Naltrexone in alcohol dependence.
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Biomedical subjects
Publications and source records attributed to J R Volpicelli.
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In 237 male inpatients with alcohol dependence, clinical, demographic and biochemical data were analyzed in relation to alcohol tolerance. All subjects had a history of marked tolerance. At the time of assessment, 46% of subjects continued to meet the criteria for marked tolerance and 54% of the subjects reported a loss or decreased tolerance. Subjects with decreased tolerance were older than those with high tolerance and had a longer duration of illness. The age of onset was similar in both groups. Patients with decreased tolerance had more mental confusion and psychotic symptoms, and were less likely to be currently married.
OBJECTIVE: Subjective effects of alcohol in alcoholics treated with naltrexone or placebo were compared. METHOD: In a previously reported double-blind clinical trial of 50 mg/day of naltrexone or placebo for treatment of alcoholism, 36 of 70 detoxified male veterans deviated from abstinence. Of these 36, 29 subsequently reported on the subjective effects of drinking during the trial. RESULTS: A larger proportion of naltrexone-treated subjects (seven of 12) than placebo-treated subjects (two of 17) reported that the "high" produced by alcohol during the study was significantly less than usual. The naltrexone-treated subjects also drank less alcohol than the placebo-treated subjects during the first drinking episode. There was no difference between groups in reported intoxication, craving, memory, or loss of temper. CONCLUSIONS: The lower alcohol consumption by the naltrexone-treated subjects may have resulted from naltrexone's blockage of the pleasure produced by alcohol.
The pooled results of 99 subjects from our Veterans Affairs population show that naltrexone-treated subjects had a greater reduction in alcohol craving, number of drinking days, and alcoholic relapse rates when compared with placebo-treated subjects. Based on our findings and results from other double-blind trials of naltrexone, we conclude that naltrexone is a safe and useful adjunct in the rehabilitation of alcohol-dependent patients. Increased baseline levels of psychological distress and craving as well as higher levels of somatic distress, anxiety, phobic anxiety, and obsessive-compulsive symptoms predicted an increased number of drinking days during the study. Significant interactions between naltrexone treatment, initial craving, and somatic distress suggest that naltrexone may be useful for subjects who present with high levels of craving and somatic symptoms.
During the past 25 years, numerous animal studies have demonstrated a relationship between alcohol consumption and opiates. Converging lines of evidence suggest that (1) alcohol consumption enhances opioid receptor activity and (2) conditions associated with relative deficiencies in opioid receptor activity stimulate increases in alcohol preference. This evidence leads to the hypothesis that alcohol drinking is reinforced, in part, by enhanced opioid receptor activity; thus, these effects should be blocked by opiate antagonists. In fact, the animal data are consistent with this prediction. Opiate antagonists reduce excessive alcohol intake without reducing the ingestion of other biologically important reinforcers.
Seventy male alcohol-dependent patients participated in a 12-week, double-blind, placebo-controlled trial of naltrexone hydrochloride (50 mg/d) as an adjunct to treatment following alcohol detoxification. Subjects taking naltrexone reported significantly less alcohol craving and days in which any alcohol was consumed. During the 12-week study, only 23% of the naltrexone-treated subjects met the criteria for a relapse, whereas 54.3% of the placebo-treated subjects relapsed. The primary effect of naltrexone was seen in patients who drank any alcohol while attending outpatient treatment. Nineteen (95%) of the 20 placebo-treated patients relapsed after they sampled alcohol, while only eight (50%) of 16 naltrexone-treated patients exposed to alcohol met relapse criteria. Naltrexone was not associated with mood changes or other psychiatric symptoms. Significant side effects (nausea) occurred in two naltrexone-treated subjects, and one naltrexone-treated subject complained of increased pain from arthritis. These results suggest that naltrexone may be a safe and effective adjunct to treatment in alcohol-dependent subjects, particularly in preventing alcohol relapse.
Rats were exposed to repeated sessions of inescapable footshock, and behavioral depression was subsequently assessed by measuring escape performance during exposure to escapable shock in a different testing environment. Free-running circadian activity rhythms were assessed using running wheels for approximately three weeks before and after administration of inescapable shock. Several animals showed lengthening of free-running period and decreases in activity level following shock. Similar effects were also seen in rats that were removed from their running wheels, placed within the shock apparatus, and not given shock, but not in nonhandled control animals. Furthermore, period lengthening in shocked and handled rats was positively correlated with escape performance, suggesting that circadian rhythm alterations occurred in those animals that were best able to cope with shock or handling-related stressors. In contrast, individual differences in circadian period and activity level during baseline conditions were not predictive of either escape performance or circadian rhythm alterations. These results suggest that successful behavioral adaptation to stress may be associated with alterations of circadian rhythmicity.
Two studies explore the relationship between rhythmicity and behavioral depression. Behavioral depression was induced using inescapable footshock, and assessed by measuring subsequent responses to escapable shock, in rats housed under different light-dark conditions. Experiment 1 compared escape performance in free-running and entrained animals following inescapable shock. Free-running and entrained animals did not exhibit differential vulnerability to the effects of inescapable shock. In addition, there were no systematic effects on phase following shock. However, several free-running animals showed increased circadian period following shock, and lengthening of period was significantly correlated with escape performance. Individual differences in baseline period or phase were not predictive of escape performance. In Experiment 2, "aftereffects" of entrainment to long or short light-dark cycles were utilized to create groups of animals with long or short free-running periods. After the administration of inescapable shock, escape performance was tested. There were no significant differences among experimental groups in escape performance. These results suggest that plasticity of circadian period, but not baseline period per se, may be associated with the ability to adapt to environmental challenges.
Rats given a choice between a 5% alcohol solution and water will dramatically increase alcohol preference on the days following experience with inescapable electric footshocks, compared with unshocked animals. Although, total alcohol preference did not differ during shock days, an interaction occurred between shock stress and alcohol preference. Rats that initially preferred alcohol decreased alcohol preference during shock days, whereas, rats that initially avoided alcohol increased alcohol preference during shock days. Therefore, the stress of inescapable electric footshock has bidirectional effects on alcohol preference. These bidirectional effects depend on the temporal dynamics of alcohol consumption in relation to the shock experience and the initial alcohol preference.
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We compared the effectiveness, safety, and costs of outpatient (n = 87) and inpatient (n = 77) detoxification from alcohol in a randomized, prospective trial involving 164 male veterans of low socioeconomic status. The outpatients were evaluated medically and psychiatrically and then were prescribed decreasing doses of oxazepam on the basis of daily clinic visits. The inpatient program combined comprehensive psychiatric and medical evaluation, detoxification with oxazepam, and the initiation of rehabilitation treatment. The mean duration of treatment was significantly shorter for outpatients (6.5 days) than for inpatients (9.2 days). On the other hand, significantly more inpatients (95 percent) than outpatient (72 percent) completed detoxification. There were no serious medical complications in either group. Outcome evaluations completed at one and six months for 93 and 85 percent of the patients, respectively, showed substantial improvement in both groups at both follow-up periods. At one month there were fewer alcohol-related problems among inpatients and fewer medical problems among outpatients. However, no group differences were found at the six-month follow-up, nor were differences found in the subsequent use of other alcoholism-treatment services. Costs were substantially greater for inpatients ($3,319 to $3,665 per patient) than for outpatients ($175 to $388). We conclude that outpatient medical detoxification is an effective, safe, and low-cost treatment for patients with mid-to-moderate symptoms of alcohol withdrawal.
In two experiments rats given unpredictable feeding schedules gained less weight over a 24 or 30 day training period than rats which consumed an equivalent amount of food on a predictable schedule. These results suggest that irregular feeding schedules disrupt food utilization.
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Attention has recently focused on the possibility of an interaction between ethanol and the endorphin system. In this study the opiate blocker naltrexone prevents the expected post-shock increase of ethanol consumption. This provides further evidence that endogenous opiates are involved in the voluntary drinking of ethanol in rats.
Rats experienced inescapable, escapable, or no electric shock 1 day after being implanted with a Walker 256 tumor preparation. Only 27 percent of the rats receiving inescapable shock rejected the tumor, whereas 63 percent of the rats receiving escapable shock and 54 percent of the rats receiving no shock rejected the tumor. These results imply that lack of control over stressors reduces tumor rejection and decreases survival.
A pilot study (N = 80) was conducted to determine if (1) prospective substance-dependent patients randomly selected to be reminded (TC) of their scheduled intake evaluation the day before their first appointment would have a higher show rate than those not contacted (NC); and (2) if TC subjects administered a satisfaction questionnaire 1-3 days after intake would exhibit higher treatment retention rates at one week and one month posttreatment entry than NC subjects not exposed to the questionnaire. The findings suggest that reminding prospective patients of their initial scheduled appointments and following up with phone calls to those who fail to show can improve the rate at which patients will initiate treatment, provided initial appointments are scheduled in a timely manner (7 days or less). Similarly, the combination of the reminder call and the satisfaction questionnaire were associated with higher treatment retention rates for those whose initial appointments were scheduled in a timely manner.
The effect of control of food reinforcement or shock termination on alcohol drinking was examined in two experiments. In the first experiment, rats unable to control the delivery of food pellets preferred alcohol more than rats which had control over food. Similarly, in the second experiment, rats unable to control electric footshock termination preferred alcohol more than rats which could escape shock. These results showed that the psychological dimension of control over environmental events influences alcohol preference in rats.