Current Pharmaceutical Design - Volume 16, Issue 19, 2010

Alcohol dependence represents a chronic, relapsing condition with a multifactorial aetiology that includes genetic, neurobiological, psychological, and environmental components. Evidence for the effectiveness of medications in alcohol dependence treatment along with the increased number of compounds available is increasing the use of adjunctive pharmacotherapies. In particular, pharmacotherapies could conceivably address some of the biological aspects of alcohol dependence. Treating a complex behavioral disorder such as alcohol dependence with both pharmacotherapy and psychosocial therapy may give people the best options for recovery. To address the exciting developments in the use of pharmacotherapies for alcohol dependence, we planned this special issue for Current Pharmaceutical Design, entitled “Old and new pharmacotherapies in the management of patients with alcohol dependence”. The overall purpose of this special issue is to provide a resource, that researchers and clinicians interested in the pharmacotherapy of alcohol dependence may use, as well as to stimulate how current findings and ongoing research may improve the treatment of our alcohol-dependent patients.

Supervised intake of the alcohol deterrent (AD) disulfiram has proven to be an effective adjunct to biopsychosocial alcoholism therapy for more than 60 years. This article summarizes disulfiram literature between 1937 and 2000 and reviews 13 clinical trials of disulfiram in alcoholism treatment from the years 2000 to 2008. After giving an update of general safety issues and recent case reports concerning safety problems with disulfiram, we focus on the introduction of psychotherapeutic application of supervised disulfiram. The results of our review show: (1) Disulfiram proved to be an effective therapeutic tool in all clinical studies published from 2000 to 2008. (2) Comparisons with other pharmacological agents - naltrexone, acamprosate, topiramate and gamma-hydroxybutyrate - indicate that disulfiram was equal in two trials but superior in the majority of trials. (3) Therapy programs that make use of the psychological effects of supervised disulfiram have - independently of the dose - better results than programs that neglect psychological effects. As a consequence, we suggest that supervised low-dose disulfiram (not more than 100mg/d), will show highest success when it is carefully integrated into psychotherapeutic alcoholism therapy. The major program of psychotherapy with disulfiram comprises the steps “Initial psychoeducation about the effect of disulfiram and its therapeutic implications”, “Advanced psychoeducation”, and “Disulfiram as coping skill and extension of repertoire of coping skills”. As psychological mechanisms of supervised disulfiram we suggest: (1) deterrence; (2) (auto)suggestion; (3) therapeutic ritual around (4) a frequently renewed active decision process; (5) continuous reinforcement of a sober lifestyle and development of new coping skills.

Naltrexone, a broad opioid-receptor antagonist, was the first medication since disulfiram to be approved by the United States of America Food and Drug Administration for the treatment of alcohol dependence. In the initial clinical trials in the early 1990s, oral naltrexone, 50 mg, was shown to significantly reduce the risk of relapsing to heavy drinking compared to placebo. These early trials were followed by other trials throughout the world such that by 2010 about 4,000 individuals had been studied. Meta-analyses of these trials revealed that oral naltrexone is effective in reducing relapse to heavy drinking but less effective in enhancing abstinence. The effect size is modest, in the .15 to .2 range, which has impacted the adoption of naltrexone use by clinicians. Intramuscular versions of naltrexone active for one month have also shown efficacy. The tolerability of naltrexone is reasonable with the most common side-effect being nausea. Hepatotoxicity with naltrexone has not emerged as a clinical problem at the standard 50 mg dose though at higher doses hepatoxicity is of concern. The length of treatment with naltrexone has not been well studied though many clinicians recommend one year of treatment. Efforts are underway to identify predictors of naltrexone response but, to date, no predictor has achieved clinical utility. It is anticipated that the role of naltrexone and other opioid antagonists in the treatment of alcohol dependence will continue to be refined and that this class of medications will come to be seen as an important option in the clinical care of the patient with alcohol dependence.

By updating John Littleton's work published 15 years ago this review summarizes recent work on pharmacodynamic aspects of acamprosate and the perspective for future developments. In addition to insights into the role of glutamatergic receptor systems, craving and relapse inspired by acamprosate, clinical research points towards one question: if we knew how acamprosate works, we might also be able to generate hypotheses, for whom it does work. Recent research on acamprosate tightly links pre-clinical and clinical research that includes molecular biology, animal models, pharmacogenetic and imaging genetic trials, and clinical efficacy studies. To increase the efficacy of this drug, targeted treatment and individualized therapy approaches seem useful and necessary.

Predicated upon a neuropharmacological conceptual model, there is now solid clinical evidence to support the efficacy of topiramate for the treatment of alcohol dependence. Topiramate treatment can be initiated whilst the alcohol-dependent individual is still drinking — just when crisis intervention is most likely to be needed by a patient with or without his or her family asking the health practitioner for assistance. Because topiramate can be paired with a brief intervention, there is now the exciting possibility of treating most alcohol- dependent individuals in office-based practice or generic treatment settings. Topiramate's additional effects on other impulsedyscontrol disorders make it a particularly interesting compound for the treatment of other comorbid drug or psychiatric disorders. Additionally, future studies should explore whether topiramate can be combined with other putative therapeutic agents to increase its efficacy. One notable clinical challenge in the development of topiramate as a pharmacotherapy to treat alcohol dependence is the determination of the smallest dose that can result in efficacy, thereby achieving the optimum balance between therapeutic benefit and adverse event profile. Animal data do provide support for topiramate's general anti-drinking effects but also indicate that its mechanisms of action might rely on several complex pharmacobehavioral changes. Additional preclinical studies are needed to elucidate more clearly the basic mechanistic processes that underlie topiramate's efficacy as a treatment for alcohol dependence. Preclinical information that topiramate may have differential effects based on genetic vulnerability opens up the possibility of future methods to optimize treatment.

Preclinical studies show that antagonism of the GABAB receptor may represent an effective neuropharmacological approach to treat alcohol dependence. Consistent with preclinical evidence, the majority of the human studies have demonstrated that the prototype GABAB receptor antagonist baclofen may represent an effective mediation to treat alcohol-dependent individuals. Specifically, baclofen has shown to reduce alcohol withdrawal symptoms, as well as to reduce alcohol craving and intake, and to promote alcohol abstinence. Notably, baclofen has shown a safe profile when administered to alcoholics, including those with liver cirrhosis. In summary, baclofen represents a safe and effective medication to treat alcohol dependence, thus holding promise as a new pharmacotherapy. However, large studies are needed to confirm the present findings.

Gamma aminobutyric acid (GABA) represents the major inhibitory neurotransmitter of the central nervous system. Ethanol as well as benzodiazepines (BDZs) and some anticonvulsant drugs directly affect GABAA receptors inducing similar anxiolytic, sedativehypnotic, and anticonvulsant effects. Since BDZs have proven their efficacy in ameliorating symptoms and in decreasing the risk of seizures and delirium tremens, they are the drugs of choice for the treatment of alcohol withdrawal syndrome (AWS). However, due to their addictive potential and lack of safety when combined with alcohol, BDZs are usually not recommended for the maintenance of alcohol abstinence. Other GABA-ergic medications represent potentially promising drugs useful in the treatment of AWS and in maintaining alcohol abstinence. Indeed, available studies have demonstrated that clomethiazole, gabapentin and gamma hydroxybutyrate (GHB) present a similar efficacy to BDZs in suppressing AWS. In addition, current evidence also indicates that gabapentin and GHB do not have significant interactions with ethanol that render them safe to use in maintaining alcohol abstinence. Moreover, gabapentin and valproic acid may be beneficial in maintaining alcohol abstinence in alcoholics with psychiatric co-morbidity. Pregabalin, neurosteroids, tiagabine, and vigabatrin need further clinical evidence of efficacy, safety and tolerability. Thus, given the importance of GABA-ergic mechanisms in the development and maintenance of alcohol dependence, and the very interesting results currently achieved, more research on GABA-ergic agents is warranted.

Research suggests that alcoholics show comparatively lower levels of serotonin (5-HT) than non-alcoholics. Medications aimed at increasing synaptic 5-HT have long been studied as potential treatments for alcoholism. Studies with selective serotonin reuptake inhibitors (SSRI) in a heterogeneous population of non-depressed alcoholics have produced inconsistent results. Further exploration involved whether or not treatment of co-morbid alcoholism and depression was a more practical approach. However, even in the presence of co-occurring depression, antidepressants in general lack the power to demonstrate a significant reduction of alcohol use among alcohol dependent patients with carefully diagnosed major depression. Further statistical analysis has also determined that perhaps genotypic and phenotypic variations differ for persons with alcohol dependence including those with or without comorbid alcohol dependence and depression suggesting important subgroups might respond differently to treatments. Clinical trials have also used the anxiolytic buspirone, a 5-HT1A partial agonist, as many alcoholics suffer from anxiety. When controlling for baseline anxiety, buspirone was no more effective than placebo for alcoholic patients. Another serotonergic drug, ritanserin, did not demonstrate effectiveness in relapse prevention in alcohol dependence. However, research on the use of the 5-HT3 antagonist ondansetron for alcohol dependence continues to provide promising results, particularly for patients with early onset alcoholism. As demonstrated by the studies with serotonergics, responses based on individual variables suggest that alcoholics may respond differentially based on various serotonin 5-HT subtypes. Of course, future studies need to further delineate and confirm the differences between these alcoholic subtypes.

An extensive literature supports the role of dopamine in the development and maintenance of alcohol dependence. Yet the organization of brain dopamine is complex, with multiple dopamine receptor subtypes and distinct effects on reinforcement, craving, motivation and behavior. Several modestly effective pharmacological treatments for alcoholism, including naltrexone, baclofen and ondansetron, affect dopaminergic systems indirectly. Direct dopamine antagonists, including tiapride, quetiapine, ondansetron and clozapine have been shown to be somewhat effective in reducing alcohol consumption in controlled clinical trials. The partial dopamine agonist, aripiprazole has shown mixed efficacy. Dopaminergic medications can have significant side effects. A better understanding of how dopamine affects the various aspects of addictive behavior may lead to more effective medications.

In this article, we review studies of genetic moderators of the response to medications to treat alcohol dependence, the acute response to alcohol, and the response to the psychotherapeutic treatment of heavy drinking. We consider four neurotransmitter systems: opioidergic, dopaminergic, GABAergic, and glutamatergic and focus on one receptor protein in each: OPRM1 (the μ-opioid receptor gene), DRD4 (the D4 dopamine receptor gene), GABRA2 (GABAA receptor α-2 subunit gene), and GRIK1 (the kainate receptor GluR5 subunit gene). We conclude that because parallel developments in alcoholism treatment and the genetics of alcohol dependence are beginning to converge, using genotypic information, it may be possible to match patients with specific treatments. Of greatest clinical relevance is the finding that the presence of an Asp40 allele in OPRM1 modestly predicts a better response to naltrexone treatment. Promising findings include the observations that a polymorphism in GABRA2 predicts the response to specific psychotherapies; a polymorphism in DRD4 predicts the effects of the antipsychotic olanzapine on craving for alcohol and drinking behavior; and a polymorphism in GRIK1 predicts adverse events resulting from treatment with the anticonvulsant topiramate. Although variants in other genes have been associated with the risk for alcohol dependence, they have not been studied as moderators of the response either to treatment or acute alcohol administration. We recommend that, whenever possible, treatment trials include the collection of DNA samples to permit pharmacogenetic analyses, and that such analyses look broadly for relevant genetic variation.

Human laboratory studies have a rich history in the alcoholism field and several important determinants of alcohol use disorders have been successfully modeled under controlled laboratory conditions. Laboratory paradigms have been employed to identify biobehavioral risk markers for alcohol misuse and more recently, have been integrated with behavioral genetic, neuroimaging, and pharmacological approaches to further elucidate the neuropathophysiology of addiction and to screen for efficacious treatments. This review will address the rationale and application of human laboratory models to advance pharmacotherapy development for alcohol dependence. It is argued that when properly implemented, laboratory models may help scientists and clinicians understand mechanisms of pharmacotherapy response, which in turn may inform efforts to optimize the currently available and newly developed treatments for alcoholism. Limitations and future directions are discussed.

Treating alcohol use disorders represents a main goal in public health, but the effect of current medications is modest. Thus, in the last few years, research has been focusing on identifying new neuropharmacological targets for alcohol dependence. This review will summarize recent research, which has identified new targets to treat alcohol dependence. A variety of systems have been investigated, such as the endocannabinoid system, modulators of glutamatergic transmission, corticotropin-releasing factor (CRF), neuropeptide Y (NPY), nociceptin, glial cell line-derived neurotrophic factor (GDNF), acetaldehyde (ACD), substance P and Neurokinin 1 (NK1) receptor, nicotinic acetylcholine receptors (nAchRs), alpha-adrenergic receptor, and many others. Compared to preclinical studies, only a few clinical studies have been conducted so far. Thus, there is a critical need to translate successful preclinical results into human clinical trials. However, since some clinical studies have failed to replicate preclinical findings, future research will have not only to identify more efficacious medications, but also delineate the best match between a particular pharmacotherapy with a specific alcoholic subtype.