20. Future perspectives on relapse prevention

Editors: Spanagel, Rainer; Mann, Karl F.

Title: Drugs for Relapse Prevention of Alcoholism, 1st Edition

Copyright 2005 Springer

> Table of Contents > Future perspectives on relapse prevention

Future perspectives on relapse prevention

Rainer Spanagel

Karl F. Mann

Department of Psychopharmacology and Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, University of Heidelberg, J5, 68159 Mannheim, Germany

In 1751, William Hogarth successfully launched what in present times would be known as a public awareness campaign: in his famous work, he contrasted the chaotic gin lane with a neat and well-organized beer street (Figs 1 and 2). His intervention was most influential in a debate which in its conclusion was to witness a sharp rise in community tax on gin, with the consequence of having a dramatic drop in gin consumption in Old England. While these circumstances are well known, they are providing some of the first evidence that taxes are a main regulator of alcohol intake rate per inhabitant. Another aspect of his campaign merits equal attention, namely, the fact that he suggested something like a substitution therapy. Thus, in his view, gin drinking ought to be substituted and replaced by the less harmless consumption of beer. From today's perspective, Hogarth's provocative idea recently became reality, with the novel concept of harm reduction in conjunction with substitution therapy. Thus, a new generation of compounds that substitute for the discriminative stimulus properties of alcohol - namely, uncompetitive NMDA receptor antagonists - might have the ability of altering current day-to-day treatment programs for alcoholic patients.

Harm reduction in combination with substitution therapy

In line with the results from drug discrimination studies in animals, clinical experiments have indicated that NMDA receptors mediate, at least in part, the subjective effects of ethanol. Krystal et al. [1] have shown that ketamine - an uncompetitive NMDA receptor antagonist - produced dose-related ethanol-like effects in detoxified alcoholics. The effects of ketamine were more similar to the sedative than to the stimulant effects of ethanol and the subjects rated ketamine as more similar to ethanol than to marijuana or cocaine. Importantly, ketamine did not increase craving for ethanol. In a more recent study, Soyka and co-workers [2] have also found that the low-affinity uncompetitive NMDA receptor antagonist dextromethorphan can produce some ethanol-like subjective effects in both alcoholics and controls. These findings prompted the idea

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that these compounds have the ability to substitute for acute alcohol intake. Due to the lack of producing craving by themselves, they could be used in relapse prevention. This idea is outlined in several chapters of the present book and constitutes one important pillar of a major theory in the alcohol field - the glutamatergic theory of alcoholism. It derives from the findings that high intoxicating doses of ethanol decrease the activity of glutamate signaling in the brain. As a consequence of chronic alcohol intake, adaptive changes in the glutamate system are observed, which result in a hyper-glutamatergic state [3, 4]. Considering the fact that at least 70-80% of excitatory neurons work via glutamatergic

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neurotransmission, augmented activity of the glutamate system due to chronic alcohol intake puts our brain into a hyper-excitatory state. In such a situation alcohol can be regarded as a cure, which has the ability to normalize general brain activity. Thus, it is suggested that a hyper-glutamatergic state is a trigger for alcoholic patients to further drink alcohol in a withdrawal state or to relapse after a period of abstinence. That this most likely represents a pharmacologically driven behavior has recently been demonstrated in the alcoholdeprivation-effect model of relapse drinking behavior [5]. Thus, following alcohol deprivation, an increase in alcohol consumption is observed after having

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regained access to alcohol. This behavior, however, is completely abolished by experimentally administered ethanol using the intraperitoneal route. In conclusion, the acute pharmacological effect of ethanol may fully substitute for such a complex behavior as relapse. It is therefore only a logical step further that substitution drugs such as uncompetitive NMDA receptor antagonists should dampen hyper-glutamatergic activity and also abolish or reduce relapse drinking behavior, a hypothesis which has been successfully and repeatedly demonstrated in laboratory animals [5, 6 and 7].

Fig. 1. Gin Lane, engraving by William Hogarth, 1751. (The British Museum, London, UK.)

Fig. 2. Beer Street, engraving by William Hogarth, 1751. (The British Museum, London, UK.)

Recent clinical findings, however, have not been in line with this hypothesis. In a currently still unpublished study, the efficacy of neramexane, a low-affinity NMDA receptor antagonist, was tested in a multi-center randomized, double-blind, placebo-controlled study. 249 alcoholic patients and the same number of control subjects were included in this study. One dose of neramexane versus placebo was tested. The outcome was negative: the verum group did not differ from the placebo group in terms of number of relapses and total abstinence days during the 6-month treatment period. It is important to note, however, that a low dose of neramexane was used, which is unfavorable in a substitution study, as preclinical studies indicate that only high doses would be helpful in preventing relapse behavior [5, 6 and 7]. Furthermore, compliance was a problem in this study. Although the use of a low dose of neramexane, in addition to the compliance problem, might have influenced the outcome of this study, the negative results obtained are a threat to the glutamatergic theory of alcoholism and forces researchers to reassess their interpretations and conclusions in this regard. Thus, in a more critical perspective, one has to state that ethanol's interactions with the glutamatergic system are still far from clear. In fact, many important questions remain unanswered. For example, it is of crucial importance to examine whether long-lasting changes in the glutamatergic system occur in alcohol-dependent animals as well as in alcoholic patients. Thus, further preclinical and clinical studies including molecular, genetic, neuroimaging and behavioral techniques should address the following points: (I) Identification of adaptations within the glutamatergic system and its signalling pathways associated with chronic alcohol use as well as the time course of these adaptive processes. In particular, it should be examined whether long-term or even persistent changes within the glutamatergic system can account for craving and relapse in laboratory animals. With the aid of recently improved in vivo spectroscopic measurements of glutamate [8], those examinations may now also be conducted in abstinent alcoholic patients. (II) Further assessment of interactions of various NMDA receptor antagonists with specific alcohol-induced behavioral effects including aversive, reinforcing and subjective actions. (III) Evaluation of different classes of NMDA receptor antagonists as potential anti-craving/anti-relapse drugs in clinical studies. (IV) Systematic studies on the genetic basis for the susceptibility of alcohol dependence and relapse behavior within the glutamatergic system.

All these studies are necessary to ultimately provide substantial support for the concept of substitution therapy. However, even if the scientific basis of a

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substitution therapy would be of substantial and sound nature, it cannot be foreseen whether the majority of professionals in the addiction field would accept such a treatment concept. In particular, psychologists, social workers, members of self-help groups and counselors are quite hesitant in promoting the use of any kind of medication. Thus, it will be an issue of enhancing educational activities so as to increase the acceptance of these medications for the benefit of our patients. Another way to encourage professionals who are still reluctant in prescribing anti-relapse drugs, is to combine pharmacotherapy with behavioral and/or psychosocial therapy.

Pharmacotherapy in combination with behavioral and psychosocial therapy (COMBINE)

This book concentrates on pharmacological relapse prevention only. The whole field of behavioral and psychosocial interventions for relapse prevention was deliberately excluded. The authors agree with the vast majority of colleagues who, on the basis of empirical evidence, acknowledge the need for combining both treatment strategies [9]. However, this would certainly merit a book in its own right, especially since the individual cocktail for a given patient, in other words a targeted approach, is far from being clear at this point. However, some progress can be expected from project COMBINE. In this large-scale study, more than 1300 patients are treated with either acamprosate, naltrexone, placebo or with a combination of acamprosate and naltrexone. Whilst half the patients receive a low dose standard supportive therapy (Medical Management), the other half receives more intense psychotherapy, cognitive behavioral intervention [10]. Additionally, one group is treated by cognitive behavioral intervention without medication. The results of the study will be available in 2005/2006 and should help us better understand the contribution of each drug alone, their interaction and especially the interaction with two forms of psychotherapy. One single-center study by Kiefer et al. [11] already suggests that a combination of naltrexone and acamprosate may be more effective than either drug alone. It is hoped that the results of the COMBINE study will further support this finding and may finally end in an algorithm which may tell us more about an evidence-based stepped care approach for the individual patient.

Individual adapted pharmacotherapy (PREDICT): improving clinical efficacy

A German study that has been closely planned with the Steering Committee of project COMBINE aims to identify responders to either acamprosate or to naltrexone treatment a priori. In order to predict treatment response, different craving types are assessed in this study. There are at least two different pathways

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which can induce alcohol craving and relapse [12] - in other words, it is suggested that there are at least two different craving types. In the project PREDICT, the goal is to see whether naltrexone is specifically effective among individuals who experience positive motivational effects upon alcohol consumption and whether acamprosate is most effective among patients who consume alcohol to counteract conditioned withdrawal and negative mood states [13]. Animal studies are performed in close parallel to the clinical project PREDICT. Thus, changes in reinstatement of alcohol-seeking behavior in rats are analyzed in response to the same craving-inducing situations and the same pharmacological treatments that are used in humans. It has already been observed that reinstatement of alcohol-seeking behavior induced by alcohol-associated cues can be blocked by naltrexone and acamprosate [14]; however, it still remains an open question whether one of these drugs also interferes with withdrawal-induced reinstatement of alcohol-seeking behavior.

Another issue that is considered in project PREDICT is the genetic make-up of an individual. Thus, response to pharmacological treatment may be influenced by genetic polymorphisms of drug target genes. Developing a new approach which takes into account craving/relapse-specific stimuli and situations as well as genetic make-up may hold the potential for a break-through in the management and prevention of relapse. In fact, only recently, it was shown that genetic differences in the mu opioid receptor might predict naltrexone efficacy [15]. In summary, the effectiveness of acamprosate and naltrexone seems to be valid beyond doubt [16], although more research needs to be done in identifying potential responders. One major question remains, however, namely, why are these medications so rarely prescribed?

Involvement of the pharmaceutical industry in bridging the gap between the academic world and alcoholic patients

The chapters of this book have outlined the evidence for the pharmacological treatment of alcoholism. While the prevalence rates for alcohol dependence and harmful use (abuse) are on the order of more than 5% of the population in developed countries, the pharmaceutical industry is still hesitant in promoting their products. A recent survey in the US of 1,388 physicians specialized in substance abuse has revealed that only 13% prescribed naltrexone and a mere 9% prescribed disulfram (acamprosate was registered in the US in April 2004 and is, therefore, not included in this survey). In contrast, these addiction specialists prescribed anti-depressants for their primary alcohol-dependent patients in 46% of the cases and benzodiazepines in 11%, both being medications known for no detectable effectiveness in prevention of relapse to alcoholism. Interestingly, these physicians felt much more educated about anti-depressants or neuroleptics than about anti-craving substances [17]. The same article refers to 171,000 prescriptions for naltrexone and 246,000 prescriptions for disulfram in 1999. In the same year, 6,662,000 prescriptions were given for

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anti-psychotic and 23,138,000 for the leading anti-depressant drugs. To a certain extent, these numbers reflect the money being spent for marketing. For example, 7.8 million free samples of sertraline and 1.4 million samples of risperidone were distributed in 1999. In contrast, DuPont Pharma, the producer of naltrexone, never distributed free samples of Revia. The same holds true for journal advertisements, etc. In summary, $60 million for the promotion of sertraline and $20 million for risperidone were spent in 1999, in contrast to $0 for naltrexone. It seems to be this apparent lack of interest on the part of the pharmaceutical industry which contributes to the low use of anticraving/relapse drugs by alcohol-dependent patients. In a recent debate with representatives of the pharmaceutical industry, the challenges of marketing strategies and further drug development in alcoholism have been outlined by an expert group [18].

A major challenge that was recognized by this expert group is that the development of marketing strategies and drugs by the pharmaceutical industry is hampered by their unenthusiastic and reluctant attitude to invest money in the field of alcoholism. In order to advance in this respect, industry's commitment in this field ought to be enhanced, especially by means of socio-political pressure. Until the very present, most of the advancements in alcohol research and drug development for relapse prevention are currently taking place in university-based laboratories, but this rarely progresses to higher levels of clinical trials. As demonstrated in this book, preclinical research has produced potentially interesting targets and drugs; however, a full-scale clinical trial of a candidate medication is always an expensive undertaking and rarely supported by funding bodies. One solution to this problem would be that before cost-intensive phase II/III studies are initiated on the basis of preclinical findings, small orientation studies using few patients and controls would aid in rapidly translating preclinical findings into clinical trials. Although small orientation studies always bear the danger of false positive and false negative results, they would certainly be a good help in guiding companies in the decision-making on cost-intensive endeavors. A convincing example of this approach is the medication development of acamprosate. Thus, the effectiveness of acamprosate to decrease alcohol consumption was first demonstrated in preclinical studies [19]. Then, in a small orientation study by Lhuintre et al. [20], it was shown that of the 70 patients who completed the study, 33 received acamprosate and 37 placebo. 20 patients on acamprosate did not relapse, compared with 12 on placebo. Following this study, several multi-center, double-blind, placebo-controlled studies were initiated and based on the successful results of these studies, acamprosate was approved in most of the European countries [21]. Again, small orientation studies can be easily performed at universities and this knowledge could finally be used by the pharmaceutical industry to perform phase II/III studies with cost-intensive monitoring.

However, so as to achieve approval of a novel anti-relapse drug, it is necessary to conduct clinical trials in a manner deemed acceptable to the regulatory authorities in different countries. In contrast to many other areas of medication

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development, there are no agreed guidelines from the regulatory authorities for the conduct of clinical trials in alcoholism. Consequently, there is a degree of variability in the conduct of trials amongst different centers and among countries as well. Clinical trials in Europe also tend to be more naturalistic and more prolonged than trials in the US, making it difficult to compare data across continents. Identified areas in which guidelines would be particularly valuable include minimizing the bias associated with patients leaving trials prematurely, and a preferred main end-point in assessing outcomes. However, it must be recognized that the preferred main end-point probably cannot be identical for all medications because of the need to match clinical end-point with the mechanism of action of the drug. For example, although anti-relapse drugs such as naltrexone and acamprosate might share an end-point such as cumulative abstinent days during the trial, this would not be appropriate for an agent aimed at reducing excessive drinking (e.g., galanthamine) without necessarily producing abstinence at all. Such an agent might be therapeutically very valuable but would not be identified as effective by a purely abstinence-based outcome measure. Overall, it is clear that pre-trial motivation for patients in reducing their alcohol consumption must be assessed and incorporated into study design and/or statistical analysis. Also, ideally, outcome measures should reflect clinical relevance, quality of life and economic cost/benefit analysis. Regardless of the complexity, it would certainly increase the industry's enthusiasm for the development of medications if some guidelines for acceptability were issued by the appropriate regulatory authorities.

Educational programs for improving the clinical and social climate for pharmacological relapse prevention

A major factor in the low level of clinical use of validated pharmacotherapy in the area of alcoholism may be the general public's view that alcoholism is a behavior disorder , rather than a medical condition . This notion is compounded by the important current role of psychosocial treatment in alcoholism and by the role of the social services in recovery and rehabilitation. This has led to some opposition (or at least antipathy) to medical treatment of alcoholism by the psychosocial community, who may feel that their position could be undermined by effective pharmacotherapy. Unless these barriers are overcome, medications that are effective treatments will have a hard time to reach the patients and therefore will not become profitable. This alone is sufficient in dissuading the pharmaceutical industry, or any other researcher interested in the practical value of his/her research, from becoming committed to medication development for alcoholism. This failure to penetrate a potential market is perhaps the major challenge to an effective drug development strategy. Better dissemination of information and more aggressive educational marketing (by government and professional organizations, as well as industry) are required if medication development in alcoholism is to have a brighter future. This is particularly

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important for primary healthcare practitioners. The major challenges appear to be in explaining and marketing drugs for alcoholism so that physicians and patients alike may genuinely accept them. Additionally, there is a compelling need to explain and integrate medical and psychosocial treatments so that there is less opposition to the introduction of a pharmacotherapy.

Conclusion

For relapse prevention, two effective drugs are currently on the market and many more drug targets and compounds have already been developed. The effectiveness of acamprosate and naltrexone may further be improved by either combining the two drugs or by combining the drug with behavioral and psychosocial therapy (project COMBINE). Yet another possibility to improve their clinical efficacy is to identify treatment responders a priori, either by matching with a specific craving type or by matching with the genetic make-up of a particular alcoholic patient (project PREDICT). Although both concepts may improve clinical efficacy of acamprosate and naltrexone, one has to emphasize that both compounds are clearly superior to a combined treatment of placebo and behavioral/psychosocial therapy. However, compared to other classes of psychopharmacological therapeutics, anti-relapse drugs are rarely prescribed. This is even more surprising, considering the fact that differences in the clinical efficacy among anti-depressants and active placebos are small [22]. Nevertheless, anti-depressants have for many years now conquered the world market. The question as to why anti-relapse drugs are so infrequently prescribed is best left addressed to the pharmaceutical industry. They are still hesitant in using appropriate marketing strategies, with only little interest in investing money in further drug development. Another problem, which adds to the low prescription rates, is the general public's view that alcoholism is a behavioral disorder . This stigma is reinforced by the majority of professionals in the addiction field including psychologists, social workers, members of self-help groups and counselors, who are quite hesitant in promoting the use of any kind of medication. The only way out of this dilemma is a better dissemination of information and more aggressive educational marketing by government and professional organizations. The main player in the future in this regard, however, could be the pharmaceutical industry, but only if they take it upon themselves to conquer this potentially lucrative market, with the main beneficiaries being the patients themselves.

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