the challenges of dissemination: your role in the development of addiction medicine specialists...
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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
No
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
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
TargetMedicationTargetMedication
Medications for Treating AD
FDA Approved
GABA/GlutamateGABA/glutamate5-HT3 Receptor
Mu Opioid ReceptorGABAB ReceptorCRF1 Receptor
NalmefeneBaclofenAntalarmin
Rimonabant
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
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
TargetMedicationTargetMedication
Medications for Treating AD
FDA Approved
GABA/GlutamateGABA/glutamate5-HT3 Receptor
Mu Opioid ReceptorGABAB ReceptorCRF1 Receptor
NalmefeneBaclofenAntalarmin
Rimonabant
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
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
TargetMedicationTargetMedication
Medications for Treating AD
FDA Approved
GABA/GlutamateGABA/glutamate5-HT3 Receptor
Mu Opioid ReceptorGABAB ReceptorCRF1 Receptor
NalmefeneBaclofenAntalarmin
Rimonabant
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
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
TargetMedicationTargetMedication
Medications for Treating AD
FDA Approved
GABA/GlutamateGABA/glutamate5-HT3 Receptor
Mu Opioid ReceptorGABAB ReceptorCRF1 Receptor
NalmefeneBaclofenAntalarmin
Rimonabant
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
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?