Defining the role of corticotropin releasing factor binding protein in alcohol consumption.

The corticotropin releasing factor (CRF) exerts its effects by acting on its receptors and on the binding protein (CRFBP), and has been implicated in alcohol use disorder (AUD). Therefore, identification of the exact contribution of each protein that mediates CRF effects is necessary to design effective therapeutic strategies for AUD. A series of in vitro/in vivo experiments across different species were performed to define the biological discrete role of CRFBP in AUD. First, to establish the CRFBP role in receptor signaling, we developed a novel chimeric cell-based assay and showed that CFRBP full length can stably be expressed on the plasma membrane. We discovered that only CRFBP(10 kD) fragment is able to potentiate CRF-intracellular Ca2+ release. We provide evidence that CRHBP gene loss increased ethanol consumption in mice. Then, we demonstrate that selective reduction of CRHBP expression in the center nucleus of the amygdala (CeA) decreases ethanol consumption in ethanol-dependent rats. CRFBP amygdalar downregulation, however, does not attenuate yohimbine-induced ethanol self-administration. This effect was associated with decreased hemodynamic brain activity in the CRFBP-downregulated CeA and increased hemodynamic activity in the caudate putamen during yohimbine administration. Finally, in alcohol-dependent patients, genetic variants related to the CRFBP(10 kD) fragment were associated with greater risk for alcoholism and anxiety, while other genetic variants were associated with reduced risk for anxiety. Taken together, our data provide evidence that CRFBP may possess both inhibitory and excitatory roles and may represent a novel pharmacological target for the treatment of AUD.

Leptin levels are reduced by intravenous ghrelin administration and correlated with cue-induced alcohol craving.

Increasing evidence supports the role of appetite-regulating pathways, including ghrelin and leptin, in alcoholism. This study tested the hypothesis that intravenous exogenous ghrelin administration acutely decreases endogenous serum leptin levels, and that changes in leptin levels negatively correlate with alcohol craving. This was a double-blind, placebo-controlled human laboratory study. Non-treatment-seeking, alcohol-dependent, heavy drinkers (n=45) were randomized to receive intravenous ghrelin or placebo, followed by a cue-reactivity procedure, during which participants were exposed to neutral (juice) and alcohol trial cues. There was a main effect for intravenous ghrelin administration, compared with placebo, in reducing serum leptin levels (P<0.01). Post hoc analysis showed significant differences in serum leptin levels at the alcohol trial (P<0.05) that persisted at the end of the experiment (P<0.05). By contrast, there were no significant differences in serum leptin levels at the juice trial (P=not significant (NS)). The change of serum leptin level at the alcohol trial correlated with the increase in alcohol urge (P<0.05), whereas urge to drink juice was not correlated with the leptin change at the juice trial (P=NS). These findings provide preliminary evidence of ghrelin-leptin cross-talk in alcoholic individuals and suggest that their relationship may have a role in alcohol craving.

D-cycloserine to enhance extinction of cue-elicited craving for alcohol: a translational approach.

Cue-elicited craving for alcohol is well established but extinction-based treatment to extinguish this response has generated only modest positive outcomes in clinical trials. Basic and clinical research suggests that D-cycloserine (DCS) enhances extinction to fear cues under certain conditions. However, it remains unclear whether DCS would also accelerate extinction of cue-elicited craving for alcohol. The goal of the current study was to examine whether, compared with placebo (PBO), DCS enhanced extinction of cue-elicited craving among treatment-seeking individuals with alcohol use disorders (AUDs). Participants were administered DCS (50 mg) or PBO 1 h before an alcohol extinction paradigm in a simulated bar environment on two occasions. The extinction procedures occurred 1 week apart and were fully integrated into outpatient treatment. Subjective craving for alcohol was the primary variable of interest. Follow-up cue reactivity sessions were conducted 1 week and 3 weeks later to ascertain persisting DCS effects. Drinking outcomes and tolerability were also examined. DCS was associated with augmented reductions in alcohol craving to alcohol cues during the first extinction session and these effects persisted through all subsequent sessions, suggesting facilitation of extinction. Participants in the DCS condition reported significant short-term reductions in drinking, although these did not persist to follow-up, and found the medication highly tolerable. These findings provide evidence that DCS enhances extinction of cue-elicited craving for alcohol in individuals with AUDs in the context of outpatient treatment. The potential clinical utility of DCS is discussed, including methodological considerations and context-dependent learning.

Baclofen promotes alcohol abstinence in alcohol dependent cirrhotic patients with hepatitis C virus (HCV) infection.

Hepatitis C virus (HCV) and alcoholic liver disease (ALD), either alone or in combination, count for more than two thirds of all liver diseases in the Western world. There is no safe level of drinking in HCV-infected patients and the most effective goal for these patients is total abstinence. Baclofen, a GABA(B) receptor agonist, represents a promising pharmacotherapy for alcohol dependence (AD). Previously, we performed a randomized clinical trial (RCT), which demonstrated the safety and efficacy of baclofen in patients affected by AD and cirrhosis. The goal of this post-hoc analysis was to explore baclofen's effect in a subgroup of alcohol-dependent HCV-infected cirrhotic patients. Any patient with HCV infection was selected for this analysis. Among the 84 subjects randomized in the main trial, 24 alcohol-dependent cirrhotic patients had a HCV infection; 12 received baclofen 10mg t.i.d. and 12 received placebo for 12-weeks. With respect to the placebo group (3/12, 25.0%), a significantly higher number of patients who achieved and maintained total alcohol abstinence was found in the baclofen group (10/12, 83.3%; p=0.0123). Furthermore, in the baclofen group, compared to placebo, there was a significantly higher increase in albumin values from baseline (p=0.0132) and a trend toward a significant reduction in INR levels from baseline (p=0.0716). In conclusion, baclofen was safe and significantly more effective than placebo in promoting alcohol abstinence, and improving some Liver Function Tests (LFTs) (i.e. albumin, INR) in alcohol-dependent HCV-infected cirrhotic patients. Baclofen may represent a clinically relevant alcohol pharmacotherapy for these patients.

Naltrexone and cue exposure with coping and communication skills training for alcoholics: treatment process and 1-year outcomes.

BACKGROUND: Promising treatments for alcoholics include naltrexone (NTX), cue exposure combined with urge-specific coping skills training (CET), and communication skills training (CST). This study investigated the effects of combining these elements as treatment adjuncts. METHODS: A 2 x 2 design investigated the effects of CET combined with CST, as compared with an education and relaxation control treatment, during a 2-week partial hospital program (n = 165) followed by 12 weeks of NTX (50 mg/day) or placebo during aftercare (n = 128). Drinking outcomes were assessed at 3, 6, and 12 months after discharge from the partial hospital. Process measures included urge, self-efficacy (confidence about staying abstinent in risky situations), and self-reported coping skills. Medically eligible alcohol-dependent patients were recruited. RESULTS: Among those compliant with medication on at least 70% of days, those who received NTX had significantly fewer heavy drinking days and fewer drinks on days that they drank than those receiving placebo during the medication phase but not during the subsequent 9 months. CET/CST-condition patients were significantly less likely to report a relapse day and reported fewer heavy drinking days at the 6- and 12-month follow-ups than patients in the control treatment. Interactions of medication with behavioral treatments were not significant. Process measures showed that NTX resulted in lower weekly urge ratings, and those in CET/CST used more of the prescribed coping skills after treatment, reported fewer cue-elicited urges, and reported more self-efficacy in a posttest role-play test. Drinking reductions at 3, 6, and 12 months correlated with more use of coping skills, lower urge, and higher self-efficacy. CONCLUSIONS: The results suggest the probable value of keeping alcoholics on NTX for longer periods of time and the importance of increasing compliance with NTX. They also support the earlier promising effects of CET and CST as adjuncts to treatment programs for alcoholics by maintaining treatment gains over at least a year. The value of the urge-specific and general coping skills and of self-efficacy and urge constructs was demonstrated in their association with drinking outcomes.

The role of craving in alcohol use, dependence, and treatment.

This article represents the proceedings of a symposium at the 2000 RSA Meeting in Denver, Colorado. The organizer and chair was Barbara A. Flannery, and the co-chairs were Barbara A. Flannery and Helen Pettinati. The presentations were (1) Animal models of alcohol craving and relapse, by Amanda Roberts; (2) Real-time field assessment of alcohol craving, by Ned Cooney; (3) Medications and alcohol craving, by Robert Swift; (4) The assessment of craving: Insights from the clinic and clinical laboratory studies, by Raymond Anton; (5) A comparison of three alcohol craving questionnaires, by Barbara Flannery; (6) and Assessing posttreatment urge to drink, by Damaris Rohsenow.

Predictors of compliance with naltrexone among alcoholics.

OBJECTIVE: Naltrexone has been found to be an effective adjunct to treatment to reduce the rate of drinking among alcoholics. However, adherence to the medication has been of considerable concern; the high rates of noncompliance with the medication limits the benefits that could potentially be realized from this pharmacotherapy. Knowledge of predictors of noncompliance could result in interventions targeted at these variables. METHOD: Participants were 128 alcohol-dependent patients who participated in a clinical placebo-controlled trial of naltrexone. Upon discharge from a 1- to 2-week partial hospital program, patients were randomly placed into 12 weeks of naltrexone (50 mg/day) or placebo (n = 64 per condition). Patients met with a physician and a research assistant weekly for 4 weeks then biweekly for 8 weeks. RESULTS: Compliance (number of days taking medication) was not predicted by demographic or pretreatment alcohol use variables. Number and severity of side effects in the first week, particularly nausea and fatigue, predicted early termination. Compliance was not predicted by commitment to abstinence or self-efficacy about abstinence, but was greater among patients who believed more strongly that the medication would help them stay sober. Compliance was not predicted by general level of urge to drink during the first week on medication but compliance was greater among those with a higher urge to drink in response to alcohol stimuli in the laboratory. CONCLUSIONS: Implications for approaches to increase compliance include reducing side effects and increasing patients' beliefs in the efficacy of naltrexone.

Naltrexone's effects on reactivity to alcohol cues among alcoholic men.

The mechanisms of naltrexone's effects on urges to drink during abstinence are unclear. Naltrexone may suppress either urges to drink specifically or appetitive responses in general. The effects of naltrexone on cue reactivity to alcoholic and sweet nonalcoholic beverages were investigated. Alcohol-dependent men (N = 53) in treatment received naltrexone (50 mg) or placebo. Four hours later, they received baseline assessment, exposure to fruit juice, and exposure to their usual alcoholic beverage in 3-min trials. Naltrexone reduced urge to drink and self-reported attention to the alcohol cues, not at the initial exposure but after repeated exposures to alcohol cues. Naltrexone reduced negative affect across baseline and alcohol trials. No effects of naltrexone on responses to the nonalcoholic appetitive beverage cues were found, suggesting that general appetite suppression does not mediate the effects of naltrexone on urges.

Opioid antagonists and alcoholism treatment.

The increasing evidence for a neurobiologic basis for alcoholism has spurred the search for pharmacologic agents to treat alcohol abuse. The complex set of symptoms and behaviors that characterizes alcoholism has been linked to dopaminergic and opioid neurotransmitter systems, suggesting that opioid antagonists, such as naltrexone, may alter the positive reinforcement effects and craving involved in alcoholism. Laboratory and clinical investigations of naltrexone have demonstrated the potential for this agent to reduce craving, increase the aversive effects of alcohol, decrease drinking days, and increase abstinence. While naltrexone and other opioid antagonists, such as nalmefene, may be effective components of an alcohol-treatment program, they should only be used in combination with psychosocial interventions, such as support groups and psychotherapy.

Naltrexone's effect on cue-elicited craving among alcoholics in treatment.

BACKGROUND: Advancing knowledge of biobehavioral effects of interventions can result in improved treatments. Thus, a standardized laboratory cue reactivity assessment has been developed and validated to assess the cognitive and psychophysiological responses to a simulated high-risk situation: alcohol cues. The present study investigates the effects of a pharmacotherapy (naltrexone) on a laboratory-based, cue-elicited urge to drink among abstinent alcoholics in treatment. METHODS: Alcohol-dependent subjects were randomized to 12 weeks of naltrexone or placebo after completing a partial hospital program. After approximately 1 week on medication, all received cue reactivity assessment. RESULTS: Significantly fewer patients taking naltrexone reported any urge to drink during alcohol exposure than did those on placebo. Those with any urges reported no decrement in level of the urges. Mean arterial pressure decreased significantly for those on placebo, but not for those on naltrexone, whereas cue-elicited decreases in heart rate were not affected by the medication. CONCLUSIONS: The results have implications for models of relapse and naltrexone's effects. Cue reactivity methodology has utility for investigating hypothesized mediators of therapeutic effects of pharmacotherapies as well as behavioral treatments.

Effects of naltrexone with nicotine replacement on smoking cue reactivity: preliminary results.

Although several studies have examined the effects of opioid antagonists on smoking behavior, there have been no reports of the potentially therapeutic combination of naltrexone and nicotine replacement therapy. The primary objective of the present study was to determine whether naltrexone reduced reactivity to smoking cues among abstinent smokers treated with nicotine replacement. Twenty participants were instructed to abstain from smoking cigarettes for 9 h while using nicotine replacement therapy. Participants were subsequently treated with either naltrexone (50 mg) or placebo before being exposed to smoking cues. Results indicated that the smokers who received the placebo responded to smoking cue exposure with increases in urge to smoke and increases in negative affect. Participants who received naltrexone did not show any increase in urge or negative affect and showed a decrease in withdrawal symptoms after exposure to smoking cues. Although preliminary, the findings suggest that naltrexone may work in combination with nicotine replacement therapies to block the effects of smoking stimuli in abstinent smokers.

Medications and alcohol craving.

The use of medications as an adjunct to alcoholism treatment is based on the premise that craving and other manifestations of alcoholism are mediated by neurobiological mechanisms. Three of the four medications approved in the United States or Europe for treating alcoholism are reported to reduce craving; these include naltrexone (ReVia), acamprosate, and tiapride. The remaining medication, disulfiram (Antabuse), may also possess some anticraving activity. Additional medications that have been investigated include ritanserin, which has not been shown to decrease craving or drinking levels in humans, and ondansetron, which shows promise for treating early onset alcoholics, who generally respond poorly to psychosocial treatment alone. Use of anticraving medications in combination (e.g., naltrexone plus acamprosate) may enhance their effectiveness. Future studies should address such issues as optimal dosing regimens and the development of strategies to enhance patient compliance.

Alcoholic patients' experience and attitudes on pharmacotherapy for alcoholism.

Clinical studies have demonstrated that pharmacotherapies may improve alcoholism treatment, when combined with traditional psychosocial therapies. Recently, the opioid antagonist, naltrexone, has been approved as an adjunct in alcoholism treatment, and several other pharmacotherapies for alcoholism are under development. Because of the abstinence orientation of many patients, we assessed attitudes regarding medications, and explored whether alcoholic patients would consider taking medication as part of their alcoholism treatment. Active patients (n = 127) in three alcohol treatment settings were surveyed with an anonymous questionnaire which asked demographics, personal alcoholism history and questions about medication use. They were asked whether they felt disulfiram and naltrexone were helpful for alcoholics and whether they would take the medications. The findings indicate that the patients were divided about the use of pharmacotherapy for the treatment of alcoholism. The strongest predictor of willingness to take medication was a belief that the medication would be helpful.

Integration of health care economics for addiction treatment in clinic care.

Over the past decade, radical changes have occurred in the availability and funding of treatment services for individuals with addictive disorders. Traditional inpatient and residential treatments have been replaced by outpatient settings. "Standard" addiction treatments, such as 28-day inpatient hospitalizations, are largely a thing of the past. The process of treatment planning has also changed. Treatment decisions now depend on third-party coverage rather than severity of illness. The procedures for determining eligibility and obtaining authorization for treatment are often ponderous and impersonal and determined through administrative procedures that are external to the treatment facility. The criteria used to determine the type of treatment seem arbitrary rather than clinically based.

Ondansetron alters human alcohol intoxication.

There is considerable evidence that serotonin-3 (5-HT3) receptor antagonists modulate some of the behavioral effects of alcohol, and may decrease alcohol consumption. To better clarify the mechanism of action of 5-HT3 antagonists on these behaviors, we investigated the effects of the 5-HT3 antagonist, ondansetron, on several subjective and objective measures of alcohol intoxication in social drinkers. Twelve nonalcoholic, social drinkers received either 8 mg ondansetron, p.o., or placebo during one of two test sessions in a crossover, double-blind protocol. Both conditions were followed by a standard, intoxicating dose of alcohol. Subjective and objective measures of intoxication including mood, physical sensations, performance changes, and alcohol pharmacokinetics were determined. To control for ondansetron effects, 10 additional subjects received either ondansetron or placebo, followed by a nonintoxicating, "placebo" dose of alcohol during a second crossover double-blind protocol. Ondansetron was found to augment certain stimulant, sedative, and discriminant effects of alcohol, without affecting psychomotor performance or alcohol pharmacokinetics. Ondansetron had minimal effects on subjects receiving placebo alcohol. These data suggest that the reductions in alcohol consumption observed in animals and humans treated with ondansetron may be mediated by increases in subjective intoxication, and/or increases in the aversive effects of alcohol.

Effect of naltrexone on human alcohol consumption.

Opioid neurotransmitter systems have been shown to mediate certain aspects of alcohol consumption in animals and in humans. Use of opioid antagonists appears to decrease alcohol consumption in animals. Controlled clinical trials have indicated that alcohol-dependent subjects who are treated with a combination of naltrexone, an opioid antagonist, and traditional psychological and social therapies consume less alcohol and have lower relapse rates. The neurobiological mechanisms by which naltrexone acts to reduce alcohol consumption are still being investigated; however, there is evidence that naltrexone modifies the reinforcing effects of alcohol. Some researchers suggest that the reinforcing stimulant effects of alcohol and other psychoactive substances play a primary role in initiating and maintaining substance abuse and dependence. These effects may be mediated through the action of endogenous opioids. This article discusses the possible mechanisms of action of naltrexone and reviews human and animal studies that support the use of naltrexone in the treatment of alcohol dependence.

Naltrexone-induced alterations in human ethanol intoxication.

OBJECTIVE: Outpatient clinical trials with an opioid antagonist, naltrexone, found that this agent reduces relapse drinking in abstinent alcoholics. It is unknown which aspects of intoxication may be affected by naltrexone. The authors investigated the effects of naltrexone on several subjective and objective measures of ethanol intoxication. METHOD: In a double-blind crossover study, 19 nonalcoholic drinkers received a regimen of naltrexone, 50 mg p.o., or placebo on two different occasions, each time followed by a standard, intoxicating dose of ethanol. Subjective and objective measures of intoxication including mood, physical sensations, performance changes, and ethanol pharmacokinetics were determined. As a control for naltrexone effects, 12 additional subjects received naltrexone or placebo followed by a non-intoxicating, "placebo" dose of ethanol. RESULTS: Naltrexone augmented certain sedative and discriminant effects of ethanol and reduced positive reinforcing effects without affecting psychomotor performance or ethanol pharmacokinetics. Naltrexone had minimal effects in subjects receiving placebo ethanol. CONCLUSIONS: The data are compatible with the clinical findings and suggest that the reduction in ethanol consumption by alcoholics following naltrexone administration may occur because of greater subjective intoxication, greater aversive effects, or less positive reinforcement from ethanol.