Bupropion and naltrexone for smoking cessation: A double-blind randomized placebo-controlled clinical trial.

Combination of non-nicotine pharmacotherapies has been underexamined for cigarette smoking cessation. A randomized, double-blind, parallel-group double-dummy study evaluated two medications, bupropion (BUP) and naltrexone (NTX), in treatment-seeking cigarette smokers (N = 121) over a 7-week treatment intervention with 6-month follow-up. Smokers were randomized to either BUP (300 mg/day) + placebo (PBO) or BUP (300 mg/day) + NTX (50 mg/day). The primary outcome was biochemically verified (saliva cotinine, carbon monoxide) 7-day, point-prevalence abstinence. BUP + NTX was associated with significantly higher point-prevalence abstinence rates after 7-weeks of treatment (BUP + NTX, 54.1%; BUP + PBO, 33.3%), P = 0.0210, but not at 6-month follow-up (BUP + NTX, 27.9%; BUP + PBO, 15.0%), P = 0.09. Continuous abstinence rates did not differ, P = 0.0740 (BUP + NTX, 26.2%; BUP + PBO, 13.3%). Those receiving BUP + NTX reported reduced nicotine withdrawal, P = 0.0364. The BUP + NTX combination was associated with elevated rates of some side effects, but with no significant difference in retention between the groups.

Evaluation of heterogeneity in pharmacotherapy trials for drug dependence: a Bayesian approach.

AIMS: Difficulty identifying effective pharmacotherapies for cocaine dependence has led to suggestions that subgroup differences may account for some of the heterogeneity in treatment response. Well-attested methodological difficulties associated with these analyses recommend the use of Bayesian statistical reasoning for evaluation of salient interaction effects. METHODS: A secondary data analysis of a previously published, double-blind, randomized controlled trial examines the interaction of decision-making, as measured by the Iowa Gambling Task, and citalopram in increasing longest sustained abstinence from cocaine use. RESULTS: Bayesian analysis indicated that there was a 99% chance that improved decision-making enhances response to citalopram. Given the strong positive nature of this finding, a formal, quantitative Bayesian approach to evaluate the result from the perspective of a skeptic was applied. CONCLUSIONS: Bayesian statistical reasoning provides a formal means of weighing evidence for the presence of an interaction in scenarios where conventional, Frequentist analyses may be less informative. [Supplementary materials are available for this article. Go to the publisher's online edition of The American Journal of Drug and Alcohol Abuse for the following free supplemental resource: Appendix 1].

Psychiatric aspects of impulsivity.

OBJECTIVE: The authors discuss the relationship of impulsivity to psychiatric disorders and present selected hypotheses regarding the reasons for these relationships. METHOD: Previous research has shown significantly higher levels of impulsivity among patients with conduct disorder, personality disorders, substance use disorders, and bipolar disorder, compared to other psychiatric patients or healthy comparison subjects. A literature review of the theoretical bases of the relationship between these disorders and impulsivity is presented. Measurements of impulsivity and treatment options are discussed in relation to the physiology of impulsivity and the disorders in which it is a prominent feature. RESULTS: Impulsivity, as defined on the basis of a biopsychosocial approach, is a key feature of several psychiatric disorders. Behavioral and pharmacological interventions that are effective for treating impulsivity should be incorporated into treatment plans for these disorders. CONCLUSIONS: The high comorbidity of impulsivity and selected psychiatric disorders, including personality disorders, substance use disorders, and bipolar disorder, is in a large part related to the association between impulsivity and the biological substrates of these disorders. Before treatment studies on impulsivity can move forward, measures of impulsivity that capture the core aspects of this behavior need to be refined and tested on the basis of an ideologically neutral model of impulsivity.

Motivational interviewing with cocaine-dependent patients: a pilot study.

A brief motivational interviewing (MI) intervention was evaluated within the context of an outpatient, cocaine-detoxification program. MI was hypothesized to assist patients in completing the detoxification program and to improve outcomes during subsequent treatment. Participants (N = 105) were randomly assigned to MI or to detox-only conditions. Results indicated that although participants completed the detoxification program at equal rates, completers who received MI increased use of behavioral coping strategies and had fewer cocaine-positive urine samples on beginning the primary treatment. MI patients with lower initial motivation were more likely to complete detoxification.

Fluoxetine treatment of cocaine-dependent patients with major depressive disorder.

Sixty-eight male and female individuals with both DSM-IV diagnoses of cocaine dependence and major depressive disorder were randomly assigned to one of two medication conditions (placebo vs. 40 mg per day) as part of a double-blind, placebo-controlled clinical efficacy trial of fluoxetine for the treatment of this dual diagnosis. During the 12-week outpatient treatment phase all participants also received individual cognitive-behavioral psychotherapy targeting both cocaine use and depression. Depressive symptoms remitted as a function of time in treatment, with no significant medication effects found. Fewer cocaine positive urines were found during the first 6 weeks of treatment in the placebo group compared with the 40-mg group. Cocaine use and depressive symptoms during treatment were significantly correlated. The findings fail to support the role of fluoxetine for treatment of cocaine use and depression in dually-diagnosed patients.

Naltrexone and relapse prevention treatment for cocaine-dependent patients.

A double-blind, placebo-controlled clinical trial examining the joint action of naltrexone (NTX) in combination with relapse prevention (RP) therapy for the treatment of cocaine dependence was conducted. Eighty-five participants who achieved initial abstinence during the intake evaluation and detoxification phase of the study were randomized into 1 of 4 combined NTX (0 vs. 50 mg) by therapy (RP vs. Drug Counseling) experimental conditions for the 12-week outpatient treatment phase of the study. A random effects regression model to test for group differences on percentage of cocaine-positive urines indicated a significant time by medication by therapy interaction, suggesting less cocaine use over time among subjects receiving RP-50 mg than those in the other conditions. No differences were found for retention or time until first cocaine-positive urine. Naltrexone was well tolerated by participants, with acceptable rates of medication compliance observed. Treatment integrity measures confirmed successful manipulation of the psychotherapy. These results are consistent with the notion that substance use in dependent patients can be reduced with a combination of coping skills training and pharmacologic treatments.

The impact of impulsivity on cocaine use and retention in treatment.

To determine whether impulsivity was related to severity of drug use and treatment outcome, 50 cocaine dependent subjects underwent baseline measures of severity of current cocaine use and the Barratt Impulsiveness Scale (BIS-11). The hypothesis of the study was that there would be a significant correlation between impulsivity and cocaine use severity. As predicted, there was a significant correlation between BIS-11 total scores and self-reported average daily cocaine use as well as cocaine withdrawal symptoms. A subset of 35 patients underwent a 12-week double-blind placebo controlled trial of buspirone and group therapy. Subjects with high baseline impulsivity remained in the study a significantly shorter period than did subjects with lower baseline impulsivity. This study shows that impulsivity is a significant predictor of cocaine use and treatment retention, and suggests the need for targeting impulsivity in cocaine dependence treatment.

Cocaine dependence with and without comorbid depression: a comparison of patient characteristics.

This study compared depressed cocaine dependent patients (CD, N=50) with patients who were cocaine dependent only (CO, N=101) on pre-treatment psychiatric symptomatology, substance use, and psychosocial functioning. Results indicated that the CD group had more overall distress and poorer psychiatric functioning than the CO group. CD individuals scored higher on all subscales of the SCL-90-R, had a higher prevalence of antisocial personality disorder, reported higher craving for cocaine, lower self-efficacy to refrain from drug use, and lower perceived social support. These findings support the need for more intensive treatment approaches for dually-diagnosed patients.

Risperidone for the treatment of cocaine dependence: randomized, double-blind trial.

A partial blockade of the multiple actions of cocaine is one strategy by which cocaine dependence may be treated. Risperidone, a 5-hydroxytryptamine and dopamine D2 antagonist, is an atypical antipsychotic and was a candidate medication for the treatment of cocaine dependence. One hundred ninety-three cocaine-dependent subjects were enrolled in a 12-week, randomized, double-blind, placebo-controlled trial. Subjects initially received either placebo or 4 or 8 mg of risperidone, with a subsequent change to active doses of 2 mg and 4 mg. Subjects attended the clinic twice each week, provided urine samples, obtained medication, and underwent one behavioral therapy session per week. The study was terminated at the interim analysis. Retention was worse for the 4- and 8-mg active medication groups. Side effects were primarily associated with the 8-mg dose, although neither 2 mg nor 4 mg was well accepted by subjects. There was no reduction in cocaine use associated with risperidone. The results suggest that although antagonists might be a useful treatment approach, such as in the treatment of opiate dependence, risperidone is unlikely to find broad acceptance with the treatment-seeking population.

Laboratory measures of methylphenidate effects in cocaine-dependent patients receiving treatment.

Two experiments examined the effects of methylphenidate in male and female patients enrolled in an outpatient treatment program for primary cocaine dependence. The first study was a component of a double-blind efficacy trial wherein 57 patients were first tested in a human laboratory for their initial responsiveness to medication. Patients were randomly assigned to receive either placebo or methylphenidate treatment and received their first dose in the human laboratory environment before continuing in outpatient treatment. Methylphenidate was given as a 20-mg sustained-release dose (twice daily) plus an additional 5-mg immediate-release dose combined with the morning dose. Methylphenidate increased heart rate and subjective ratings; however, the subjective effects were primarily of a "dysphoric" nature, and significant effects were limited to increases in anxiety, depression, and anger on the Profile of Mood States; shaky/jittery ratings on a visual analog scale; and dysphoria on the lysergic acid diethylamide (LSD) scale of the Addiction Research Center Inventory. Methylphenidate did not increase cocaine craving nor ratings suggesting abuse potential (i.e., Morphine-Benzedrine Group or drug-liking scores, etc.). None of the drug effects observed in the human laboratory was of clinical concern, and no subject was precluded from continuing in the outpatient study. After outpatient treatment completion, 12 patients were brought back into a second double-blind human laboratory study in which three doses (15, 30, and 60 mg) of immediate-release methylphenidate were administered in an ascending series preceded and followed by placebo. Methylphenidate produced dose-related increases in heart rate, subjective ratings of shaky/jittery, and LSD/dysphoria without significantly altering cocaine craving or stimulant euphoria ratings. These results suggest that stimulant substitution-type approaches to the treatment of cocaine dependence are not necessarily contraindicated because of cardiovascular toxicity or medication abuse potential. However, they also suggest that the subjective effects of methylphenidate may not be positive enough for an adequate replacement approach.

Effects of long-term treatment with proton pump inhibitors in gastro-oesophageal reflux disease on the histological findings in the lower oesophagus.

BACKGROUND: The application of hyperplasia of the basal cell layer and elongation of the papillae in the squamous epithelium of the distal oesophagus, as histological criteria for the diagnosis of gastro-oesophageal reflux disease (GORD), continues to be controversial. An unanswered question is whether these changes may regress under long-term treatment with proton pump inhibitors (PPI). This fact prompted us to investigate the effect of PPI treatment on the histological changes observed in the lower oesophagus. METHODS: 295 patients with endoscopically confirmed erosive GORD were investigated by endoscopy/biopsy prior to and during the course of a 12-month PPI treatment regimen (8 weeks acute treatment with 30 mg lansoprazole/day followed by long-term treatment with 15 or 30 mg lansoprazole or 20 mg omeprazole/day). The parameters studied were the frequency of ulcers and erosions and the hyperplasia of the basal cell layer and elongation of the papillae prior to treatment and on day 56 (D56), after 6 months (M6) and after 12 months (M12) of treatment. RESULTS: In the various treatment groups, the results showed no statistically significant differences. Ulcers and erosions (prior to treatment 21% and 31%, respectively) were detected statistically significantly less frequently under PPI treatment (ulcers, D56: 1%, M6 and M12, 0%; erosions, D56: 2%, M6: 4%, M12, 3%). While high-grade hyperplasia of the basal cell layer and elongation of the papillae was found in 51% of the cases prior to treatment, the corresponding figures were only 3% (D56, M6) and 2% (M12). In contrast, the percentage of cases with normal oesophageal epithelium increased from 8% before treatment to 55% (D56), 66% (M6) and 63% (M12). CONCLUSIONS: Our study shows not only that erosions and ulcers heal under PPI treatment, but also that hyperplasia of the basal cell layer and elongation of papillae in the squamous epithelium of the oesophageal mucosa may normalize, and are thus presumably not 'normal physiological variants'.

Smoking cessation in women with cardiac risk: a comparative study of two theoretically based therapies.

This gender-specific research study compares the relative effectiveness of two theory-based interventions targeting women who smoke. Women with coronary artery disease (CAD; n = 53) or CAD risk factors (n = 107) were randomly assigned to either coping-skills Relapse Prevention (RP) treatment or an educational/supportive treatment based on Health Belief Model (HBM) principles. RP was comparable, but not superior to HBM treatment, as indicated by the lack of differential smoking outcomes at 3 and 6 months. RP was more effective than HBM for women with low self-efficacy, as predicted. The presence of a smoking-related disease had a substantial effect on smoking status, in that the odds of being abstinent at 6 months were 2.2 times greater for non-diagnosed women when compared with CAD women. These findings indicate that more potent relapse prevention interventions are needed to increase cessation rates in women who smoke, especially those with established heart disease.

Context modulates effects of nicotine abstinence on human cooperative responding.

The effects of ad libitum smoking, abstinence, and 0-, 2-, and 4-mg nicotine gum on human cooperative responding were examined. Participants were provided the opportunity to respond cooperatively or independently to episodes initiated by a computer-simulated other person. Participants could also initiate episodes that ostensibly provided the other person the opportunity to respond cooperatively or independently of the participant. Working cooperatively added points to both the participant's and other person's counters. Working independently added points only to the participant's counter. Results demonstrated that abstinence decreased cooperative responses during episodes initiated by the computer-stimulated other person. Relative to abstinence and placebo gum conditions, ad libitum smoking and administration of 2- and 4-mg nicotine gum increased these cooperative responses. No gender differences were observed. The number of cooperative episodes initiated by the participants was not affected significantly by the smoking or gum conditions. Nicotine increased reports of vigor and decreased abstinence-engendered reports of depression, anger, confusion, and tension. The difference in the effects of nicotine abstinence on the 2 classes of cooperative responding demonstrates that the social contingency mediates the behavioral effects of abstinence.

Cocaine craving: an evaluation across treatment phases.

This study examined the relationship between verbal reports of craving and actual cocaine use across different treatment phases using a longitudinal design. Participants (n = 32) were cocaine-dependent patients who completed an inpatient chemical dependency program and then participated in an 8-week outpatient relapse prevention program. Craving ratings and urine samples were collected during hospitalization, at 12 weekly outpatient treatment sessions, and at 1, 2, 4, 8, 12, and 24-week follow-up. Craving increased significantly from inpatient to outpatient treatment. Cocaine-abstinent participants reported lower craving across outpatient treatment and follow-up compared to moderate and heavy cocaine users. The overall relationship between craving and total proportion of cocaine positive urines was highly significant. Implications of these findings for advancing our theoretical and practical knowledge about craving and cocaine use, are explored.

Medication take-home doses and contingency management.

Two studies examined contingent take-home medication doses during treatment of opiate or cocaine dependence. In the first study, methadone maintenance patients were randomly assigned to one of two 8-week baseline take-home (TH) conditions differing in frequency of clinic visits per week. This was followed by a 12-week contingency management (CM) procedure in which frequent THs resulted from drug-free urines. Participants receiving more frequent THs during baseline had lower illicit drug use during the first 6 weeks of CM. In the second study, fluoxetine (0-, 20-, 40-mg) TH doses were similarly contingent in treatment of cocaine dependence. The 40-mg group used less cocaine during contingency than did other groups. The combination of fluoxetine and environmental contingencies may produce benefit where neither alone is sufficient.