Transcript 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 Program
National 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 wellbeing 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.
Harmful Drinking – The Present
Global Challenge
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
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.
Harmful Drinking is a Leading Risk Factor for
Disease Burden in the U.S.
•
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 20012005
*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)
80
70
Use
Binge
Heavy
60
Percent
50
40
30
20
10
0
12
13
14
15
16
17
18
19
20
Age
2005 Substance Abuse and Mental Health Services Administration National Survey on Drug Use and
Health (NSDUH) http://www.samhsa.gov/
21
Maternal Alcohol Use during Pregnancy by
Country
100
92
90
89
90
80
78
50
87
81
78
69 72
68
70
60
85
61
57
56
48
53
67
55
60
58
54
51
45
42
44
40
27
30
20 12
10
21
9
11
16
20 18
18
11
1
5
30
28
14
18
25
14
6
37
32
20
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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
Location (Reference
Year)
United States: MidWestern Medium Size
City (May et al. 2009)
Italy; Lazio Region
(May and Ceccanti,
2007)
South Africa: Western
Cape (2007)
South Africa: Northern
Cape (Urban et al.
2008)
Population
Socioeconomic
Status
FAS*
(FAS+pFAS)
Rate per 1000
75% white; 25% AI,
Af. A, and Asian
Middle SES with full
range -low to Upper
6 – 11
(14 – 25)
Predominantly white
Middle SES
4–9
(27 – 55)
85% Mixed Ancestry,
15% European White
Low Middle SES
White: Middle –
Upper SES
51 – 67
(68 – 90)
64% Mixed Ancestry
36% Native Black
Low & Middle SES
67
(75 – 119)
*IOM 1996 prevalence estimated in U.S. for FAS at 0.5 – 2 /1000
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
8
Odds for development in subsequent 3 yrs
Alcohol
Dependence
Odds Ratio
6
4
2
0
Never
1/mo
1-3/mo
1-2/wk
3-4/wk
Frequency of Risk Drinking
Daily/near
daily
Two Distinct Patterns of Drinking Produce the
Most Harm
Binge Drinking
(too much, too
fast)
5+/4+ drinks/2
hours
acute consequences
including:
 unintentional death and injury
 homicide and violence
 suicide attempts
particularly prevalent among
adolescents and young adults
Heavy Drinking
(too much, too
often)
frequent 5+/4+
drinks/day
chronic consequences including:
 liver cirrhosis
 cardiovascular diseases
 pancreatitis
 dementia
 alcohol dependence
Between Individual Variations in Responses to Alcohol
(Why drink; Drink more; Drink despite)
 Pharmacokinetics: absorption, distribution, and
metabolism of alcohol
3-4 fold
Pharmacodynamics: subjective and objective responses to
alcohol
2-3 fold
About one-half of these differences is genetic.
No single treatment intervention works for all.
Heterogeneity of Treatment Populations: Severity
Screening
Prevention
Facilitated self-change
Brief counseling
Behavioral and Medication
Therapy
Disease
management
None
At-risk*
Harmful use
* >4 drinks/day, 14 drinks/week (men)
>3 drinks/day, 7 drinks/week (women)
Dependence
(Early)
Dependence
(Chronic)
Many Psychiatric Conditions Co-occur with
DSM-IV Alcohol Dependence

drug dependence
37x

nicotine dependence
7x

antisocial personality disorder
6x

mood disorder (especially major
depression)
4x

anxiety disorders
3x
McGlynn EA et al. N Engl J Med 2003;348:26352645.
NIAAA Division of Treatment and Recovery Research
Portfolio
Active Grants; July 2014
Total Costs (Millions) = $73.2 (n=184)
Medication
Development
(n=36)
$15.9, 22%
Behavioral
Therapy / Training /
Health Services/
Other (n=148)
$57.3, 78%
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
 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
Medications for Treating AD
FDA Approved
Medication
Target
Year Approved
Disulfiram
Aldehyde Dehydrogenase
1949
Research from animal models over the past 25 years has provided
targets for pharmacotherapy
Naltrexone
Mu Opioid Receptor
Acamprosate
Glutamate and GABA
Related
Naltrexone Depot
Mu Opioid Receptor
promising
promising
1994
-
2004
2006
Under Investigation
Medication
Target
Medication
Topiramate
Valproate
Ondansetron
GABA/Glutamate
GABA/glutamate
5-HT3 Receptor
Nalmefene
Baclofen
Antalarmin
Rimonabant
Target
Mu Opioid Receptor
GABAB Receptor
CRF1 Receptor
CB1 Receptor
 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
Targets for Alcohol Dependence
• 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.
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
oxytocin
topiramate
oxytocin
glutamate/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 reductase
glucocorticoid
NIAAA-Supported Clinical Trials:
Phase II
Medications
Target
oxcarbazepine
Na channel
citicoline
phospholipase A2 ?
mirtazapine
naltrexone
5-HT2/3 and α1 adrenergic
opioid
NIAAA-Supported Clinical Trials:
Phase II
Medications
Ondansetron + topiramate
varenicline + prazosin
naltrexone + memantine (lab study)
valproate + naltrexone
Target
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 to
Specific Medications
Pharmacogenomic Advances
Medication
Genetic SNP Site
naltrexone
A118G OPRM1
ondansetron
LL5/ - HTTLPR
TT rs1042173
AG rs 1150226
GG rs1176713
AC rs17614942
CC rs2832407
topiramate
Key Objectives for Next Decade
1.
2.
3.
4.
5.
6.
7.
Identify and validate new molecular targets
Develop and implement screening models using animal
models and human laboratory paradigms
Bridge gaps in the drug development process
Conduct clinical trials more efficiently using enhanced
methodology and facilitation of proof of concept trials
Advance personalized medicine in pursuit of new
therapeutics
Facilitate adaptation of alcohol medications in treatment
settings
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 evidencebased 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?