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Alcohol Use, Abuse, and Dependence

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1 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

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

3 National Institute on Alcohol Abuse and Alcoholism Mission
NIAAA’s mission is to support and promote the best science on alcohol and health for the benefit of all. In this pursuit, we use multidisciplinary and transdisciplinary approaches to increase the understanding of normal and abnormal biology and behavior related to alcohol use, to improve diagnosis, prevention and treatment, and to enhance quality health care. The identification of research priorities and resource development areas for alcohol research is an ongoing process at NIAAA. For more information on our plans for the future, please click on the following link to the five year strategic plan:

4 Alcohol Use

5 Alcohol: Our Most Primitive Intoxicant
Egypt (el-Guebaly N, el-Guebaly A, 1981, Int J Addict., 16: ) 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: ) 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) Beverage alcohol is an ancient artifact of human culture and likely our most primitive intoxicant. Archaeologists have found evidence of fermented beverages of rice, honey and fruit in neolithic Chinese pottery dating to 7000 BC (McGovern et al., 2004, PNAS, 101: ), and scholars trace the origin of barley beer to Egypt, circa 4200 BC (el-Guebaly & el-Guebaly,1981, Int J Addict., 16: ). The historical record contains many references to wine, which figured prominently in ancient Greek and Roman religious ceremonies and celebrations, for example (Sournia J.C., 1990, A History of Alcoholism).

6 Ancient Warnings About Alcohol and Harmful Use Through the Ages
BC - Downfall of Egyptian and Chinese Empires and Dynasties attributed to excessive alcohol use BC- Grecian Scholars issued advisories on drunkenness and moderate drinking Plato – No use under age 18, between 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 The ancients were familiar with problems associated with excessive drinking and sought to protect their societies from alcohol’s ill effects. Excessive drinking was discouraged in ancient Greece, where it was customary to drink diluted wine – three parts water to one part wine. Drinking undiluted wine, or becoming drunk were behaviors attributed to barbarians (Nencini P. 1997, Subst Use Misuse, 32(1): 89-96). In the Laws of Plato, the 5th century BC Greek philosopher outlined appropriate behavior with regard to alcohol. Drinking was forbidden for those under 18, as a “precaution against the excitableness of youth.” Moderate drinking was allowed between ages 18 and 30, with no restrictions on drinking after age 40 (Plato, The Laws, Book II). During the Middle Ages, physicians began to describe specific pathologies resulting from excessive alcohol consumption. Muhammad Rhazes, a Persian physician of the 9th century AD, noted that regular drunkenness could result in delirium, hemiplegia, sudden death, and numerous other illnesses. In the 11th century AD, Simeon Seth, a physician in Constantinople, wrote that drinking wine to excess caused inflammation of the liver (Sournia J.C. 1990, A History of Alcoholism).

7 Total Per Capita Consumption in Gallons of Ethanol by State - United States, 2003
Today, modern epidemiological studies have amassed an extensive catalog of the adverse health and social harms caused by alcohol misuse, which is now universally recognized as a leading cause of morbidity and mortality. About 18 million Americans suffer from alcohol abuse or dependence, and alcohol-related problems cost U.S. society an estimated $185 billion annually. There is substantial regional variation in the patterns of alcohol consumption in the U.S. Lowest apparent per capita consumption is found in the Northeast and Mid-Atlantic regions. Lakins, N et al., (2005) Surveillance Report #73: Apparent Per Capita Alcohol Consumption: National, State, and Regional Trends, 1977– Available on the NIAAA Web site at

8 Cumulative Distribution of Alcohol Consumption in the United States
This slide illustrates the distribution of alcohol consumption in the United States. While the U.S. has a lower per capita consumption than many other countries, problems arise from the fact that a small percentage of the population consumes most of the alcohol. NIAAA National Epidemiological Survey on Alcohol and Related Conditions (NESARC) ( ).

9 Drinking Patterns: Rates and Risks 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 glass of , or 1.5 ounces of 80 proof distilled spirits . Moderate drinking is defined by the NIAAA as consuming up to two drinks per day for men and one drink per day for women and older adults.  While moderate drinking may offer some benefits to some individuals, drinking at this level poses real risks for others.  For example, women who are pregnant or considering pregnancy, persons driving or operating heavy machinery, and those taking one or more of the more than 150 medications that interact with alcohol should not drink even moderately.  Persons who are vulnerable to developing alcohol dependence should be encouraged to refrain from alcohol use.  

10 Drinking Patterns: Rates and Risks High-Risk Drinking
Nearly 3 in 10 U.S. adults engage in these high-risk drinking patterns1 Men: more than 14 drinks in a typical week more than 4 drinks on any day Women: more than 7 drinks in a typical week more than 3 drinks on any day Research reveals the importance of drinking patterns to alcohol outcomes. For example, alcohol’s acute effects arise from drinking too much, too fast. The resulting impaired brain function can lead to unintentional death and/or injury; violence and/or homicide; suicide; risky sexual behavior and/or sexual assault; and vandalism and property damage. Chronic effects comprising a broad array of organ damage-related ailments caused by drinking too much, too often, include cirrhosis of the liver; cardiovascular disease; pancreatitis; dementia; plus at least another 50 disease entities including alcohol dependence. 1 Source: NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2003

11 Drinking Patterns: Rates and Risks 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 Drinking in a manner that will cause intoxication clearly poses risks to the drinker.   A term frequently used to describe this pattern is binge drinking.  Different definitions have been used for this pattern of drinking. To provide clarification, the National Advisory Council on Alcohol Abuse and Alcoholism (NAC) in 2004 developed a standard definition for binge drinking as a pattern of drinking alcohol that brings the blood alcohol concentration to 0.08 gram percent (the legal limit for drinking and driving in all states) or above.  The NAC further noted that for a typical adult male, this BAC level may be obtained after the consumption of 5 drinks in a 2 hour period, and for females, 4 drinks in the same time period.   Binge drinking is common across most life stages.  Fifty percent of college students who drink engage in binge drinking, and twenty percent do so twice or more every three weeks.  More than two-thirds of binge drinking episodes in the U.S. occur among adults age 26 and older, and half of all binge drinking episodes occur among people who otherwise drink moderately.   

12 U.S. Adult Drinking Patterns and Risks 2001-2002: Odds Ratios
Alcohol screening limits—number of drinks: In a typical WEEK—14 (men), 7 (women) On any DAY— 4 (men), 3 (women) The Odds of Having An Alcohol Use Disorder are Increased by a Factor of. . . Drinking Pattern Percent of U.S. adults aged 18 or older Abuse without dependence Dependence with or without abuse Never exceeds the weekly or daily screening limits 72 % Reference group (1.0) Reference group Exceeds only the weekly limit 2 % 7.8 12.4 Exceeds only the daily limit less than once a week 14 % 17.0 33.0 Exceeds only the daily limit once a week or more 31.1 82.0 Exceeds both weekly & daily limits once a week or more 10 % 219.4 This slide illustrates how exceeding recommended daily and/or weekly alcohol limits affects risk for alcohol abuse and dependence among adults in the U.S. The abuse potential is magnified for those who begin drinking at young ages. Individuals who begin drinking in their early teens have a much greater risk of becoming alcohol dependent at some point in their lives, and also are at greater risk of developing dependence more quickly and at younger ages, than people who start drinking at age 21 (Hingson et al. (2006), Arch Pediatr Adolesc Med., 160(7): ). NIAAA National Survey on Alcohol and Related Conditions, ( )

13 Harmful Drinking Pattern Across the Lifespan Number of Days in Past 30 Drank 5 or More Drinks
This slide illustrates the distribution of harmful drinking patterns, by gender, in the United States, and serves as a guide for alcohol policy and prevention. A wide range of alcohol policies may affect alcohol consumption and other behaviors relating to alcohol, and can have important influences on public health outcomes.  In the United States, laws, regulations, and jurisprudence address various aspects of alcohol use ranging from alcohol taxation to behaviors affected by alcohol, such as drinking and driving.  Scientific research has identified a number of alcohol-related policies that have significant effects on public health outcomes.  Examples of these include a reduction in the number of traffic fatalities (by raising the minimum drinking age to 21, enforcing stricter drinking and driving penalties), a reduction in child abuse and sexually transmitted diseases (by raising taxes on alcohol beverages), and enhancement of access to alcohol treatment programs (State-mandated provision in health care financing).  In general, alcohol policies are designed to serve individuals at all levels of the lifespan through harm reduction and prevention of alcohol-related illness or injury. U.S. Substance Abuse and Mental Health Services Administration, 2003 National Survey on Drug Use and Health (NSDUH)

14 Relative Risk of an Alcohol-Related Health Condition as a Function of Daily Alcohol Intake
Corrao, et al (2004) recently reviewed the dose–risk relationship between alcohol consumption and major alcohol-related diseases. The review found that in general, disease risks begin to rise with any drinking and increase further with higher intake. Risk increases significantly for drinkers, beginning at an intake of 25 g per day, for cancers of the oral cavity and pharynx, esophagus, larynx, breast, liver, colon, and rectum, as well as liver cirrhosis, hypertension, chronic pancreatitis, and injuries and violence. The risk of hemorrhagic stroke increases significantly at 50 g per day and 100 g per day. The risk of ischemic stroke increases at 100 g per day. Coronary heart disease risk decreases significantly at 25 g per day and 50 g per day, and increases at 100 g per day. Adapted from Corrao et al. (2004), Preventive Medicine, 38:613–619

15 Odds of Co-Occurrence of Current (12-month) DSM-IV Alcohol Dependence and Selected Psychiatric Conditions Disorder Odds Anxiety Disorders 2.6x Mood Disorders (especially Major Depression) 4.1x Personality Disorders 4.0x Antisocial Personality Disorder 7.1x Drug Dependence 36.9x Nicotine Dependence 6.4x In addition to the many adverse health effects that result directly from alcohol misuse, co-morbid conditions often present further complications for individuals with alcohol abuse problems. Alcohol abuse and dependence commonly occur in individuals who suffer from mood, anxiety, and personality disorders as well as the effects of other drugs of abuse.   For example, an estimated 90% of cocaine addicts have alcohol problems. It also has been estimated that as many as 60% of patients presenting at community mental health centers have co-morbid alcohol and other drug abuse disorders.  Patients suffering from both disorders often have poorer treatment outcomes and are more likely to drop out of treatment. Unfortunately, effective pharmacological and behavioral treatments have yet to be established for the various conditions of co-morbid alcohol and other drug abuse disorders. The high co-morbidity between alcohol and tobacco dependence poses special problems.  Fifty to ninety percent of alcoholics smoke, a rate that is three times higher than among the population as a whole.  Alcoholics smoke heavily, are more addicted to nicotine and are less successful at quitting smoking, which puts them at a greater risk for the synergistic effects of alcohol and nicotine on the development of certain cancers and cardiovascular diseases. NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2004.

16 National Institute on Alcohol Abuse and Alcoholism
Burden of Disease Attributable to Alcohol Among the 10 Leading Risk Factors for Disease In Developed Countries The World Health Organization ranks alcohol third among preventable risk factors for premature death in developed nations. The international community is taking action to reduce alcohol-related morbidity and mortality. The World Health Report 2002:

17 Alcohol Abuse

18 Definition and Diagnostic Criteria for Alcohol Abuse/ Harmful Use of Alcohol
DSM-IV Alcohol Abuse ICD-10 Harmful Use 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: 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 B. The symptoms have never met the criteria for alcohol dependence B. No concurrent diagnosis of the alcohol dependence syndrome  Since the early 1900s, numerous definitions of Alcohol Use Disorders (AUD’s) have been proposed.  Currently, in the United States, the clinical standard used for defining and diagnosing AUD’s is the American Psychiatric Association’s Diagnostic and Statistical Manual, Fourth Edition (DSM-IV). Definitions of alcohol abuse (this slide) and dependence (slide 21) appearing in the DSM-IV both describe maladaptive patterns of alcohol use leading to clinically significant impairment or distress.  In this slide, criteria for abuse are compared to criteria for harmful use of alcohol as defined by the World Health Organization’s International Classification of Disease. Of the 8.5% of U.S. adults (17.6 million people) who met diagnostic criteria for Alcohol Use Disorders in , 4.65% (9.7 million) were classified with Alcohol Abuse and 3.81% (7.9 million) were classified with Alcohol Dependence. *Ninety percent of those diagnosed as having Alcohol Abuse endorse this criterion. Others are 20% or less (Dawson, DA. Unpublished NESARC Analysis, 2006)

19 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 Many contemporary researchers have questioned the arbitrary differentiation between the DSM-IV alcohol abuse and dependence categories.  Determining whether abuse and dependence symptom criteria represent distinct dimensions, or are related to the same underlying dimension or construct, will be important in future nosologic work in this area. In addition, several studies have suggested that alcohol abuse is not a prodrome or precursor of alcohol dependence. * NESARC and the NIAAA National Longitudinal Alcohol Epidemiological Survey (NLAES)

20 Alcohol Dependence (Alcoholism)

21 Elements of Alcohol Dependence: DSM-IV and ICD-10 (3 of 7 during one year required for diagnosis)
1. Tolerance 2. Withdrawal: relief/avoidance Pharmacological 3. Impaired control* Maladaptive larger/longer unsuccessful attempts to quit/control 4. Compulsive Use* craving (ICD-10) only) neglect activities time spent use despite negative consequences Severity of Addiction Alcohol Dependence is a complex disease characterized by a persistent and progressive pattern of abnormally intense alcohol-seeking behavior that, over time, results in loss of control over drinking, a preoccupation with drinking, compulsive use, and the development of tolerance and dependence. The current diagnosis for alcohol dependence or alcoholism is categorical (3 out of 7 cut point). Recent publications are convincing that existing criteria can be scaled across a continuum representing severity of dependence. At best, only one of the four DSM abuse criteria map to mild dependence and three to severe dependence. * elements of addiction

22 Prevalence of DSM-IV Alcohol Dependence in 2001-2002 was 3.8%
Prevalence of Past-year DSM-IV Alcohol Dependence by Age United States, Prevalence of DSM-IV Alcohol Dependence in was 3.8% Alcohol Dependence is a common disorder. The data shown here are from the NIAAA National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) and a national survey of adolescents conducted by the Substance Abuse and Mental Health Services Administration. NESARC is a representative sample of the U.S. population including 43,093 individual over the age of 18 from non-institutionalized households. More information can be found on the following websites: 18 + yrs. - NIAAA NESARC ( Grant et al. (2004) Drug and Alcohol Dependence, 74: ) 12-17 yrs - U.S. Substance Abuse and Mental Health Services Administration 2003 National Survey on Drug Use and Health (NSDUH)

23 Etiology of Alcohol Use Disorders

24 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 The initiation and continuation of alcohol use by an individual is influenced by numerous factors, chiefly the individual’s genetic makeup, the environments to which he or she is exposed, and complex mechanisms through which genes interact with one another and with the environment.   These same factors determine an individual’s pattern of alcohol consumption and the risks for developing alcohol dependence (alcoholism) or other alcohol use disorders.     Research has also revealed that neither genetic nor environmental factors are static.  That is, the emergence and progression of drinking behavior and of drinking consequences are influenced by multiple ongoing changes in biology, physiological and psychological development, and environment that occur over the course of a person’s life.  These observations are in accord with a broader recognition that human development continues throughout life, rather than stopping after adulthood is reached.  The influence of alcohol on biology and behavior is dynamic and changes as an individual moves from childhood into adolescence and through the various stages of adulthood.

25 Alcoholism: A Common Complex Disease
 More than three decades of research has firmly established that genetic factors account for more than half of the risk for alcoholism and environmental factors account for the remainder. This statement, however, belies the true complexity of the mechanisms underlying the risk for, and protection against, alcohol abuse and alcohol dependence.  Genes and environmental factors interact in very complex ways.

26 Initiation of Drinking
Developmental Trajectory of AUD Initiation and Continuation of Drinking Initiation of Drinking Progression Alcoholic Drinking Extent of Influence The initiation and continuation of alcohol use by an individual is influenced by numerous factors, chiefly the individual’s genetic makeup, the environments to which he or she is exposed, and complex mechanisms through which genes interact with one another and with the environment.   These same factors determine an individual’s pattern of alcohol consumption and the risks for developing alcohol dependence (alcoholism) or other alcohol use disorders.     Environmental (familial and non familial) Personality/Temperament (Endophenotype) Pharmacological effects of ethanol (Intermediate Phenotypes)

27 Gene-Environment Interactions in Alcohol Dependence
As with many other complex diseases, there is no single genetic or environmental factor that can fully account for the risk of alcoholism.  The development of such complex behavioral and other medical disorders likely depends upon the specific genetic factors interacting with one another, the interaction of multiple environmental risk factors, and the interaction of genetic and environmental factors. The combinations of genetic and environmental factors may produce syndromes of varying intensity.

28 About one-half of these differences is genetic
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 Individuals differ in how fast they metabolize alcohol (pharmacokinetics) and in the extent to which they are affected by a given dose of alcohol (pharmacodynamics).   These individual differences affect drinking behavior, the potential for the development of alcohol dependence, and the risk for developing alcohol-induced organ damage.  Therefore, understanding these differences will provide important information about alcohol’s health effects throughout the lifespan.   About one-half of these differences is genetic

29 Metabolism of Ethanol and Acetaldehyde in Hepatocyte
The major pathway for the metabolism of alcohol is found in the liver and involves the enzyme alcohol dehydrogenase (ADH).  Alcohol is metabolized to acetaldehyde, a highly reactive and potentially toxic molecule.  In most circumstances, acetaldehyde is rapidly metabolized by another enzyme, aldehyde dehydrogenase (ALDH) to acetate.  Because of the rapid enzymatic conversion of acetaldehyde to acetate, the concentration of acetaldehyde in the cell is typically a thousand-fold lower than that of alcohol, and the eventual product of this pathway, acetate.  Both alcohol and acetate are found at millimolar levels following drinking, while acetaldehyde is found at micromolar concentrations.  [The legal intoxicating blood alcohol level in all states in the U.S. is 80 mg%, which is 17.4 mM.  The normal baseline level for acetaldehyde in humans is 9 µM, or 40 µgram%.  After alcohol ingestion, the acetaldehyde level in most individuals will increase to µM, or 90 – 130 µgram%.  Metabolism of a dose of alcohol achieving a blood alcohol concentration of 80 mg% may result in elevation of tissue acetate levels by 100 mg%.]  When the level of acetaldehyde increases, an individual may experience very dysphoric feelings and the potential for toxic reactions with various cellular components increases.

30 Age at Onset: DSM-IV Age of First Use of Alcohol, Nicotine, and Cannabis
Adolescents are the healthiest cohort in the population in terms of organic disease but, at the same time, they experience relatively high rates of mortality and morbidity due to their behavior, including the use of alcohol.  Across many species including humans, adolescence is a time of heightened risk-taking and for many young people in our society, some of that risk-taking involves alcohol use.  Further, adolescence is a period of increasing socialization often involving alcohol.  For some, the increased social demands of adolescence may be accompanied by increased anxiety heightening the risk for alcohol use.  In this way, alcohol use has become intertwined with the normal developmental processes of adolescence.  And alcohol use both affects development and is affected by developmental processes. Source: NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2003

31 Prevalence of Lifetime Alcohol Dependence by Age of First Alcohol Use and Family History of Alcoholism Some of the first evidence of the importance of the lifespan perspective for understanding alcohol use disorders emerged less than ten years ago in an analysis of data derived from NIAAA’s National Longitudinal Alcohol Epidemiologic Study (NLAES).  This analysis indicated that persons who begin drinking at younger ages have a significantly increased risk for the development of alcoholism. This finding was replicated in the recent NESARC study, as shown in this slide. These data show that young people who begin drinking before age 15 were four times more likely to develop alcohol dependence during their lifetime than those who begin drinking at age 21.  This is true for individuals from families where a parent had a history of alcoholism (Parental History Positive) and for individuals with no parental history of alcoholism (Parental History Negative).  Therefore, while parental history clearly contributes to the risk for developing alcoholism, likely a reflection of genetic risk factors, early initiation of drinking is also an important predictor of risk for the eventual development of alcoholism. Parental History Positive Total Parental History Negative

32 Daily Consumption by P and NP Rats Responding on a Two-Bar Operant Task for Water and Different Concentrations of Ethanol % ethanol Water (ml/day) ( ml/day) g/kg/day Ethanol 2 5 10 15 20 25 40 30 *p=<0.05 The search for both genetic and environmental risk factors includes both human population genetics investigation, as well as studies involving animal models.  Specifically, selected animal strains are used to model the endo- and intermediate phenotypes involved in the development of human alcohol dependence.   While animal models of alcohol tolerance and alcohol preference have been developed in the past, refinement of current models is still required in order for them to more closely parallel those features of the clinical syndrome phenotype, including modeling such contributing traits as anxiety, propensity for relapse, and obsessive-compulsive behaviors such as craving. Murphy JM, Gatto GJ, McBride WJ, Lumeng L, Li TK ((1989). Alcohol. 6(2):

33 Treatment of Alcohol Use Disorders

34 Treatment of, and Recovery from, Alcohol Dependence
In the U.S., only a small proportion of individuals with Alcohol Use Disorders seek or receive treatment for their alcohol problems. Epidemiological data suggest that in any given year only about 12% seek help for their drinking (broadly defined to include a spectrum of help ranging from Alcoholics Anonymous to specialized alcoholism treatment). Over the course of their lifetime, only 24% receive any kind of treatment. When people do seek treatment, they typically do so between the ages of 40 and 44 years. Thus, the existing treatment system tends to accommodate middle-aged individuals, despite the peak prevalence for AUDs among younger individuals (Grant et al., 2004, Drug and Alc Dep., 74: ). Many younger persons “mature out” of AUDs as they age, and many drinkers recover or remit from AUD without any professional intervention. Some investigators have referred to this phenomenon as “natural recovery.” Of persons with “past” Alcohol Dependence in the survey year, 25% were still dependent, 27.3% were in partial remission, 11.8% were asymptomatic risk drinkers, 17.7% were low-risk drinkers, and 18.2% became complete abstainers (Dawson et al.,2005, Addiction, 100(3): ). To further illustrate the natural history of Alcohol Dependence, the inset displays past-year drinking status of the NESARC survey population by interval since Alcohol Dependence onset. In , 64.9% of those who had experienced dependence onset within the past 5 years remained dependent compared with only 6.9% of those who had experienced an onset of dependence 20 or more years earlier. Similarly, only 6.0% of persons with recent onset were abstinent or low-risk drinkers compared with 61.0% of those whose dependence originated 20 or more years earlier.

35 Heterogeneity of Treatment Populations: Severity
There is no single definition for “severity” of alcohol use disorders. For some, it represents the magnitude of psychosocial or biomedical consequences; others measure severity in terms of DSM or ICD symptom counts. Some investigators view severity in terms of chronicity of the disorder or the actual quantity of alcohol consumed. With this caveat in mind, this slide suggests a spectrum of interventions that could be applied based upon the clinical severity of the disorder. For at-risk drinkers and persons with hazardous use of alcohol, clinicians may facilitate self-change through brief counseling to prevent complications and the progression to a more severe disorder. For those with early to chronic Alcohol Dependence, a range of behavioral and pharmacological therapies are available, with increasingly intensive interventions for increasing severity. As with other chronic illnesses, the most severe cases require intermittent or sustained disease management.

36 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 Most individuals who seek alcoholism treatment do so during the midlife period.  Currently available treatments, which include behavioral therapies and those that employ behavioral treatment with newly available medications, help many such individuals successfully recover from alcohol dependence.  With minor exceptions, therapeutic approaches using different models yield similar results, and there is only minimal interaction with a wide variety of demographic and clinical patient characteristics.

37 Primary Target Population(s)
Behavioral Therapies 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 Historically, research on professional psychosocial interventions focused first on development of theoretical frameworks to explain change and to direct intervention efforts. Examples of such frameworks include cognitive-behavioral, twelve-step, and motivational enhancement. Subsequent research in this area included studies to refine the internal validity of studies of these frameworks using therapy manuals, training, and monitoring; development and use of well-validated and reliable instruments; and improved research designs such as randomized controlled trials. The results were unexpected: treatments with very different conceptual frameworks and intervention techniques have approximately equivalent (and reasonably good) outcomes (e.g., abstinence or significantly decreased drinking and consequences). Furthermore, relatively brief, non-intensive treatments yield outcomes as good as more intensive treatments. These results suggest that non-specific factors such as a decision to seek help, installation of hope, empathy and the therapeutic alliance may be more important than specific factors hypothesized by treatment models. Selected References: Moyer et al. (2002) Addiction, 97: ; Miller et al. (2002) Addiction, 97: ; O’Farrell et al. (2000) J. Sub.Abuse Treat., 18: 51-54

38 FDA Approved Medications for Treating Alcohol Dependence
Target Year Approved Disulfiram Aldehyde Dehydrogenase 1949 Research from animal models over the past 25 years has provided promising targets for pharmacotherapy Naltrexone Mu Opioid Receptor 1994 Acamprosate Glutamate and GABA-Related 2004 Naltrexone Depot 2006 While for many years alcoholism treatment approaches relied almost exclusively on behavioral therapy, efforts to develop medications for alcohol use disorders have expanded rapidly in recent years. Three agents are now approved for use in the United States and many other countries. As is the case with medications for other chronic diseases, these medications have been found to be highly effective with some patients but others have failed to respond to them. 

39 Medications for Treating Alcohol Dependence – Under Investigation
Target Topiramate GABA/Glutamate Valproate Ondansetron 5-HT3 Receptor Nalmefene Mu Opioid Receptor Baclofen GABAB Receptor Antalarmin CRF1 Receptor Rimonabant CB1 Receptor New medications that provide effective therapy to a broader spectrum of alcoholic individuals would be of value for the treatment of alcohol dependence.  Research findings revealing that drinking and alcohol-seeking behavior are influenced by multiple neurotransmitter systems, neuromodulators, hormones, and intracellular networks provides evidence that there are a number of potential target sites for which new pharmaceuticals may be developed. Potential target sites include neurotransmitter systems related to opioids, serotonin, dopamine, glutamate, gamma-aminobutyric acid (GABA), cannabinoids, the hypothalamic-pituitary-adrenal (HPA) axis, adenosine, neuropeptide systems (for example, neuropeptide Y, corticotrophin releasing factor), signal transduction pathways (such as, protein kinase A and protein kinase C); and gene transcription factors (delta fos B and cAMP response element-binding protein [CREB]).  Indeed, many such agents are under investigation. 

40 Examples of NIAAA-Supported Clinical Pharmacotherapy Trials for AUDs and Co-morbid Psychiatric Conditions Co-morbidities Medication(s) AD/Depression naltrexone; sertraline AD/Bipolar valproate; naltrexone AUD/anxiety disorders venlafaxine (Effexor) AD/schizophrenia clozapine (Clozaril) AD/tobacco dependence bupropion (Zyban) AD/cocaine dependence topiramate (Topamax) As stated earlier, alcoholics more often than not present to treatment with comorbid conditions, most often illicit drug dependence, nicotine dependence, antisocial personality disorder, mood and affective disorders (especially major depression), and anxiety disorders (Grant et al., 2004, Drug and Al Dep., 74: ). Although the development of pharmacologic strategies to treat comorbid alcoholics is at an early stage, some advances are noteworthy. As noted previously, disulfiram for comorbid alcohol and cocaine dependence shows promise, and research is underway to evaluate topiramate for the same population. Similarly, researchers during the past two decades have shown that the selective serotonin reuptake inhibitors (SSRIs) ameliorate symptoms of depression, anxiety, or both conditions in at least some subpopulations of alcohol dependent patients (Pettinati et al., 2000, Alc. Clin. and Exp. Res., 24(7): ) and, importantly, do not lower seizure thresholds as do tricyclic antidepressants. However, despite some initial positive indications, SSRIs have not been shown to beneficially affect core symptoms of alcohol dependence (Garbutt et al. 1999, JAMA,281(14): ; Nunes and Levin 2004, JAMA, 291(15): ). Current NIAAA-supported studies that explore the use of existing medications to treat comorbid conditions include those in this slide. The high comorbidity between alcohol and tobacco dependence poses special problems for alcoholism treatment. In addition to exacerbating health risks, smoking affects the process and course of alcoholism recovery and may serve as a precipitant to relapse. So far, first-line pharmacologic treatment for tobacco dependence, such as nicotine replacement and bupropion, have shown limited efficacy in alcoholic smokers; consequently, a need exists to develop effective drug therapies for co-occurring alcohol and nicotine dependence.

41 NIAAA Clinician’s Guide Helping Patients Who Drink Too Much
Based on important studies in alcohol treatment research, NIAAA has published a guide for primary care physicians, nurses, and other front line health and mental health care professionals. This guide incorporates findings from the NESARC study of alcohol problem incidence and prevalence, numerous clinical trials on the efficacy of brief intervention, and results of project COMBINE, a large multi-site trial of alcohol treatment combining medications and behavioral strategies.

42 Conclusion: Alcohol Research Strengths and Opportunities
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 In conclusion, while much has been discovered over the past 30 years about the nature and extent of alcohol use disorders and their treatment, there is still much more to be learned. The most promising avenues of research on alcohol abuse and alcoholism are outlined in this slide. Multidisciplinary and transdisciplinary approaches, if applied in the most strategic manner, will increase understanding in many areas: normal and abnormal biology and behavior related to alcohol use; improved diagnosis, prevention, treatment, and finally, enhanced quality healthcare for all. For more information, go to the NIAAA web site:

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