Naltrexone's effects on reactivity to alcohol cues among alcoholic men
Robert M Swift2000, Journal of Abnormal Psychology
Sign up for access to the world's latest research
checkGet notified about relevant papers
checkSave papers to use in your research
checkJoin the discussion with peers
checkTrack your impact
Abstract
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 such as naltrexone have shown particular promise as pharmacologic adjuncts to treatment for alcohol dependence Volpicelli, Alterman, Hayashida, & O'Brien, 1992). However, the mechanisms of naltrexone's effects on drinking behavior are not clear. Both the reinforcing effects of alcohol and craving may be mediated by the activation of mesolimbic dopamine neurons (e.g., . Naltrexone reduces mesolimbic dopaminergic activity after alcohol ingestion in animals and may reduce the urge to drink through modulation of mesolimbic dopaminergic activity. If naltrexone reduces urges to drink, individuals may be less likely to drink or to drink heavily. In clinical trials, weekly craving ratings were sporadically lower after naltrexone treatment than
Related papers
Naltrexone's Effect on Cue-Elicited Craving Among Alcoholics in Treatment
Alcoholism: Clinical and Experimental Research, 1999
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.
Naltrexone Alters Subjective and Psychomotor Responses to Alcohol in Heavy Drinking Subjects
Neuropsychopharmacology, 2000
Preclinical studies support endogenous opioid system involvement in alcohol reinforcement and consumption; however, recent clinical trials and human laboratory studies have provided mixed findings of the effects of naltrexone (a non-selective opioid antagonist) on alcohol responses. This study used a within-subject design ( n ϭ 23) to investigate naltrexone effects (0, 50 and 100 mg qd) on subjective and psychomotor responses to alcohol (none, moderate, high) in heavy drinkers. Before alcohol administration, subjects reported decreased desire to drink alcohol when maintained on 50 mg compared with placebo naltrexone. Following alcohol administration, active naltrexone significantly increased subjective ratings of sedative, and unpleasant/sick effects and decreased ratings of liking, best effects and desire to drink. Naltrexone generally did not alter subjective or objective indicators of drunkenness. Finally, high doses of naltrexone and alcohol interacted to produce the greatest decreases in liking and best effects. Findings support the role of endogenous opioids as determinants of alcohol's effects and suggest that naltrexone may be particularly clinically useful in those treatment patients who continue to drink heavily. [Neuropsychopharmacology 22:480-492, 2000]
Effects of Naltrexone on Alcohol Self‐Administration in Heavy Drinkers
Alcoholism: Clinical and Experimental Research, 1999
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 β‐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 ...
Naltrexone Persistently Reduces Rats' Intake of a Palatable Alcoholic Beverage
Alcoholism-clinical and Experimental Research, 1996
Rats were given 30 days of opportunity to take a sweetened alcoholic beverage and water for 2 hr/day. At first, they took little alcohol, but subsequently took, on average, 2.3 g/kg of alcohol/daily session. They also took sufficient water, during the 2-hr period, to maintain their health and to steadily gain weight. At the end of the 30 days, they were divided into four groups so that their intakes of alcohol were similar. All groups continued on the daily regimen, but each group received different injections. One group received placebos, whereas the other two groups received either 5.0 or 10.0 mg/kg, respectively, of naltrexone daily, 30 min before the drinking session. The fourth group received 5.0 mg/kg of naltrexone 12.5 hr before the session and another 5.0 mg/kg 30 min before the session. This regimen of dosing and daily opportunities to drink continued for 30 days. With the end of injections, subjects continued on the regimen for another 5 days. Naltrexone, dose-relatedly, reduced rats' intake of alcoholic beverage. Furthermore, with respect to reducing intake of alcohol, no tolerance or refractoriness were observed across the 30 days of dosing. Within a couple of days after dosing, levels of intake returned to predosing levels.
Alcohol Consumption Is Enhanced After Naltrexone Treatment
Alcoholism: Clinical and Experimental Research, 2007
Background: It is well known that alcohol increases opioid activity, which can contribute to the reinforcing effect of alcohol. Clinical studies have supported reductions in alcohol consumption among alcoholic patients during treatment with opioid antagonists (OAs) and its use is recommended for this purpose. Experimental studies have demonstrated opioid receptor up-regulation after several days of OA treatment, which increases the availability of these receptors. On this basis, the physiological conditions in the period immediately after the OA treatment could increase the reinforcing value of alcohol and in this way enhance alcohol consumption. Methods: To test this hypothesis, 2 groups of Wistar male rats were used in the present study. After assessing the baseline of voluntary alcohol (10% v/v) consumption, subjects were treated with either the OA naltrexone (Ntx), (2 mg/kg/d/rat) or a saline solution (0.2 mL/d/male) for 7 days. Subsequently, all subjects were given a free choice between ethanol (10%) and water for 5 days. To study a possible cumulative effect, this procedure was sequentially repeated 4 times with each group. Water and food were available ad libitum throughout the experiment. Results: After each period of 7 days of Ntx use, alcohol consumption increased significantly with respect to the baseline and each equivalent period in the control group. When the subjects were exposed to alcohol again 1 week after the last of the 4 sequential periods, alcohol drinking was higher than the baseline in the Ntx group, but not in the control group. Water consumption was decreased during Ntx treatment in the control group in periods 1, 2, and 4. Food intake and body weight did not show differences between groups throughout the study; however, a decrease in food intake was observed over time regardless of treatment. Conclusion: These results show that alcohol intake may increase after the Ntx treatment, particularly when alcohol is not available during treatment with the OA, and that this may be due to a higher availability of opioid receptors in that period.
The effect of naltrexone and acamprosate on cue-induced craving, autonomic nervous system and neuroendocrine reactions to alcohol-related cues in alcoholics
European Neuropsychopharmacology, 2007
Introduction: Acamprosate and naltrexone have been shown to be effective in relapse prevention of alcoholism. It is hypothesized that naltrexone exerts its effects primarily on cue-induced craving and neuroendocrine cue reactivity, whereas acamprosate exerts its effect primarily on autonomic nervous system reactions to alcohol-related cues. Experimental procedures: In a randomized double-blind experiment, 131 abstinent alcoholics received either acamprosate (n =56), naltrexone (n = 52) or placebo (n = 23) for three weeks and participated in two cue-exposure sessions: the first the day before and the second at the last day of medication. Results: Consistent with the hypotheses, naltrexone reduced craving more than acamprosate, and acamprosate reduced heart rate more than naltrexone. No medication effect was found on cueinduced cortisol. Discussion: The findings provide some evidence for differential effects of naltrexone and acamprosate: naltrexone may exert its effect, at least partly, by the reduction of cue-induced craving, whereas acamprosate may exert its effect, at least partly, by the reduction of autonomic nervous system reactions to alcohol-related cues.
Effects of naltrexone and LY255582 on ethanol maintenance, seeking, and relapse responding by alcohol-preferring (P) rats
Alcohol, 2012
Research indicates opioid antagonists can reduce alcohol drinking in rodents. However, tests examining the effects of opioid antagonists on ethanol seeking and relapse behavior have been limited. The present study examined the effects of two opioid antagonists on ethanol maintenance, seeking, and relapse responding by alcohol-preferring (P) rats. Adult P rats were self-trained in two-lever operant chambers to self-administer 15% (vol/vol) ethanol on a fixed-ratio 5 (FR5) versus water on a FR1 concurrent schedule of reinforcement in daily 1-h sessions. After 10 weeks, rats underwent extinction training, followed by 2 weeks in their home cages. Rats were then returned to the operant chambers without ethanol or water to measure responses on the ethanol and water levers for four sessions. After a subsequent 2 weeks in the home cage, without access to ethanol, rats were returned to the operant chambers with ethanol and water available. Effects of antagonists on maintenance responding were tested after several weeks of daily 1-h sessions. Naltrexone (NAL; 1e10 mg/kg, subcutaneously [s.c.]; n 5 8/dose), LY255582 (LY; 0.03e1 mg/kg, s.c.; n 5 8/dose), or vehicle were injected 30 min before the first session (in the absence of ethanol), following 2 weeks in their home cages, and for four consecutive sessions of ethanol self-administration under maintenance and relapse conditions. Both NAL and LY reduced responses on the ethanol lever without any fluids present, and ethanol selfadministration under relapse and on-going drinking conditions, with LY being more potent than NAL. Both NAL and LY were less effective in reducing responding in the absence of ethanol than in reducing ethanol self-administration. Overall, the results indicate that the opioid system is involved in mediating ethanol seeking, and ethanol self-administration under relapse and on-going alcohol drinking, but that different neurocircuits may underlie these behaviors. Published by Elsevier Inc.
Effect of naltrexone on alcohol "high" in alcoholics
American Journal of Psychiatry, 1995
Effects of Naltrexone Administered Repeatedly Across 30 or 60 Days on Ethanol Consumption Using a Limited Access Procedure in the Rat
Alcoholism: Clinical and Experimental Research, 1998
The present study examined the effects of naltrexone, 1.0 mgfkg, administered repeatedly across both 30 and 60 days on the consumption of an unsweetened ethanol solution by outbred Wistar rats in a limited access procedure. Naltrexone significantly suppressed consumption of ethanol across both 30 and 60 days. These results provide no evidence for the development of tolerance based on such factors as receptor upregulation or supersensitivily due to the repeated administration of naltrexone across extended periods. Ethanol consumption during the final one-third of the nabexone sessions, for both the 30-and 60-day groups, was significantly lower than during the initial sessions. These results suggest an associative component. That is, the rats apparently learned that ethanol consumption was no longer reinforcing across repeated exposures. After termination of naltrexone treatment, consumption of ethanol immediately increased. However, consumption in those rats who were administered naltrexone for 60 days remained significantly suppressed, compared with consumption in those rats who were administered naltrexone for 30 days. These results suggest that naltrexone reduces ethanol consumption by blocking endogenous opioid receptors that mediate, at least in part, ethanol's reinforcing properties. In addition, these data suggest that longer clinical use of naltrexone, as a pharmacological adjunct to psychosocial treatment for alcohol-dependent patients, may be beneficial in reducing the number of relapses experienced.
Conditioned Effects Produced by Naltrexone Doses That Reduce Ethanol-Reinforced Responding in Rhesus Monkeys
Alcoholism: Clinical and Experimental Research, 1999
Clinical trials have shown that naltrexone is effective in treating alcohol dependence; nausea and dysphoria have been reported as "side effects" in many of these studies. In primates, naltrexone reduces reinforced responding for oral ethanol, sucrose, and phencyclidine. This study was designed to determine if naltrexone reduces reinforced responding for various solutions by producing an interoceptive stimulus that may result in a conditioned taste aversion. Four opioid antagonist-naive rhesus monkeys responded for solutions from a two-spout operant panel for 30 min per day. During a conditioning phase, the monkeys received novel Kool-Aid@ solutions paired with either saline or naltrexone (0.32 mgikg) given 30 min before the session. The monkeys then had seven choice sessions between the saline-paired solution or the naltrexone-paired solution. During the conditioning phase, the naltrexone reduced responding after five naltrexone/solution pairings. In addition, a conditioned taste aversion was produced; the naltrexone-paired solution maintained significantly less responding than did the saline-paired solution during the choice phase. In the next phase, the saline and naltrexone were given "unpaired" from any distinct part of the operant session, and another seven choice sessions followed. Naltrexone had no effect when given "unpaired" from the operant session. Then, another conditioning phase was undertaken followed by another series of choice sessions. During the replication of the conditioning, naltrexone reduced responding by the second pairing, although no conditioned aversion was observed in the subsequent choice sessions. Thus, given in the same manner (dose, route, and pretreatment time) as situations in which naltrexone reduces oral ethanol-, sucrose-, and phencyclidine-reinforced responding, naltrexone produced a conditioned taste aversion. These results suggest that naltrexone-induced nausea and its conditioned effects should be considered in naltrexone's effect in alcoholics. HE ENDOGENOUS opioid system may mediate the T reinforcing properties of ethanol. Attenuating ethanolrelated behaviors, naltrexone (NTX) and other opioid antagonists may block ethanol-induced opioid activation. Many studies document the effect of opioid antagonists on ethanol-related behaviors.' For example, in monkeys, NTX decreased ethanol drinking during free access to ethanol.233 In addition, NTX reduces oral and intravenous ethanolreinforced re~ponding.~,~ Also effective in clinical studies of alcohol dependence, NTX reduced craving, increased abstinence, and decreased r e l a p~e .~,~ NTX is currently being used as an adjunct in treating alcohol dependence.
Naltrexone treatment produces dose-related effects on food and water intake but daily alcohol consumption is not affected
Nutritional Neuroscience, 2008
There is evidence that naltrexone, an opioid antagonist, affects alcohol and food consumption. Though food intake is inherently involved when naltrexone effects on alcohol consumption have been studied, the differential effect of this opioid antagonist on both food and alcohol intake has not yet been reported. The present study analyzed the effect of a single daily dose of naltrexone on alcohol, food and water intake when these substances were available on a continuous basis. Wistar male rats were treated with s.c. injections of either naltrexone (2 or 10 mg/kg/day/rat) or a saline solution, 0.2 ml/day/rat for 7 days. This period was followed by a lapse of 7 days with no treatment (PT period), and this sequence of naltrexone or saline treatment followed by a period without treatment was repeated four times. Neither 2 mg/kg nor 10 mg/kg of naltrexone affected alcohol consumption, though the higher dose of naltrexone (10 mg/kg) increased food intake with respect to both the PT periods and the saline group and decreased water consumption with respect to the corresponding PT periods. Naltrexone at 2 mg/kg produced a decrease in food intake but only with respect to the PT periods. These results suggest that the effects of a single dose of naltrexone on alcohol consumption may not be evident when 24-h access to alcohol is assessed; however, naltrexone may produce different dose-related effects on food and water intake, suggesting that they may be mediated by distinct opioid system mechanisms.
Moderators of Naltrexone’s Effects on Drinking, Urge, and Alcohol Effects in Non-Treatment-Seeking Heavy Drinkers in the Natural Environment
Alcoholism: Clinical and Experimental Research, 2007
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.
Effects of Naltrexone on the Ethanol-Induced Changes in the Rat Central Dopaminergic System
Alcohol and Alcoholism, 2005
Aims: The opioid antagonist naltrexone may reduce ethanol reward, but the underlying neurochemical mechanisms has yet to be clarified. The afferent projections to the nucleus accumbens from the ventral tegmental area (VTA) provide a potential substrate by which endogenous opioids may modulate the dopaminergic rewarding effects of ethanol. We assessed mRNA levels of tyrosine hydroxylase (TH), a major regulatory enzyme in the dopamine synthesis and levels of dopamine and its metabolites after chronic ethanol administration with and without concomitant naltrexone. Methods: Sprague-Dawley rats were exposed to chronic ethanol consumption (5%, 4 weeks) with and without concomitant naltrexone administration. Levels of TH mRNA in the VTA and substantia nigra (SN) and dopamine and its metabolites in the striatum of the rats were measured by in situ hybridization and by high performance liquid chromatography, respectively. Results: Chronic ethanol consumption increased TH mRNA levels in the VTA, but did not cause any significant change in the SN. With naltrexone treatment, ethanol-induced increase in the TH mRNA level was reduced in the VTA. Chronic ethanol consumption did not cause any change in the levels of dopamine and its metabolites in most brain regions. Only in the striatum, ethanol consumption with naltrexone treatment significantly increases the dopamine level. Conclusion: This finding supports the presence of interactions of opioid and dopaminergic systems in the VTA in mediating ethanol reward, and thus naltrexone attenuates the rewarding properties of ethanol by interfering with the ethanol-induced stimulation of the mesolimbic dopaminergic pathway.
Effects of naltrexone on the acquisition of alcohol intake in male and female periadolescent and adult alcohol-preferring (P) rats
International Journal of Adolescent Medicine and Health, 2006
Ethanol-reinforced behaviour in the rat: effects of naltrexone
European Journal of Pharmacology, 1999
It has been repeatedly reported that endogenous opioid pathways play an important role in ethanol drinking behaviour. In line with these findings, a non-selective opioid receptor antagonist, naltrexone, seems to reduce relapse rates in detoxified alcoholics. The aim of Ž. Ž. Ž. the present study was to evaluate the effects of naltrexone on i ethanol self-administration; ii extinction of responding for ethanol; iii reinstatement of ethanol-seeking induced by non-contingent presentations of ethanol-associated stimuli. Male Wistar rats were trained to lever-press for 8% ethanol in an operant procedure where ethanol was introduced in the presence of sucrose. The selectivity of naltrexone's actions was assessed by studying its effects on water-reinforced behaviour in separate control experiments. Acute injections Ž. Ž of naltrexone 1 or 3 mgrkg did not alter ethanol self-administration. Repeated treatment with naltrexone 3 mgrkg, before three. consecutive self-administration sessions progressively reduced ethanol intake. In the extinction procedure, acute administration of 3 Ž. mgrkg naltrexone suppressed responding previously reinforced with ethanol. Similarly, naltrexone 1-3 mgrkg potently and dose-dependently inhibited reinstatement of ethanol-seeking produced by non-contingent deliveries of the liquid dipper filled with 8% Ž. ethanol. In the control experiments, lower doses of naltrexone 1-3 mgrkg did not exert any effect on either reinforced or Ž. Ž. non-reinforced extinction lever-pressing for water. These results indicate that: i subchronic treatment with naltrexone leads to Ž. progressive reduction of ethanol self-administration; ii single doses of naltrexone may increase extinction and attenuate cue-induced reinstatement of ethanol-reinforced behaviour.
A Double-Blind, Placebo-Controlled Study of Naltrexone in the Treatment of Alcohol-Dependence Disorder: Results from a Multicenter Clinical Trial
Alcoholism-clinical and Experimental Research, 2002
Background A 12-week, multicenter, double-blind, randomized, parallel-group clinical trial to compare naltrexone and placebo was carried out to determine the efficacy, safety, and tolerability of naltrexone together with a psychosocial intervention in the treatment of alcoholism.Methods A total of 202 alcohol-dependent patients were assigned to 12 weeks’ treatment with either naltrexone or placebo. The relapse rate was evaluated by means of intention-to-treat analyses. Alcohol consumption, craving, adverse events, and changes in the biochemical markers of heavy drinking and possible toxicity were evaluated in the 192 patients who were considered to be assessable.Results The survival function for patients who were treated with naltrexone was significantly better than that of the patients who were treated with placebo (Kaplan-Meier log rank = 4, df = 1, p < 0.05). In addition, 7.9% of patients who were treated with naltrexone relapsed as compared with 18.8% of those who received placebo [χ2= 5.89, df = 2, p= 0.050]. In comparing naltrexone with placebo-treated patients, the most common adverse events were abdominal pain [8.6% vs. 1%; (χ2= 6.1, df = 1, p < 0.05)] and headache [7.5% vs. 1% (χ2= 5.1, df = 1, p < 0.05)].Conclusions Naltrexone was well-tolerated, as the rate of adverse events was low, and safe, as it did not interfere with the normalization of biochemical markers of heavy drinking or alter liver function markers. Naltrexone seemed to reduce relapse rate to heavy drinking, but we found no differences in other alcohol consumption variables between naltrexone- and placebo-treated groups. Although the naltrexone group showed a tendency to consume fewer drinks per drinking day and had a longer time to first drink, differences were not statistically significant.
Naltrexone Dampens Ethanol-Induced Cardiovascular and Hypothalamic- Pituitary-Adrenal Axis Activation
Neuropsychopharmacology, 2001
physiological responses and their association with alcohol liking. Using a within-subjects design, heavy drinking men (N ϭ 19) were maintained on each of three naltrexone doses (0, 50, and 100 mg, p.o.) over an 8-day inpatient stay. Within each naltrexone dose, subjects had three alcohol challenge sessions (none, moderate, high) in random order. Autonomic, subjective and endocrine measurements were collected regularly prior to and following alcohol administration. High-dose alcohol ingestion increased heart rate, diastolic blood pressure, skin temperature, ACTH, cortisol and liking of drink effects; responses following the moderate alcohol dose were less consistent. Naltrexone significantly dampened alcohol-induced increases in heart rate, diastolic blood pressure, hormone levels and subjective liking of drink effects. This dampening of cardiovascular and hormonal responses may contribute to the therapeutic effectiveness of naltrexone for reducing alcohol liking and decreasing relapse in alcohol-dependent persons.
A Multicentre, Randomized, Double-Blind, Placebo-Controlled Trial of Naltrexone in the Treatment of Alcohol Dependence or Abuse
Alcohol and Alcoholism, 2000
The opioid antagonist, naltrexone, is reported, in single centre studies, to improve the clinical outcome of individuals with alcohol dependence participating in outpatient psychosocial programmes. This is the first multicentre controlled study to evaluate the efficacy and safety of naltrexone as adjunctive treatment for alcohol dependence or abuse. Patients who met criteria for alcohol dependence (n = 169) or alcohol abuse (n = 6) were randomly assigned to receive double-blind oral naltrexone 50 mg daily (n = 90) or placebo (n = 85) for 12 weeks as an adjunct to psychosocial treatment. The primary efficacy variable was time to first episode of heavy drinking; secondary efficacy assessments included time to first drink, alcohol consumption, craving, and changes in the serum biological markers gamma-glutamyl transferase (GGT), and aspartate and alanine aminotransferases. Compliance was assessed by tablet counts and, in the naltrexone-treated group, by measurement of urinary concentrations of 6-β-naltrexol. Forty-nine (58%) patients randomized to placebo and 53 (59%) randomized to naltrexone did not complete the study. In intention-to-treat analyses, there was no difference between groups on measures of drinking. The median reduction from baseline of serum GGT (P < 0.05) and the reductions in alcohol craving (Obsessive and Compulsive Drinking Scale: OCDS) were greater in the naltrexone group (P < 0.05), from approximately halfway through the study. Of 70 patients (35 placebo; 35 naltrexone) who met an a priori definition of compliance (80% tablet consumption, attendance at all follow-up appointments), those allocated to naltrexone reported consuming half the amount of alcohol (P < 0.05), had greater median reduction in serum GGT activity (P < 0.05), and greater reduction in alcohol craving (OCDS total score: P < 0.05; Obsessive subscale score: P < 0.05), compared to patients in the placebo group. Use of naltrexone raised no safety concerns. Naltrexone is effective in treating alcohol dependence/abuse in conjunction with psychosocial therapy, in patients who comply with treatment.
Naltrexone effects on subjective responses to alcohol in the human laboratory: A systematic review and meta-analysis
Addiction Biology, 2019
Naltrexone (NTX) has been widely studied for the treatment of alcohol use disorder with overall support for its efficacy. The mechanisms of action of naltrexone are thought to involve attenuation of the hedonic effects of alcohol and potentiation of its aversive effects. In order to provide a quantitative estimate of the effects of naltrexone on subjective response to alcohol, the aims of this meta-analytic review are to examine the effects of naltrexone across four domains of subjective response. Meta-analyses of naltrexone effects on alcohol craving (k = 16, N = 686), stimulation (k = 15, N = 675), sedation (k = 18, N = 777), and negative mood (k = 9, N = 281) suggested that under laboratory conditions and compared with placebo, naltrexone reduces craving (Hedges g = −0.252; SE = 0.054; 95% CI, −0.375 to −0.130; P < 0.01), reduces stimulation (g = −0.223; SE = 0.067; 95% CI, −0.372 to −0.074; P < 0.01), increases sedation (g = 0.251; SE = 0.064; 95% CI, 0.112-0.389; P < 0.01), and increases negative mood (g = 0.227; SE = 0.047; 95% CI, 0.100-0.354; P < 0.01). Results were robust when drinks per month and alcohol dose were added to the models as covariates. The effects of naltrexone varied by severity of alcohol use with medication effects on craving and stimulation being observed in sample of both heavy drinkers and AUD individuals. These results are consistent with the hypothesized mechanisms of action of NTX, although the effects are of small magnitude. This meta-analysis aggregates across multiple human laboratory studies of NTX's effects on subjective response to alcohol, providing a comprehensive summary of a key mechanism of NTX efficacy, namely, alteration of the subjective experience of alcohol.
Effects of naltrexone on neural and subjective response to alcohol in treatment-seeking alcohol-dependent patients
Alcoholism, clinical and experimental research, 2014
Positively reinforcing properties of alcohol are in part mediated by activation of the ventral striatum (VS). Alcohol-induced release of endogenous opioids is thought to contribute to this response. Preclinical studies show that the opioid antagonist naltrexone (NTX) can block this cascade, but its ability to do so in treatment-seeking alcoholics has not been examined. Our objective was to study the effects of NTX on alcohol-induced VS activation and on amygdala response to affective stimuli in treatment-seeking alcohol-dependent inpatients. Sixty-three treatment-seeking alcoholics were randomized to receive NTX (50 mg) or placebo (PLC) daily. On Day 7, participants underwent an alcohol cue reactivity session, and craving was measured using the Penn Alcohol Craving Scale. On Day 9, participants received a saline infusion followed by an alcohol infusion and also viewed affective stimuli in a magnetic resonance scanner. Irrespective of medication treatment condition, the alcohol infus...
Cited by
Naltrexone and Cue Exposure With Coping and Communication Skills Training for Alcoholics: Treatment Process and 1-Year Outcomes
Alcoholism: Clinical and Experimental Research, 2001
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.
Genetic Moderators of Naltrexone's Effects on Alcohol Cue Reactivity
Alcoholism: Clinical and Experimental Research, 2006
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 m-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-treatmentseeking heavy drinkers.
The Novel μ-Opioid Receptor Antagonist GSK1521498 Decreases both Alcohol Seeking and Drinking: Evidence from a New Preclinical Model of Alcohol Seeking
Neuropsychopharmacology, 2015
Distinct environmental and conditioned stimuli influencing ethanol-associated appetitive and consummatory behaviors may jointly contribute to alcohol addiction. To develop an effective translational animal model that illuminates this interaction, daily seeking responses, maintained by alcohol-associated conditioned stimuli (CSs), need to be dissociated from alcohol drinking behavior. For this, we established a procedure whereby alcohol seeking maintained by alcohol-associated CS is followed by a period during which rats have the opportunity to drink alcohol. This cue-controlled alcohol seeking procedure was used to compare the effects of naltrexone and GSK1521498, a novel selective µ-opioid receptor antagonist, on both voluntary alcohol-intake and alcohol-seeking behaviors. Rederived alcohol-preferring, alcohol-nonpreferring and high alcohol-drinking replicate 1 lines of rats (Indiana University, USA) first received 18 sessions of 24-h home-cage access to 10% alcohol and water under a 2-bottle choice procedure. They were trained subsequently to respond instrumentally for access to 15% alcohol under a second-order schedule of reinforcement, in which a prolonged period of alcohol-seeking behavior was maintained by contingent presentations of an alcohol-associated CS acting as a conditioned reinforcer. This seeking period was terminated by 20 min of free alcohol drinking access that achieved significant blood alcohol concentrations. The influence of pre-treatment with either naltrexone (0.1-1-3 mg/kg) or GSK1521498 (0.1-1-3 mg/kg) prior to instrumental sessions was measured on both seeking and drinking behaviors, as well as on drinking in the 2-bottle choice procedure. Naltrexone and GSK1521498 dose-dependently reduced both cuecontrolled alcohol-seeking and alcohol-intake in the instrumental context as well as alcohol intake in the choice procedure. However, GSK1521498 showed significantly greater effectiveness than naltrexone, supporting its potential use for promoting abstinence and preventing relapse in alcohol addiction.
Alcohol Withdrawal and Conditioning
Alcoholism: Clinical & Experimental Research, 2005
This review contains the proceedings from a symposium held at the RSA conference in 2003 on "Alcohol Withdrawal and Conditioning." The presentations covered a range of interactions between conditioning and alcohol withdrawal, in both animal behavior and the clinic. Dr. D.N. Stephens first described his studies exploring the consequences of alcohol dependence and repeated experience of withdrawal on the conditioning process. His data suggested that repeated withdrawal from moderate alcohol intake impairs amygdala-dependent mechanisms for learning about aversive events. Dr. H. Becker then detailed studies examining the consequences of repeated ethanol withdrawal experience on subsequent ethanol drinking behavior in mice, and conditions in which motivational properties of odor cues that are associated with different phases of ethanol withdrawal influence such relapse behavior. The data suggested that cues associated with acute withdrawal or "recovery" from withdrawal may serve as modulating factors in influencing subsequent ethanol drinking behavior, and that the timing of the cues determines their consequences. Dr. F. Weiss described recent findings from animal models of relapse that suggested the efficacy of alcohol-associated contextual stimuli in eliciting alcohol-seeking behavior resembles the endurance of conditioned cue reactivity and cue-induced cocaine craving in humans. The interactive effects of stress and ethanol-related environmental stimuli were found to be dependent on concurrent activation of endogenous opioid and corticotropin-releasing factor systems. Conditioning factors (i.e., exposure to drug-associated stimuli) and stress could therefore interact to augment vulnerability to relapse. Dr. C. Drummond then addressed the clinical aspects of conditioning during alcohol withdrawal and described studies showing exposure of alcoholics to alcohol-related cues elicited greater subjective and physiological responses than exposure to neutral cues. The former responsivity showed a relationship with a measure of motivation to drink alcohol. Finally, Dr. C. Cunningham provided a summary of the concepts involved in the presentations and discussed the conditioning processes that affect behavior during and after alcohol withdrawal.
Genetically selected Marchigian Sardinian alcohol-preferring (msP) rats: an animal model to study the neurobiology of alcoholism
Addiction Biology, 2006
The present article provides an up-to-date review that summarize almost 18 years of research in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats. The results of this work demonstrate that msP rats have natural preference for ethanol characterized by a spontaneous binge-type of drinking leading to pharmacologically significant blood ethanol levels. This rat line is highly vulnerable to relapse and presentation of stimuli predictive of alcohol availability or footshock stress can reinstate extinguished drug-seeking up to 8 months from the last alcohol experience. The msP rat is highly sensitive to stress, shows an anxious phenotype and has depressive-like symptoms that recover following ethanol drinking. Interestingly, these animals have an up-regulated corticotrophin releasing factor (CRF) receptor 1 system. From clinical studies we learned that alcoholic patients often drink ethanol in the attempt to self-medicate from negative affective states and to search anxiety relief. We propose that msP rats represent an animal model that largely mimics that human alcoholic population that due to low ability to engage in stress-coping strategies drink ethanol as a tension relief strategy and for self-medication purposes.
Chronic Treatment with Novel Brain-Penetrating Selective NOP Receptor Agonist MT-7716 Reduces Alcohol Drinking and Seeking in the Rat
Neuropsychopharmacology, 2014
Since its discovery, the nociceptin/orphanin FQ (N/OFQ)-NOP receptor system has been extensively investigated as a promising target to treat alcoholism. Encouraging results obtained with the endogenous ligand N/OFQ stimulated research towards the development of novel brain-penetrating NOP receptor agonists with a pharmacological and toxicological profile compatible with clinical development. Here we describe the biochemical and alcohol-related behavioral effects of the novel NOP receptor agonist MT-7716. MT-7716 has high affinity for human NOP receptors expressed in HEK293 cells with a Ki value of 0.21 nM. MT-7716 concentration-dependently stimulated GTPγ(35)S binding with an EC50 value of 0.30 nM and its efficacy was similar to N/OFQ, suggesting that MT7716 is a full agonist at NOP receptors. In the two bottle choice test MT-7716 (0, 0.3, 1, and 3 mg/kg, bid) given orally for 14 days dose-dependently decreased voluntary alcohol intake in Marchigian Sardinian rats. The effect became gradually stronger following repeated administration, and was still significant 1 week after discontinuation of the drug. Oral naltrexone (30 mg/kg, bid) for 14 days also reduced ethanol intake; however, the effect decreased over the treatment period and rapidly disappeared when drug treatment was discontinued. MT-7716 is also effective for preventing reinstatement caused by both ethanol-associated environmental stimuli and stress. Finally, to investigate the effect of MT-7716 on alcohol withdrawal symptoms, Wistar rats were withdrawn from a 7-day alcohol liquid diet. MT-7716 significantly attenuated somatic alcohol withdrawal symptoms. Together these findings indicate that MT-7716 is a promising candidate for alcoholism treatment remaining effective with chronic administration.
Leptin levels are reduced by intravenous ghrelin administration and correlated with cue-induced alcohol craving
Translational Psychiatry, 2015
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 lept...
Loading Preview
Sorry, preview is currently unavailable. You can download the paper by clicking the button above.