Andrea C. King

Effect of naltrexone on subjective alcohol response in subjects at high and low risk for future alcohol dependence

Abstract We investigated specific subjective effects of naltrexone pretreatment or placebo during various intervals on the breath alcohol level (BAL) curve in nonalcoholic volunteers. Fifteen high-risk (social drinkers with an alcoholic father) and 14 low-risk (no alcoholic relatives in at least two generations) subjects were tested in a double-blind, placebo-controlled study of the effects of 50 mg oral naltrexone on response to a moderate dose of alcohol. Dependent measures included subjective stimulation and sedation subscales from the Biphasic Alcohol Effects Scale (BAES) and mood subscales from the Profile of Mood States (POMS). At rising BALs, high-risk subjects showed a naltrexone-related attenuation of BAES stimulation. This effect was not evident in low-risk subjects, who directionally showed the opposite effect, although nonsignificant. For both groups, there were no significant naltrexone-related effects for BAES sedation; however, naltrexone did affect several POMS scales on alcohol response, such as decreased vigor, and increased fatigue, tension, and confusion. Confusion was significantly elevated for the high-risk group during rising BALs of the naltrexone session. The results suggest a differential response to naltrexone, based on paternal history of alcoholism and level of stimulation experienced during alcohol drinking.

Rewarding, stimulant, and sedative alcohol responses and relationship to future binge drinking

CONTEXT Excessive consumption of alcohol is a major problem in the United States and abroad. Despite many years of study, it is unclear why some individuals drink alcohol excessively while others do not. It has been postulated that either lower or greater acute responses to alcohol, or both, depending on the limb of the breath alcohol concentration curve, contribute to propensity for alcohol misuse. OBJECTIVE To prospectively assess the relationship of acute alcohol responses to future binge drinking. DESIGN Within-subject, double-blind, placebo-controlled, multidose laboratory alcohol challenge study with intensive follow-up. Each participant completed 3 randomized sessions examining responses to a high (0.8 g/kg) and low (0.4 g/kg) alcohol dose and placebo, followed by quarterly assessments for 2 years examining drinking behaviors and alcohol diagnoses. SETTING Participants recruited from the community. PARTICIPANTS High-risk heavy social drinkers aged 21 to 35 years who habitually engage in weekly binge drinking (n = 104) and light drinker controls (n = 86). INTERVENTION We conducted 570 laboratory sessions with a subsequent 99.1% follow-up (1506 of 1520). MAIN OUTCOME MEASURES Biphasic Alcohol Effects Scale, Drug Effects Questionnaire, cortisol response, Timeline Follow-Back, Drinker Inventory of Consequences-Recent, and DSM-IV alcohol abuse and dependence. RESULTS Alcohol produced greater stimulant and rewarding (liking and wanting) responses and lower sedative and cortisol responses in heavy vs light drinkers. Among the heavy drinkers, greater positive effects and lower sedative effects after alcohol consumption predicted increased binge drinking frequency during follow-up. In turn, greater frequency of binge drinking during follow-up was associated with greater likelihood of meeting diagnostic criteria for alcohol abuse and dependence. CONCLUSIONS The widely held low level response theory and differentiator model should be revised: in high-risk drinkers, stimulant and rewarding alcohol responses even at peak breath alcohol concentrations are important predictors of future alcohol problems. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00961792.

Hypothalamic-pituitary-adrenocortical (HPA) axis response and biotransformation of oral naltrexone: preliminary examination of relationship to family history of alcoholism.

We examined HPA axis response to 50 mg oral naltrexone compared with placebo in 17 healthy male and female nonalcoholic subjects, approximately half of whom had a positive family history of alcoholism (FH+) and half of whom who did not (FH−). Mood response and naltrexone biotransformation were also examined at various intervals. Subjects participated in two morning test sessions (50 mg naltrexone or identical placebo pill) after an overnight stay in the Rockefeller University GCRC. For the total sample, ACTH and cortisol significantly increased after naltrexone compared with placebo (p < .05). Secondary analyses showed the FH+ subgroup had a different pattern of response over time compared with the FH− subgroup, with heightened ACTH and cortisol, and decreased vigor ratings, during naltrexone (p < .05). The results demonstrate that orally administered naltrexone acutely disinhibits the HPA axis, and that individuals with an assumed greater biological vulnerability to addiction, by virtue of familial alcoholism, had altered regulation of the HPA axis in part under the control of the endogenous opioid system. 166 words.

Efficacy of naltrexone in smoking cessation : A preliminary study and an examination of sex differences

This double-blinded, placebo-controlled trial evaluated the efficacy of naltrexone as an adjunct to standard smoking cessation treatment. Participants (N = 110) were adult male and female nicotine-dependent smokers who expressed interest in quitting smoking. All subjects received six sessions of behavioral counseling (1 hr/session for 6 weeks), and 1 month of the nicotine patch (21 mg for the first 2 weeks, 14 mg the third week, 7 mg the fourth week). Subjects were randomly assigned to the naltrexone or placebo group. The naltrexone group started at 25 mg daily for 3 days prior to the quit date, and increased to 50 mg/day on the quit date and following 8 weeks. At the end of medication treatment, the naltrexone group had better quit rates versus the placebo group (48% quit on naltrexone vs. 41% on placebo), but this difference was not statistically significant. However, men and women differed on several measures: in the placebo group, women had significantly lower quit rates than men (39% vs. 67%, p<.05), but in the naltrexone group, women had quit rates comparable with those of men (58% vs. 62%, p = ns). Further examination revealed that naltrexone significantly reduced mens and womens cessation-related weight gain and selectively reduced womens urge to smoke to relieve negative affect and withdrawal. The results suggest continued examination of naltrexone as an adjunct in smoking cessation, particularly in female smokers, who have historically shown worse outcomes with traditional treatment methods.

Naltrexone Alteration of Acute Smoking Response in Nicotine-Dependent Subjects

There are mixed results on the effects of opioid antagonists on acute nicotine response in humans. The present study examined the effects of a single dose of 50 mg oral naltrexone relative to placebo on smoking response in 22 chronic smokers during short-term nicotine abstinence, after acute smoking and subsequent smoking deprivation, and on smoking behavior in a choice paradigm. The results showed that naltrexone significantly reduced immediate postcigarette ratings of smoking craving and desire to smoke and increased light-headedness, dizziness, and head rush (ps < 0.05). Reductions in craving and smoking desire persisted during a subsequent 1 h nonsmoking interval. Naltrexone also was found to significantly reduce the total number of cigarettes smoked in the choice interval, which was supported by objective measures of both reduced CO and plasma nicotine levels (ps < 0.01). Exploratory analyses on potential individual difference factors revealed that smokers with the highest levels of craving during abstinence showed the most pronounced naltrexone attenuation of smoking response. The results support the continued exploration of naltrexone as an adjunct to smoking cessation, especially in identified smoker subgroups most sensitive to the effects of opioid antagonism.

The drug effects questionnaire: psychometric support across three drug types.

RationaleThe Drug Effects Questionnaire (DEQ) is widely used in studies of acute subjective response (SR) to a variety of substances, but the format of the DEQ varies widely across studies, and details of its psychometric properties are lacking. Thus, the field would benefit from demonstrating the reliability and validity of the DEQ for use across multiple substances.ObjectiveThe current study evaluated the psychometric properties of several variations of DEQ items, which assessed the extent to which participants (1) feel any substance effect(s), (2) feel high, (3) like the effects, (4) dislike the effects, and (5) want more of the substance using 100-mm visual analog scales.MethodsDEQ data from three placebo-controlled studies were analyzed to examine SR to amphetamine, nicotine, and alcohol. We evaluated the internal structure of the DEQ for use with each substance as well as relationships between scale items, measures of similar constructs, and substance-related behaviors.ResultsResults provided preliminary psychometric support for items assessing each DEQ construct (feel, high, dislike, like, and more).ConclusionsBased on the study results, we identify several common limitations of extant variants of the DEQ and recommend an improved version of the measure. The simplicity and brevity of the DEQ combined with its promising psychometric properties support its use in future SR research across a variety of substances.

Naltrexone attenuates acute cigarette smoking behavior

This within-subjects, placebo-controlled laboratory study was designed to examine the effects of naltrexone on cigarette response in 44 chronic smokers (23 male, 21 female). Each participant received either 50-mg oral naltrexone or identical placebo during the morning of the session after maintaining overnight abstinence. Subsequently, the participant was administered a smoking cue (holding lit cigarette) to examine craving and associated features of smoking, and instructed to smoke a cigarette 1 h later. This was followed by a smoking interval in which participants could choose to smoke up to four more cigarettes over a 2-h period. Subjective measures (withdrawal, craving, affect, and side effects) and smoking behavior were assessed throughout the session. Naltrexone significantly reduced the total number of choice cigarettes smoked and expired carbon monoxide levels (Ps<.05). Naltrexone significantly increased total side effects, especially for sedation (P<.01). Further, naltrexone significantly increased overall negative affect, and decreased positive affect 1 h after smoking the first cigarette (Ps<.05). However, naltrexone did not affect acute withdrawal or smoking urges. Despite mixed findings, women reported more overall naltrexone-induced withdrawal (P<.05) and side effects (P<.08) compared to men. Although the exact mechanism is unknown, the findings support an opioid antagonist attenuation of smoking behavior.

Enhancing the self-report of alcohol consumption in the community: two questionnaire formats.

Two questionnaire formats for assessing alcohol consumption in a community sample were compared. Subjects completed the Semi-Quantitative Food Frequency Questionnaire and a questionnaire specifically targeting alcohol use. Across all alcoholic beverages, subjects reported lower consumption on the alcohol questionnaire than on the food frequency questionnaire. The results suggest that food frequency questionnaires may provide a better means for enhancing self-report of alcohol use than questionnaires that target solely alcohol intake.

Effects of alcohol on brain responses to social signals of threat in humans

Alcohol is a known exogenous modulator of negative affect (anxiety, tension) in both animals and humans. It has been proposed that the anxiolytic effects of alcohol are mediated via the amygdala, an area critical to fear perception and responding. However, little is known about the acute effects of alcohol on amygdala reactivity to threatening information in humans. We used functional magnetic resonance imaging and a validated task to probe amygdala responses to social signals of threat in 12 healthy, social drinkers after a double-blind crossover administration of alcohol or placebo. We found that alcohol significantly reduced amygdala reactivity to threat signals. The current findings fit well with the notion that alcohol may attenuate threat-based responding and provide a potential brain-based mechanism for the link between alcohol and anxiety and/or social threat perception.

Effects of naltrexone on smoking cessation outcomes and weight gain in nicotine-dependent men and women.

Abstract This study examined whether the opioid receptor antagonist naltrexone is efficacious in smoking cessation and whether sex moderates the response. We assessed smoking quit rates and weight gain in a double-blind randomized trial comparing oral naltrexone (n = 162) with placebo (n = 154) in nicotine-dependent participants who wanted to quit smoking. The medication was gradually titrated up to 50 mg during the week before the quit date and then maintained at this dose for 12 weeks. For the first 4 weeks after the quit date, all participants received a nicotine patch to mitigate tobacco withdrawal and attended weekly individual cognitive-behavioral smoking cessation counseling sessions. After this time, participants continued with naltrexone or placebo through 12 weeks. Follow-up assessments were conducted at 26 and 52 weeks. During treatment, naltrexone (vs placebo) increased quit rates, attenuated smoking urge, and reduced weight gain. At follow-up, after medication discontinuation, the effect of naltrexone on improving quit rates was no longer evident. Men and women experienced different benefits from naltrexone; men showed greater reductions in smoking, whereas women showed greater reductions in weight gain. In sum, naltrexone showed acute efficacy in treating nicotine dependence, but after the medication was discontinued, the effect on quit rate was not maintained. Further study of naltrexone in smoking cessation treatment and reduction of cessation-related weight gain, as well as preclinical investigation of mechanisms underlying sex differences, is warranted.