What Can Science Contribute to the Treatment of Alcoholism?

George F. Koob, Ph.D. Director

National Institute on Alcohol Abuse and Alcoholism National Institutes of Health

Flow of Talk 1. Conceptual Framework for Addiction: Stages of the Addiction Cycle 2. Neurobiological Circuits as Targets for Treatment 3. Current Treatments 4. Future Treatments

Addiction

Addiction — Defined as a chronically relapsing disorder

that is characterized by a compulsion to seek and take drug or stimulus, loss of control in limiting intake, and emergence of a negative emotional state (e.g. dysphoria, anxiety, irritability) when access to the drug or stimulus is prevented (here, defined as the “dark side” of addiction)

Stages of the Addiction Cycle

Treatment for Alcoholism

What We Know Works: • Screening and Brief Interventions • Family Therapy • Motivational Interviewing • Cognitive-Behavioral Therapy (CBT) • Mutual Help Groups • Aftercare/Continuing Care • Medications: Acamprosate (Campral) and Naltrexone (Vivitrol)

Conceptual Framework for Neurobiological Bases of the Transition to Excessive Drinking

Bottom Line

1. Addiction is an incentive salience-reward deficit disorder.

2. Addiction is a stress surfeit disorder.

3. Addiction is an executive function disorder.

•  1954 - Disulfiram (Antabuse) approved by the FDA for treatment of alcoholism

•  Prior to 1991 – less than half dozen clinical pharmacotherapy grants

•  After 1991- Request for Applications (RFA) issued leading to the

funding of 10 clinical pharmacological trials

•  1994 - Oral naltrexone approved by FDA •  2004 - Acamprosate approved by FDA •  2006 – Extended-release injectable naltrexone (Vivitrol) approved

by FDA •  2007 – NIAAA Clinical Investigations Group (NCIG) trial

established (three Phase 2 trials completed to date)

•  2013 – Nalmefene approved by EMA

Medications Development for Alcoholism-Milestones

Existing and Future Medications for Addiction: Binge/Intoxication Stage

Existing medications • disulfiram (Antabuse) • naltrexone (Vivitrol)

Future targets • partial agonists (intoxication blockers) • ghrelin

Existing and Future Medications for Addiction: Withdrawal/Negative Affect Stage

Existing medications • acamprosate (Campral)

Future targets • GABA modulators (homeostatic resetters) • CRF1 antagonists (stress reducers) • κ opioid antagonists (dysphoria reducer)

Existing and Future Medications for Addiction: Preoccupation/Anticipation “Craving” Stage

Existing medications • acamprosate (Campral)

Future targets • GABA modulators (homeostatic resetters such as gabapentin- Norontin) • CRF1 antagonists (stress reducers) • Glutamate modulators (habit reducers)

•  Mission: To improve the care and treatment of those affected by AUD, high-risk drinking, and alcohol-related medical disorders by supporting the development of effective and safe medications that are accepted and used by clinicians and patients.

•  Overall Goal: Translate promising medications from discovery to preclinical and human clinical testing to real-world effectiveness and implementation studies.

NIAAA Medications Development Program for Alcohol Use Disorder (AUD), High-Risk

Drinking, and Alcohol-Related Medical Disorders

Conceptual Framework For Medications Development Animal Models Group Human Laboratory Models Group NIAAA Clinical Investigation Group (NCIG) Network of Sites for Proof of Concept Trials

Molecular Targets

Animal Models

Human Laboratory

Models

Clinical Trials

Validation Process: Bidirectional Integration

National Center for Advancing Translational Science (NCATS)

Discovering New Therapeutic Uses (NTU) for Existing

Molecules Program

•  Applicants identify new uses for compounds from pharma’s “virtual medicine cabinet”

•  Participants include AstraZeneca, Janssen, Pfizer, and Sanofi

•  26 Agents available – including 12 for pediatric indications and 18 new agents

•  Memorandum of Understanding – Between NIH and Industry Partners

•  Industry partners provide pre-clinical and clinical supply including placebo

Screening & Brief Intervention for Adults

•  An evidence-based guide for primary health care practitioners to provide screening for their adult patients, provide brief intervention for risk drinkers, diagnose DSM-IV alcohol use disorders and provide treatment or referral to specialty treatment services.

•  The Guide makes it is easier for clinicians to address alcohol use with their patients.

•  The Guide provides up-to-date information on the latest evidence-based practices, including medications.

NIAAA Clinician’s Guide - 2005 Edition Updated in 2007

Screening & Brief Intervention for Youth

•  A brief, easy to score, empirically-based screen for risk, alcohol use, and problems that overcomes time constraints and other common barriers to youth alcohol screening.

•  It is based on just two questions – one about friends’ drinking and the other about personal drinking frequency. Analysis of data from more than 160,000 youth indicated these questions had the greatest predictive power.

•  The Guide is endorsed by the American Academy of Pediatrics.

•  A Medscape course based on the guide with CME credit is available – to date over 15,000 clinicians have been Medscape. certified.

NIAAA Alcohol Screening Guide

Vivian Faden Joanne Fertig Bob Huebner Raye Litten

Patricia Powell Kate Tepas-Wise Kenneth Warren

Bridget Williams-Simmons

Special Thanks

George F. Koob, Ph.D. Director

National Institute on Alcohol Abuse and Alcoholism National Institutes of Health

Thank You!