Moving Addiction Medications From Lab to Practice

The gap between the number of investigational addiction treatment drugs and the few actually available on the market--along with the relatively small number of physicians prescribing medications approved for patients with drug dependence--was the theme of several forums at the May 2006 American Society of Addiction Medicine (ASAM) conference in San Diego. Among these sessions was the pointedly titled symposium, "Breaking the Bottleneck of Research Adoption."

"There's a lot of concern about the amount of research that gets done that never finds its way into the field," declared the symposium moderator, Joan Zweben, PhD, of the University of California, San Francisco.

Jack Stein, PhD, deputy director of the Division of Epidemiology Services and Prevention Research at the National Institute on Drug Abuse (NIDA) indicated that NIDA is embarking on research into the adoption and implementation of new treatments, with the aim of improving dissemination of information and facilitating the provision of treatment. Stein has been disappointed with some previous efforts in this direction, such as mailings of guid-ance brochures and practice manuals that are later found discarded or unopened.

"We're faced with the paradox of non-evidenced-based implementation of evidence-based programs," Stein said.

From his initial review of the literature on diffusion of new technologies, Stein offered several factors that could favor treatment adoption: the treatment should present an advantage over existing options; its implementation should be relatively compatible with existing practice; it should be able to be tried in limited populations before full implementation; and it should produce observable, measurable outcomes.

Adoption is not just a function of practitioners embracing evidence-based methods, Stein observed; it is influenced by a host of other factors. "We need to look at some of those program-level elements," he said, "the organizational-cultural components and then, on another level, the system-level issues--the legal, the regulatory issues, the financial aspects."

Implementing use of drugs for alcoholism

The lack of research on implementation and adoption was also lamented at a symposium sponsored by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), with presenters discussing progress of medications for alcoholism moving from research bench to patient bedside. Mark Willenbring, MD, Director of Treatment and Recovery Research, NIAAA, noted that new treatments for alcoholism are slow to evolve and be adopted, not just because of the difficulties in drug development research, but also because of ideologic barriers and lack of funding for alcoholism treatments.

"We have a very fragmented system without good integration of medical care into treatment programs," he said.

The development of new products to treat alcoholism is a high priority for the National Institutes of Health, and Willenbring indicated that the current effort involves "one of the more highly developed research programs at NIAAA." He acknowledged, however, that the NIAAA is involved more in studies of product efficacy than in the evaluations of effectiveness that could provide more clinically relevant information for practitioners to consider in adopting new interventions.

Efficacy studies tend to be less expensive, he explained, and benefit the sponsoring manufacturers by supporting the application for FDA approval. There is also an existing infrastructure for conducting efficacy studies, Willenbring noted, which is not available for studies of drug effectiveness or treatment adoption.

For the latter studies, Willenbring commented, "its going to require trans-disciplinary research, which is not necessarily easy to fund or to do, and sustained attention. We're going to have to address the stigma and the treatment infrastructure problems."

John Littleton, MD, PhD, of the University of Kentucky concurred with Willenbring on how market and societal forces can affect drug development for alcoholism. He estimated the cost of bringing a compound to market, including that for the inevitable failed candidates, to be over $1 billion; this outweighs any projected return from the current $150 million annual market for medications to treat alcoholism. Littleton anticipates, however, that there would be a larger market for new drugs that are proved more effective, given the number of people with alcohol dependence who are not adequately treated.

Littleton's group at the University of Kentucky has used NIAAA funding to form a "High Throughput Screening" program to reduce the cost of identifying candidate compounds for alcoholism treatment. The program targets the neuroreceptors that are affected by or that mediate protracted alcohol withdrawal and craving and works to synthesize compounds that are active at these sites. Compounds that appear promising in animal models and pass toxicity screening are proposed for clinical trials and commercial development.

Although this program can increase the efficiency of drug development, Littleton reported that it has been difficult to undertake such drug synthesis and screening within a university setting. He is currently in discussions with the University of Kentucky administration about accommodating separate "drug discovery cells," which would operate with different rules and workers than those in academic research.

"Universities are not set up for this kind of research, and the people who work in universities get bored by doing this kind of stuff," Littleton remarked. "They don't want to do the same tests over and over again every day."

Two alcohol addiction researchers at the Scripps Research Institute in La Jolla, California, described their progress in developing, respectively, new animal models for testing drug treatment of alcoholism and a human model to measure the effectiveness of interventions for alcohol craving.

George Koob, PhD, broadly distinguished between animal models of alcohol dependency that reflect reduced impulse control and animal models of compulsive behavior. He suggested that naltrexone (Depade, ReVia), which has demonstrated effectiveness at prolonging periods between heavy drinking, may be more active in mediating the first condition. Acamprosate (Campral), which has been found to reduce craving that persists well after consumption has stopped, is more likely to be active in animal models of compulsion to drink, according to Koob.

"Different medications may have unique profiles of effects in animal models that provide a Rosetta stone for interpretation of the clinical treatment potential of compounds directed at novel targets," Koob said.

Alternative approaches to studying abstinence

Barbara Mason, PhD, has developed clinical paradigms to test interventions for facilitating abstinence in alcohol-dependent volunteers, without their consuming alcohol in the test condition. Through a combination of self-reporting on visual analog-scaled questions and confirmatory physiologic measures during and following an array of drinking cues and stress precipitants, Mason has defined characteristics of a heightened vulnerability to relapse.

"Our human laboratory model of protracted abstinence offers a critical alternative to existing paradigms that involve alcohol administration," Mason declared.

While Mason will not provide alcohol to this vulnerable population even to study therapeutic interventions, she does not consider volunteers without alcohol dependence as a suitable alternative. "I would argue that the study of nondependent individuals is inappropriate for the study of protracted abstinence," Mason explained, "because they don't have the neural adaptive changes that occur in the alcohol-dependent individual that these medications may act to normalize."

From demonstrating efficacy to evaluating effectiveness

Although the NIAAA sponsors more studies of medication efficacy in selected populations than of their effectiveness with other treatments and within different practice settings, Willenbring emphasized the importance of conducting this research as well. "There are really key questions about how to integrate pharmacotherapy into existing treatment systems that are unanswered," Willenbring said.

One effort to explore the effectiveness of medication alone or in combination, and when it is provided along with primary care medical management or specialist behavioral intervention, is the NIAAA-sponsored Project COMBINE. The Combined Pharmacotherapies and Behavioral Interventions (COMBINE) study is a randomized placebo-controlled trial conducted over a 3-year period at 11 US sites involving monotherapy and combination therapies of naltrexone, acamprosate, and behavioral therapies in 1383 recently alcohol-abstinent subjects.

The first paper from this study was published in the Journal of the American Medical Association during the ASAM conference, 3 days before being described in a symposium by lead author, Raymond Anton, MD, of the Medical University of South Carolina, Charleston. Anton reported that patients who received medical management with naltrexone and/or specialist-provided "combined behavioral intervention" (CBI) had more days of abstinence and/or more days until the first heavy drinking day than did those who received acamprosate with or without CBI; acamprosate did not demonstrate greater effect than placebo. He also noted that patients who received only CBI did not do as well as either those who received CBI and placebo, or placebo alone.

Anton indicated that the researchers were surprised that acamprosate had not demonstrated effectiveness, given the number of previous positive trials and the decade of successful use of the medication in Europe before its approval in the United States. A possible contributing factor was that only 4 days of outpatient abstinence was required for admittance to this study, in contrast to the longer prestudy inpatient abstinence required in most of the positive trials with acamprosate.

"Medical management of alcohol dependence with naltrexone appears to be feasible," the investigators concluded, "and, if implemented in primary and other health care settings, could greatly extend patient access to effective treatment."¹

Littleton had cautioned, earlier in the symposium, that the Project COMBINE results should not obscure the previously demonstrated value of acamprosate to assist longer-term abstinent patients or to serve as a model compound from which to derive more effective products. "It indicates that we need to do a better job of ascertaining how best to apply the medication," he commented.

This is the second of 2 articles on the 2006 ASAM Medical-Scientific Conference. The first (Psychiatric Times, August 2006) reported on obstacles to provision of treatment for addiction.

References:

References

1.

Anton RF, O'Malley SS, Ciraulo DA, et al. Combined pharmacotherapies and behavioral interventions for alcohol dependence.

JAMA

2006;295:2003-2017.