Update on neuropharmacological treatments for alcoholism: scientific basis and clinical findings

The past decade has seen an expansion of research and knowledge on pharmacotherapy for the treatment of alcohol dependence. The Food and Drug Administration (FDA)-approved medications naltrexone and acamprosate have shown mixed results in clinical trials. Oral naltrexone and naltrexone depot formulations have generally demonstrated efficacy at treating alcohol dependence, but their treatment effect size is small, and more research is needed to compare the effects of different doses on drinking outcome. Acamprosate has demonstrated efficacy for treating alcohol dependence in European trials, but with a small effect size. In U.S. trials, acamprosate has not proved to be efficacious. Research continues to explore which types of alcohol-dependent individual would benefit the most from treatment with naltrexone or acamprosate. The combination of the two medications demonstrated efficacy for treating alcohol dependence in one European study but not in a multi-site U.S. study. Another FDA-approved medication, disulfiram, is an aversive agent that does not diminish craving for alcohol. Disulfiram is most effective when given to those who are highly compliant or who are receiving their medication under supervision. Of the non-approved medications, topiramate is among the most promising, with a medium effect size in clinical trials. Another promising medication, baclofen, has shown efficacy in small trials. Serotonergic agents such as selective serotonin reuptake inhibitors and the serotonin-3 receptor antagonist, ondansetron, appear to be efficacious only among certain genetic subtypes of alcoholic. As neuroscientific research progresses, other promising medications, as well as medication combinations, for treating alcohol dependence continue to be explored.     

Assessing the efficacy of medical treatments for alcohol use disorders

Alcohol use disorders (AUDs) are common health problems that have a significant impact on society as a whole. There is a need for more effective treatments. In the last two decades, evidence for the efficacy of pharmacological approaches to treatment has increased. Although it has long been clear that medications are needed for the treatment of the alcohol withdrawal syndrome, the important role of medications in the longer-term treatment of AUDs has only recently been appreciated. In particular, naltrexone, acamprosate and topiramate appear to be efficacious treatments, especially when combined with psychosocial interventions that emphasise compliance with medication and encourage treatment retention. The goal of this review is to bring together the existing literature supporting the usefulness of pharmacological treatments for the alcohol withdrawal syndrome, for longer-term treatment of AUDs, and for comorbid AUDs and other psychiatric disorders. In addition, opportunities for future research will be identified.     

Development of medications for alcohol use disorders: recent advances and ongoing challenges

During the past decade, efforts to develop medications for alcoholism have burgeoned. Three agents, disulfiram, naltrexone and acamprosate, are now approved in a large number of countries. Although many patients have benefited from existing medications, their effects are moderate, and some alcoholics fail to respond to them. A host of new agents are currently under active investigation. Critical barriers must be overcome to ensure that future efforts in the development of medications for alcohol use disorders reach full fruition. These challenges include: establishing key targets for drug discovery; validating animal and human screening models; and developing biomarkers to help predict treatment success. In addition, it is important to formulate methodological and statistical strategies to efficiently conduct alcohol pharmacotherapy trials; to specify genetic and phenotypic patient characteristics associated with efficacy and safety for lead compounds; to forge productive alliances among governmental agencies, the pharmaceutical industry and academic researchers to further drug development; and, ultimately and perhaps most difficult, to engage the practitioner community to incorporate medications into the alcohol treatment process.     

Assessing the efficacy of medical treatments for alcohol use disorders

Alcohol use disorders (AUDs) are common health problems that have a significant impact on society as a whole. There is a need for more effective treatments. In the last two decades, evidence for the efficacy of pharmacological approaches to treatment has increased. Although it has long been clear that medications are needed for the treatment of the alcohol withdrawal syndrome, the important role of medications in the longer-term treatment of AUDs has only recently been appreciated. In particular, naltrexone, acamprosate and topiramate appear to be efficacious treatments, especially when combined with psychosocial interventions that emphasise compliance with medication and encourage treatment retention. The goal of this review is to bring together the existing literature supporting the usefulness of pharmacological treatments for the alcohol withdrawal syndrome, for longer-term treatment of AUDs, and for comorbid AUDs and other psychiatric disorders. In addition, opportunities for future research will be identified.     

Naltrexone and disulfiram in patients with alcohol dependence and current depression

OBJECTIVE: Although disulfiram and naltrexone have been approved by the Food and Drug Administration for the treatment of alcoholism, no medications have been approved for individuals with alcohol dependence and comorbid psychiatric disorders. In particular, the effect of these medications on alcohol use outcomes and on specific psychiatric symptoms is still unknown in patients with the most common co-occurring disorder, major depression. METHOD: Two hundred fifty-four patients with a major Axis I psychiatric disorder and comorbid alcohol dependence were treated for 12 weeks in an outpatient medication study conducted at 3 Veterans Administration outpatient clinics. Randomization included (1) open randomization to disulfiram or no disulfiram, and (2) double-blind randomization to naltrexone or placebo. This resulted in 4 groups: (1) naltrexone alone, (2) placebo alone, (3) disulfiram and naltrexone, and (4) disulfiram and placebo. Primary outcomes were measures of alcohol use. Secondary outcomes included psychiatric symptoms assessed by the Hamilton Depression Rating Scale, alcohol craving, gamma-glutamyltransferase levels, and adverse events. RESULTS: One hundred thirty-nine subjects (54.7%) met the current Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for major depression. There was no relationship between the diagnosis of depression and medication treatment on alcohol use outcomes, psychiatric symptoms, or the reporting of side effects for these medications. There was a significant interaction between diagnosis, medication group, and craving, where subjects with depression on disulfram reported lower craving over time than subjects with depression on naltrexone. CONCLUSIONS: The results suggest that disulfiram and naltrexone are safe pharmacotherapeutic agents for dually diagnosed individuals with depression for the treatment of alcohol use disorders.     

Pharmacogenetically driven treatments for alcoholism: are we there yet?

Pharmacogenetic analyses of treatments for alcohol dependence attempt to predict treatment response and side-effect risk for specific medications. We review the literature on pharmacogenetics relevant to alcohol dependence treatment, and describe state-of-the-art methods of pharmacogenetic research in this area. Two main pharmacogenetic study designs predominate: challenge studies and treatment-trial analyses. Medications studied include US FDA-approved naltrexone and acamprosate, both indicated for treating alcohol dependence, as well as several investigational (and off-label) treatments such as sertraline, olanzapine and ondansetron. The best-studied functional genetic variant relevant to alcoholism treatment is rs1799971, a single-nucleotide polymorphism in exon 1 of the OPRM1 gene that encodes the μ-opioid receptor. Evidence from clinical trials suggests that the presence of the variant G allele of rs1799971 may predict better treatment response to opioid receptor antagonists such as naltrexone. Evidence from clinical trials also suggests that several medications interact pharmacogenetically with variation in genes that encode proteins involved in dopaminergic and serotonergic neurotransmission. Variation in the DRD4 gene, which encodes the dopamine D(4) receptor, may predict better response to naltrexone and olanzapine. A polymorphism in the serotonin transporter gene SLC6A4 promoter region appears related to differential treatment response to sertraline depending on the subject's age of onset of alcoholism. Genetic variation in SLC6A4 may also be associated with better treatment response to ondansetron. Initial pharmacogenetic efforts in alcohol research have identified functional variants with potential clinical utility, but more research is needed to further elucidate the mechanism of these pharmacogenetic interactions and their moderators in order to translate them into clinical practice.     

Clinical uses of naltrexone: a review of the evidence

The implication of the opioidergic system in the pathogenesis of various substance use disorders has led to renewed interest in expanding the clinical uses of naltrexone, an opioid antagonist. This article examines the evidence for the efficacy of naltrexone in a variety of substance use and psychiatric disorders. Naltrexone can be an effective treatment for alcohol and opioid dependence if issues of compliance are adequately addressed. Thus far, no definitive role has been found for naltrexone in the treatment of other psychiatric disorders. Further research needs to be done in self-injurious behavior, gambling, cocaine, and nicotine dependence.     

Combining psychosocial treatment with pharmacotherapy for alcohol dependence

Pharmacotherapy for alcohol dependence is always delivered in a psychosocial context that may affect the outcome of the treatment. The rigorous study of different psychotherapeutic treatments for alcohol dependence has shown several distinct approaches to be effective. This article reviews the combination of alcohol dependence pharmacotherapies, including disulfiram, naltrexone, and acamprosate, with different psychosocial interventions. Many psychosocial interventions for alcohol dependence, including Alcoholics Anonymous, can be integrated successfully with pharmacotherapy. Psychosocial interventions, ranging from brief medical management to more intensive manualized psychotherapies, have all been shown to produce positive outcomes in certain studies, depending on the specific medication and the study context. Particularly successful combinations may include the use of behavioral marital therapy plus a disulfiram contract for patients taking that medication, and the combination of naltrexone or acamprosate with cognitive-behavioral therapy or psychosocial support. Ongoing research examining the optimal combinations of medications with different psychosocial treatments for alcohol dependence may further inform the field.     

Improving naltrexone response: an intervention for medical practitioners to enhance medication compliance in alcohol dependent patients

The effectiveness of naltrexone, a FDA-approved medication for alcohol dependence, can be improved if we support and help patients to consistently take their medication. We illustrate how patient noncompliance with treatment negatively affects outcome, and, we describe a new intervention to enhance medication compliance. Outcome was evaluated for 196 alcohol dependent outpatients who were treated with 50 mg/day naltrexone or placebo for 12 weeks. For patients who adhered to the prescribed treatment, relapse rates were lower with naltrexone than placebo (10% vs. 38.6%, p < 0.001). For noncompliant patients, relapse rates were high and comparable between naltrexone- and placebo-treated patients (42.9% vs. 40%). In a second study of 100 alcohol dependent outpatients, we introduced an intervention that resulted in better medication compliance rates compared to a previous naltrexone study of patients who did not receive the intervention (77.0% vs. 60.8%, p < 0.01). This provided some support for the use of an intervention that targets medication compliance when prescribing naltrexone.     

The status of naltrexone in the treatment of alcohol dependence: specific effects on heavy drinking

BACKGROUND: In almost 2 decades of naltrexone research for treating alcoholism, there have been 29 published randomized placebo-controlled trials of opioid antagonists, primarily naltrexone, for the treatment of alcohol dependence. The present review builds on prior systematic reviews while maximizing the number of included studies to date, for the purpose of resolving inconsistencies in naltrexone's reported efficacy across trials. Clinical trial results in this article are evaluated by the type of outcome measure used to determine naltrexone's treatment advantage, that is, measures related to reducing heavy drinking versus those related to increasing abstinence. METHODS: We conducted a Medline search to identify double-blind studies from 1990 to the present (2006) that evaluated the use of anopiate antagonist for the treatment of alcohol dependence. There were 29 studies identified, representing 5997 alcohol-dependent patients, which met our study inclusion criteria for this review. Studies were evaluated in this review on 4 prespecified drinking outcomes-2 related to "any drinking" and 2 related to "heavy or excessive drinking." RESULTS: In the treatment of alcohol dependence, we found that 19 (70%) of 27 clinical trials that measured reductions in "heavy or excessive drinking" demonstrated an advantage for prescribing naltrexone over placebo, whereas only 9 (36%) of 25 clinical trials that measured abstinence or "any drinking" found an advantage for medication over placebo. CONCLUSION: The majority of double-blind clinical trials in the literature favored prescribing naltrexone for alcohol dependence to reduce heavy drinking. This finding is consistent with our understanding of naltrexone's mechanism of action of decreasing excessive drinking by reducing the reward associated with drinking alcohol. Thus, we conclude that outcome measures related to heavy or excessive drinking are most relevant to defining naltrexone's therapeutic effects. Factors influencing naltrexone response (treatment adherence and distinct patient subgroups) are also discussed.     

Pharmacological treatment of comorbid PTSD and substance use disorder: Recent progress

Previous research has identified a strong association between posttraumatic stress disorder (PTSD) and substance use disorder (SUD), necessitating the development of treatments that address both conditions. Some pharmacotherapies are effective for the treatment of PTSD and SUD alone, however; no medications have been proven to be effective for the combination of these conditions. We review the recent advances in pharmacological treatment of comorbid PTSD and SUD. A randomized clinical trial of sertraline, a serotonin reuptake inhibitor (SSRI), did not show overall efficacy for comorbid PTSD and alcohol dependence (AD), although it may have efficacy among light drinkers. Another clinical trial demonstrated the efficacy of both disulfiram and naltrexone for the treatment of AD in individuals with PTSD. A more recent clinical trial suggested that norepinephrine uptake inhibitors may also have efficacy for the treatment of comorbid PTSD and AD. In animal and preliminary human studies, brain norepinephrine and glutamate/GABA have emerged as potential treatment targets for comorbid PTSD and SUD. Noradrenergic medications that are promising for comorbid PTSD and SUD include prazosin, guanfacine, and atomoxetine. Promising glutamate/GABA medications include topiramate, memantine, acamprosate, N-acetylcysteine (NAC), and ketamine. The safety and efficacy of these medications for the treatment of PTSD and SUD need to be tested in controlled clinical trials.     

The association between naltrexone compliance and daily supervision

Most studies investigating the efficacy of naltrexone maintenance as a treatment for illicit heroin use have reported poor patient compliance in taking naltrexone. A number of studies have, however, reported better compliance when patients receive family therapy, or when patients resided in a supportive family environment. These studies suggest that patient outcomes on naltrexone maintenance may be better if there is ongoing family support to continue naltrexone use. The current study investigated 6-month outcome status in 300 illicit heroin users who commenced naltrexone maintenance in a community-based out-patient treatment programme. The study aimed to assess the relationship between vigilance of naltrexone supervision by salient others over the first 6 weeks of treatment and patient status at 6 months. Supervision of naltrexone at week 6 was a predictor of a patient's status at 6 months, with those receiving less supervision of 3-4 days more likely to have returned to heroin use or be assessed as 'heroin use undetermined'. In contrast, patients who still received naltrexone supervision for 6 or 7 days per week at week 6 were more likely to be taking naltrexone or were naltrexone- and heroin-free at 6 months. It is argued that since relapse to heroin use is a common occurrence, vigilant supervision of naltrexone dosing in a supportive environment may improve patient retention and reduce relapse. It is suggested that poor outcomes reported in many previous studies may reflect use of inadequate supportive frameworks that encourage naltrexone compliance.     

Improving clinical outcomes for naltrexone as a management of problem alcohol use

Despite being a relatively effective and safe treatment, the clinical management of alcohol abuse/dependence by oral naltrexone can be compromised due to the patient''s non-compliance with daily use of this medication. Over the past decade an increasing body of research has suggested that the use of sustained release depot naltrexone preparations can overcome this issue and deliver improved clinical outcomes. However, at the same time, research findings from diverse areas of pharmacogenetics, neurobiology and behavioural psychology have also been converging to identify variables including genetic markers, patient psychosocial characteristics and drug use history differences, or clusters of these variables that play a major role in mediating the response of alcohol abuse/dependent persons to treatment by naltrexone. While this article does not attempt to review all available data pertaining to an individual alcohol dependent patient''s response to treatment by naltrexone, it does identify relevant research areas and highlights the importance of data arising from them. The characterization of clinical markers, to identify those patients who are most likely to benefit from naltrexone and to tailor a more individual naltrexone treatment, will ultimately provide significant benefit to both patients and clinicians by optimizing treatment outcome.     

Neuropharmacological treatments for alcoholism: scientific basis and clinical findings

Preclinical studies have exploded our knowledge about the behavioral and biological underpinnings of alcoholism. These studies suggest that certain neurotransmitters, particularly those interacting with the opioid, N-methyl-d-aspartate, and monoamine systems, may play a critical role in the expression of alcohol-drinking and other behaviors associated with its abuse liability. Built upon this foundation, important advances have been made in the development of therapeutic medications for the treatment of alcoholism. Of the medications reviewed, acamprosate’s potential appears to be the most widely established. In the USA, naltrexone was approved by the Food and Drug Administration in 1995 for the treatment of alcoholism; however, the results of some studies have been less encouraging. Naltrexone’s reliance on high compliance rates for efficacy may, eventually, limit its potential in clinical settings offering generic treatment for alcoholism. The relative paucity of dose-response studies on naltrexone’s effects in treating alcoholics is an important gap in the literature. Recent data from a large clinical trial suggests that ondansetron, a serotonin₃ antagonist, offers new hope for the treatment of early onset alcoholics; a type of alcoholism most difficult to manage with psychosocial measures alone. Different subtypes of alcoholic may, therefore, have varying treatment responses to serotonergic agents. Matching subtypes of alcoholic to effective treatment medications based upon their different biologies remains an important therapeutic goal. Combinations of effective pharmacological agents need exploration as they may prove to be synergistic, and could shepherd in a new era of treatments aimed at multiple neurotransmitter targets associated with the alcoholism disease. The coming decade promises more powerful tools for characterizing drug effects on alcohol drinking, thereby closing the gap between animal models of addiction and the human condition. Received: 7 October 1999 / Final version: 23 December 1999     

Naltrexone vs. nefazodone for treatment of alcohol dependence. A placebo-controlled trial.

This study compared the effects of nefazodone, a serotonergic antidepressant, with the opioid antagonist naltrexone, and an inactive placebo in 183 alcohol-dependent subjects receiving weekly relapse prevention psychotherapy. Following a single-blind, placebo lead-in period, subjects were randomly assigned to receive study medication, which they took under double-blind conditions for 11 weeks. Naltrexone treatment was associated with significantly more adverse neuropsychiatric and gastrointestinal effects, poorer compliance, and a greater rate of treatment attrition. There were no reliable between-group differences in drinking behavior. These results indicate that nefazodone is not efficacious for treatment of alcohol dependence. Furthermore, the clinical utility of naltrexone seems to be limited by its adverse effects, a finding that has important implications for efforts to develop medications to treat alcohol dependence.     

The therapeutic potential of gamma-hydroxybutyric acid for alcohol dependence: balancing the risks and benefits. A focus on clinical data

There is an increasing interest in studying the role of GABAergic medications in the treatment of alcohol dependence. The GABAergic drug gamma-hydroxybutyric acid (GHB) has been investigated in Europe as a possible treatment for alcohol dependence. In some European Countries, GHB has been approved as a treatment for alcohol dependence. However, this drug has also shown addictive properties, therefore raising questions about its safety in treating alcohol-dependent subjects. More recent research is focusing on the possibility of identifying alcohol-dependent subtypes without risk of developing GHB abuse. Finally, GHB and naltrexone combined together represent a possible approach deserving future investigations.     

Naltrexone in the treatment of male alcoholics - an effectiveness study in Singapore

Naltrexone has been demonstrated in western studies to be a useful pharmacological adjunct within treatment programmes for alcoholic patients. We report the first study of its efficacy and usefulness in an Asian region. This project was designed to allow naltrexone's performance to be assessed under routine clinical conditions but with patients selected on the basis of their being likely to comply. Following in-patient detoxification, 53 male alcohol-dependent patients admitted to the Alcohol Treatment Centre at Woodbridge Hospital, Singapore, were enrolled in a 12-week, placebocontrolled trial of naltrexone hydrochloride (50 mg/day). Subjects were randomized on a 2:1 basis, with 35 receiving naltrexone and 18 receiving placebo. Analyses identified that a higher percentage of naltrexone patients completed the study (40% vs. 22%). In the study non-completers, the dropout rate due to drinking relapse was also lower in the naltrexone group (9% vs. 43%). Of the 39 patients for whom drinking status over the trial could be ascertained, fewer naltrexone-treated patients drank (33% vs. 53%). Alcohol craving scores also showed a selective and distinct reduction in the naltrexone-treated group. Results suggest that naltrexone may be an effective and safe aid to treatment of alcohol dependent patients in Asian patients, for whom the aims are to reduce alcohol craving and drinking reinstatement, but where compliance is likely to be low.     

Medication assisted treatment of drug abuse and dependence: global availability and utilization

Clinical trials and clinical studies, using patented drugs and drugs off patent, provide data that impact the best treatment practices for substance abuse and dependence. In the United States, medications have been approved for use in the treatment of both alcohol and opioid dependence. Medications are used in the detoxification from drug abuse and dependence in the symptomatic relief of withdrawal. For long term treatment or medical maintenance treatment, medications eliminate the physiological effects of drug use by blocking drug-receptor binding in the brain. Therefore, patented drugs showing interactions with neurotransmitters in the brain, are attractive candidates for treatment efficacy trials. An effective long term treatment paradigm for reducing drug dependence is the combinatorial use of medications that block the effects of drug use with behavior change counseling and psychotherapy. Medications used for the long term treatment of opioid dependence are methadone, buprenorphine, and naltrexone. Pharmacotherapies used in the treatment of alcohol dependence include acamprosate, antabuse and naltrexone. A reliable indicator for successful treatment of drug dependence is time in treatment. Patients remain in long term treatment when they perceive that their health care environment is supportive and non-stigmatizing and with a good patient-provider relationship where their needs are identified and met. Additional medications are needed for individual comprehensive substance abuse treatment plans, particularly for individuals who abuse stimulants. Patented drugs remain an important source of candidate pharmacotherapies comprising medication assistant treatment, part of a comprehensive treatment plan for drug dependence that addresses the medical, social, and psychological needs of the patient. Adapting this drug treatment paradigm globally requires identifying and testing new drug candidates while building and changing programs to patient centered treatment programs that promote access to care and treatment and integrate medical, psychological, and social services.     

Substance abuse and schizophrenia: pharmacotherapeutic intervention

Substance use disorder is common in patients with schizophrenia and dramatically worsens their outcome. The typical antipsychotic medications, introduced more than 50 years ago, are effective for the treatment of psychosis but may have only limited efficacy in patients with these co-occurring disorders because patients continue to use substances while taking them. In preliminary studies, however, several of the atypical antipsychotic medications have shown promise for reducing alcohol and drug use in patients with schizophrenia. A neurobiological formulation is discussed, suggesting that the use of substances in patients with schizophrenia may be based on a dysfunction within the dopamine-mediated brain reward circuitry and that clozapine, in particular, may potentially ameliorate this dysfunction and lessen the desire for substance use. Medications for the treatment of alcohol use disorders, such as disulfiram, naltrexone, and acamprosate, as well as other adjunctive medications, may also be useful. Further studies are required to establish a solid evidence base of best practices for the use of medications in these patients.