What Science Can Teach Us About The

Treatment of Alcohol Use Disorders

George F. Koob, Ph.D.

Director

National Institute on Alcohol Abuse and Alcoholism

American Society of Clinical Psychopharmacology

5-30-19

Cost and Scope of Alcohol-Related Problems in US

• In 2017, 5.7% (14.1 million) of

people 18+ reached criteria for

alcohol use disorder (AUD)

• ~ 88,000 people die annually

from alcohol-related causes

• ~ 50% of all liver disease deaths

attributable to alcohol misuse

• Increase in the intensity of

binge drinking, ED visits and

hospitalizations in last 10 years

• <10% of people with AUD get

any treatment and fewer than

4% receive pharmacotherapy

Sources: Prevalence – NSDUH (2017) ages 18+ using DSM-IV criteria, NCI (2014), CDC (2016); Cost – CDC (2015), National Drug Intelligence

Center - National Drug Threat Assessment (2011), 2014 Surgeon General’s Report, NHLBI (2012), Hutchinson et al, 2006, Hingson et al, 2017

1.2

14.5

28.6

6.6

14.1

0 20 40

HIV/AIDS

Cancer

Tobacco

Illicit drugs

Alcohol

Millions in the US

Prevalence of disorder/disease

36

217

295

193

249

0 200 400

HIV/AIDS

Cancer

Tobacco

Illicit drugs

Alcohol

Billions of dollars

Cost to society

“Deaths of Despair”

Source: Case, A and Deaton, A (2015) Rising morbidity and mortality in midlife

among white non-Hispanic Americans in the 21st century. PNAS 112: 15078-

15083.

Flow of Talk1. The Science: Neurocircuitry Overview of Alcohol Use Disorder (AUD)- Neurofunctional domains, Hyperkatifeia

3. Diagnosis: Addiction Neuroclinical Assessment, Alcohol Biosensor

4. Treatment: Novel Treatments for AUD and ALD

5. Emerging Challenges for AUD: Extreme Binge Drinking, Drinking in Women and Aged, AUD and Comorbidity, Pain and AUD, Sleep and AUD, and Medical Education

Drug Addiction

Addiction — Defined as a chronically relapsing disorder that is characterized by a compulsion to seek and take drug, loss of control in limiting intake, and emergence of a negative emotional state (e.g., dysphoria, anxiety, irritability, defined as “hyperkatifeia”) when access to the drug is prevented

Conceptual Framework for Neurobiological Bases

Driving Substance Use Disorders

Adapted from: Koob, GF and Volkow ND, 2010. Neuropsychopharmacology Reviews 35: 217- 238;

George O, Koob GF., 2013 Proc Natl Acad Sci USA, 110:4165-4166

Hyperkatifeia

1. Defined as the increased intensity of negative emotional/motivational symptoms and signs observed during withdrawal from abused drugs

2. Derived from the Greek word katifeia for dejection, sadness, or negative emotional state

3 “Hyperkatifeia” refers to the increases in emotional distress and emotional pain experienced by individuals with addiction during abstinence.

4. “Hyperkatifeia” is hypothesized to represent elements such as dysphoria, irritability, alexithymia, or simply symptoms often described as ill at ease, uncomfortable within one’s own skin, or simply not hedonically normal, symptoms historically difficult to define.

Shurman, J, Koob, GF, Gutstein, HB. Opioids, pain, the brain and hyperkatifeia: A framework for the rational use of opioids. Pain Medicine 11 (2010) 1092- 1098

Positive and Negative Reinforcement - Definitions

Positive Reinforcement — the process by which presentation of a stimulus (drug) increases the probability of a response (nondependent drug taking paradigms).

Negative Reinforcement — a process by which removal of an aversive stimulus (negative emotional state of drug withdrawal - defined as “hyperkatifeia”) increases the probability of a response (dependence-induced drug taking)

Etiology of Addiction

Progression of the Addictive Process

Indiv

idual fa

cto

rs:

Genetics,

Life S

tress

Escalating/Compulsive Use

Dependence/Withdrawal

Rewardpositive

reinforcement

Reliefnegative

reinforcement

Protracted

AbstinenceRelapse

RewardDA, 5-HT,

GABA, GLU

Opioid Peptides

Glucocorticoids

DependenceDysregulation of reward neurotransmitters

Dysregulation of Brain Stress Systems

CRF, Dynorphin, Substance P, Hypocretin,

NPY, Nociceptin, Oxytocin

Glucocorticoids

RelapseGlutamate

Dopamine

CRF

Glucocorticoids

Neurocircuitry/ Neurochemistry of the

Withdrawal Negative Affect Stage

Adapted from: Koob, GF 2008 Neuron 59:11-34 and George O, Koob GF.

Proc Natl Acad Sci USA, 2013, 110:4165-4166.

Diagnosis: Neuroclinical Assessment

Associations with Neurocircuits Provides a Framework for

improved Diagnosis, Prevention and Treatment

Adapted from Koob. Curr Top Behav Neurosci. 2011

Modified from: Kwako LE, Momenan R, Litten RZ, Koob GF, Goldman D. Addictions neuroclinical assessment: a

neuroscience-based framework for addictive disorders. Biological Psychiatry, 2016, 80:179-189

This study examined three key

neurobiological domains that are

critical to the addiction cycle

(incentive salience, negative

emotionality, and executive

function) in a large, diverse

clinical sample of individuals

representing the spectrum of

AUD.

Measures of addiction,

personality, cognition, behavior,

and exposure to early-life stress

were collected. Using a multiple

indicators, multiple causes

approach, the study confirmed the

relevance of the three

neurofunctional domains to AUD.

Validation of 3 Neurofunctional Domains in AUD

by Deep Behavioral Phenotyping

From: Kwako LE, Schwandt ML, Ramchandani VA, Diazgranados N, Koob GF,

Volkow ND, Blanco C, and Goldman D. Neurofunctional domains derived from deep

behavioral phenotyping in alcohol use disorder. Am J Psychiatry. 2019

Incentive

Salience

Executive

Function

Negative

Emotionality

AUD diagnosis

Gender

Emotional abuse

Sexual abuse

Emotional neglect

Positive urgency

Neuroticism

Extraversion

Agreeableness

Trait anxiety

Aggression

AUD diagnosis

Race

Emotional abuse

Sexual abuse

Family history

Age at first drink

ADHD

Attentional impulsivity

Motor impulsivity

Non-planning impulsivity

Conscientiousness

Negative urgency

Premeditation

Perseverance

Positive urgency

MADRS depression

Trait anxiety

Distress when unable to drink

Preoccupation with alcohol

Time thinking about alcohol

Strength of urge to drink

AUD diagnosis

Race

Emotional abuse

Emotional neglect

PREDICTORS INDICATORSLATENT

FACTORS

• Winning prototype submitted by BACtrack, a company known for

designing and selling portable breath alcohol testers for consumer

use

• Their entry, the BACtrack Skyn:

– Worn on the wrist

– Detects alcohol using a fuel cell technology

similar to that used in roadside testing devices

– Offers continuous, non-invasive BAC monitoring

– Stores data to a smartphone via Bluetooth

• Opportunity to spread the word - NIAAA will issue additional

challenges to stimulate inventors to create and adapt different

technologies that measure alcohol directly in blood or interstitial

fluid for real time quantification in a wearable device.

Diagnosis: Wearable Alcohol Biosensor Challenges

1st Prize: $200,000

2nd Prize: $100,000

Treatment: Developing Medications to Treat AUD

• NIAAA Division of Medications Development:

• SBIR/STTR program facilitates studies leading to FDA IND application

• Human laboratory screening studies bridge gap between preclinical and

clinical trials

• NIAAA Clinical Investigations Group (NCIG) conducts “fast success/fast

fail” phase II clinical trials with 18 month turn-around time

• Intramural program conducts clinical studies on novel compounds with AUD

treatment potential

Molecular

Targets

Animal

Models

Human

Laboratory

Models

Clinical

Trials

Treatment: Novel AUD Targets by Stage of the

Addiction Cycle

Dopamine receptors (DRD2)

GABAA receptors (GABRA2)

Opioid receptors (OPMR1)

Acetylcholine receptors (CNRNA5)

Glycine receptors (GLRA1)

Serotonin receptors (HTR3A)

Serine/Threonine Kinases (MTOR)

Cannabinoid receptors (CNR1)

GIRK channels (KCNJ6)

Norepinephrine receptor

(ADRB2)

Hypocretin (Orexin)

receptor (HCRTR1)

Neuropeptide Y receptor

(NPY1R)

CRF receptor (CRHR1)

Kappa opioid receptor

(OPRK1)

Substance P receptor

(TACR1)

Nociceptin receptor

(OPRL1)

Oxytocin receptor (OXTR)

Vasopressin receptor

(AVPR1B)

Glucocorticoid receptor

(NR3C1)

Neuroimmune factors

(NFKB1)

Phosphodiesterases (PDE10A)

Protein kinases (PRKCE)

Transcription factors (CREB1,

FOSB)

NMDA & AMPA receptors

(GRIN2B, GRIA1)

Metabotropic glutamate

receptors (GRM8)

Actin cytoskeleton (ACTB)

Matrix Metallopeptidase (MMP9)

Enabling of New Drug INDs for Development of

Medications to Treat Alcohol Use Disorders

(U44/UT2)

• Small business (SBIR) or Small business and

academic partner (STTR) opportunity

• Purpose: Translating research discoveries into new

treatments for AUD or alcohol related diseases by

supporting efforts to achieve an IND.

• Mechanism: U44/UT2 – cooperative agreement –

work closely with NIAAA Medication’s Development

staff.

• Budget: Up to $1.0M total costs per year for Phase I

and up to $1.5M total costs per year for Phase II may

be requested.

https://grants.nih.gov/grants/guide/pa-files/PAR-15-153.html

https://grants.nih.gov/grants/guide/pa-files/PAR-15-154.html

Emerging Issues – Extreme Binge Drinking

Binge drinking – 4+ drinks for women, 5+ drinks for men, on an occasion

Extreme binge drinking – consuming 2 or more times these thresholds

• Nearly 32 million adults engaged in extreme binge drinking

(Hingson, R. et. al. 2017, Am. J. Prev. Med.)

• Gaps between women and men are narrowing for

prevalence, frequency and intensity of drinking, early onset

drinking, having AUD, drunk driving, and self-reported

consequences (Slade et al., 2016; White et al, 2017)

• Women more likely to experience blackouts, liver

inflammation, brain atrophy, cognitive deficits, certain

cancers, and to experience negative affect during

withdrawal and stress or anxiety-induced relapse (Becker and

Koob, 2016)

• But we still know very little about why

• Out of 230 structural neuroimaging studies on substance

use over 23 years only 26% evaluated sex differences (Lind et

al., 2017)

Emerging Issues – Alcohol and Women’s Health

Sources – Lind K et al (2017) Drug Alc Dependence; Slade T et al (2016) BMJ Open; White A et al (2015) ACER

Emerging Issues – More People Aged 65+ Are

Drinking and Binge Drinking

Source – Breslow R, et al (2017) Trends in Alcohol Consumption Among Older Americans:

National Health Interview Surveys, 1997 to 2014. ACER, 41, 976-986

Emerging Issues: Addressing AUD and Co-Occurring

Conditions

• AUD frequently co-occurs with other SUDs and mental health

conditions (e.g., depression, bipolar disorder, anxiety disorders, PTSD)

• AUD patients with co-occurring mental health conditions tend to have

poorer prognosis

• NIAAA supports research to elucidate the relationship between AUD

and co-occurring conditions and develop preventive and treatment

interventions

• FOA: Alcohol-PTSD Co-morbidity: Preclinical

Studies of Models and Mechanisms

• Issued in collaboration with Cohen

Veterans Bioscience

• To develop, validate, or apply animal

models for mechanistic studies of

comorbid PTSD and AUD

Emerging Issue: Alcohol Misuse Causes Pain and

Pain Causes Alcohol Misuse

Overdose

Alcohol

Use

Opioid

Use

Imp

uls

ivit

y (

Neg

ati

ve U

rgen

cy)

Sensory &

Emotional Pain

Suicide

Binge/Intoxication

Preoccupation/

Anticipation

“Craving”

Withdrawal/

Negative Affect

16-25% chronic pain patients

drink heavily or have AUDK Witkiewitz & KE Vowles (2018) Alcohol Clin Exp Res

43%-73% of individuals with AUD

have moderate to severe painK Witkiewitz & KE Vowles (2018) Alcohol Clin Exp Res

Acute alcohol (at binge

levels) is analgesic

(relieves pain)T Thompson et al. (2017) Journal of Pain

Chronic alcohol and withdrawal

produce hyperalgesia

(increased pain sensitivity)S Edwards et al. (2012) Neuropharmacology

Adapted from Dr. Mark Egli, NIAAA

Emerging Issue: Alcohol Use Disorder and Sleep

Disturbance – A Feed Forward Allostatic Framework

Koob and Colrain, Neuropsychopharmacology

Reviews, In submission

Priority: Closing the Treatment Gap

• In the US, fewer than 10% of people with AUD receive any

form of treatment

• Routine health care presents a unique opportunity for

prevention, early intervention, and treatment of AUD

• However, many health care providers:

– Do not perform alcohol screening

– Are not aware of evidence-based

treatments

– Do not know where to refer patients

for treatment

Goals

Improve physician training in substance abuse

prevention and treatment at all levels

and

Integrate prevention, early intervention, and

treatment into routing health care

In Development: NIAAA Clinician’s Toolkit

• What every clinician needs to know about alcohol

– Presentation in primary care

– Role in common co-occurring conditions

– Neuroscience

– Alcohol misuse across the lifespan

– Diagnostic criteria, recommended drinking limits

– Alcohol withdrawal syndrome

– Evidence-based therapies/medications

– Addressing stigma

– Interactions with commonly used medications

• Suggestions for practice

– How to start the conversation

– Clinician’s Guide, Screening Tools, Rethinking

Drinking, etc.

Gaps in Translation

1. The framework: The neurofunctional domain encompassing the withdrawal/ negative affect stage has been neglected

3. Diagnosis: Addiction Neuroclinical Assessment measures and better biomarkers are a first step.

4. Treatment: Need to bridge two valleys of death: IND and phase III; Need to educate the medical community

5. Emerging Challenges for AUD: Extreme Binge Drinking, Drinking in Women and Aged, AUD and Comorbidity, Pain and AUD, Sleep and AUD.

NIAAAYour source for credible,

evidence-based

information about

prevention, diagnosis and

treatment of alcohol use

disorders

www.niaaa.nih.gov