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National Institute on Alcohol Abuse and Alcoholism Alcohol Research and Health: Preventing and Treating Alcoholism and Alcohol-Related Disorders Ting-Kai Li, M.D. Director, National Institute on Alcohol Abuse and Alcoholism (NIAAA) National Institutes of Health U.S. Department of Health and Human Services September 6, 2006 Washington, D.C. and Alcoholism Institute National National Institut e ononAAlcohol lcoholAbuse Abuse and Alcoholism 2 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 and Alcoholism Institute National National Institut e ononAAlcohol lcoholAbuse Abuse and Alcoholism 3 Extent of Alcohol-Related Health Problems in the United States 18 million Americans (8.5% of the population age 18 and older) suffer from alcohol abuse or dependence Actual Causes of Death, United States - 2000 18.1% Tobacco Poor Diet and physical inactivity 15.2% Alcohol Consumption Alcohol Consumption 3.5% 3.1% Microbial agents 2.3% Toxic agents Over 4 million of our young (18% of the population ages 12-17) report drinking monthly with more than half engaging in high-risk drinking patterns Motor vehicle Firearms 1.8% Actual Causes of Death are the major external (nongenetic) modifiable factors that contribute to death in the United States 1.2% Sexual behavior 0.8% Illicit drug use 0.7% Mokdad AH, Marks JS, Stroup DF, Gerberding JL. JAMA (2004). 29:1238-45; Mokdad AH, Marks JS, Stroup DF, Gerberding JL. (2005). JAMA 19;293:293-4. Alcohol consumption was the third leading actual cause of death in 2000 (an estimated 85,000 deaths annually) Alcohol problems cost U.S. society an estimated $185 billion annually Prevalence of Past-year DSM-IV Alcohol Dependence by Age United States, 2001-2002 14% 12% One-Year Prevalence and Alcoholism Institute National National Institut e ononAAlcohol lcoholAbuse Abuse and Alcoholism 4 10% 8% Most people seek treatment at this age 6% 4% Prevalence of DSM-IV Alcohol Dependence in 2001-2002 was 3.8% 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 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) and Alcoholism Institute National National Institut e ononAAlcohol lcoholAbuse Abuse and Alcoholism 6 Heterogeneity of Drinking Behavior: Diagnosis Alcohol use disorders 8.5% of the population None At-risk Harmful use Dependence (Early) Dependence (Chronic) Exceeds daily limits* with increasing frequency Never exceeds daily limits No current symptoms (problems) Current symptoms *Daily limits: up to 5 (men)/4 (women) • Current symptoms • Severe • Withdrawal • Co-morbidity • Relapsing Treatment of, and Recovery from, Alcohol Dependence 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) Past-year Status by Interval Since Onset of Dependence n=4,422 100% Abstainer 90% % PPY Population and Alcoholism Institute National National Institut e ononAAlcohol lcoholAbuse Abuse and Alcoholism 7 80% 70% Low-risk drinker 60% 50% Asymptomatic risk drinker (subclinical dependence) 40% 30% Partial Remission 20% 10% 0% Still Dependent <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 Interventions include: Brief intervention Behavioral therapies (e.g., motivational enhancement, cognitive behavioral, 12-steps) Pharmacological therapies and Alcoholism Institute National National Institut e ononAAlcohol lcoholAbuse Abuse and Alcoholism 8 Inherent Heterogeneity of Alcohol Dependence Alcoholism is a common complex disease involving the interplay of genetic and environmental factors 60% genetic, both alcohol specific and non-specific Gene-Environment Interactions in Alcohol Dependence Genes + Environment = different types of alcoholism with different characteristics and levels of severity G11 G22 G33 G44 G55 E11 E22 E33 E44 E55 Alcohol Dependence (Severe) G11 G22 E11 E33 G55 E44 Alcohol Dependence (Moderate) G22 Alcohol Dependence (Mild) G33 G44 E22 40% environment, both shared & non-shared E22 E55 and Alcoholism Institute National National Institut e ononAAlcohol lcoholAbuse Abuse and Alcoholism 9 Heterogeneity of Treatment Populations: Severity Facilitated self-change Brief counseling Behavioral &Medication Therapies Disease management Prevention None At-risk Harmful use Dependence (Early) Dependence (Chronic) and Alcoholism Institute National National Institut e ononAAlcohol lcoholAbuse Abuse and Alcoholism 10 Heterogeneity of Treatment Populations Co-occurring disorders drug dependence nicotine dependence antisocial personality disorder mood disorder (especially major depression) anxiety disorders 37x 7x 6x 4x 3x and Alcoholism Institute National National Institut e ononAAlcohol lcoholAbuse Abuse and Alcoholism 11 Helping Patients Who Drink Too Much: A Clinician's Guide 2005 Products Coming Soon ● Updated medications information incorporating the approval of a long-acting injectable form of naltrexone and results from Project COMBINE ● Medications management support tool kit for non-specialists prescribing medications for alcohol dependence ● Additional online support including a dedicated web page for the Guide and related resources http://www.niaaa.nih.gov and Alcoholism Institute National National Institut e ononAAlcohol lcoholAbuse Abuse and Alcoholism 12 FDA Approved Medications for Treating Alcohol Dependence Medication Target Disulfiram Aldehyde Dehydrogenase Year Approved 1949 Research from animal models over the past 25 years has provided promising targets for pharmacotherapy Naltrexone Mu Opioid Receptor 1994 Acamprosate Glutamate and GABARelated 2004 Naltrexone Depot Mu Opioid Receptor 2006 and Alcoholism Institute National National Institut e ononAAlcohol lcoholAbuse Abuse and Alcoholism 13 Multiple Neurotransmitter Systems Involved in Multiple Aspects of Alcohol Use Behavior Yield Multiple Promising Targets Reward Stress/Anxiety Disinhibition opioid neuropeptide Y serotonin CRF dopamine nociceptin cannabinoid norepinephrine glutamate GABA and Alcoholism Institute National National Institut e ononAAlcohol lcoholAbuse Abuse and Alcoholism 14 Medications for Treating Alcohol Dependence – Under Investigation Medication Target Topiramate GABA/Glutamate Valproate GABA/Glutamate Ondansetron 5-HT3 Receptor Nalmefene Mu Opioid Receptor Baclofen GABAB Receptor Antalarmin CRF1 Receptor Rimonabant CB1 Receptor and Alcoholism Institute National National Institut e ononAAlcohol lcoholAbuse Abuse and Alcoholism 15 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) and Alcoholism Institute National National Institut e ononAAlcohol lcoholAbuse Abuse and Alcoholism 16 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 and Alcoholism Institute National National Institut e ononAAlcohol lcoholAbuse Abuse and Alcoholism 17 Phases of Medications Development Supported by NIAAA And Industry Preclinical Studies Clinical Studies Discovery Screening Phase 1 Phase 2 Neuroscience Animal Models Safety & dosage Efficacy & side effects Phase 3 Efficacy verification & safety Phase 4 ● Postmarketing effectiveness & safety ● New indications Supported by NIAAA Public-Private Partnership and Alcoholism Institute National National Institut e ononAAlcohol lcoholAbuse Abuse and Alcoholism 18 Personalized Medicine Improve Disease Phenotyping risk factor identification scalable criteria and markers for severity of disease Improve Understanding of Relationship of Alcohol and Co-occurring Brain Disorders Pharmacogenomics – genetic variations in response to medications