.htm

National Institute on Alcohol Abuse and Alcoholism

Alcohol Use
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Alcohol: Our Most Primitive Intoxicant
National Institute on Alcohol Abuse and Alcoholism

Egypt (el-Guebaly N, el-Guebaly A, 1981, Int J Addict.,
16:1207-21)
barley beer is probably the oldest drink in the world with its origin in Egypt prior to 4200 BC

China (McGovern et al., 2004, PNAS, 101:17593-17598)
7000 BC - the production of a prehistoric mixed fermented beverage of rice, honey and fruit (neolithic village of Jiahu in Henan province) 2000 BC- unique cereal beverages (Shang and Western Zhou Dynasties)

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National Institute on Alcohol Abuse and Alcoholism

Ancient Warnings About Alcohol and Harmful Use Through the Ages
1600-1050 BC - Downfall of Egyptian and Chinese Empires and

Dynasties attributed to excessive alcohol use
460-320 BC- Grecian Scholars issued advisories on drunkenness and

moderate drinking Plato – No use under age 18, between 18-30 use in moderation, no restrictions for use by those older than 40 Aristotle and Hippocrates were both critical of drunkenness
11th Century AD - Simeon Seth, a physician in the Byzantine Court,

wrote that drinking wine to excess caused inflammation of the liver, a condition he treated with pomegranate syrup

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Total Per Capita Consumption in Gallons of Ethanol by State - United States, 2003
National Institute on Alcohol Abuse and Alcoholism

■DC

■ 1.99 or below (10) ■ 2.00-2.24 (15) ■ 2.25-2.49 (16) ■ 2.50 or over (10)

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Cumulative Distribution of Alcohol Consumption in the United States
National Institute on Alcohol Abuse and Alcoholism

Percent of Consumption

 65% of the population are drinkers*  Males reported drinking 74% and females 26% of all alcohol consumed  73% of the alcohol is consumed by 10% of the population

100 80 60 40 20 0 0 10 20 30 40 50 60 70 80 90 100

Percentile Group (High to Low)

* Individuals who reported drinking at least one drink in past 12-months

NIAAA National Epidemiological Survey on Alcohol and Related Conditions (NESARC) (2001-2002).

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Drinking Patterns: Rates and Risks
National Institute on Alcohol Abuse and Alcoholism

Moderate Drinking Most people abstain or drink moderately placing them at low risk for alcohol use disorders. In general, Moderate Drinking is up to 2 drinks/day for men; up to 1 drink/day for women
(USDA/HHS Dietary Guidelines, 2005)
One drink: one 12- ounce can or bottle of beer or wine cooler , one 5- ounce glass of wine , or 1.5 ounces of 80 - proof distilled spirits .

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Drinking Patterns: Rates and Risks
National Institute on Alcohol Abuse and Alcoholism

High-Risk Drinking Nearly 3 in 10 U.S. adults engage in these high-risk drinking patterns1
Men: Women: more than 14 drinks in a typical week more than 4 drinks on any day more than 7 drinks in a typical week more than 3 drinks on any day

Source: NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2003
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Drinking Patterns: Rates and Risks
National Institute on Alcohol Abuse and Alcoholism

Binge Drinking
The National Advisory Council on Alcohol Abuse and Alcoholism has recommended the following definition of Binge Drinking
A “binge” is a pattern of drinking alcohol that brings blood alcohol concentration (BAC) to 0.08 gm% or above. For the typical adult, this pattern corresponds to consuming 5 or more drinks (male) or 4 or more drinks (female) in about 2 hours. Binge drinking is clearly dangerous for the drinker and for society

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U.S. Adult Drinking Patterns and Risks 2001-2002: Odds Ratios
National Institute on Alcohol Abuse and Alcoholism

Alcohol screening limits—number of drinks:
In a typical WEEK—14 (men), 7 (women) On any DAY— 4 (men), 3 (women)
Drinking Pattern Never exceeds the weekly or daily screening limits Exceeds only the weekly limit Exceeds only the daily limit less than once a week Exceeds only the daily limit once a week or more Exceeds both weekly & daily limits once a week or more Percent of U.S. adults aged 18 or older 72 % 2% 14 % 2% 10 %

The Odds of Having An Alcohol Use Disorder are Increased by a Factor of. . .
Abuse without dependence Reference group (1.0) 7.8 17.0 31.1 31.1 Dependence with or without abuse Reference group (1.0) 12.4 33.0 82.0 219.4

NIAAA National Survey on Alcohol and Related Conditions, (2001-2002)

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Harmful Drinking Pattern Across the Lifespan
Number of Days in Past 30 Drank 5 or More Drinks
National Institute on Alcohol Abuse and Alcoholism

4.5 4 3.5 3 2.5
Males Females

Days

2 1.5 1 0.5 0
12 13 14 15 16 17 18 19 20 21 22-23 24-25 26-29 30-34 35-49 50-64 65+

Age
U.S. Substance Abuse and Mental Health Services Administration, 2003 National Survey on Drug Use and Health (NSDUH)

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Relative Risk of an Alcohol-Related Health Condition as a Function of Daily Alcohol Intake
National Institute on Alcohol Abuse and Alcoholism
30 25

Relative Risk

50 g/day
20

100 g/day

15

10

5

0 Oral cavity and pharynx Esophagus Breast Essential hypertension Coronary heart disease Ischemic stroke Hemorrhagic Liver cirrhosis Chronic stroke pancreatitis

Condition
Adapted from Corrao et al. (2004), Preventive Medicine, 38:613–619

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National Institute on Alcohol Abuse and Alcoholism

Odds of Co-Occurrence of Current (12-month) DSM-IV Alcohol Dependence and Selected Psychiatric Conditions

Disorder
Anxiety Disorders Mood Disorders (especially Major Depression) Personality Disorders Antisocial Personality Disorder Drug Dependence Nicotine Dependence
NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2004.

Odds
2.6x 4.1x 4.0x 7.1x 36.9x 6.4x

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Burden of Disease Attributable to Alcohol Among the 10 Leading Risk Factors for Disease In Developed Countries
National Institute on Alcohol Abuse and lcoholism National Institute on Alcohol Abuse and AAlcoholism

Tobacco Blood pressure Alcohol Cholesterol Overweight Low fruit and vegetable intake Physical inactivity Illicit drugs Unsafe sex Iron deficiency
0% 2% 4% 6% 8% 10% 12% 14%

% Total Number of Health Years Lost to Death/Disability
The World Health Report 2002: http://www.who.int/whr/2002/en/whr2002_annex14_16.pdf

National Institute on Alcohol Abuse and Alcoholism

Alcohol Abuse
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Definition and Diagnostic Criteria for Alcohol Abuse/ Harmful Use of Alcohol
National Institute on Alcohol Abuse and Alcoholism

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DSM-IV Alcohol Abuse
A. A maladaptive pattern of alcohol use leading to
clinically significant impairment or distress, as manifested by one or more of the following occurring within a 12-month period:

ICD-10 Harmful Use
A. A pattern of alcohol use that is causing
physical and/or mental damage to health.

 recurrent drinking resulting in a failure to fulfill

major role obligations  recurrent drinking in physically hazardous situations*  recurrent alcohol-related legal problems  continued use despite having persistent or recurrent alcohol-related social or interpersonal problems

*Ninety percent of those diagnosed as having Alcohol Abuse endorse this criterion. Others are 20% or less (Dawson, DA. Unpublished NESARC Analysis, 2006)

B. The symptoms have never met the criteria for alcohol
dependence

B. No concurrent diagnosis of the alcohol
dependence syndrome

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National Institute on Alcohol Abuse and Alcoholism

Do Alcohol Use Disorders Fall Along a Continuum of Severity?
 Data from NIAAA’s two general population sample epidemiological

studies* and others (e.g., Langenbucher et al., 2004; Krueger et al., 2004; Kahler and Strong, 2006; Saha et al., 2006; Proudfoot et al., 2006) agree that:

 Alcohol Use Disorders are not bi-axial (abuse and dependence), but fall along a continuum of severity  Current criteria for alcohol abuse are not associated only with a milder form of alcohol use disorder; most tap into the more severe end of an alcohol use continuum  Current criteria for abuse and dependence contain redundancies
* NESARC and the 1991-1992 NIAAA National Longitudinal Alcohol Epidemiological Survey (NLAES)

National Institute on Alcohol Abuse and Alcoholism

Alcohol Dependence (Alcoholism)
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Elements of Alcohol Dependence: DSM-IV and ICD-10
(3 of 7 during one year required for diagnosis)
National Institute on Alcohol Abuse and Alcoholism

1. Tolerance 2. Withdrawal: relief/avoidance 3. Impaired control*
• larger/longer • unsuccessful attempts to

Pharmacological

quit/control

Maladaptive

4. Compulsive Use*
• craving (ICD-10) only) • neglect activities • time spent • use despite negative

Severity of Addiction

consequences
* elements of addiction

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Prevalence of Past-year DSM-IV Alcohol Dependence by Age United States, 2001-2002
National Institute on Alcohol Abuse and Alcoholism

14% 12%

One-Year Prevalence

10% 8% 6% 4% 2% 0%
12-17 18-20 21-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69

Most people seek treatment at this age

Prevalence of DSM-IV Alcohol Dependence in 2001-2002 was 3.8%

Age
18 + yrs. - NIAAA NESARC ( Grant et al. (2004) Drug and Alcohol Dependence, 74:223-234) 12-17 yrs - U.S. Substance Abuse and Mental Health Services Administration 2003 National Survey on Drug Use and Health (NSDUH)

National Institute on Alcohol Abuse and Alcoholism

Etiology of Alcohol Use Disorders
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National Institute on Alcohol Abuse and Alcoholism

Alcohol use, abuse, and dependence are complex behavioral traits influenced by many factors:
genetic and biological responses environmental influences stages of development, from childhood to early adulthood

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Alcoholism: A Common Complex Disease
National Institute on Alcohol Abuse and Alcoholism

additive, both alcohol specific and non-specific

Genes:60%

Environment: 40%
both shared and non-shared

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Developmental Trajectory of AUD
Initiation and Continuation of Drinking
National Institute on Alcohol Abuse and Alcoholism

Initiation of Drinking

Progression

Alcoholic Drinking

Extent of Influence

Environmental (familial and non familial) Personality/Temperament (Endophenotype) Pharmacological effects of ethanol (Intermediate Phenotypes)

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Gene-Environment Interactions in Alcohol Dependence
National Institute on Alcohol Abuse and Alcoholism

Genes + Environment =
different types of alcoholism with different characteristics and levels of severity
G1 1 E1 1 G2 2 E2 2 G3 3 E3 3 G4 4 E4 4 G5 5 E5 5

Alcohol Dependence (Severe)

G1 1 E1 1

G2 2 E3 3

G5 5 E4 4

Alcohol Dependence (Moderate)

Alcohol Dependence (Mild)

G2 2 E2 2

G4 4

G3 3 E2 2 E5 5

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National Institute on Alcohol Abuse and Alcoholism

Between Individual Variations in Responses to Alcohol (Why drink; Drink more; Drink despite) Pharmacokinetics: absorption, distribution, and metabolism of alcohol 3-4 fold Pharmacodynamics: subjective and objective responses to alcohol 2-3 fold

About one-half of these differences is genetic

Metabolism of Ethanol and Acetaldehyde in Hepatocyte
National Institute on Alcohol Abuse and Alcoholism

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CYTOSOL
ADH ADH CH3CH2OH (mM) NAD+ CH3CHO (μM) NADH
NAD+ NADH

ALDH1 ALDH1 CH3COOH (mM) CH3COOH (mM) ALDH2 ALDH2 CH3CHO
NAD+ NADH

NADH Shuttle

CH3COOH
NAD+ NADH

TCA TCA CO2 H2O

electron electron transport transport Energy Yield: 7 Kcals/g

ATP

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Age at Onset: DSM-IV Age of First Use of Alcohol, Nicotine, and Cannabis
National Institute on Alcohol Abuse and Alcoholism

Percentage in each age group who begin using alcohol

35% 30% 25% 20% 15% 10% 5% 0% 5 10 15 20 25

Age of First Alcohol Use Age at first Nicotine Use Age of First Cannabis Use

30

35

40

45

50

Age
Source: NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2003

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Prevalence of Lifetime Alcohol Dependence by Age of First Alcohol Use and Family History of Alcoholism
National Institute on Alcohol Abuse and Alcoholism

1991-1992 60

60 50

2001-2002

50
% Prevalence

40 30 20 10 0 13 14 15 16 17 18 19 20 21
Age at First Use of Alcohol

% Prevalence

40 30 20 10 0 <=13 14 15 16 17 18 19 20 >=21
Age at First Use of Alcohol

Source: Grant and Dawson. (1988). J. Substance Abuse, 10(2):163-73

Source: 2001-2002 National Epidemiologic Survey on Alcohol nad Related Conditions; Laboratory of Epidemiology and Biometry; DICBR, NIAAA, Bethesda, MD.

Parental History Positive Total Parental History Negative

Daily Consumption by P and NP Rats Responding on a TwoBar Operant Task for Water and Different Concentrations of Ethanol
National Institute on Alcohol Abuse and Alcoholism

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Ethanol ( ml/day) *p=<0.05 Water (ml/day) Murphy JM, Gatto GJ, McBride WJ, Lumeng L, Li TK ((1989). Alcohol. 6(2):127-31. 2 5 10 15 20 25 30 40

g/kg/day

% ethanol

National Institute on Alcohol Abuse and Alcoholism

Treatment of Alcohol Use Disorders
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Treatment of, and Recovery from, Alcohol Dependence
National Institute on Alcohol Abuse and Alcoholism

% PPY Population

• Many recover, or remit, without professional interventions • Early interventions are successful in reducing chronicity and severity • Treatment success rates are 30%-60% depending on outcome measure (e.g., abstinence, heavy drinking, social functioning) • Interventions include:

Past-year Status by Interval Since Onset of Dependence
100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% <5 5 to 9 10 to 19 20+ Interval (Years)
Dawson et al., (2005). Addiction. 2005 Mar;100(3):296-8. NIAAA National Epidemiological Survey on Alcohol and Related Conditions, 2001-2002
Still Dependent Asymptomatic risk drinker (subclinical dependence) Partial Remission Low-risk drinker

n=4,422
Abstainer

Brief intervention Behavioral therapies (e.g., motivational enhancement, cognitive behavioral, 12steps) Pharmacological therapies

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Heterogeneity of Treatment Populations: Severity
National Institute on Alcohol Abuse and Alcoholism

Screening
Prevention Facilitated self-change Brief counseling Behavioral and Medication Therapy

Disease management

None

At-risk*

Harmful use

Dependence (Early)

Dependence (Chronic)

* >4 drinks/day, 14 drinks/week (men) >3 drinks/day, 7 drinks/week (women)

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National Institute on Alcohol Abuse and Alcoholism

Clinical Trials in the Last Fifteen Years Have Shown:
• Different kinds of behavioral therapies work equally well (e.g., motivational enhancement, cognitive behavioral, 12-steps) • Naltrexone with Disease Management works and potentially can be used in primary care settings

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Behavioral Therapies
National Institute on Alcohol Abuse and Alcoholism

Treatment Intervention

Primary Target Population(s)
High-risk drinkers Alcohol abusers √ √ Alcohol- dependent √ √ √ √ √

Brief intervention Motivational enhancement therapy Cognitive behavioral therapy Couples (marital) and family therapies Community reinforcement

Selected References: Moyer et al. (2002) Addiction, 97: 279-292; Miller et al. (2002) Addiction, 97: 265-277; O’Farrell et al. (2000) J. Sub.Abuse Treat., 18: 51-54

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FDA Approved Medications for Treating Alcohol Dependence
National Institute on Alcohol Abuse and Alcoholism

Medication
Disulfiram

Target
Aldehyde Dehydrogenase

Year Approved
1949

Research from animal models over the past 25 years has provided promising targets for pharmacotherapy
Naltrexone Acamprosate Naltrexone Depot Mu Opioid Receptor Glutamate and GABARelated Mu Opioid Receptor 1994 2004 2006

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National Institute on Alcohol Abuse and Alcoholism

Medications for Treating Alcohol Dependence – Under Investigation
Medication
Topiramate Valproate Ondansetron Nalmefene Baclofen Antalarmin Rimonabant

Target
GABA/Glutamate GABA/Glutamate 5-HT3 Receptor Mu Opioid Receptor GABAB Receptor CRF1 Receptor CB1 Receptor

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National Institute on Alcohol Abuse and Alcoholism

Examples of NIAAA-Supported Clinical Pharmacotherapy Trials for AUDs and Co-morbid Psychiatric Conditions
Co-morbidities
AD/Depression AD/Bipolar AUD/anxiety disorders AD/schizophrenia AD/tobacco dependence AD/cocaine dependence

Medication(s)
naltrexone; sertraline valproate; naltrexone venlafaxine (Effexor) clozapine (Clozaril) bupropion (Zyban) topiramate (Topamax)

NIAAA Clinician’s Guide
Helping Patients Who Drink Too Much
National Institute on Alcohol Abuse and Alcoholism

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 Based on the AUDIT-C:
1. How often do you have a drink containing alcohol? 2. How many drinks containing alcohol do you have on a typical day when you are drinking? 3. How often do you have 6 or more drinks on an occasion?

 The third question alone is:

sensitive for heavy drinking (79%) and alcohol abuse/ dependence (81%) specific (83%) for heavy drinking, abuse and dependence1


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Bush et al, Arch Intern Med. 1998;158:1789-1795

Information and training materials for the NIAAA Clinician’s guide are available at: http://pubs.niaaa.nih.gov/publications/practitioner/CliniciansGuide2005/Guide_Slideshow.htm

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Conclusion: Alcohol Research Strengths and Opportunities
National Institute on Alcohol Abuse and Alcoholism

 Alcohol pharmacogenetics

human and animal models
 Animal models

genes, pathways and networks, and GxE interactions
 Epidemiology

longitudinal general population and high-risk studies
 Treatment

behavioral pharmacological