abuse perspectives of the national institute on alcohol
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Na
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Na
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Alc
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National Institute on Alcohol Abuse and Alcoholism
National Institute on Alcohol Abuse and Alcoholism
National Institute on Alcohol Abuse and Alcoholism
National Institute on Alcohol Abuse and Alcoholism
Perspectives of the National Institute on Alcohol Abuse and Alcoholism
Kenneth R. Warren, Ph.D.Acting Director
September 1, 2009
presentation to the
NIH Substance Use, Abuse, and Addiction Working Group
Scientific Management Review Board
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Na
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More To Be Lost Through Merger Than To Be Gained
More To Be Lost Through Merger Than To Be Gained
The Bottom Line:
There are several scientific issues for which collaboration on research activities by NIAAA and NIDA are logical and appropriate
However, a merger is NOT necessary to achieve such collaboration (indeed, NIAAA has joint projects with many Institutes including NIDA)
In addition, many of NIAAA’s scientific issues are not shared with NIDA
Importantly, for the alcohol area there are many reasons why a merger could have negative consequences
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Na
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Disadvantages of a Merger for NIAAA: Value LostDisadvantages of a Merger for NIAAA: Value Lost
At the outset
Disruptive for both Institutes when the same end is achievable through collaboration
In the long run
Loss of focus on issues that are not shared across both Institutes (e.g., for NIAAA - metabolism, organ pathology, beneficial effects of drinking, aspects of social policy research)
Alcohol and illicit drug use have unique political histories: heightened public and political concern on antisocial behavior and crime poses a risk for resource shifting away from alcohol in a “common IC” –
Particularly of concern in that alcohol and health issues are far more prevalent than health issues related to all illicit drug use combined
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Na
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Some History Some History
NIAAA was created in 1970 following efforts by prominent business executives and legislators (themselves individuals who had experienced alcoholism) who were concerned about treatment of alcohol issues in mainstream medicine:
Rationale in Report Language included lack of attention to these issues by NIH Institutes
The Comprehensive Alcohol Abuse and Alcoholism Prevention, Treatment, and Rehabilitation Act of 1970 established a research program on the full range of medical issues including alcoholism and alcohol organ pathology – placed in NIAAA
NIDA was created in 1972 (operationalized in 1974) by the Drug Abuse Office and Treatment Act of 1972 and the War on Drugs, a “frontal assault on our number one public enemy” (Richard M. Nixon 3/21/72)
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Na
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NIAAA: Some BackgroundNIAAA: Some Background
The NIAAA Mission (has been and remains): To understand how alcohol use impacts normal and abnormal biological functions and behavior across the lifespan and at all levels of drinking thereby targeting:
Alcohol Abuse and Alcoholism
Alcohol-derived organ pathologies
Public health problems resulting from acute and chronic alcohol use (e.g., alcohol poisoning, accidental injury and death)
Thereby improving the health and well-being of the nation
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Na
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Alcohol is legal and a part of the social context in many countries and cultures and is used in ceremonial occasions such as marriages, and births, and to enhance the enjoyment of social gatherings
Alcohol is legal and a part of the social context in many countries and cultures and is used in ceremonial occasions such as marriages, and births, and to enhance the enjoyment of social gatherings
Alcohol is a Unique Agent
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Na
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Alcohol is Used by the Majority of Adult Americans
Alcohol is Used by the Majority of Adult Americans
65% of the U.S. adult population drink alcohol at various times during the year = 144 million Americans.
Of those, 126 million do NOT have an Alcohol Use Disorder.
59% of drinkers (85 million Americans)NEVER exceed high risk drinking limits
18 million Americans (that is 8.5% of adults or 13% of drinkers) suffer from an Alcohol Use Disorder: Alcohol Dependence; AlcoholAbuse or both (another important target population)
59 million drinkers without AUDs do occasionally exceed high-risk drinking limits, placing them at risk for AUDs. (An important target population for NIAAA research dissemination efforts)
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Alcohol Use Disorders Surpass Other Drug Use Disorders
Alcohol Use Disorders Surpass Other Drug Use Disorders
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Na
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Prevalence of lifetime alcohol use disorder among individuals with selected lifetime drug use disordersPrevalence of lifetime alcohol use disorder among
individuals with selected lifetime drug use disorders
30.3
61.4
81.589.9 89.4 90.9 88.8 87.8 88.4 85.5
0
20
40
60
80
100
General pop.
Nicotine
Cannabis
Inhalants
Hallucinogens
Cocaine
Amphetamines
Sedatives
Tranquilizers
Opioids
P
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alco
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(%)
Source: 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), n=43,093 (unpublished data)
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Drug Use Disorders Are Rare Among Persons with Alcohol Use DisordersDrug Use Disorders Are Rare Among Persons with Alcohol Use Disorders
36.0
22.8
8.4 5.9 5.0 4.0 3.1 2.9 1.0 0.60
20
40
60
80
100
Nicotine
Cannabis
Cocaine
Amphetamines
Hallucinogens
Opioids
Sedatives
Tranquilizers
InhalantsHero
in
P
reva
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life
time
drug
use
dis
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indi
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with
life
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alco
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Source: 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), n=43,093 (unpublished data)
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In Fact, Alcohol Use Disorders are More Often Co-morbid With Psychiatric Disorders than Drug
Disorders
In Fact, Alcohol Use Disorders are More Often Co-morbid With Psychiatric Disorders than Drug
Disorders
19%Mood Disorders (including major depression)
33.8% Nicotine Dependence
29%Personality Disorders
17%Anxiety Disorders
Drug Use Disorders 13%
Disorder Rate
Co-morbidity Rates for 12-monthDSM-IV Psychiatric and Drug Disorders Among Individuals
with Alcohol Use Disorders in the U.S. Population
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Research on the Pharmacology and Treatment of Drug (including Nicotine) and Psychiatric Disorders
Co-morbid With Alcohol Disorders is a Part of NIAAA’s Agenda
Research on the Pharmacology and Treatment of Drug (including Nicotine) and Psychiatric Disorders
Co-morbid With Alcohol Disorders is a Part of NIAAA’s Agenda
NIAAA Support for Research on Co-Morbidities
Category Number of Grants Total Dollars
Alcohol & Nicotine 23 $10,013,706
Alcohol & Illegal Drug 14 $3,568,714
Alcohol & Gambling 4 $1,144,742
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Understanding of the Nature and Extent of Alcohol Dependence Has Changed Over the
Last Decade
Understanding of the Nature and Extent of Alcohol Dependence Has Changed Over the
Last Decade
Prior to NIAAA’s large (40,000+) general population epidemiologic studies (NLAES and NESARC), alcohol dependence was thought to be a chronic disease affecting primarily the middle-aged
Earlier studies had captured only clinical populations
NESARC revealed the highest prevalence of alcohol dependence among Young Adults (18-30 yrs)
NESARC analysis identified 5 distinct subtypes
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Characteristics Cluster 131.5%
Cluster 219.4%
Cluster 318.8%
Cluster 421.1%
Cluster 59.2%
Working Name“Young Adult
Subtype”“Functional
Subtype”
“Intermediate Familial Subtype”
“Young Antisocial Subtype”
“Chronic Severe Subtype”
Age Group Young Adults Middle Aged Middle AgedYoung Adults
Middle Aged
Onset of AD from Drinking Initiation 2.8 yrs. 18.4 yrs. 15.0 yrs. 2.9 yrs 13.2yrs.
Multigenerational Familial Alcoholism
Antisocial Personality Disorder
DSM-IV Alcohol Abuse Criteria
Mood Disorders
Anxiety Disorders
More than 50% Regular Smoking
Other Substance Use Disorders
Some Cannabis
only
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Changing Understanding of Alcohol Dependence
Changing Understanding of Alcohol Dependence
Most individuals in highly prevalent Sub-Types (Clusters 1-4) never seek clinical help for their Alcohol Dependence.
Majority of affected individuals are well-adjusted and successfully functioning in society
Screening and Intervention for the majority of Sub-Types are best undertaken in primary care settings.
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One Question that can be Addressed Since NESARC is Whether Alcoholism a Chronic
Relapsing Disease?
One Question that can be Addressed Since NESARC is Whether Alcoholism a Chronic
Relapsing Disease?
72% of individuals who develop an AUD have only one episode – and often recover eventually without clinical intervention
For the 28% who relapse, the average is 5 relapse episodes
So the answer is more often No though for some it is Yes.
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There is a Changing Dimension for Stigma Associated with Alcoholism
There is a Changing Dimension for Stigma Associated with Alcoholism
In the 38-year history of NIAAA, great progress has been made in de-stigmatizing this historically ostracized disease thereby increasing the likelihood that individuals would seek treatment
This is particularly true for the majority of afflicted individuals who are successful members of society with an AUD who do not use illicit drugs or abuse prescription drugs
Linking alcohol dependence with illicit drug use which is not ubiquitous or socially acceptable will be a set-back for the de-stigmatizing advances made.
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Current NIAAA Research PortfolioCurrent NIAAA Research PortfolioCategory % Portfolio
Tissue and organ pathologies including and health benefits of alcohol consumption
31.1% Brain pathology (consequence of alcohol misuse, rather than the study of processes of addiction) is 28% of this category or 8.8% of overall portfolio)
Treatment of alcohol dependence and alcohol-related organ pathology
19.3%
Subpopulation-specific issues 17.8%
Ethanol pharmacodynamics, tolerance, and withdrawal (the segment most comparable to “addiction” but extends across a broader spectrum of processes)
11.9%
Genetics 10.7%
Fetal Alcohol Spectrum Disorders 5.3%
Public policy/public safety 3.9%
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Physiological and Pathologic Effects of Alcohol Consumption
Physiological and Pathologic Effects of Alcohol Consumption
Brain
Multiple NeurotransmitterSystem Targets
Cardiovascular System
CardiomyopathyHypertensionStrokeArrhythmiasBlood platelet dysfunctionModerate drinking &CAD
Skeletal Muscles Myopathy
Blood Platelet Dysfunction
Lungs
Acute Respiratory Distress Syndrome
Gastrointestinal TractEsophageal Cancer Gastritis
Metabolic Syndrome
Pancreas Pancreatitis
FetusFAS/D
Immune System Deficiency
Endocrine SystemHPA/HPG/ HPT Dysfunction
Bone Osteoporosis
Liver
Hepatic steatosisFibrosisCirrhosisHepatocellularcarcinoma
DependenceStructural DamageCognitive DeficitsDementia
Peripheral Neuropathy
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Beneficial Effects of Moderate Alcohol UseBeneficial Effects of Moderate Alcohol Use
Decreased Risk of Coronary Artery Disease
HDL ; LDL
Decreased platelet aggregation
Increased fibrinolysis
Ischemic/reperfusion
Decreased risk of Ischemic Stroke
Metabolic Syndrome and Type 2 Diabetes
Decreased Osteoporosis
Decreased risk of dementia
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Alcohol Research: Systems Approach Alcohol Research: Systems Approach
The wide range of physiologic and pathologic effects of alcohol on many organs requires that alcohol research be conducted from a broad systems approach, where the effects of alcohol on one organ elicits metabolic changes that affect other organs, for example alcohol’s effects on:
Increasing permeability of the intestinal mucosa resulting in anincrease in LPS which affects liver and brain pathology
Lipid metabolism affecting the vascular system, CHD risk (- and +), dementia risk (- and +)
Hormones from gut, pancreas, adipose tissue affecting drinking behavior: e.g., CCK, ghrelin (?); PYY (?)
Neuro-immune factors (chemokines) affecting multiple organs
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Metabolic Consequences of Alcohol Consumption
Metabolic Consequences of Alcohol Consumption
Another key factor that may contribute to alcohol’s broad effects is that it is consumed at levels more typical of a food than a pharmacologic agent
A standard alcoholic beverage (12 oz beer, 5 oz wine, 1 ½oz distilled spirits) has 14 grams of ethanol
An individual consuming 6 drinks is ingesting 84 grams of ethanol; 588 calories from ethanol
Consequently, alcohol can have profound metabolic effects
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Metabolic Consequences of Alcohol Metabolism Metabolic Consequences of Alcohol Metabolism
Oxidative Pathways of Alcohol
Metabolism
Tissue Damage(apoptosis)
Tissue Damage(apoptosis)
• NAD+ regeneration via mitochrondrialelectron transport chain
• microsomalCYP2E1*
• NAD+ regeneration via mitochrondrialelectron transport chain
• microsomalCYP2E1*
IncreaseTranscription
Factors(e.g., NFkB, AP-1)
IncreaseTranscription
Factors(e.g., NFkB, AP-1)
ROS Production
ROS Production
IncreaseInflammatory
Cytokines(e.g., TNF , IL-1,
IL-6)
IncreaseInflammatory
Cytokines(e.g., TNF , IL-1,
IL-6)
Mic
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CYP2E1CYP2E1CH3CH2OH
NADPH + H+ +O2
CH3CHONADP+ + 2H2O
*
Mic
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CYP2E1CYP2E1CH3CH2OH
NADPH + H+ +O2
CH3CHONADP+ + 2H2O
CYP2E1CYP2E1CH3CH2OH
NADPH + H+ +O2
CH3CHONADP+ + 2H2O
*
Lipid peroxidation(+ Acetaldehyde)
AutoimmunityDNA Damage
ROS GSH
Tissue Damage(apoptosis)
Tissue Damage(apoptosis)
• NAD+ regeneration via mitochrondrialelectron transport chain
• microsomalCYP2E1*
• NAD+ regeneration via mitochrondrialelectron transport chain
• microsomalCYP2E1*
IncreaseTranscription
Factors(e.g., NFkB, AP-1)
IncreaseTranscription
Factors(e.g., NFkB, AP-1)
ROS Production
ROS Production
IncreaseInflammatory
Cytokines(e.g., TNF , IL-1,
IL-6)
IncreaseInflammatory
Cytokines(e.g., TNF , IL-1,
IL-6)
Mic
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CYP2E1CYP2E1CH3CH2OH
NADPH + H+ +O2
CH3CHONADP+ + 2H2O
*
Mic
roso
me
CYP2E1CYP2E1CH3CH2OH
NADPH + H+ +O2
CH3CHONADP+ + 2H2O
CYP2E1CYP2E1CH3CH2OH
NADPH + H+ +O2
CH3CHONADP+ + 2H2O
*
Lipid peroxidation(+ Acetaldehyde)
AutoimmunityDNA Damage
ROS GSH
Alcohol Metabolism, ROS Production, and
Tissue Damage
Alcohol also inhibits methionine synthase impairing biosynthesis of SAMeand potentially leading to hypomethylation in epigenetics (DNA, histones)
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Short palpebral fissure
Indistinct philtrum
Thin upper lip
Research on Fetal Alcohol Syndromeand Fetal Alcohol Spectrum Disorders Research on Fetal Alcohol Syndromeand Fetal Alcohol Spectrum Disorders
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Fetal Alcohol Syndrome (FAS) and Partial FAS (pFAS) are the Leading Acquired Neurodevelopmental
Disabilities in the U.S. Data from School-Based Active Case Ascertainment
Fetal Alcohol Syndrome (FAS) and Partial FAS (pFAS) are the Leading Acquired Neurodevelopmental
Disabilities in the U.S. Data from School-Based Active Case Ascertainment
Country(Location, Reference Year)
FAS(FAS+pFAS)
Percent (/100)
United States(Midwestern City, 2008)
0.6 – 1.1(1.4 – 2.5)
Italy(Lazio Provence, 2007)
0.4 – 0.9(2.7 – 5.5)
South Africa(Western Cape, 2007)
5.1 – 6.7(6.8 – 9.0)
South Africa(Northern Cape, 2008)
6.0 – 11(14 – 25)
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Priority Areas of FAS(D) Research Priority Areas of FAS(D) Research
Case Recognition (improved dysmorphology)
Defining the full neurodevelopmental phenotype
Development of neurodevelopmental interventions for affected individuals
Integration of screening for risk drinking and case recognition into primary care
Changing social norms on drinking in pregnancy
Further elucidation of underlying etiologic mechanism
Development of interventions to target teratogenic action of alcohol
Exploration of alcohol in SIDS (joint with NICHD)
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3dMD’s Stereo Photogrammetry Approach3dMD’s Stereo Photogrammetry Approach
Modern Modern computational math computational math applied to a applied to a technique proven technique proven over 150 years over 150 years means confidence in means confidence in the approachthe approach
Focal Point from Top Stereo Camera
Focal Point from Bottom Stereo Camera
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Etiology of FASD—Multiple MechanismsEtiology of FASD—Multiple Mechanisms
Genes active in early gestation: Pax6, Otx 6, Sox 3 and NCAM, TBX5, VAX2
Oxidative stress
Mitochondria oxidative injury & apoptosis
Impaired cell adhesion, e.g., L1
Epigenetic effects on histones and DNA – (e.g., HPA axis tone)
Altered response to trophic factors: IGF, NGF, ADNF (SAL), and ADNP (NAP) & others
Neurotransmitter system: NMDA (NR2B-NR2A), excitotoxicity; Serotonin; plus others!
Impaired gliadevelopment and migration, myelination
Others…
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NIAAA Medications Development Research (Partnering with Industry to Cross the “Valley of Death”)
NIAAA Medications Development Research (Partnering with Industry to Cross the “Valley of Death”)
Medications with Proven Efficacy
Medication Target
Disulfiram Aldehyde Dehydrogenase (FDA approval 1949)
Naltrexone Mu Opioid Receptor (FDA approval 1994)
AcamprosateGlutamate and GABA-Related (FDA approval 2004)
Naltrexone Depot Mu Opioid Receptor (FDA approval 2006)
Topiramate (AD) GABA/Glutamate (off-label)
Examples of Potential Therapeutics Under Investigation
Medication Target/Type
Valproate (AD) GABA/Glutamate
Ondansetron (AD) 5-HT3 Receptor
Nalmefene (AD) Mu Opioid Receptor
Baclofen (AD) GABAB Receptor
Antalarmin (AD) CRF1 Receptor
Rimonabant (AD) CB1 Receptor
Refanalin (liver fibrosis) heptic-growth-factor-mimetic
NAPVSIPQ and SALLRSIPA (FAS/D) neuroprotective peptides/L1 receptor
Choline (FAS/D) ACH (?)
Intake
AnxietyAnxietyAnxietyAnxiety
StressStressStressStress
RelapseRelapse
FAS/D
Withdrawal
Liver Fibrosis
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Development Phase
topiramate (Topamax)* Anticonvulsant (glutamate/GABA) Ortho-McNeil Phase II
gabapentin (Neurontin)* Anticonvulsant (glutamate/GABA) Parke-Davis (Pfizer) Phase II
levetiracetam (Keppra)* Anticonvulsant (glutamate/GABA) UCB Phase II
zonisamide (Zonegran)* Anticonvulsant (glutamate/GABA) Dainippon Phase II
pregabalin (Lyrica) Anticonvulsant (glutamine/GABA) Pfizer Phase IIondansetron (Zofran)* Serontonin 5-HT3 GlaxoSmithKline Phase IIolanzapine (Zyprexa)* D1-4, 5-HT2A, 5-HT2c Eli Lilly Phase IIquetiapine (Seroquel) D1, D2, 5-HT1A, 5-HT2 Astra Zeneca Phase IIbaclofen (Lioresal)* GABAB Novartis Phase IIprazosin (Minipress)* α1 adrenergic Pfizer Phase IIduloxetine (Cymbalta) 5-HT, NE Transporter Eli Lilly Phase IIPuerarin Extract of kudzu Phase IIvarenicline (Chantix) Nicotinic α4β2 Pfizer Phase I
rimonabant (Acomplia)* Cannabinoid CB1 Sanofi - Aventis Phase I
LY686017 NK1 Eli Lilly Phase I
aripiprazole (Abilify) D2, 5-HT1A, 5-HT2
Otsuka/Bristol-Myers Squibb
Phase I
Kudzu Unknown Phase I
mecamylamine (Inversine) Nicotinic Merck Phase I*Generic version is currently available
Current Industry for Medications Development forAlcohol Dependence
Current Industry for Medications Development forAlcohol Dependence
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NIAAA Research – Science Supporting PracticeEvidence-Based Guidelines for Primary Care Clinicians
NIAAA Research – Science Supporting PracticeEvidence-Based Guidelines for Primary Care Clinicians
CME credit available at: www.niaaa.nih.gov/guide
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NIAAA Research – Science Supporting Public Health and WellnessConsumer Guide
NIAAA Research – Science Supporting Public Health and WellnessConsumer Guide
Our goal for the Consumer Guide Re-Thinking Drinking (as with our Clinician’s Guide) is to help facilitate a healthy relationshipwith alcohol for those many adults who choose to drink thereby helping them to avoid the adverse health and personal consequences associated with harmful alcohol use
For those individuals with Alcohol Use Disorders, our goal is to develop a range of treatment options (behavioral and pharmacologic) that are accessible, acceptable, affordable, and appealing to clients, and thereby close the treatment gap for alcohol use disorders
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Kenneth R. Warren, Ph.D.Acting Director
National Institute on Alcohol Abuse and Alcoholism
Thank you!Thank you!
http://www.niaaa.nih.gov