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.     

Genetic moderators of naltrexone's effects on alcohol cue reactivity

BACKGROUND: Naltrexone (NTX) reduces drinking and craving in alcoholic individuals in treatment and also in heavy drinkers. Polymorphisms in the D4 dopamine receptor (DRD4) gene and mu-opiate receptor gene (OPRM1) may moderate NTX's effects on craving. This study examined these candidate genes as moderators of the effects of NTX on cue-elicited urge to drink in non-treatment-seeking heavy drinkers. METHOD: Data from the subset of 93 participants who consented for genetic testing in a larger study of medication effects were used to examine pharmacogenetic hypotheses. The non-treatment-seeking male and female heavy drinkers (62% alcohol dependent) were genotyped for the variable number of tandem repeats polymorphism in the DRD4 gene [L=7 or more (n=34), S=less than 7 (n=56)] and Asn40Asp single-nucleotide polymorphism in the OPRM1 gene [29 aspartate (Asp) carriers and 59 asparagine (Asn) homozygotes]. Ten days after randomization to NTX (50 mg) or placebo, participants completed an alcohol cue reactivity assessment. RESULTS: Any medication effects were all accounted for by interaction with genotype. Naltrexone increased urge for alcohol in Asp carriers across alcohol and neutral beverage cue trials and had no effect on homozygous Asn carriers. Asp40 carriers on either medication had greater decreases (from resting baseline) in mean arterial blood pressure across all beverage cue trials compared with Asn carriers. For DRD4, no differential medication effects by DRD4 polymorphism were found. Alcohol dependence diagnosis did not moderate the effects of gene and medication on cue-elicited measures. DISCUSSION: The differential responses to NTX due to variation in the OPRM1 gene may help explain conflicting results in clinical trials and suggest directions for patient-treatment matching.     

Effects of naltrexone on alcohol self-administration in heavy drinkers

The mechanisms underlying the suppressant effects of naltrexone (NTX) on ad libitum alcohol drinking in a bar/restaurant setting were investigated in heavy beer drinkers. Fifty-one male and female heavy drinkers (mean age = 22) received 50 mg of NTX or placebo (PBO), p.o., on two separate occasions in a randomized, double-blind crossover protocol. After 7 days of taking medication, subjects were provided with the opportunity to consume beer ad libitum during two, 90-min test sessions that were held 1 to 2 weeks apart. Blood samples were collected on test days to ensure medication compliance and to measure blood levels of NTX and the active beta-naltrexol. Less beer was consumed during NTX treatment. NTX decreased urges to consume alcohol. NTX-treated subjects also took significantly longer to finish each glass of beer and were more likely to terminate beer drinking early. Self-report stimulation and ratings of positive mood states were lower during NTX treatment. Negative side effects of NTX, such as nausea and headache, were reported more frequently with NTX. Not all of the subjects decreased their beer intake on NTX, and some subjects drank more beer. Nonresponders to NTX were not related to blood levels of the active metabolite beta-naltrexol or to a family history of alcoholism. Overall, the results of this study suggest that NTX affects a number of the components of alcohol drinking sequence, including lowering cravings, decreasing the positive reinforcing effects of alcohol, and increasing headache and nausea, each of which may contribute to reducing alcohol intake.     

Effects of heavy drinking, binge drinking, and family history of alcoholism on regional brain metabolites

BACKGROUND: The main goals are to investigate the effects of chronic active heavy drinking on N-acetylaspartate (NAA) and other metabolites throughout the brain and to determine whether they are affected by family history (FH) of alcoholism and long-term drinking pattern. METHODS: Forty-six chronic heavy drinkers (HD) and 52 light drinkers (LD) were recruited from the community and compared on measures of regional brain structure using magnetic resonance imaging and measures of common brain metabolites in gray matter (GM) and white matter (WM) of the major lobes, subcortical nuclei, brainstem, and cerebellum using short-echo time magnetic resonance spectroscopic imaging. Regional atrophy-corrected levels of NAA, myoinositol (mI), creatine, and choline-containing metabolites were compared as a function of group, FH of alcoholism, and bingeing. RESULTS: Frontal WM NAA was lower in FH-negative HD than FH-positive HD and tended to be lower in women than men. Creatine-containing metabolites in parietal GM were higher in HD than LD. FH-negative compared with FH-positive HD also had more mI in the brainstem and tended to have lower NAA and more mI in frontal GM. Although parietal GM NAA was not significantly lower in HD than LD, it was lower in non-binge drinkers than bingers. Frontal WM NAA was lower in HD than LD, with the difference driven by a small number of women, FH-negative HD, and older age. Lower frontal WM NAA in HD was associated with lower executive and working memory functions and with lower P3b amplitudes at frontal electrodes. CONCLUSIONS: Community-dwelling HD who are not in alcoholism treatment have brain metabolite changes that are associated with lower brain function and are likely of behavioral significance. Age, FH, and binge drinking modulate brain metabolite abnormalities. Metabolite changes in active HD are less pronounced and present with a different spatial and metabolite pattern than reported in abstinent alcoholics.     

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.     

Course of DSM-IV alcohol dependence in a community sample: effects of parental history and binge drinking

BACKGROUND: The role of positive family history in the etiology of alcohol dependence has been demonstrated repeatedly but little is known about the effect of this risk factor on the chronicity of alcohol dependence once it has begun. METHODS: We studied the effects of parental and sibling history in conjunction with frequency of binge drinking in a sample of 169 community residents who met criteria for DSM-IV alcohol dependence at the baseline interview. Subjects were re-interviewed approximately 1 year later and the status of their alcohol-dependence disorders (remitted or chronic) was determined. RESULTS: Parental history of alcoholism was significantly related to chronicity of alcohol dependence, as was frequency of binge drinking. CONCLUSIONS: Failure to find an effect for family history on chronicity would have suggested that the effect was transient, perhaps interacting with time-limited environmental vulnerability. The finding of a positive relationship between family history and chronicity suggests that the relationship between familial/ genetic background and alcohol dependence is stable.     

Relationships among the level of response to alcohol and the number of alcoholic relatives in predicting alcohol-related outcomes

BACKGROUND: The low level of response (LR) to alcohol is related to a family history (FH) of alcohol use disorders (AUDs), and each predicts alcohol-related outcomes. Few studies have evaluated the interrelationships between the number of alcoholic relatives, LR, and a range of alcohol-related outcomes. This study tests the hypotheses that there will be an inverse relationship between LR and FH and that LR will be a better predictor of the maximum quantity of alcohol consumed. METHODS: Data were extracted from personal interviews with 376 males from 20 years of follow-up in the San Diego Prospective Study. Level of response had been established at about age 20 through alcohol challenges in this population, about half of whom had at least one alcoholic relative. Face-to-face follow-ups with both the subjects and additional informants were carried out 10, 15, and 20 years later. These analyses used correlations and regressions to evaluate the relationship between the 2 major predictors (FH and LR) and 5 alcohol-related outcomes over 20 years of follow-up. RESULTS: As predicted, the alcohol challenge-based LR correlated significantly with the number of alcoholic relatives (up to -0.17 for subjects with clearly high and low LR scores). Each of the 2 predictors correlated with the 5 outcomes, including the maximum quantity of alcohol consumed since original testing, maximum frequency, nondiagnostic alcohol-related problems, the number of 11 DSM-IV (Fourth Diagnostic and Statistical Manual of Mental Disorders) abuse and dependence items, and having developed alcohol abuse or dependence. In hierarchical regression analyses, LR contributed significantly to the prediction of all 5 outcomes, even when considered in the context of FH, with only LR predicting drinking quantity and frequency, but both items adding to the prediction of alcohol-related problems and diagnoses. These results were not affected by the intensity of usual drinking when LR had been measured at age 20. CONCLUSIONS: Both FH and LR contributed to a range of alcohol-related outcomes, with LR alone significantly predicting maximum quantity and frequency in regression analyses.     

Sequelae of systemic hypertension in alcohol abstainers, light drinkers, and heavy drinkers

A link exists between alcohol intake and increased blood pressure (BP), with many studies showing increased hypertension prevalence in heavy drinkers. The harmful and beneficial effects of alcohol can confound the study of the long-term risks of alcohol-related hypertension. We therefore studied cardiovascular sequelae separately in heavy drinkers, light drinkers, and abstainers among 127,212 subjects with BP and alcohol intake ascertained at 1978 to 1985 health examinations. Subsequent cardiovascular end points included mortality risk, hospitalization risk, and outpatient diagnosis of hypertension. Analyses were performed for all subjects and stratified by 5 alcohol-drinking categories (from never drinkers to >or=3 drinks/day). With <120/80 mm Hg as the referent, Cox proportional hazards models were used to estimate relative risks and 95% confidence intervals for 3 higher BP categories (120 to 129/80 to 84, 130 to 139/85 to 89, and >or=140/90 mm Hg). The covariates were age, gender, race, body mass index, education, and smoking. The risk of all outcomes was progressively higher for increasing BP categories, with a similarly increased risk for abstainers, light drinkers, and heavy drinkers. The interaction tests for alcohol and BP were not statistically significant for the mortality and hospitalization outcomes. Interpretation was limited by an inability to separate subjects with increased BP from alcohol consumption from those with other etiologies. In conclusion, the data indicate that the risks of hypertension are similar regardless of the amount of alcohol consumption.     

Adult transition from at-risk drinking to alcohol dependence: the relationship of family history and drinking motives

Background:  Prospective studies have not previously examined whether a family history of alcoholism and drinking motives conjointly predict a diagnosed DSM-IV alcohol abuse or dependence in adults, despite a large literature that each is associated with alcohol consumption. The focus of this study is the conjoint, prospective examination of these risk factors in a 10-year longitudinal study of adults who were at-risk drinkers at baseline.
Methods:  Prospective, population-based cohort of drinkers aged 18 or older from a Northeastern U.S. area initially evaluated for history of alcohol use disorders and drinking motives in 1991 to 1992. New onset dependence was studied in those who never met the criteria for alcohol dependence at baseline ( n  = 423), and new onset abuse was studied in those who never met the criteria for alcohol abuse at baseline ( n  = 301) and who did not develop dependence during the follow-up.
Results:  Family history significantly interacted with 2 baseline drinking motives in predicting new onsets of DSM-IV alcohol dependence: drinking to reduce negative affect (OR 3.38; 95% CI 1.05, 10.9) and drinking for social facilitation (OR 3.88; CI 1.21, 12.5). Effects were stronger after conditioning the drinking motives on having a positive family history of alcoholism. In contrast, in predicting new onsets of alcohol abuse, drinking motives did not have direct effects or interact with family history.
Conclusions:  Those who drank to reduce negative affect or for social facilitation at baseline were at greater risk of alcohol dependence 10 years later if they also had a family history of alcoholism. These results suggest an at-risk group that can be identified prior to the development of alcohol dependence. Further, the findings suggest utility in investigating the interaction of drinking motives with measured genetic polymorphisms in predicting alcohol dependence.     

Density of familial alcoholism and its effects on alcohol use and problems in college students

Background:  Previous studies of family history of alcoholism (FHA) in college students have typically relied on dichotomous indices of paternal drinking. This study examined the prevalence of FHA and its effects on alcohol use and problems using a density measure in a sample ( n  =   408) of college students.
Methods:  Undergraduate students completed an anonymous survey in exchange for course credit. Data was collected between 2005 and 2006.
Results:  Using a density measure of FHA, we observed an overall prevalence rate of 65.9% and a rate of 29.1% for FHA in both first and second-degree relatives. Structural equation modeling (SEM) was used to investigate relations among FHA, alcohol use/problems and previously identified etiological risk factors for alcohol use disorders (AUD). Results indicated a significant positive association between FHA and alcohol-related problems and this relationship was mediated by age of onset of drinking, behavioral undercontrol and current cigarette use. Behavioral undercontrol also mediated the relationship between gender and alcohol problems. Additionally, FHA was associated with an earlier age of onset of drinking and this was related to greater alcohol use.
Conclusions:  Assessing density of FHA in future trajectory research may capture a greater number of students at risk for acute alcohol-related problems and/or future development of AUDs. Future preventive interventions with this population, which should begin well before the college years, may benefit from considering personality factors and incorporating smoking cessation to help identify at-risk students and assist those who wish to cut down on their alcohol use but find that smoking acts as a trigger for increased drinking.     

Sleep following alcohol intoxication in healthy, young adults: effects of sex and family history of alcoholism

Background: This study evaluated sex and family history of alcoholism as moderators of subjective ratings of sleepiness/sleep quality and polysomnography (PSG) following alcohol intoxication in healthy, young adults. Methods: Ninety‐three healthy adults [mean age 24.4 ± 2.7 years, 59 women, 29 subjects with a positive family history of alcoholism (FH+)] were recruited. After screening PSG, participants consumed alcohol (sex/weight adjusted dosing) to intoxication [peak breath alcohol concentration (BrAC) of 0.11 ± 0.01 g% for men and women] or matching placebo between 20:30 and 22:00 hours. Sleep was monitored using PSG between 23:00 and 07:00 hours. Participants completed the Stanford Sleepiness Scale and Karolinska Sleepiness Scale at bedtime and on awakening and a validated post‐sleep questionnaire. Results: Following alcohol, total sleep time, sleep efficiency, nighttime awakenings, and wake after sleep onset were more disrupted in women than men, with no differences by family history status. Alcohol reduced sleep onset latency, sleep efficiency, and rapid eye movement sleep while increasing wakefulness and slow wave sleep across the entire night compared with placebo. Alcohol also generally increased sleep consolidation in the first half of the night, but decreased it during the second half. Sleepiness ratings were higher following alcohol, particularly in women at bedtime. Morning sleep quality ratings were lower following alcohol than placebo. Conclusions: Alcohol intoxication increases subjective sleepiness and disrupts sleep objectively more in healthy women than in men, with no differences evident by family history of alcoholism status. Evaluating moderators of alcohol effects on sleep may provide insight into the role of sleep in problem drinking.     

An extract of the Chinese herbal root kudzu reduces alcohol drinking by heavy drinkers in a naturalistic setting

BACKGROUND: Of the available medications for treating alcohol-related problems, none are universally effective, and all have side effects that may limit their use. Extracts of kudzu containing a variety of isoflavones have been shown to reduce alcohol drinking in rats and hamsters. METHODS: The present study was designed to test the efficacy of a kudzu extract in a clinical population. Male and female "heavy" alcohol drinkers were treated with either placebo or a kudzu extract for 7 days and then given an opportunity to drink their preferred brand of beer while in a naturalistic laboratory setting. Participants served as their own controls, and order of treatment exposure was counterbalanced. Drinking behavior was monitored by a digital scale that was located in the top of an end table. RESULTS: Kudzu treatment resulted in significant reduction in the number of beers consumed that was paralleled by an increase in the number of sips and the time to consume each beer and a decrease in the volume of each sip. These changes occurred in the absence of a significant effect on the urge to drink alcohol. There were no reported side effects of kudzu treatment. CONCLUSION: These data suggest that an extract of this leguminous plant may be a useful adjunct in reducing alcohol intake in a naturalistic setting.     

A double-blind evaluation of gabapentin on alcohol effects and drinking in a clinical laboratory paradigm

INTRODUCTION: There has been increasing interest in the use of anticonvulsant agents in the treatment of alcoholism. Anticonvulsant agents have mostly been evaluated as an alternative to benzodiazepines in the treatment of alcohol withdrawal. Among the advantages of using anticonvulsant agents in this capacity is their purported lack of interaction with alcohol (i.e., interactions that could increase psychomotor deficits, cognitive impairment, and increase intoxication). This is particularly important in the treatment of alcohol withdrawal and relapse prevention in outpatients. Unfortunately, these untoward clinical interactions between anticonvulsants and alcohol in alcoholic patients have not been thoroughly assessed. The current clinical laboratory study was conducted to evaluate the safety and tolerability of the anticonvulsant gabapentin in alcoholic subjects. In addition, the ability of gabapentin to reduce alcohol craving and consumption was evaluated. METHODS: Thirty-five non-treatment-seeking alcoholic subjects were enrolled in a subacute human laboratory study and received double-blind treatment with up to 1,200 mg of gabapentin (n=18) or placebo (n=17) for 8 days. The safety and tolerability of gabapentin were monitored in the natural environment during the first 5 days of medication treatment and during a free-choice limited access consumption paradigm following an initial drink of alcohol in a bar-lab setting on Day 7. RESULTS: There was no overall effect of gabapentin on drinking or craving; however, it was tolerated (e.g., mood and sedation) as well as placebo over 5 days of natural drinking. During the bar-lab drinking session, there were no differences in subjective high or intoxication between subjects treated with gabapentin or placebo. DISCUSSION: This study provides initial evidence that the anticonvulsant gabapentin is safe if used in conjunction with alcohol consumption in alcoholic individuals. Further study is needed with this and other lab models to determine the utility and safety of gabapentin in the treatment of alcoholism.     

Association between the functional polymorphism of catechol-O-methyltransferase gene and alcohol consumption among social drinkers

BACKGROUND: A common functional genetic polymorphism in the catechol-O-methyltransferase (COMT) gene (Val158 Met) results in 3- to 4-fold differences in COMT enzyme activity and dopamine inactivation rate. Previous studies have shown that type I alcoholism is more common among subjects with low activity COMT genotype (LL), compared with high activity (HH) or heterozygotic (LH) genotypes. METHODS: We studied alcohol consumption and the COMT genotype in middle-aged Finnish men (n 896), who represented an unselected ethnically homogenous population sample and reported using alcohol during the past year. Average alcohol use in pure ethanol (grams per week) was compared between subjects with LL genotype and subjects with LH or HH genotypes. RESULTS: Men with LL genotype (30% of all subjects) reported 27% higher weekly alcohol consumption compared with the two other genotype groups (p < 0.05). The difference remained statistically significant after a multivariate adjustment for sociodemographic factors and prior or existing diseases (p = 0.031). CONCLUSIONS: The results indicate that COMT polymorphism may contribute significantly to alcohol intake not only in alcoholics but also in a general male population.     

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.     

Effects of stress on alcohol consumption in rats selectively bred for high or low alcohol drinking

BACKGROUND: Stress has long been thought to influence the initiation and maintenance of alcohol drinking in humans. However, results of studies in animals suggest that the relationship between stress and alcohol drinking is not well understood. The purpose of this study was to examine the effect of unpredictable and uncontrollable restraint stress on alcohol consumption in two sets of rat lines selectively bred for alcohol preference (P) and high alcohol drinking (HAD1) and for alcohol nonpreference (NP) and low alcohol drinking (LAD1). METHODS: Male P (n = 26) and NP (n = 26) and HAD1 (n = 17) and LAD1 (n = 20) rats were counterbalanced on the basis of alcohol intake and assigned, in matched pairs, to either a stress (Stress) or a no-stress (Control) group. All rats were given a free choice between a 10% v/v alcohol solution and water, with food freely available. Unpredictable, uncontrollable stress, which consisted of immobilization in a nylon restraint sleeve for 30 to 120 min/day, was applied for 10 consecutive days. RESULTS: Stress moderately reduced alcohol intake in both P and HAD1 rats versus controls and had no effect on alcohol intake in either the NP or the LAD1 rats during the 10 days of stress application. Alcohol intake was increased for the first 5 days after stress termination in P rats but not in HAD1 rats. Alcohol intake remained stable for several weeks in both the NP and LAD1 lines after stress termination and then increased during the last 15 days of the 35-day poststress period in NP rats, but not in LAD1 rats. CONCLUSIONS: A reduction in alcohol intake during stress in rats with a genetic predisposition toward high alcohol intake seems to be a moderate but consistent finding, whereas an increase in alcohol intake after stress termination is less consistent and may be influenced by genetic background.