National Advisory Council on Alcohol Abuse and Alcoholism

Summary of the 113th Meeting

September 20-21, 2006

The National Advisory Council on Alcohol Abuse and Alcoholism convened for its 113th meeting at 5:30 p.m. on September 20, 2006, at the Fishers Lane Conference Center in Rockville, Maryland, in a closed session, and again in open session at 9:00 a.m. on September 21. Dr. Tina Vanderveen presided over the closed review of grant applications on September 20, and Dr. Ting-Kai Li, Director of the National Institute on Alcohol Abuse and Alcoholism, presided over the open session on September 21.

In accordance with the provisions of Sections 552b(C)(6), Title 5, U.S.C. and 10(d) of Public Law 92-463, the meeting on September 20, 2006, was closed to the public for the review, discussion, and evaluation of individual applications for Federal grant-in-aid funds.

Council Members Present:

Michael E. Charness, M.D.
Cheryl J. Stephens Cherpitel, M.P.H., Dr.P.H.
Victor M. Hesselbrock, Ph.D.
Joannes B. Hoek, Ph.D.
Gail A. Jensen, Ph.D.
Mack C. Mitchell, M.D.
Stacia A. Murphy
Stephanie S. O'Malley, Ph.D.
Kenneth J. Sher, Ph.D.
Richard T. Suchinsky, M.D. (ex-officio)
Alan C. Swann, M.D.
Boris T. Tabakoff, Ph.D.
Hope Taft
Robert E. Taylor, M.D., Ph.D.

Chairperson: Ting-Kai Li, M.D.

Executive Secretary: Karen P. Peterson, Ph.D.

Senior Staff:

Vivian B. Faden, Ph.D., Ralph W. Hingson, Sc.D., M.P.H., Robin I. Kawazoe, George Kunos, M.D., Ph.D., Howard Moss, M.D., Antonio Noronha, Ph.D., Tina Vanderveen, Ph.D., Kenneth R. Warren, Ph.D., Mark Willenbring, M.D., Samir Zakhari, Ph.D.

Other Attendees on September 21, 2006

Approximately 50 additional observers attended the open session, including representatives from constituency groups, liaison organizations, NIAAA staff, and members of the general public.

Call to Order of the Closed Session, September 20, 2006

Dr. Tina Vanderveen called the closed session of the 113th meeting of the Council to order at 5:30 p.m. on Wednesday, September 21, 2006, for consideration of grant applications. She reviewed procedures and reminded Council members of regulations pertaining to conflict of interest and confidentiality. Members absented themselves from the discussion and evaluation of applications from their own institutions and in situations involving any real, apparent, or potential conflict of interest. The closed session adjourned at 7:15 p.m.

Call to Order of the Open Session and Introductions, September 21, 2006

Dr. Li called the open session to order on September 21, 2006, at 9:00 a.m. and welcomed participants. Members of the Council, NIAAA staff, and audience members introduced themselves.

Director's Report

Referring to the published "Director's Report," Dr. Li highlighted the following Institute activities:

• Budget. The U.S. House of Representatives and Senate Appropriations Committees have marked up the FY 2007 appropriations bill. The House bill would provide $28.3 billion for the National Institutes of Health (NIH) and $433.3 million for NIAAA, a 0.5 percent decrease from the FY 2006 appropriation. The Senate bill would increase slightly the President's proposed budget for NIH and NIAAA (at $28.6 billion and $436.6 million, respectively). The timing of future Congressional action is uncertain. The estimated value of the Biomedical Research and Development Index for FY 2006 has been revised from 5.5 percent to 3.8 percent.
  
  
• Director's activities. Dr. Li presented an update of NIAAA activities to the Research Society on Alcoholism (RSA) at a meeting in Baltimore and spoke to the International Society for Biomedical Research on Alcoholism in Sydney, Australia. He asserted the need to pursue quantification of alcohol exposure within the description of alcohol-related disorders and noted that "alcohol abuse" as a diagnostic category is probably not tenable from evidence-based results. Dr. Li also spoke at a well-attended briefing of the Congressional Addictions Caucus on medications development.
  
  
• NIAAA staff and organizational changes. Dr. Li reported that Abraham Bautista, Ph.D., joined NIAAA as Chief, Extramural Project Review Branch. Drs. Roger Sorensen, Lindsey Grandison, Ellen Witt, and Lisa Neuhold received recognition awards for their work on Blueprint for Neuroscience teams. Dr. Ricardo Brown was named NIAAA Minority Health and Health Disparities Research Coordinator. After having retired from NIAAA, Mr. Stephen Long now serves as Associate Director for Administration of University of Maryland's Cancer Center. Ms. Robin Kawazoe now serves as both Acting Executive Officer and Acting Deputy Director. Dr. Peter Silverman has been named Deputy Scientific Director of the Intramural Program. Staff participated in NIAAA's second annual scientific staff retreat.
  
  
• NIAAA research programs. Despite a relatively flat budget, NIAAA is achieving its priority to support new and young investigators. NIAAA has increased the number of full-time fellowship training slots from 56 to 68, with an anticipated total for FY 2006 of 83 slots, a 22 percent increase over FY 2005 levels. In the career mechanisms area, fellowships have increased from 76 to 88; career awards are projected to increase to 90 in the next fiscal year. In FY 2005, New and Competing Regular Research (RO1) awards increased by 12 percent while the total number of R01 awards increased by 2 percent.
  
  
• Research reports. Dr. Ralph Hingson and colleagues have published a paper describing analysis of National Epidemiological Survey on Alcohol and Related Conditions (NESARC) data on the impact of early drinking on subsequent alcohol dependence; the NESARC data replicate National Longitudinal Alcohol Epidemiological Study (NLAES) findings of a decade earlier. Two NIAAA papers appeared in the Proceedings of the National Academy of Sciences related to alcohol's effects GABAa receptors. Dr. Li noted that more articles on alcohol research are being published in high-impact journals and acknowledged NIAAA staff efforts in speaking and organizing symposia at national and international meetings.
  
  
• Outreach activities. NIAAA has supported Leadership to Keep Children Alcohol Free. The Leadership has recently established a foundation. The organization has worked with NIAAA and other Federal agencies to encourage publication of the Surgeon General's Call to Action on Under-Age Drinking; the document is currently under review. NIAAA has worked with the National Nursing Association on a nursing curriculum to be posted on the Internet, and the Association of Addiction Nurses and the University of Delaware School of Nursing are collaborating in development of an online Continuing Medical Education course.
  
  
• Multimedia products from NIAAA
  
  
  • Dr. Li highlighted the recent issue of NIAAA's Alcohol Research and Health, which focused on the latest analyses of NESARC findings. The rich database has engendered a large volume of secondary analyses, and a Request for Applications (RFA) has met with good response.
    
    
  • The updated "Helping Patients Who Drink Too Much: A Clinician's Guide" has been highly successful. Dr. Mark Willenbring explained that people appreciate the simplicity of the screening. It addresses nondependent heavy drinking and moves the field toward medical management of alcohol dependence. Currently printed in English and Spanish, the publication is being translated into other languages. Enhancements to the 2006 edition, to be issued in October 2006, include some COMBINE findings and information about the new injectable sustained-release naltrexone.
  
  
  
• Upcoming activities. Forthcoming activities include an Extramural Advisory Board review of the Alcohol and HIV/AIDS portfolio in October 2006. Dr. Fulton Crews will deliver the 2006 Keller Lecture on November 7 on "Mechanisms of Neurodegeneration and Regeneration during Alcohol Addiction and Recovery."

Staff Updates on Initiatives

• Underage Drinking Research Team

Dr. Vivian Faden reported to Council on the accomplishments and continuing work of the NIAAA Team on Underage Drinking.

First, Dr. Faden reported that Alcohol Research and Health's October 2005 issue summarized the state-of-the-science in underage drinking at that time as well as served as a starting point for NIAAA's Initiative on Underage Drinking. NIAAA released the issue at an October 31-November 1, 2005 national meeting on underage drinking sponsored by the Substance Abuse and Mental Health Services Administration (SAMHSA). At this meeting, NIAAA took responsibility for providing the science on underage drinking, both through presentations and by providing written products like the October 2005 issue of Alcohol Research and Health. Dr. Li, as well as other NIAAA staff and grantees presented at the meeting. This widely distributed issue of AR&H also was the basis for an Alcohol Alert.

Next Dr. Faden reported that in FY2006, an RFA entitled "Underage Drinking: Building Healthcare System Responses" resulted in the issuance of four awards, two of which were funded with contributions from the National Center on Minority Health and Disparities.

Dr. Faden shared that the Underage Drinking Team has had substantial input into the Surgeon General's Call to Action To Prevent and Reduce Underage Drinking, and that work is continuing on this document.

NIAAA's Team on Underage Drinking sponsored a meeting in April 2006 on diagnosing alcohol use disorders in youth. A draft report has been prepared and the final report will be available soon.

The Underage Drinking Team recently formed a policy and communications subgroup, comprised of NIAAA staff and a number of extramural scientists from the Team's external Steering Committee. The group will focus on disseminating the information developed by the Initiative on Underage Drinking to multiple constituencies. The groups' first project is a one-pager on alcohol and the developing brain.

Dr. Faden reported that an upcoming issue of Alcohol Research and Health will be dedicated to presenting information about underage drinking in a developmental framework. It will be based on four review papers produced by the Initiative's Steering Committee of outside experts. In addition, these four papers together with NIAAA commissioned reviews on treatment and prevention of underage drinking are to be published as a journal supplement.

Dr. Faden also observed that the NIAAA Team on Underage Drinking has been instrumental in bringing the developmental approach to the Interagency Coordinating Committee on Preventing Underage Drinking. In addition, the team has been collaborating with other ICs in NIH. For example NIAAA participated in two National Institute on Drug Abuse (NIDA) RFAs; NIAAA has funded two projects as a result of one of these and has made a soft commitment in the second. The team also has established a connection with an intramural researcher at NIMH who will ask NIAAA-developed alcohol questions of youth who come into his study of the developing brain.

Coming attractions include a meeting on screening for adolescent drinking and alcohol use disorders, which will focus on screening instruments and barriers to screening youth for underage alcohol use. And finally, NIAAA is planning an RFA on alcohol and the developing brain for FY2007.

Discussion. In response to a question from Ms. Taft, Dr. Faden stated that the upcoming issue of Alcohol Research and Health will be available within a few months; the brain one-pager also will be ready for publication around that time. Dr. Faden asked Council for input on alcohol and tobacco questions for surveys. Dr. O'Malley asked whether the NIMH project asks questions of mothers about in utero exposures; Dr. Faden responded in the negative.

• Centers and Training Team

Dr. R. Thomas Gentry described the NIAAA Centers and Training Team as a working group composed of Institute staff from Grants Management, Extramural Review and Program Officers representing all four extramural divisions. The team's purview includes alcohol research centers (Ps), institutional NRSA training programs (T32s), individual NRSA fellowships (Fs), career development awards (Ks) and training related programs such as grant supplements to promote diversity.

In FY-2006 NIAAA sponsored a total of 18 Alcohol Research Centers (ARC) which together provide leadership in innovative research, serve as national resources for education and information dissemination and provide the setting for advanced research training in alcohol studies. The NIAAA Centers program is designed to provide a stable environment while promoting the integration of alcohol research specialties through translational and interdisciplinary collaborations. Currently NIAAA has released RFAs for three levels of alcohol research centers (ARCs): the Specialized Alcohol Research Centers (P50s), the Comprehensive Alcohol Research Centers (P60s) and the new Developmental Exploratory Alcohol Research Centers (P20s), each with an application receipt date of December 20, 2006. The Comprehensive ARC expands on the traditional Specialized Center by adding a component for outreach, education or information dissemination. The P20 mechanism is designed to enable investigators to develop a new Center focused on novel scientific approaches or filling significant gaps in alcohol research. In addition, a fourth RFA for Resource Core Alcohol Research Center Awards (P30) is in preparation. Members of the Centers and Training Team are also working with Dr. Robert E. Taylor in planning for the next biennial meeting of the NIAAA Center directors (being held in March, 2007) to be hosted by the Howard University Alcohol Research Center, and focused on the theme "Alcohol Abuse and Alcoholism in Ethnic Populations."

NIAAA currently sponsors Alcohol Research Institutional Training Programs (T32s) at 30 different academic and research institutions, about half of which are also Alcohol Research Centers. These Institutional National Research Service Awards (NRSA) support approximately 200 pre- and post-doctoral trainees; thus serving a critical role to ensure future availability of well-trained researchers in the wide variety of alcohol-related fields. In response to the 2006 PA, NIAAA received ten applications for T32 institutional training awards to be reviewed by Council in February of 2007. Noting that all ten applications were competing renewals, the team recognized the need to encourage competition for novel research topics and the inclusion of new groups of mentors in order to best serve the needs of alcohol investigators making their contributions in the future.

A major accomplishment in the NIAAA training program has been the steady increase in the number of awards made for individual NRSA Fellowships (F30, F31, F32 and F32s) from a total of 49 in FY 2002 to 83 in FY 2006. This success reflects one aspect of the Institute's commitment to a policy of maintaining research training despite increasingly limited resources. Also reflecting the Institute's "Pathways to Independence" initiative, NIAAA has been able to increase the number of Mentored Research Scientist Development Awards (K01s) and is actively working to reverse the recent slip in the number of Independent Scientist Awards (K02s). Moreover, the new NIAAA transition award (K22) and the NIH transition award (K99/R00) are expected to facilitate career development and transition from post-doctoral to faculty-level research positions in the future. Finally, Dr. Roger Sorensen has led the development of a new Senior Scientist Research and Mentorship Award (K05), which is unique in that it adds to the standard Senior Scientist Award the requirement for mentoring new investigators and junior faculty. This innovative mechanism has drawn interest from other NIH institutes one of which (NIDA) has agreed to co-sponsor the initial PA released yesterday.

As an expression of the Institute's commitment to diversity training, the team's purview includes the NIAAA Diversity Supplement Program which awards supplements to active grants for the support of disadvantaged or under-represented investigators. This program is supervised by Dr. Judith Arroyo and in FY 2006 supported a total of 8 supplemental awards out of a total of 15 applications received.

Discussion. In a response to a question from Dr. O'Malley, Dr. Sorensen answered that the new K05 mechanism allows one competitive renewal, and clarified that the mechanism requires mentorship of two to five individuals at any one time. Dr. Judith Arroyo confirmed for Dr. Sher that most funds allocated for diversity supplements go to the category of young investigators, such as junior faculty. Dr. Arroyo reported that an increase in the total amount requested per young investigator (at 75 or more percent effort) had risen from $80,000 in FY 2005 to about $120,000 in FY 2006. To distribute funds more evenly, some applicants were asked to reduce the scope of proposed projects. Dr. Gentry explained to Dr. Swann that K02 awards are renewable only once. Dr. O'Malley observed that some institutions do not apply for K awards because of their low indirect reimbursement rate. Dr. Tabakoff noted that many institutions require faculty to cover 70-80 percent of their salaries on grants and recipients of K awards are precluded from salary supplementation with additional Federal funds. Dr. Sorensen explained that the new Senior Scientist Research and Mentorship Award addresses this issue by supporting 75 percent salary up to the current federally-legislated amount and specifically allowing additional salary supplementation from other grants.

Stress, Genes, and Addiction: Recent Developments in Mouse Behavioral Models

Andrew Holmes, Ph.D., Acting Chief, Section on Behavioral Science and Genetics, Laboratory for Integrative Neuroscience, NIAAA, explained that his work with mice as a model system addresses the use of animal models to better understand the pathophysiology of addiction and thereby find better treatments. His research investigates the role of volition, or executive control, in addiction. In animal learning, executive control involves the ability to inhibit inappropriate behaviors and impulses, capacity to make decisions and guide actions towards adaptive outcomes, or flexibility to shift away from a behavior that becomes maladaptive. In the drug-addiction process, executive control may be involved in risk taking and novelty seeking, impulsivity, and compulsivity, and lack of executive control can catalyze the drug addiction state. New research shows that exposure to drugs of abuse can affect executive control function. Addicts tend to be more impulsive and poor decision-makers and exposure to drugs of abuse can weaken an individuals' executive control over their behavior. Key issues include determining the neural basis of executive control, the genes and molecules involved, and whether new therapeutic approaches may be devised that work by strengthening executive control. Dr. Holmes noted several advantages in using mice, including the ability to conduct experiments not possible with humans; relatively low cost; homology of neural, physiological, genetic, and behavioral systems; and a long history of use in the field of behavioral genetics. He asserted that advances in mouse molecular genetics have potential to advance understanding of addictions and find better treatments.

Dr. Holmes explained that his group's work utilizes a touchscreen operant system. In a Skinner box, mice are asked to perform cognitive executive problems, a method that offers a high degree of experimental control over presentation of stimuli and rewards; is flexible and expandable; tests for different forms of cognition; taps mice's natural tendency to investigate novel stimuli with their noses; and is translatable, which permits drawing comparisons and making generalizations across species.

Dr. Holmes demonstrated measurement of behavioral flexibility using the touchscreen system in reversal learning. Mice must learn something new and inhibit their prior learned response, a good test for behavioral flexibility and the ability to exert inhibitory control over behavior. Before animals learn the new response, they experience a decrease in performance and perseverate in the previously learned response. Differences are dramatic between the human brain and the brains of lower-order animals, particularly in the prefrontal cortex (PFC). Following discrimination learning and reversal learning, slices of mouse brain were examined for activity in these regions using staining for extracellular-related kinase (ERK), a molecule implicated in learning and memory. The brain slices showed recruitment and activation of neurons in the mouse PFC after reversal learning and their absence in animals that performed just discrimination learning-evidence of the role of mouse PFC in executive control.

To identify genes and molecules mediating these executive behaviors, Dr. Holmes uses an array of mutant mice and pharmacological tools. He demonstrated the example of glutamate AMPA GluR1 receptor, a molecule richly expressed in rodent PFC and shown to also be involved in addictive behavior. Genetically engineered mice that lack this receptor perform discrimination tests similarly to normal mice, but in extinction learning, mice lacking the receptor perform more poorly at inhibiting their responses on the touchscreen. Eventually the knockout mice achieve the levels of normal mice, but they have difficulty in inhibiting their desire to touch the screen to obtain the award.

Dr. Holmes stated that conditioned reinforcers appear to be potent drivers to drug-seeking and relevant to addiction. During conditioning, in addition to receiving a food pellet, mice hear a beep and the "ATM" window illuminates. During extinction, the window dispenses no pellets, but the two conditioned reinforcers-the beep and the lights-appear. In animals lacking the receptor, the power of the conditioned reinforcers to drive them back to reward-seeking behavior was much greater than in normal mice. In an experiment that removes the conditioned reinforcers and presents animals with free pellets and then no pellets, no differences are seen between the knockout animals and normal counterparts.

Future research directions include developing tests for executive function in mice that examine direct measures of inhibitory control and impulsivity. Once the battery of assays is available, the group can continue its work to identify involved brain regions, neural systems, genes, and molecules. The laboratory also is studying the effects of exposure to stress on executive functions and the effects of chronic exposure to drugs of abuse, including alcohol. This research may lead to thinking about treating addiction and alcoholism in a new way, by developing therapeutics that increase one's volition or executive control over behaviors.

Discussion. Dr. Sher noted that the work parallels research in humans on executive functioning and observed the imprecision in the literature on the concept of executive control. Dr. Faden stated that in human addiction the challenge is to extinguish behavior that remains rewarding. Dr. Holmes welcomed discussions about working with clinical populations to make the tasks in his work more sophisticated and translatable. Dr. O'Malley suggested conducting experiments with an immediate reward but delayed punishment, to reflect the way in which addicts think. Dr. Holmes responded that an analogous task is for the mouse to choose between one stimulus with an immediate pellet or another stimulus with a delay that produces three pellets. Dr. Holmes replied to a question from Dr. Hoek that the group used a general marker for activation and subsequent gene expression in neurons in the PFC. Dr. Hoek noted that ERK1 appears to have an inhibitory function; it might be possible to generate a higher activated state as reflected in ERK2 response. Dr. Holmes observed that results of nonselective inhibition of ERK with kinase inhibitors have been perplexing. He responded to Ms. Murphy that the overarching goal of his work is to prevent addiction by developing drugs that increase capacity to exert executive control. Dr. Tabakoff suggested experiments with animals previously given alcohol in high doses to inform the processes of neuroadaptation or neurodegeneration, to determine whether the system is simply changed in its control or whether another system becomes prominent during the process. Dr. Holmes stated that he is working on ethanol vapor chambers to expose animals chronically and then test them on tasks. Data with chronic stress exposure shows strong adaptations in mice PFC that corresponds to deficits in some behaviors and similar adaptations in PFC neurons might occur with psychostimulant exposure.

Extramural Advisory Board Report Update: Mechanisms of Alcohol Addiction (Neuroscience)

Fulton T. Crews, Ph.D., Director, Bowles Center for Alcohol Studies, University of North Carolina-Chapel Hill, and Chair, NIAAA Extramural Advisory Board (EAB), presented the EAB's recommendations for the portfolio review on Mechanisms of Alcohol Action, Part II Neuroscience, which was held in June 2006. The interdisciplinary team reviewed preclinical activities in NIAAA's neuroscience portfolio representing a FY 2006 investment of $40-$50 million. The group discussed a range of issues including the role of animal models in informing our understanding of alcohol's actions on the brain and the development of alcohol dependence; the role of hereditary and development processes in influencing the actions of alcohol; cognitive, motivational, and associative learning mechanisms of habitual, compulsive alcohol misuse; neuroadaptation mechanisms promoting excessive alcohol use; and molecular and cellular mechanisms of plasticity and their relationship to the stimulus actions of ethanol and the progressive neural changes associated with addiction. Dr. Crews emphasized the magnitude, complexity, and importance of the research questions involved in this aspect of research.

Dr. Crews stated that all the Board's recommendations are to be taken in the context of a translational, feasible approach to understanding aspects of the transition from controlled to compulsive drinking. Prospective human studies that include genetic methodologies were recommended as likely to be particularly useful. In addition, efforts should be made to foster applications of new technologies and innovative approaches to address specific hypotheses regarding compulsive drinking and alcohol dependence. Attention to quantity and frequency of alcohol use is of particular importance. Discovering mechanisms involved in the transition to compulsive alcohol misuse will reveal factors common to other addictions and compulsions, as well as unique alcohol actions that are manifested in distinct characteristics of alcohol dependence. The specific recommendations for priorities are: 

1. Learning and tolerance mechanisms. Explore learning, cognitive, and tolerance mechanisms that facilitate or inhibit the escalation of drinking (within and across drinking bouts) in human and animal paradigms, and identify actions in relevant molecular and neural systems supporting these mechanisms. Specific areas of emphasis:

a. Thorough assessment of ethanol tolerance in human laboratory studies
b. Interrelationships among cellular, molecular, and behavioral manifestations of tolerance as they relate to controlled and compulsive drinking and examine the influence of opponent processes
c. Neural plasticity mechanisms involved in development of compulsive alcohol drinking as they relate to ethanol tolerance and the transfer of control between neural systems supporting instrumental behavior, information processing, and motivation.

2. Endophenotypes (risk and genetics). Identify physiological, temperamental, and cognitive traits and responses to alcohol associated with risk for or protection from developing alcohol dependence and study mechanistically based hypotheses in animal and human laboratory paradigms. Specific areas of emphasis:

a. Effects of ethanol on measures of impulsivity, motor and emotional response, and physiological measures in controlled studies in humans
b. Hypothesis-driven experiments using animal modeling approaches that adequately capture traits and responses associated with risk for alcohol dependence in humans and incorporating measures of stress-response, subjective interoceptive effects of ethanol, and imaging. Models should be relevant to important features of the human condition.

3. Adolescent-to-adult transitions. Study alcohol's actions upon and interactions with genetic, physiological, hormonal, temperamental, neurocognitive, and social-affective factors associated with transitions into adolescence and adulthood that establish drinking patterns leading to compulsive drinking and examine the role of gender and early life events on this trajectory.

4. Epigenetics. Determine the mechanisms and examine the role of epigenetic modifications in the etiology or progression of alcoholism and alcohol-relevant behaviors, examining the influence of alcohol exposure at various life stages and interactions with stressors and other internal and external moderators.

Discussion. Dr. Sher concurred in the importance of resuming studies of tolerance using the newer technologies. Dr. Charness suggested addressing the issue of dual diagnoses, to which Dr. Crews responded that modeling comorbidity in rodents is more complex than modeling compulsive drinking. Dr. Mark Egli concurred in the importance of the issue; he suggested looking at how executive function may interact with or facilitate development of comorbidities. Dr. Charness observed that some comorbidities, such as smoking, could be modeled in animals. Dr. Egli responded that nicotine reinforcement can be studied in rats, but it is not the same as smoking. Dr. O'Malley suggested that some work on nicotine exposure may be relevant in the context of co-exposure with alcohol. Dr. Sher commented that research on humans and mammals focusing on cross-thalamus mechanisms can fit into this discussion. Reinforcement and self-control encompass most of the variance and conceptualization of both Axis 1 and Axis 2 comorbidity. Dr. Swann considered the term comorbidity to be misleading; some of the same mechanisms (for example, impulsivity, compulsivity, and behavioral sensitization to reinforcers) underlie comorbid conditions. Robust cross-behavioral sensitization exists between alcohol and nicotine. Dr. Tabakoff asserted that the etiological question is whether the comorbidity-smoking, depression, or anxiety-drives the drinking behavior, and how much is part of the human condition. Dr. Hesselbrock asserted that the study of alcohol dependence among young people must focus on the stages from age of first drink, or its precursors, to the onset of regular drinking. He noted that many common risk factors exist, with no clear insight on what drives the varying magnitudes or modalities of the disorder. Dr. Hesselbrock also stated that the COGA study is finding common genetic vulnerabilities and environmental and personality factors that may push people in one or another direction. He went on to state that longitudinal studies will be important to understand common and specific mechanisms for producing alcohol-related problems. Dr. Crews responded that the feasibility of studying comorbidities in animals is an issue at this time; more insight from human comorbidity research will be required to enable modeling in animals. Dr. Tabakoff noted that rat genetic models of anxiety and depression exist, making study feasible.

Action: The report of the EAB was accepted by the Council.

Results of the COMBINE Study: Combining Medications and Behavioral Interventions in Treating Alcohol Dependence

Stephanie O'Malley, M.D., described the COMBINE study published in JAMA in 2006. This complex trial involved naltrexone and acamprosate, medical management (MM), and a specialized model of counseling called Combined Behavioral Intervention (CBI). The study, a 16-week, double-blind, placebo-controlled trial with 1-year follow-up, found no evidence for the effectiveness of acamprosate with this patient population. It did find that naltrexone or CBI, in combination with MM, improved treatment outcome. The importance of the study is the implication that primary care-based interventions have potential to increase demand for and access to alcoholism treatment. Only 7.5 percent of people with a diagnosis of alcohol dependence currently receive any treatment.

When COMBINE was planned in the late 1990s, NIAAA had already completed research on behavioral interventions, including the large cooperative, multi-site trial known as Project MATCH. The field saw the potential for pharmacological treatment using two new medications then available (naltrexone and acamprosate), and pressures from managed care increased interest in less intense, outpatient types of therapy. One important unknown at the outset of the COMBINE study was which specific combination of medication and behavioral treatment that would be most effective and appropriate for changing system needs. Previous evidence supported the efficacy for both drugs, but they were thought to work in different ways; combination therapy was anticipated to produce a better effect. The intent also was to contrast therapies of moderate intensity versus lower intensity. CBI incorporated the putative effective ingredients from a variety of known behavioral treatments. MM encouraged medications compliance, taught about alcoholism and medications, supported abstinence, and provided referrals to peer support groups. The services were delivered by health care professionals.

The study was conducted at 11 sites nationwide, plus a coordinating center. MM required 9 brief sessions over 16 weeks with a health care professional, with a decreasing level of care. CBI involved up to 20 individual sessions with a therapist. Dr. O'Malley described the experimental design and subjects' qualifications and disqualifications for eligibility. Eight conditions were established in a 9-cell design that evaluated the placebo effect. She enumerated the assessment schedule, noted the wide range of domains, and stated that primary outcome measures included percent days abstinent and time to first heavy drinking day. She described the statistical methodology-a traditional factorial ANOVA model-with a secondary analysis based on the follow-up period. Dr. O'Malley stated that the study exceeded its recruitment target, with mostly male subjects but also good representation of women. Representation of ethnic minorities in this study was one of the largest. Internal validity apparently was achieved-MM and CBI were delivered with high fidelity, and adherence to medications was good. Importantly, drinking data was complete during the treatment period on 94 percent of participants and on 82 percent over the 16-month follow-up. Dr. O'Malley stated that the study used a higher dosage than typical to allow for the possibility of dose reduction for people with side effects.

The study found:

1. Large improvement overall was seen in all patients, as is typical of most alcohol studies. Alcohol-free days tripled and total drinks decreased by about 80 percent.
2. There was a main effect of naltrexone on time to first heavy drinking day. The group that received naltrexone and MM experienced a higher percent days abstinent than those that received MM only. In addition, there was a significant naltrexone and behavioral intervention interaction that was observed for percent days abstinent. This interaction was also observed in several secondary outcome measures, demonstrating the reliability of the effect.
3. There was no effect of acamprosate. This surprising finding was consistent for both primary outcomes as well as several secondary outcome measures.
4. Naltrexone significantly reduced craving compared to placebo in the entire sample.
5. CBI plus MM had a higher percent days abstinent than in those receiving placebos and MM only.
6. Surprisingly, combining medications as well as combining medication with CBI did not improve treatment outcome.
7. A secondary measurement, Good Clinical Outcome, was also evaluated in this study. It was defined as having no more than 2 days heavy drinking (four or more drinks per drinking occasion for females and five or more drinks per drinking day for men) and no alcohol problems over the last eight weeks of treatment. There was a significant interaction for this measure between naltrexone and CBI in which naltrexone and CBI, or both enhanced positive outcomes in the presence of MM.
8. During treatment, those receiving CBI without pills or MM had lower percent days abstinent than those receiving placebo plus MM alone or placebo plus MM and CBI. The two groups receiving placebo plus MM were more likely to attend Alcoholics Anonymous meetings during reatment and were less likely to withdraw from treatment. However, these factors did not account for the significant differences between the CBI only and placebo plus MM and MM plus CBI groups.
9. One year after treatment, the direction of the differences in the outcome measures continue among the groups, although frequency and amount of drinking increased.

Dr. O'Malley identified several limitations to the study: assessment effects that may have added to the overall success rate; recruitment and treatment of patients in outpatient academic centers rather than primary care centers, although primary care can do those interventions; higher than approved doses; and exclusion of participants with psychiatric and medical illnesses. She asserted that the patients recruited could be managed in primary care health care centers and need not start out in specialty care.

The study concluded that alcohol dependence can be managed successfully with naltrexone and MM, and that patients have a choice between CBI or naltrexone. Although the need is not established to combine them in the overall sample, individual patients still might benefit. Long-term models of care might include booster therapy sessions and longer-term or intermittent treatment with medication, with ongoing health care professionals monitoring progress. Implications of the study include the following: Primary care and family practices should think of treating alcoholism as part of normal health care. Similar recent trends have emerged with smoking and depression as effective medications have become available. The study broadens treatment options for people with no access to care or who are reluctant to attend specialty programs. Dr. O'Malley noted that with increased screening and identification in primary care settings, more people may be treated by specialists as needed.

Discussion. Dr. O'Malley responded to Dr. Mitchell that many subjects were not treatment naïve. He noted that among subjects who have experienced relapse, being told that medications might have a greater effect may influence success. He also asserted that because the relapsing condition is known, adoption of a longitudinal approach is indicated. Dr. O'Malley stated that in a clinical setting, patients' use of medications may vary over time. Dr. Tabakoff suggested stressing the placebo effect. Dr. Willenbring asserted the strength of the evidence in favor of MM and naltrexone, stating that the study supports physicians offering a patient either naltrexone and MM or a referral to specialty alcohol counseling. Patients will be referred to a program in the community, which could take a variety of shapes. Dr. O'Malley replied to Dr. Tabakoff that sleepiness did not appear in the combined group. Dr. O'Malley replied to Dr. Sher that the long-acting injectable naltrexone, recently approved by the FDA, found a strong effect in men but not a significant effect in women. Dr. Swann suggested that the effect of being in the study may be greater than incremental effects from specific treatments. Dr. O'Malley stated that the rich database will offer information regarding family history of alcohol use disorder that may guide treatment choices in situations when a person has more or less social support. The treatment effects were clinically visible to study staff. Dr. O'Malley commented to Dr. Moss that although clinical adherence issues did not arise in this study, other patient populations might be less adherent. Dr. O'Malley explained to Dr. Warren that the COMBINE study differed from European studies which showed acamprosate to be effective. Differences in the studies may be due, in part, to differences in the type of subjects recruited. For example, the patients in the European studies had a greater severity of alcohol dependence than those recruited in the COMBINE study. The COMBINE group will look at such dimensions as severity of dependence and history of withdrawal as potential predictors of an acamprosate effect in this database. To Dr. Li's question about significant site variations, Dr. O'Malley replied that patterns were comparable across the study sites, which were of similar size.

Council Member Round Table

Dr. Li invited Council members whose terms are expiring to speak first during this round table discussion. Dr. Taylor urged NIAAA to ensure that sufficient numbers of minorities, women, and children participate in studies, and that studies with children concentrate on the developmental path. He also urged studies with general population-based recruitment. With respect to the comment made by Dr. Taylor, Dr. O'Malley noted that COMBINE drew in a broader population of people with alcohol dependence than typically seen in specialty care or liver treatment centers. She asserted the need to test the efficacy of treatment in primary care centers and to recruit and screen there. Dr. Taylor spoke to the issue of reductions in the physician work force from the perspective of developing treatment modalities delivered in primary care. Dr. O'Malley noted that most of the study's treatment providers were nurses. Ms. Taft urged NIAAA to select Council members with knowledge gained in the field and who have a prevention perspective. She expressed appreciation for NIAAA's contributions in creating the Leadership to Keep Children Alcohol Free and to help it move to the next step. Dr. Li noted that by government regulation, the Council should represent the general population. Ms. Murphy encouraged NIAAA to develop strategies by which lay persons can connect to reduce the harm and prevent the destructive progression of alcohol use. Dr. Li said NIAAA's two greatest challenges in biomedical research are translating animal studies to humans, and making connections between researchers and the community; more collaboration to make those links is warranted. Dr. O'Malley expressed appreciation for the opportunity to participate on the Council. Dr. Li noted that Dr. Jensen, also a departing Council member, had left the meeting earlier.

Dr. Sher initiated a discussion of the implications of funding and its effect on science. He expressed concerns about discouragement in light of tighter pay lines and diminished dollars, great amounts of time expended on preparing unfunded applications, and inefficiencies and burden of the review process. Dr. Li commented that this issue is of major concern to NIH and is the subject of much thought and broad discussion. Challenges include current page limitations, the review process, and opening up opportunities for multiple principal investigators (PIs) on large projects. Dr. Sorensen stated that program staff provides guidance in the application process. Dr. Hoek complimented NIAAA's program staff on their responsiveness and proactive stance. Dr. Bautista advised Council that a new investigator committee within NIH is working to find solutions to these issues. Dr. Tabakoff commented that Study Section demographics have changed over the last 20 years, and it has become more difficult to get a sympathetic review. He raised the issue of caps on the amount of grant money per group or investigator in order to fund greater numbers of individuals. Dr. Li suggested that requiring a minimum time commitment for PIs may address that problem.

On the issue of Study Section Member workload, Dr. O'Malley suggested that shorter tenure on Study Section may encourage people to agree to serve a second term. Dr. Faden suggested a requirement of service on Study Section by individuals who have received grants. Dr. Li asserted that after the postdoc, serving on Study Section is the polishing touch to one's education. Dr. Sher raised concern about reviewers who have never had an R01 grant Dr. Vanderveen observed that many individuals volunteer to review and confirmed that reviewers on standing committees must have had research experience and a grant. NIAAA struggles to identify individuals with finely focused expertise, particularly outside the alcohol field, and welcomes suggestions, particularly for clinician scientists.

Consideration of the June 2006 Minutes and Future Meeting Dates

Council members voted unanimously to approve the minutes from the Council meeting of June 7-8, 2006. Upcoming Council meetings will take place on February 7-8, 2007, May 23-24, 2007, and September 12-13, 2007.

Adjournment

Dr. Li adjourned the meeting at 2:25 p.m.

CERTIFICATION

I hereby certify that, to the best of my knowledge, the foregoing minutes are accurate and complete.

Posted:  January 2007