1. 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

3. 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

4. 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.

5. 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%

6. 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.

7. 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 3 rd 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)

8. A Developmental Perspective: Past Month Alcohol Use, Binge Drinking (5+) and Heavy Drinking (5+ drinks 5 or more times)

9. Maternal Alcohol Use during Pregnancy by Country 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

10. 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 whiteMiddle SES 4 – 9 (27 – 55) South Africa: Western Cape (2007) 85% Mixed Ancestry, 15% European White Low Middle SES White: Middle – Upper SES 51 – 67 (68 – 90) South Africa: Northern Cape (Urban et al. 2008) 64% Mixed Ancestry 36% Native Black Low & Middle SES 67 (75 – 119)

11. 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 Odds for development in subsequent 3 yrs

12. Two Distinct Patterns of Drinking Produce the Most Harm acute consequences including: unintentional death and injury homicide and violence suicide attempts particularly 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

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

14. Heterogeneity of Treatment Populations: Severity

15. Many Psychiatric Conditions Co-occur with DSM-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

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

18. 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

19. Developing Medications for Alcohol Dependence

20. S CREENING M ODELS V ALIDATION P ROCESS : B IDIRECTIONAL I NTEGRATION Molecular Targets Molecular Targets Animal Models Animal Models Human Laboratory Models Clinical Trials Pharmacogenetic Research Collaborative Networks with Industry and Academia

21. 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

22. NIAAA-Supported Human Laboratory Studies MedicationsTarget PF-05190457 (ghrelin antagonist) GHS ibudilastphosphodiesterase guanfacine (Tenex®) β 2 adrenergic mecamylamine (Inversine®)nicotinic LY686017NK1 Pexacefront, GSK 561679CRH1 aripiprazole (Abilify®) D2, 5-HT1A, 5-HT2

23. Human Laboratory Studies MedicationsTarget fenofibrate PPAR α prazosin α1 adrenergic

24. NIAAA-Supported Clinical Trials: Phase II Trials MedicationsTarget baclofen (Lioresal®, Liofen®)GABA B 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 α 1 adrenergic prazosin (Minipress®, Vasoflex® and Hypovase®) α 1 adrenergic varenicline (Chantix®) nicotinic α 4 β 2 dutasteride (Avodart®) mifepristone 5- α reductase glucocorticoid

25. NIAAA-Supported Clinical Trials: Phase II MedicationsTarget oxcarbazepineNa channel citicolinephospholipase A2 ? mirtazapine 5-HT2/3 and α1 adrenergic naltrexoneopioid

26. NIAAA-Supported Clinical Trials: Phase II MedicationsTarget Ondansetron + topiramate varenicline + prazosin naltrexone + memantine (lab study) valproate + naltrexone

27. Personalized medicine is complex Combination of Factors Genome, transcriptome, epigenetic modifications Physiological/biochemical indicators Individual patients’ characteristics Cultural indices Family history

28. Future Research: Developing Personalized Medicine

29. Allele Variants Relevant to Specific Medications Pharmacogenomic Advances MedicationGenetic SNP Site naltrexoneA118G OPRM1 ondansetronLL5 / - HTTLPR TT rs1042173 AG rs 1150226 GG rs1176713 AC rs17614942 topiramateCC rs2832407

30. Key Objectives for Next Decade 1.Identify and validate new molecular targets 2.Develop and implement screening models using animal models and human laboratory paradigms 3.Bridge gaps in the drug development process 4.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

31. 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

32. 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.

33. 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?

34. Your role?