Prevalence of Alcohol Use Disorders 1st Round Reprint Version Prevalence of Alcohol Use Disorders NIAAA – National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) Any Alcohol Use Disorder 17.6 million (8.5%) Purpose: To provide current data on the prevalence of alcohol use disorders in the United States Key Points: The 12-month (2001-2002) prevalences of alcohol use disorders were determined by DSM-IV criteria of abuse and dependence through NIAAA diagnostic interviews (Alcohol Use Disorder and Associated Disabilities Interview Schedule [AUDADIS-IV]) of 43,093 respondents Currently, approximately 17.6 million adults (8.5%) in the United States meet the medical criteria for a diagnosis of an alcohol use disorder In the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), conducted by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) among adults in 2001-2002, it was estimated that 9.7 million persons (4.7%) were alcohol abusers 7.9 million persons (3.8%) were alcohol dependent Source: Grant BF, Stinson FS, Dawson DA, et al. Prevalence and co-occurrence of substance use disorders and independent mood and anxiety disorders:results from the National Epidemiologic Survey on Alcohol and Related Conditions. Arch Gen Psychiatry. 2004; 61:807-816. Alcohol Abuse 9.7 million (4.7%) Alcohol Dependence 7.9 million (3.8%) NIAAA= National Institute on Alcohol Abuse and Alcoholism Grant BF, et al. Arch Gen Psychiatry. 2004;61:807-816.

Epidemiology of Use and Abstention Percent This is a graph of past-year alcohol use and abstention as assessed by the first wave of NESARC. A age related decrease in alcohol use can be seen, with a particularly large drop late in life (after age 64).

Epidemiology of Heavy Use Women: > 1 drink / day Men: > 2 drinks / day Percent This is a graph of past year heavy drinking as assessed by the first wave of NESARC. Heavy drinking was defined as greater than one drink per day for women and greater than two drinks per day for men. Again, a strong, age-related decrease in heavy drinking is apparent.

12-mo. Prevalence of DSM-IV AUD Diagnoses This is a graph of past year AUDs as assessed by the first wave of NESARC. The dark portion of the bars represents alcohol dependence and the light portion of the bars represents alcohol abuse. Once again, there is a strong age-related decline in alcohol pathology. Especially notable is that fact that, for both men and women, alcohol dependence is twice as prevalent among 18-29 year olds as among any other age group. Men Women

Medications Approved in the US for Treatment of Alcohol Dependence Disulfiram (Antabuse): 1949 Naltrexone (ReVia): 1994 Acamprosate (Campral): 2004 Long-Acting Naltrexone (Vivitrol): 2006

Naltrexone Non-specific opioid receptor antagonist Dose dependent binding to m, d and k opioid receptors FDA approved as adjunctive pharmacotherapy for the treatment of alcoholism

Opioids Acute alcohol increases plasma b-Endorphin levels

Opioids Opioid antagonists reduce alcohol drinking

Clinical trials Naltrexone has been shown to Increase percentage of days abstinent from alcohol Reduce number of drinks/drinking day Increase time to relapse Decrease craving for alcohol

Naltrexone (Revia) in the Treatment of Alcohol Dependence 1st Round Reprint Version Naltrexone (Revia) in the Treatment of Alcohol Dependence 1.0 0.9 0.8 0.7 0.6 Cumulative Proportion with No Relapse 0.5 0.4 0.3 Naltrexone (N=35) Placebo (N=35) 0.2 0.1 0.0 SLIDE 41: Cumulative Relapse Rate Relapse rates presented as a survival analysis indicate a substantial difference between the placebo and naltrexone treated groups 56 1 2 3 4 5 6 7 8 9 10 11 12 Number of Weeks Receiving Medication Volpicelli et al., Arch Gen Psychiatry, 1992

Effect of Long-Acting Naltrexone on Maintenance of Abstinence 1st Round Reprint Version Effect of Long-Acting Naltrexone on Maintenance of Abstinence Subjects with 4-day lead-in abstinence 100 90 80 70 60 Percent without Relapse 50 40 30 p < 0.025 20 10 1 2 3 5 4 6 7 8 10 9 11 12 13 15 14 16 17 18 20 19 21 22 23 25 24 26 27 28 30 29 31 Weeks Placebo (n = 28) Vivitrex (n = 28)

COMBINE (Anton et al., 2006) ASAM, 2007

VA cooperative study From Krystal et al 2001

Cochrane review (Srisurapanont and Jarusuraisin 2002) NTX treatment can decrease the chance of alcohol relapse for 36% as compared to placebo treatment. In addition, the treatment is likely to reduce the chance of returning to drinking for 13%. Short-term treatment of NTX for alcoholism gives a meaningful benefit in preventing a relapse. Small to Modest efficacy!

Identifying predictors of robust treatment response to naltrexone could improve clinical practice

Potential predictors of naltrexone response Family history of alcoholism Monterosso et al., 2001; Rubio et al., 2005 OPRM1 m opioid receptor gene polymorphisms Oslin et al., 2003 Age of onset of alcohol abuse Rubio et al., 2005 Antisocial traits and heavier drinkers Rohsenow et al., 2007 Higher level of alcohol craving Volpicelli et al., 1995 Consistent drinking patterns Gueorguieva et al 2007

Laboratory models Human clinical laboratory paradigms can be used to model a variety of behaviors in controlled conditions. Careful experimental manipulations to understand the mechanisms underlying a behavior. Can be used to evaluate medication signals following a shorter treatment period

Laboratory models-Alcohol In the field of alcohol research, controlled human laboratory studies have been used to study different populations of drinkers (e.g., social drinkers, dependent drinkers, women, high-risk individuals), different types of cues (e.g., stress, social drinking, solitary drinking, peer influences), different types and schedules of alcohol (e.g., beer, wine, hard liquor, IV alcohol; fixed doses, scheduled administration, ad-lib drinking).

Laboratory models to study alcohol-naltrexone interactions Human laboratory-based paradigms have been used to evaluate naltrexone’s effects in Social drinkers e.g. Swift et al 1994, King et al 1997 Non-treatment seeking alcohol dependent drinkers e.g. Anton et al 2004; Drobes et al 2004, Krishnan-Sarin et al 2007, O’Malley et al 2002 Importantly, effects observed in laboratory studies similar to those seen in clinical trials

Alcohol Self-Administration Model (O’Malley, Krishnan-Sarin et al Day 0 Day 6 Day 7 Choice Block #1 5:00 pm Choice Block #2 6:00 pm 7 pm 4 pm Outpatient Treatment Alcohol Reactivity craving Ad-Lib Period 4 drinks per choice period (.015 g/dl) $12 tab per choice period Naltrexone pretreatment MET Intervention Discharge Priming Drink (.03 g/dl)

Naltrexone and FH of alcoholism From Krishnan-Sarin et al., 2007