the challenges of dissemination: your role in the development of addiction medicine specialists...

The Challenges of Dissemination: Your Role in the Development of Addiction Medicine Specialists

Margaret M. Murray, Ph.D.Director, Global Alcohol Research

ProgramNational Institute on Alcohol Abuse

and Alcoholism

http://www.niaid.nih.gov/ncn/graphics/logos/nih_300.gif

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Mission: To understand how alcohol use impacts normal and abnormal biological functions and behavior across the lifespan and at all levels of drinking including:

– Alcohol-associated disease (including alcohol dependence)

– 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 not only of those in the US but also of others around the world

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Why do we need specialists in addiction medicine?

– Alcohol problems are a significant global health problem, including in the United States.

– Alcohol problems are complex and require specialists to ensure to the best comprehensive patient care.

– Evidence –based prevention and treatment exist, but need to be expanded, refined, and effectively disseminated by adequately-trained experts.

As a percentage of all risk factors that cause ill

health, alcohol ranks high in many parts of

the world.Science 16 May 2008:

Vol. 320. no. 5878, pp. 862 - 863

Harmful Drinking – The Present Global Challenge

Proportion of DALYs

<0.5%

0.5-0.9%

1-1.9%

2-3.9%

4-7.9%

5-15.9%

The United Nations General Assembly on the Prevention and Control of Non-communicable

Diseases Political Declaration

• The first time that all Member States of the United Nations agreed to come together and develop an agenda to reduce the risk of NCD’s (UN General Assembly Resolution 66/2, 2011).

• Reduction in the harmful use of alcohol has been identified as one of the four behavioral measures countries must focus on as part of the global plan to reduce this risk.

• 18 million Americans (8.5% of the population age 18 and older) suffer from alcohol abuse or dependence

• Alcohol problems cost U.S. society an estimated $185 billion annually

• Alcohol consumption is among the top ten leading causes of DALYs*

• Among Actual Causes of Death Alcohol ranks 3rd with an estimated 79,000 deaths annually for 2001-2005

Harmful Drinking is a Leading Risk Factor for Disease Burden in the U.S.

*Disability-adjusted life years (years of potential life lost due to death plus years of healthy life lost to disability)

A Developmental Perspective: Past Month Alcohol Use, Binge Drinking (5+) and Heavy Drinking (5+

drinks 5 or more times)

0

10

20

30

40

50

60

70

80

12 13 14 15 16 17 18 19 20 21

Age

Per

cen

t

Use Binge Heavy

2005 Substance Abuse and Mental Health Services Administration National Survey on Drug Use and Health (NSDUH) http://www.samhsa.gov/

Maternal Alcohol Use during Pregnancy by Country

72

57

16

55

20

15

11

5158

61

25

1

37

69

48

61

78

92 90

68

78

89

18

42 44

85 87

60

30 32

81

67

912 11

2114

2827

1418 20

545356

45

18

0

10

20

30

40

50

60

70

80

90

100

Australia

Belgiu

mBra

zil

Canada

Chile

Croatia

Czech

Repub

lic

Denmar

k

Finlan

d

France

Germ

any

Ghana

Italy

Irela

ndIs

rael

Japa

n

Mex

ico

Nether

lands

New Zeala

nd

Norway

Portugal

Russia

South A

frica

Spain

Sweden

Taiwan

Uganda

United

Kingdom

United

State

s

Uruguay

The ranges are inclusive of any amount of alcohol consumed and at any point during pregnancy The upper estimate ≥85%: Denmark (92%); Finland (90%); Ireland (89%); SA (87%); Russia (85%)The lower estimate: <5% Israel (1.1%); Taiwan and the US (1.4%); Japan (4.6%)

Popova,S. University of Toronto

Epidemiology: Prevalence of Fetal Alcohol Syndrome (FAS) and partial Fetal Alcohol Syndrome (pFAS) in School Entry Students

via Active Case Ascertainment

*IOM 1996 prevalence estimated in U.S. for FAS at 0.5 – 2 /1000

Location (Reference Year) Population Socioeconomic

Status

FAS* (FAS+pFAS)

Rate per 1000

United States: Mid-Western Medium Size City (May et al. 2009)

75% white; 25% AI, Af. A, and Asian

Middle SES with full range -low to Upper

6 – 11(14 – 25)

Italy; Lazio Region (May and Ceccanti, 2007)

Predominantly white Middle SES 4 – 9(27 – 55)

South Africa: Western Cape (2007)

85% Mixed Ancestry, 15% European White

Low Middle SESWhite: Middle –

Upper SES

51 – 67(68 – 90)

South Africa: Northern Cape (Urban et al. 2008)

64% Mixed Ancestry36% Native Black Low & Middle SES 67

(75 – 119)

Frequency of Risk Drinking in U.S. Population

• NIAAA has defined risk drinking as exceeding 5+/4+ per day (14+/7+ per week) based on epidemiologic data from the NESARC and probabilities of an adverse outcome at various drinking levels

• 65% of the U.S. adult population are current drinkers • 59% of current drinkers do not report risk drinking

A lc oh o l D e p e n d e n c e

0

2

4

6

8

N e ve r 1 /m o 1 -3 /m o 1 -2 /w k 3 -4 /w k D a ily /n e a rd a i ly

F r e q u e n c y o f R is k D r in k in g

Od

ds

Ra

tio

Odds for development in subsequent 3 yrs

Two Distinct Patterns of Drinking Produce the Most Harm

acute consequences including: unintentional death and injury homicide and violence suicide attemptsparticularly prevalent among adolescents and young adults

chronic consequences including:

liver cirrhosis

cardiovascular diseases

pancreatitis

dementia

alcohol dependence

Binge Drinking(too much, too

fast)5+/4+ drinks/2

hours

Binge Drinking(too much, too

fast)5+/4+ drinks/2

hours

Heavy Drinking(too much, too

often)frequent 5+/4+

drinks/day

Heavy Drinking(too much, too

often)frequent 5+/4+

drinks/day

! Pharmacokinetics: absorption, distribution, and metabolism of alcohol

3-4 fold! Pharmacodynamics: subjective and objective responses to

alcohol2-3 fold

About one-half of these differences is genetic.No single treatment intervention works for all.

Between Individual Variations in Responses to Alcohol(Why drink; Drink more; Drink despite)

* >4 drinks/day, 14 drinks/week (men)>3 drinks/day, 7 drinks/week (women)

Disease management

None Harmful useDependence

(Early)Dependence

(Chronic)At-risk*

Prevention Facilitated self-changeBrief counseling

Behavioral and Medication Therapy

* >4 drinks/day, 14 drinks/week (men)>3 drinks/day, 7 drinks/week (women)

Disease management

Disease management

None Harmful useDependence

(Early)Dependence

(Chronic)At-risk*

Prevention Facilitated self-changeBrief counseling

Behavioral and Medication Therapy

Screening

Heterogeneity of Treatment Populations: Severity

Many Psychiatric Conditions Co-occur withDSM-IV Alcohol Dependence

3x— anxiety disorders

4x— mood disorder (especially major

depression)

6x— antisocial personality disorder

7x— nicotine dependence

37x— drug dependence

3x— anxiety disorders

4x— mood disorder (especially major

depression)

6x— antisocial personality disorder

7x— nicotine dependence

37x— drug dependence

McGlynn EA et al. N Engl J Med 2003;348:2635-2645.

Medication Development

(n=36) $15.9, 22%

Behavioral Therapy / Train-

ing / Health Services/ Other

(n=148) $57.3, 78%

NIAAA Division of Treatment and Recovery Research PortfolioActive Grants; July 2014

Total Costs (Millions) = $73.2 (n=184)

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)

· Medications with Medical Management works and potentially can be used in primary care settings

Developing Medications for Alcohol Dependence

TargetMedicationTargetMedication

Medications for Treating AD

FDA Approved

GABA/GlutamateGABA/glutamate5-HT3 Receptor

Mu Opioid ReceptorGABAB ReceptorCRF1 ReceptorCB1 Receptor

NalmefeneBaclofenAntalarmin

TopiramateValproateOndansetron

Under Investigation

Research from animal models over the past 25 years has provided promising targets for pharmacotherapy

Year ApprovedTargetMedication

2006Mu Opioid ReceptorNaltrexone Depot

2004Glutamate and GABA -Related

Acamprosate

1994Mu Opioid ReceptorNaltrexone

1949Aldehyde DehydrogenaseDisulfiram



FDA Approved


Mu Opioid ReceptorGABAB ReceptorCRF1 Receptor


Rimonabant


Under Investigation





Acamprosate





FDA Approved





Under Investigation





Acamprosate





FDA Approved




Rimonabant


Under Investigation





Acamprosate





FDA Approved





Under Investigation





Acamprosate





FDA Approved




Rimonabant


Under Investigation





Acamprosate





FDA Approved





Under Investigation





Acamprosate





FDA Approved




Rimonabant


Under Investigation





Acamprosate



The heterogeneity of AD requires a diverse repertoire of medications

NIAAA is testing agents that target different neurotransmitter systems implicated in alcohol dependence to:

drinking reward

craving and protracted abstinence syndrome

These efforts will expand and, ultimately personalize, treatment options

SCREENING MODELS

VALIDATION PROCESS: BIDIRECTIONAL INTEGRATION

Molecular

Targets

Animal Models

Human Laboratory Models

Clinical Trials

• Pharmacogenetic Research

• Collaborative Networks with Industry and Academia

• Many potential target sites have been identified for the actions of alcohol.

• This is not surprising given that alcohol is a small molecule (MW=46) that readily crosses the blood brain barrier As well as cell membranes given alcohol’s polar and hydrophobic properties.

Targets for Alcohol Dependence

NIAAA-Supported Human Laboratory Studies

Medications Target

PF-05190457 (ghrelin antagonist)

GHS

ibudilast phosphodiesterase

guanfacine (Tenex®) β2 adrenergic

mecamylamine (Inversine®)

nicotinic

LY686017 NK1

Pexacefront, GSK 561679 CRH1

aripiprazole (Abilify®) D2, 5-HT1A, 5-HT2

Human Laboratory Studies

Medications Target

fenofibrate PPAR α

prazosin α1 adrenergic

NIAAA-Supported Clinical Trials: Phase II Trials

Medications Target

baclofen (Lioresal®, Liofen®) GABAB

pregabalin (Lyrica®) glutamate/GABA

oxytocintopiramate

oxytocinglutamate/GABA

zonisamide (Zonegran®) glutamate/GABA

gabapentin (Neurontin®) glutamate/GABA

ondansetron (Zofran®) serotonin 5-HT3

duloxetine (Cymbalta®) 5-HT, NE transporter

olanzapine (Zyprexa®) D1-4, 5-HT2A, 5-HT2C

doxazosin α1 adrenergic

prazosin (Minipress®, Vasoflex® and Hypovase®)

α1 adrenergic

varenicline (Chantix®) nicotinic α4β2

dutasteride (Avodart®)mifepristone

5-α reductaseglucocorticoid

NIAAA-Supported Clinical Trials:Phase II Medications Target

oxcarbazepine Na channel

citicoline phospholipase A2 ?

mirtazapine5-HT2/3 and α1 adrenergic

naltrexone opioid

NIAAA-Supported Clinical Trials: Phase IIMedications Target

Ondansetron + topiramate

varenicline + prazosinnaltrexone + memantine (lab study)

valproate + naltrexone

Personalized medicine is complex

Combination of Factors

Genome, transcriptome, epigenetic

modifications

Physiological/biochemical indicators

Individual patients’ characteristics

Cultural indices

Family history

Future Research: Developing Personalized Medicine

Diagnostic Criteria

improve disease characterization (phenotyping) and risk factor identification

develop scalable criteria and markers for disease severity

Treatment

improve understanding of relationship of alcohol and co-occurring brain disorders

Pharmacogenomics – genetic variations in response to medications

Recovery

improve understanding of how individuals change harmful drinking patterns in various life stages and circumstances including the biological and contextual social factors that (1) contribute to the decision to change drinking behavior leading to recovery and (2) that underlie sustained recovery among individuals

Allele Variants Relevant toSpecific Medications

Pharmacogenomic Advances

Medication Genetic SNP Site

naltrexone A118G OPRM1

ondansetron LL5/ - HTTLPRTT rs1042173 AG rs 1150226 GG rs1176713 AC rs17614942

topiramate CC rs2832407

Key Objectives for Next Decade

1. Identify and validate new molecular targets2. Develop and implement screening models using

animal models and human laboratory paradigms3. Bridge gaps in the drug development process4. Conduct clinical trials more efficiently using

enhanced methodology and facilitation of proof of concept trials

5. Advance personalized medicine in pursuit of new therapeutics

6. Facilitate adaptation of alcohol medications in treatment settings

7. Facilitate collaborative networks and partnerships among government, academia, pharmaceutical/biotechnology companies, healthcare organizations, and advocacy groups

Litten et al., Addict Biol 17:513-527, 2012

NIH Approaches to Dissemination and Implementation Science

“ There is a need for research testing approaches to scaling up and sustaining effective interventions, and we propose that further advances in the field will be achieved by focusing dissemination and implementation research on five core values:• Rigor and relevance• Efficiency• Collaboration• Improved capacity• Cumulative knowledge

Definitions of Dissemination and Implementation Research

• Dissemination research is the systematic study of processes and factors that lead to widespread use of an evidence-based intervention by the target population. Its focus is to identify the best methods that enhance the uptake and utilization of the intervention .

• Implementation research seeks to understand the processes and factors that are associated with successful integration of evidence-based interventions within a particular setting (e.g., a worksite or school). Implementation research assesses whether the core components of the original intervention were faithfully transported to the real-world setting (i.e., the degree of fidelity of the disseminated and implemented intervention with the original study) and is also concerned with the adaptation of the implemented intervention to the local context .

Rabin BA, Brownson RC, Hiare-Joshu D, Kreuter MW, Weaver NL: A glossary for dissemination and implementation research in health. J Public Health Manag Pract 2008, 142:117-123.

What is the impact of your Medical Education efforts?

Is there an increase in teaching about alcohol/addiction?

Is there an increase in teaching confidence?

Are physician attitudes, skills and knowledge being improved?

Are patients being screened and identified as a result?

Are patient outcomes affected?

Your role?

the challenges of dissemination: your role in the development of addiction medicine specialists...

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