Effects of naltrexone and nalmefene on subjective response to alcohol among non-treatment-seeking alcoholics and social drinkers

BACKGROUND: Despite the relative success of opiate antagonist medication within controlled clinical trials for alcoholism, laboratory studies have not fully examined potential mechanisms for their efficacy in alcohol-dependent persons. The present study evaluated the impact of naltrexone and nalmefene on craving and subjective effects after a moderate alcohol dose among non-treatment-seeking alcoholics (n = 125) and social drinkers (n = 90). METHODS: Participants were randomly assigned to receive placebo, naltrexone (titrated to 50 mg/day), or nalmefene (titrated to 40 mg/day) for seven days before an alcohol challenge clinical laboratory session. During the clinical laboratory session, a drink of alcohol (0.4 mg/kg for men, 0.34 mg/kg for women) was provided in a bar-like setting. The effects of the alcohol dose on subjective craving, stimulation, and sedation were measured before having free access to alcohol. RESULTS: Alcoholics reported higher levels of craving than social drinkers before and after the drink as well as higher levels of alcohol-induced stimulation. Both opiate antagonist medications suppressed initial increases in craving and stimulation. CONCLUSIONS: These findings demonstrate that both naltrexone and nalmefene are associated with reduced alcohol-induced craving and stimulation among alcoholics who are not actively attempting to reduce drinking. These data provide insights into potential mechanisms that may underlie opiate antagonists' effects in the context of treatment.     

6-beta-naltrexol reduces alcohol consumption in rats

BACKGROUND: In humans, 6-beta-naltrexol is the major metabolite of naltrexone, and its effectiveness at suppressing alcohol consumption in any species has not been previously investigated. Naltrexone is an opiate antagonist that reduces excessive drinking in many species, including humans with alcohol dependence. Whether 6-beta-naltrexol is an active metabolite that contributes to the efficacy of naltrexone remains unknown. METHODS: Placebo and four doses of 6-beta-naltrexol were given by intraperitoneal injection to outbred Wistar rats and alcohol consumption was measured using a limited access model. RESULTS: 6-beta-Naltrexol reduced alcohol consumption in a dose-dependent manner. At doses 7.5, 12.5, and 25 mg/kg, 6-beta-naltrexol significantly decreased consumption of a 6% ethanol solution compared with saline control groups. CONCLUSIONS: These data suggest that there may be a potential clinical use for 6-beta-naltrexol in recovering alcoholics.     

A 6-month controlled naltrexone study: combined effect with cognitive behavioral therapy in outpatient treatment of alcohol dependence

BACKGROUND: In several studies, patients with alcohol dependence treated with the opioid antagonist naltrexone have shown fewer relapses to heavy drinking than those receiving placebo. An interaction between the naltrexone effect and the type of psychological therapy has been observed. METHODS: A 6-month, double-blind, placebo-controlled, parallel-group study was performed at 10 different investigation sites. After a placebo run-in period of 1 week, 118 patients were randomized into 4 treatment groups-50 mg of naltrexone daily or placebo in combination with either cognitive behavioral therapy (CBT) or supportive therapy. The CBT was performed over nine sessions according to the manual of Project MATCH (Matching Alcoholism Treatments to Client Heterogeneity). The supportive therapy was defined as "the treatment as usual." Alcohol consumption, craving, carbohydrate-deficient transferrin, medication compliance by tablet count, and adverse clinical events were assessed at all visits. Other liver enzymes and psychiatric symptoms were also determined. RESULTS: Ninety-one (77%) patients completed the study, and 92 (78%) were 80% compliant with the medication regimen. A lower percentage of heavy-drinking days was shown in the naltrexone group (p = 0.045) compared with the placebo group, as was a lower craving score (p = 0.029). These results are supported by the lower levels of liver enzyme activities (p < 0.010 for aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyltransferase), but not by the carbohydrate-deficient transferrin levels, in the naltrexone group. The mean time period before the first day of heavy drinking was longer for the group treated with CBT (p = 0.010), especially in combination with naltrexone (p = 0.007). Naltrexone was well tolerated, and no patients discontinued the study due to side effects. CONCLUSIONS: This study supports the effect of naltrexone in outpatient treatment of alcohol dependence and suggests that a beneficial interaction effect with CBT can be expected.     

Using topiramate or naltrexone for the treatment of alcohol-dependent patients

Background:  To compare topiramate versus naltrexone in the treatment of alcohol dependence.
Methods:  A 6-month naturalistic, randomized and open-label, trial of topiramate versus naltrexone, with assessments at enrollment and after 3 and 6 months of treatment. The setting was an outpatient alcohol clinic. One hundred and two alcohol-dependent patients who had been drinking heavily during the past month were included. Two randomized groups were created. In one, naltrexone was used as the therapeutic agent and, in the other, topiramate was chosen as the therapeutic agent. Both groups received psychological relapse prevention therapy. Outcome was measured using tools that assessed alcohol intake, cravings, disability, and quality of life; changes in biomarkers of alcohol intake were also used. With all the data, a secondary composite measure was created in order to assess each patient's global alcohol intake and its consequences.
Results:  Both groups showed substantial reduction in their drinking. Naltrexone patients had higher nicotine consumption throughout the study. Topiramate was better at reducing alcohol-related cravings throughout the study. Both treatments had a similar mean cost throughout the study.
Conclusions:  Both topiramate and naltrexone were efficacious in the treatment of alcohol dependence, and the treatment costs were similar. There is a trend for topiramate to be superior to naltrexone on critical measures of drinking; however, the study did not have adequate statistical power to establish this fact.     

Serum 6-beta-naltrexol levels are related to alcohol responses in heavy drinkers

BACKGROUND: There is strong evidence for the role of the endogenous opioid system in alcohol reinforcement and consumption; however, recent human laboratory studies and clinical trials have reported mixed effects of naltrexone (a nonselective opioid antagonist) on alcohol-related behaviors. This paper reports a secondary data analysis of a human laboratory study that examines the relationship between serum levels of 6-beta-naltrexol, the major, biologically active metabolite of naltrexone, and subjective effects of alcohol. METHODS: The study used a within-subjects design to examine the effects of naltrexone (0, 50, and 100 mg/day) on subjective responses to alcohol (none, moderate, and high dose) in heavy drinkers (n = 23). Each subject received three doses of naltrexone in random order; each naltrexone dose was administered over an 8 day period on an inpatient unit, with a 1 week outpatient washout between doses. After stabilization at each of the naltrexone doses, subjects participated in three alcohol challenge sessions (none, moderate, and high dose) in random order; thus, each subject participated in a total of nine alcohol administration sessions. RESULTS: Doubling the naltrexone dose (50 vs. 100 mg/day) doubled the mean serum 6-beta-naltrexol levels. At each naltrexone dose, there was a 4-fold range in 6-beta-naltrexol levels across subjects. Before alcohol administration, higher 6-beta-naltrexol levels were associated with higher ratings of sedation. After high-dose alcohol administration, higher 6-beta-naltrexol levels were associated with significantly lower ratings of liking and best effects. CONCLUSIONS: These findings provide further evidence of the involvement of the opioid system in the modulation of alcohol effects and suggest that serum 6-beta-naltrexol concentrations may be important in predicting therapeutic response to naltrexone.     

Complexity changes of the EEG induced by alcohol cue exposure in alcoholics and social drinkers

BACKGROUND: An understanding of the neurophysiological mechanisms underlying alcohol craving is important in the effective treatment of alcohol dependence. The aim of this study was to examine the utility of the electroencephalogram (EEG) to measure the changes in electrical brain activity of alcoholics when exposed to alcohol-specific cues. METHODS: Fifteen adult alcoholic subjects (four women) with a mean age of 35 (SD = 4.5) and 10 healthy social drinking controls (three women) with a mean age of 34 (SD = 5.6) were recruited. Subjects were serially rated for alcohol craving after presentations of pictures of control nonalcoholic and alcohol beverages. After the picture presentation, the EEG was recorded (16,384 data points for each epoch) with eyes closed. The dimensional complexity (D2) was estimated as a measure of complexity of the EEG. RESULTS: Alcoholic subjects exhibited a significant increase in the D2 values of the EEG in frontal (F3, F4), right posterior temporal (T6), and occipital (O1, O2) regions after viewing alcohol cues compared with viewing other beverage cues. These results indicate that more complex (or higher) cortical activity is induced over specific brain regions of alcoholic subjects by alcohol-specific cues. Changes in subscale of alcohol craving between nonalcoholic and alcohol pictures were correlated with changes in D2 values in the left frontal (F3) region in alcoholic subjects. CONCLUSIONS: These findings suggest that, when subjects are exposed to alcohol cues, changes in the EEG complexity are induced in frontal, right posterior temporal, and occipital areas, which may be key brain structures for alcohol craving. In addition, nonlinear measures like the D2 are useful in evaluating alcohol cue-induced brain activity from the EEG.     

A functional polymorphism of the mu-opioid receptor gene (OPRM1) influences cue-induced craving for alcohol in male heavy drinkers

BACKGROUND: The mu-opioid receptor gene (OPRM1) codes for the mu-opioid receptor, which binds beta-endorphin. The A118G polymorphism in this gene affects beta-endorphin binding such that the Asp40 variant (G allele) binds beta-endorphin 3 times more tightly than the more common Asn40 variant (A allele). This study investigated the influence of the A118G polymorphism on cue reactivity after exposure to an alcoholic beverage in male heavy drinkers. METHODS: Participants were either homozygous for the A allele (n=84) or carrying at least 1 copy of the G allele (n=24). All participants took part in a cue-reactivity paradigm where they were exposed to water and beer in 3-minute trials. The dependent variables of main interest were subjective craving for alcohol, subjective arousal, and saliva production. RESULTS: G allele carriers reported significantly more craving for alcohol than the A allele participants (as indicated by the within-subject difference in craving after beer vs after water exposure). No differences were found for subjective arousal and saliva. Both groups did not differ in family history of alcoholism. Participants with the G allele reported a significantly higher lifetime prevalence of drug use than participants homozygous for the A allele. CONCLUSIONS: A stronger urge to drink alcohol after exposure to an alcoholic beverage might contribute to a heightened risk for developing alcohol-related problems in individuals with a copy of the G allele. The G allele might also predispose to drug use in general.     

Involvement of nicotinic receptors in alcohol self-administration

BACKGROUND: Alcohol and nicotine, in the form of tobacco, are commonly co-abused. Nicotinic receptors also have been implicated in alcohol action. We designed the present study to examine the possible involvement of nicotinic receptors in alcohol self-administration. METHODS AND RESULTS: Pretreatment with lower doses (0.1-0.4 mg/kg) of nicotine, administered acutely or chronically, did not affect alcohol consumption, whereas a higher dose (0.8 mg/kg) initially suppressed alcohol consumption but stimulated alcohol consumption on repeated treatment. We observed the same pattern of nicotine effects on alcohol self-administration using an operant procedure. A dose of 0.8 mg/kg of nicotine initially suppressed operant responding for alcohol. Such suppression of alcohol self-administration was more pronounced during the first 20 min of the 60 min operant session. Responding for alcohol in the nicotine treated group, however, was significantly increased above the saline treated group by the 5th day of treatment. Mecamylamine, a noncompetitive nicotinic receptor antagonist, reduced alcohol consumption, whereas dihydro-beta-erythroidine (DHbetaE), a competitive nicotinic receptor antagonist, did not modify alcohol consumption. CONCLUSIONS: The stimulation of alcohol intake induced by nicotine treatment and the suppression of alcohol intake induced by mecamylamine provide evidence for the involvement of nicotinic receptors in alcohol consumption and/or self-administration. The failure of DHbetaE to reduce alcohol consumption, however, suggests that ethanol-nicotine interaction is mediated by other nicotinic receptor subtypes rather than alpha4beta2 receptor subtype, or that mecamylamine acts through a nonnicotinic mechanism.     

Biphasic alcohol response differs in heavy versus light drinkers

BACKGROUND: Most studies of risk factors for alcohol-related problems have focused on biological family history as a primary risk factor. However, other factors, such as early-age heavy drinking, are also risk factors for sustained or progressive heavy consumption. Little is currently known about the mechanisms underlying binge or heavy drinking. METHODS: This study examined the acute subjective and objective effects of ethanol in heavy drinkers versus light drinkers. Thirty-four subjects participated in this within-subjects study consisting of three early-evening testing sessions in which subjects consumed a beverage containing either 0.8 or 0.4 g/kg ethanol or placebo. RESULTS: Compared with lighter drinkers, heavy drinkers were more sensitive to the positive stimulant-like effects of ethanol (p < 0.05), especially during the increasing limb of the blood alcohol curve. Heavy drinkers also showed less sedation and cortisol response after alcohol than the light drinkers (p < 0.05). CONCLUSIONS: The results indicate that young adult binge drinkers show a biphasic alcohol response, with heightened sensitivity to stimulant-like alcohol effects and greater tolerance to sedative alcohol effects compared with their light-drinking counterparts.     

Liver disease in heavy drinkers with and without alcohol withdrawal syndrome

BACKGROUND: Withdrawal syndrome is a hallmark of alcohol dependence. The characteristics of alcohol consumption, closely related to dependence, could influence the development of alcoholic liver disease. The study aimed to investigate if patients with severe alcohol withdrawal syndrome have a peculiar profile of liver disease. METHODS: The study included 256 heavy drinkers (aged 19-75 years, 70.3% males) admitted to an Internal Medicine Department. Patients admitted for complications of liver disease were not included. Severe alcohol withdrawal syndrome (seizures, disordered perceptions, or delirium) developed in 150 patients (58.6%). Alcohol consumption (daily quantity, duration, and pattern [regular or irregular]) was assessed by questionnaire. Liver biopsy was performed in all cases. RESULTS: Patients with alcohol withdrawal syndrome showed a lower prevalence of liver cirrhosis and a higher prevalence of alcoholic hepatitis than patients without it. The negative association of alcohol withdrawal syndrome with liver cirrhosis persisted after we adjusted for sex, daily intake, duration, and pattern of alcohol consumption. Alcoholic hepatitis was independently associated with the irregular pattern of alcohol consumption, which was closely associated with severe alcohol withdrawal syndrome. CONCLUSIONS: The profile of liver injury is different in heavy drinkers who develop and who do not develop a severe alcohol withdrawal syndrome when admitted to the hospital.     

Efficacy of extended-release naltrexone in patients with relatively higher severity of alcohol dependence

Background: Because some literature reviews have suggested that naltrexone’s benefit may be limited to less‐severe alcohol dependence, and exclusively to reduction in heavy drinking rather than abstinence, we examined the efficacy of once per month, injectable extended‐release naltrexone (XR‐NTX 380 mg) in patients with relatively higher severity alcohol dependence. Methods: Post hoc analyses examined data from a multicenter, placebo‐controlled, 24‐week randomized trial of XR‐NTX for alcohol dependence (N = 624). We analyzed treatment effects in alcohol‐dependent patients who had higher baseline severity, as measured by: (i) the Alcohol Dependence Scale (ADS) or (ii) having been medically detoxified in the week before randomization. Efficacy was also examined via the relationship between pretreatment severity indices and reporting at least 4 days of lead‐in abstinence prior to treatment—a major predictor of good outcome in the original study. Results: Higher severity alcohol‐dependent patients, defined by the ADS, when receiving XR‐NTX 380 mg (n = 50) compared with placebo (n = 47), had significantly fewer heavy‐drinking days in‐trial (hazard ratio=0.583; p = 0.0049) and showed an average reduction of 37.3% in heavy‐drinking days compared with 27.4% for placebo‐treated patients (p = 0.039). Among those who had a detoxification just prior to randomization, these reductions were 48.9% (XR‐NTX 380 mg; n = 11) and 30.9% (placebo; n = 15) (p = 0.004). Subjects with at least 4 days of pretreatment abstinence (n = 82) versus those without (n = 542) had significantly higher pretreatment ADS scores (p = 0.002) and were more likely to require detoxification prior to randomization (p < 0.001). Patients with lead‐in abstinence experienced significantly better maintenance of initial and 6‐month abstinence. Conclusions: These secondary analyses support the efficacy of XR‐NTX 380 mg in relatively higher severity alcohol dependence for both reduction in heavy drinking and maintenance of abstinence, with implications for the role of adherence pharmacotherapy.     

The effect of naltrexone on alcohol's stimulant properties and self-administration behavior in social drinkers: influence of gender and genotype

Background: Few pharmacological treatments for alcohol dependence are available. Moreover, the best supported treatment, naltrexone hydrochloride, appears to work for only some. Methods: To investigate potential predictors of these differential responses, 40 social drinkers (20 women) were administered 6 days of treatment with naltrexone vs. placebo in a double‐blind, counterbalanced, crossover design. At the end of each treatment period, participants received a single dose of their preferred alcoholic beverage followed by the opportunity to work for additional alcohol units using a progressive ratio (PR) breakpoint paradigm. All subjects but one were genotyped for the A118G polymorphism of the mu opioid receptor gene (OPRM1). Results: Naltrexone decreased the ethanol‐induced ‘euphoria’ to a priming dose of alcohol in two subgroups: (i) in women, and (ii) in subjects with the A118G polymorphism of the mu opioid receptor gene (OPRM1). Naltrexone did not decrease motivation to work for additional alcoholic beverages on the PR task regardless of gender or genotype. Conclusions: The results add to the evidence that naltrexone decreases positive subjective effects of alcohol, with preferential effects in distinct subgroups. Similar effects in heavier drinkers might decrease alcohol use.     

Naltrexone Biotransformation and Incidence of Subjective Side Effects: A Preliminary Study

When administered orally, naltrexone undergoes extensive biotransformation and is metabolized to 6β-naltrexol and other minor metabolites. Naltrexone has been recently approved by the Food and Drug Administration for the treatment of alcohol dependence. An important clinical issue with naltrexone treatment is predicting patient compliance, which may be influenced by adverse side effects experienced during the medication. We investigated whether subjective side effects were related to urinary concentrations of naltrexone and its metabolite 6β-naltrexol 3 hr after administration of 50 mg Po naltrexone in 24 male moderate-to-heavy social drinkers. The results showed significantly higher levels of urinary 6β-naltrexol (p < 0.05) in those subjects who experienced one or more side effect (i.e., headache, nausea, anxiety, or erection). Urinary naltrexone levels did not difter between the groups. Results also showed an approximate 10:1 ratio of 6β-naltrexol to naltrexone levels and a significant positive correlation between the parent compound and metabolite, suggesting parallel renal clearance. The results of this study suggest a possible mechanism for the side effects obsetved after acute administration of naltrexone.     

Stress-induced and cue-induced craving for alcohol in heavy drinkers: Preliminary evidence of genetic moderation by the OPRM1 and CRH-BP genes

Background: Neurobiological theories of addiction have highlighted disruption in stress pathways as a central feature of addictive disorders, and pharmacological treatments targeting stress mechanisms hold great promise. This study examines genetic determinants of stress‐induced and cue‐induced craving in heavy drinkers by testing single‐nucleotide polymorphisms (SNPs) of the corticotrophin‐releasing hormone binding protein (CRH‐BP) gene and the mu‐opioid receptor (OPRM1) gene. Methods: This study combines guided imagery stress exposure and in vivo alcohol cue exposure in a sample of 64 (23 women) non‐treatment‐seeking heavy drinkers. Results: Analyses, uncorrected for multiple comparisons, revealed that a tag SNP of the CRH‐BP gene (rs10055255) moderated stress‐induced craving in this sample. The same SNP predicted greater affective responses to the stress manipulation, including greater levels of subjective tension and negative mood. The Asp40 allele of the OPRM1 was associated with greater cue‐induced alcohol craving following the neutral imagery condition. Conclusions: These initial results extend recent preclinical and clinical findings implicating the CRH‐BP in stress‐related alcoholism and confirm the role of the Asp40 allele of the OPRM1 gene in reward‐driven alcohol phenotypes. Human laboratory models of stress and cue‐induced craving may be useful in pharmacotherapy development targeting dysregulation of stress systems. Larger studies are needed to validate these preliminary findings, which should also be extended to clinical samples.     

A pilot evaluation of the safety and tolerability of repeat dose administration of long-acting injectable naltrexone (Vivitrex) in patients with alcohol dependence

BACKGROUND:: Oral naltrexone is currently used as part of a treatment regimen for alcohol-dependent patients, but its clinical utility is hampered by poor patient adherence. A long-acting injectable naltrexone formulation (Vivitrex) was designed to facilitate patient adherence by providing an extended duration of therapeutic naltrexone over 1 month, thereby eliminating the need for daily dosing. METHODS:: A multicenter, randomized, double-blind, placebo-controlled pilot study was conducted to evaluate the safety and tolerability of intramuscular repeat dose administration of this extended-release naltrexone formulation in DSM-IV alcohol-dependent patients. Thirty patients were randomized to treatment with injectable naltrexone (400 mg; n = 25) or a matching placebo injection (n = 5) and were dosed once every 28 days over 4 months. Psychosocial treatment was offered to patients in both treatment groups. Outcome measures related to drinking activity and trough plasma concentrations of naltrexone and its primary metabolite, 6-beta-naltrexol, were evaluated. RESULTS:: Injectable naltrexone was generally safe and well tolerated. Reported adverse events were mild to moderate and resolved without intervention; only two patients discontinued due to adverse events. The most common adverse events (nausea and headache) occurred at a similar rate for patients in both treatment groups. Pharmacokinetic analysis confirmed that therapeutic levels of naltrexone were delivered throughout the four 1-month treatment cycles. CONCLUSIONS:: The results of this pilot study provide the basis and methods for a larger, more definitive trial to determine the utility of this long-acting injectable naltrexone formulation in the treatment of alcohol-dependent patients.     

Moderators of naltrexone's effects on drinking, urge, and alcohol effects in non-treatment-seeking heavy drinkers in the natural environment

Background:  Naltrexone (NTX) has proven to be effective with alcoholics in treatment, with most controlled clinical trials showing beneficial effects on heavy drinking rates. However, little is known about the behavioral mechanisms underlying the effects of NTX on drinking, or about patient characteristics that may moderate NTX's effects on drinking. In this study, ecological momentary assessment (EMA) techniques were used to investigate some of the putative mechanisms of naltrexone's effects on drinking in heavy drinkers who were not seeking treatment for alcohol problems. Polymorphisms in the D4 dopamine receptor (DRD4) gene and the μ-opiate receptor (OPRM1) gene, family history of alcohol problems, age of onset of alcoholism and gender were explored as potential moderators of NTX's effects.
Methods:  After a 1-week placebo lead-in period, heavy drinkers ( n  = 180), 63% of whom were alcohol-dependent, were randomized to 3 weeks of daily naltrexone (50 mg) or placebo. Throughout the study, participants used EMA on palm-pilot computers to enter, in real time, drink data, urge levels, and subjective effects of alcohol consumption.
Results:  Naltrexone reduced percentage drinking days in all participants and reduced percent heavy drinking days in DRD4-L individuals; NTX decreased urge levels in participants with younger age of alcoholism onset; NTX increased time between drinks in participants who had more relatives with alcohol problems; and NTX reduced the stimulating effects of alcohol in women. OPRM1 status did not moderate any of NTX's effects.
Conclusions:  These results confirm earlier findings of NTX's effects on drinking and related subjective effects, and extend them by describing individual difference variables that moderate these effects in the natural environment, using data collected in real time.     

Naltrexone Increases the Latency to Drink Alcohol in Social Drinkers

We investigated the effects of naltrexone (NTX) on alcohol drinking, urge to drink alcohol, and alcohol-induced sensations and mood states in social drinkers consuming alcohol ad libitum in a cocktail bar. Sixteen college-age men and women participated in a double-blind, placebo-controlled, within-subjects, cross-over study. Subjects were tested during each of three drug conditions: NTX, 50 mg/day, po; inactive placebo; and no drug. Each treatment condition lasted 8 to 11 days. Small groups of subjects consumed alcohol ad libitum during three 2-hr evening drinking sessions, separated by ˜2 weeks. NTX treatment significantly increased the latency (time in seconds) to first sip the first ( p < 0.05) and second alcoholic beverages consumed ( p < 0.01). Moreover, the mean blood alcohol concentration at the end of the session was significantly lower when subjects were treated with NTX ( p < 0.05). No differences were found on self-report urge to drink alcohol. Subjects reported more fatigue and tension on the Profile of Mood States ( p < 0.05), before drinking, and increases in nausea on the Alcohol Sensation Scale ( p < 0.05) when treated with NTX. The increase in the latency to sip the first and second alcoholic beverages may reflect the capacity of NTX to block urge for alcohol elicited from external cues (before consuming alcohol), as well as urge for alcohol after priming from ingested alcohol. Thus, the effectiveness of NTX for reducing drinking behaviors of alcoholics may be partially caused by anticraving properties of NTX.     

Targeted versus daily naltrexone: secondary analysis of effects on average daily drinking

BACKGROUND: To extend our previous findings that naltrexone reduced the likelihood of heavy drinking on a given day among problem drinkers, while targeted administration reduced the likelihood of any drinking, we examined the effects of naltrexone and targeted administration on the continuous outcome of drinks/day. Because treatment response may differ by gender, we also compared the effects on this factor. METHODS: In a double-blind, placebo-controlled study, problem drinkers (n=150, 58% men) were randomly assigned to 8 weeks of treatment with naltrexone (50 mg/day) or placebo, either daily or on a targeted schedule. All subjects also received brief coping skills therapy. To complement the traditional regression analysis conducted previously, a zero-inflated Poisson regression model was used to examine the effects of medication, schedule of administration, and gender on the number of standard drinks consumed daily. RESULTS: Targeted naltrexone, and to a lesser extent targeted placebo, yielded a greater reduction in daily drinking than did daily placebo, an effect that did not differ by gender and that was greater than that seen for daily naltrexone treatment. Relative to daily placebo, daily naltrexone reduced the number of drinks/day only among men, at the level of a nonsignificant trend. CONCLUSIONS: Although in both genders, targeted treatments appeared to reduce the volume of drinking, treatment with targeted naltrexone was somewhat better. In contrast, heavy drinking women showed no benefit from daily naltrexone treatment. Further evaluation of the efficacy of targeted treatments and of daily naltrexone and the relationship of these treatments with gender is warranted.