The relationship between self-reported cocaine withdrawal symptoms and history of depression.

This study examined the relationship between cocaine withdrawal and lifetime history of depression (major depression, dysthymia). Participants with a history of regular cocaine use (n = 146) were administered the Structured Clinical Interview for the DSM-IV (SCID) and were asked to recall whether they experienced any of the six DSM-IV cocaine withdrawal symptoms. Results of bivariate analyses demonstrated that those meeting criteria for the cocaine withdrawal syndrome (dysphoria plus two or more other symptoms), in comparison to those who did not, were significantly (P<.001) more likely to have a lifetime history of depression. Lifetime history of depression was also more common in those individuals reporting the withdrawal symptoms of "dysphoria" (P<.001), "insomnia/hypersomnia" (P<.05), "vivid unpleasant dreams" (P<.01), and "psychomotor agitation/retardation" (P<.01). These relationships remained significant after controlling for demographics, severity of addiction, and the presence of opiate, alcohol and cannabis dependence or abuse. The withdrawal symptoms of "fatigue" and "increased appetite" were not associated with mood history. Results suggest that lifetime history of depression is strongly related to whether or not a cocaine abuser self-reports withdrawal symptoms. Several competing hypotheses regarding the nature of this relationship are discussed.

Gender differences in problem severity at assessment and treatment retention.

Women in treatment for substance abuse have been reported to have more severe problems at assessment than men but not to differ in treatment retention. To examine gender differences in problems at assessment, 30-day retention, and treatment completion, data from Detroit's publicly funded substance abuse treatment system were used. Women had significantly more severe problems at assessment, lower 30-day retention, and lower treatment completion rates than men. These gender differences in retention remained significant even after controlling for problem severity, primary drug of abuse, and referred treatment setting. There was no evidence of improvements in women's problems at assessment or retention over time during this period. Women presented with more severe problems at assessment and were less likely to stay in treatment for 30 days or to complete treatment than men. Monitoring gender differences in problems at presentation and retention outcomes is recommended to assess local need for interventions.

Novelty seeking as a predictor of treatment retention for heroin dependent cocaine users.

This study examined the relationship between novelty seeking between treatment retention and among heroin dependent cocaine users. Participants were treated with buprenorphine maintenance and contingency management. The Tridimensional Personality Questionnaire's (TPQ) Novelty Seeking scale was administered to 68 participants prior to buprenorphine induction. Demographics, mood and anxiety disorders, antisocial personality disorder, and substance use were also assessed. Variables with significant relationships with overall retention were entered into a logistic regression analysis. In addition, using a survival analysis, all variables with significant relationships with time to drop-out were entered into a multivariate proportional hazards regression with time dependent covariates. Results demonstrated that although high novelty seekers, in comparison to low novelty seekers, were more likely to drop-out by the end of treatment, they had higher retention rates during the early phases of treatment. It is suggested that buprenorphine and contingency management were viewed by participants as novel treatment components and thus facilitated high novelty seekers' success early in treatment. If replicated, results suggest that inclusion of novel treatment components might facilitate retention among this at-risk group.

Contingency management interventions for treating the substance abuse of adolescents: a feasibility study.

This article reports on the feasibility of using a contingency management intervention with adolescent smokers that has proven efficacious in adult substance abuse treatment. The study used 8 adolescent participants in an A (1 week)-B (1 week)-A (1 week) reversal design. During the 2 baseline phases, no contingencies were placed on cigarette smoking, and adolescents received money noncontingently. During the experimental intervention week, adolescents received payment contingent on not smoking. The magnitude of reimbursement available during the baseline and intervention phases was equated. Results indicated that the contingency management intervention was effective in reducing smoking, both in terms of increasing the total number of abstinences and consecutive abstinences. In addition, changes in adolescents' affective states during smoking cessation were found. Anxiety, depression, anger, and fatigue were reported, and these negative states ceased once smoking resumed.

Buprenorphine-induced changes in mu-opioid receptor availability in male heroin-dependent volunteers: a preliminary study.

A principle of opioid pharmacotherapy is that high medication doses should occupy fractionally more opioid receptors that mediate heroin effects. In this preliminary study we examined in vivo mu opioid receptor (muOR) binding in three healthy opioid-dependent volunteers during maintenance on 2 and 16 mg sublingual buprenorphine (BUP) liquid, and after detoxification (0 mg) under double-blind, placebo-controlled conditions, and once in matched controls. Binding measures were obtained with the muOR-selective radioligand [11C]carfentanil (CFN) and PET 4 hrs after BUP administration. BUP induced dose-dependent reductions in muOR availability, 36-50% at 2 mg and 79-95% at 16 mg relative to placebo. Heroin abusers also had greater muOR binding potential in the inferofrontal cortex and anterior cingulate regions during placebo, compared to matched controls. Further studies are warranted to examine the relationship of muOR availability with BUP therapeutic actions, and the clinical implications of increased muOR binding during withdrawal.

Treatment of heroin-dependent poly-drug abusers with contingency management and buprenorphine maintenance.

This study targeted poly-drug (cocaine plus heroin) abstinence among buprenorphine-maintained participants with a 12-week voucher-based reinforcement therapy (VBRT) phase versus a yoked control condition. Baseline levels of cocaine and heroin use were significant predictors of treatment outcome, regardless of treatment assignment. Overall, there were no significant group differences on treatment outcome. However, among the subsample that produced one or more poly-drug-free urine results, VBRT participants had significantly increased cocaine-but not heroin and poly-drug-abstinence, although all results were in the predicted direction. Results suggest that for those who achieve poly-drug abstinence, VBRT may enhance treatment outcome. However, improved interventions, perhaps targeting single-drug abstinence, increasing reinforcement magnitude, or both, may be necessary to promote initial poly-drug abstinence in this population.

Contingency management for accurate predictions of urinalysis test results and lack of correspondence with self-reported drug use among polydrug abusers.

Contingency management procedures have proven effective in the treatment of drug-dependent patients. These procedures, however, often require frequent urine testing, which is too costly for community treatment programs. To make urine-testing procedures more cost effective, the feasibility of reinforcing accurate predictions of urine drug screen (UDS) results was evaluated. Participants made extremely accurate UDS predictions, particularly when they made drug-positive predictions, regardless of whether predictions were reinforced. However, self-reports of recent drug use had poor correspondence with predictions of UDS results. Results suggested that if programs only tested samples predicted to be drug free, considerable cost savings could be incurred. Further research is needed to determine if validity would be enhanced by using a proportion of costs saved to provide nominal reinforcement when samples were verified to be drug free.

Abuse liability assessment of sibutramine, a novel weight control agent.

RATIONALE: Sibutramine (Meridia) is a serotonin and norepinephrine reuptake inhibitor marketed for weight control. Previous studies demonstrated low abuse potential for 20 and 30 mg sibutramine (doses near the therapeutic range); however, no data existed on supratherapeutic doses. This study, therefore, examined 25 and 75 mg sibutramine in humans compared to d-amphetamine (20 mg) as a positive control and placebo as a negative control. OBJECTIVES: The study examined the acute subjective, reinforcing, and physiological effects of sibutramine to assess its abuse liability. METHODS: Twelve polydrug abusers with no history of drug dependence participated in this double-blind, inpatient/outpatient study. Volunteers participated in four drug sessions, in which they completed subjective effects scales including the Profile of Mood States (POMS), Visual Analog Scales (VAS), and the Addiction Research Center Inventory (ARCI). The Multiple Choice Procedure (MCP) was used to evaluate reinforcing efficacy. RESULTS: Sibutramine 25 mg produced subjective effects that were indistinguishable from placebo. Sibutramine 75 mg produced significant unpleasant effects, such as Anxiety, Confusion, and decreased Vigor. On the MCP, volunteers chose to give up an average of $4.04 from their study pay rather than receive the higher dose of sibutramine again. In contrast, d-amphetamine 20 mg produced positive mood changes and was well liked. CONCLUSIONS: These data indicate sibutramine lacks amphetamine-type abuse liability when administered acutely.

Reinforcing and subjective effects of morphine in human opioid abusers: effect of dose and alternative reinforcer.

RATIONALE: Although most opioid self-administration research has been conducted with laboratory animals, such research with humans is necessary to answer questions unique to human drug-taking behavior. OBJECTIVE: We investigated the influence of morphine dose and an alternative non-drug reinforcer on choice between morphine versus money and examined the relationship between drug-reinforced behavior and subjective euphoria. METHODS: Five male opioid users participated in the 7-week study. During the first 5 weeks, a single dose of morphine (0, 4, 8, 16, or 32 mg/70 kg) was available each week. On Monday, subjects received an IM injection of the dose tested that week. On Tuesday, Thursday, and Friday, subjects could work for morphine or money under a second-order, progressive ratio schedule. For each primary ratio completed on the drug lever, subjects earned one-ninth of the available drug dose, and for each ratio completed on the money lever, subjects earned $1. Total amount of drug earned was administered in a single IM injection at the end of the session; money earned was credited to the subject's account. RESULTS: As morphine dose increased, responding for drug increased in an orderly manner and responding for money decreased. During the final phase of the study, the lowest and highest doses that maintained drug responding for each subject were repeated, and the value of the alternative reinforcer was increased to $2 per ratio. This manipulation was associated with decreased drug-maintained responding at the lowest, but not the highest, reinforcing dose of morphine. CONCLUSION: The progressive ratio, concurrent access procedure may be useful in predicting the outcome of drug abuse treatment interventions that use alternate reinforcement strategies.

Opioid reinforcement in heroin-dependent volunteers during outpatient buprenorphine maintenance.

This study examined the reinforcing effects of hydromorphone (HYD) (0, 4, 8, and 16 mg/70 kg i.m.) in heroin-dependent outpatient volunteers maintained on buprenorphine (BUP) at doses of 2, 4, and 8 mg, each for 2 weeks. Following a week of maintenance at each dose, volunteers received injections of one of the four HYD doses under double-blind conditions. Eight volunteers (abstainers) were heroin-free during HYD test weeks, whereas six volunteers remained heroin-positive (nonabstainers). Among abstainers, HYD had minimal reinforcing value, whereas in nonabstainers there were marked dose-related increases in HYD reinforcing value, which were not attenuated by increasing doses of BUP. A similar pattern was found for HYD subjective agonist effects. Heroin craving among nonabstainers was significantly higher compared with abstainers, and was reduced in a dose-related manner by HYD. Although BUP and HYD produced dose-related miosis, abstinence status had no differential effect. In summary, BUP effects on opioid reinforcement were consistent from outpatient setting (heroin abstinence) to laboratory setting (decreased HYD reinforcement), supporting the validity of this laboratory model.

Improvement in naltrexone treatment compliance with contingency management.

The efficacy of a voucher-based incentive program for improving adherence to outpatient, thrice weekly naltrexone maintenance was tested in a three group, randomized, 12-week clinical trial. Voucher incentives were given as follows: contingent group (n = 19) for each consecutive naltrexone dose ingested; non-contingent group (n = 19) on unpredictable schedule independently of taking naltrexone; no-voucher group (n = 20) none. Vouchers were exchangeable for goods and services. The contingent group had significantly longer treatment retention and ingested significantly more doses of naltrexone (consecutive and total) than either control group. Voucher incentives can significantly increase adherence to naltrexone maintenance in recently detoxified opioid dependent individuals.

Broad beneficial effects of cocaine abstinence reinforcement among methadone patients.

Escalating reinforcement for sustained abstinence has been effective in treating cocaine abuse. Under this schedule, patients receive vouchers for cocaine-free urine samples; vouchers have monetary values that increase with the number of consecutive cocaine-free urine samples. Cocaine-abusing methadone patients were randomly assigned to receive vouchers for 12 weeks under (a) an escalating schedule (n = 20), (b) an escalating schedule with start-up bonuses (n = 20), or (c) a noncontingent schedule (n = 19). Start-up bonuses were designed to provide added reinforcement for initiating abstinence; however, they did not improve outcomes. Both contingent interventions significantly increased cocaine abstinence. In addition, the contingent interventions increased abstinence from opiates and decreased reports of cocaine craving. These results replicate the efficacy of cocaine abstinence reinforcement and show that it can have broad beneficial effects.

Cocaine use early in treatment predicts outcome in a behavioral treatment program.

In this evaluation of baseline drug use as a predictor of treatment outcome, cocaine use during a 5-week baseline was compared in methadone maintenance patients who had < 5 (n = 10) versus > or = 5 (n = 9) weeks of abstinence during an experimental cocaine abstinence reinforcement treatment. Cocaine use was evaluated at the 1st and last visit and the 1st and last week of baseline and as a mean across the 5-week baseline treatment; response was calculated as a mean across 12 weeks of experimental treatment. Those who had successful outcomes (abstainers) used significantly less cocaine in the 5-week baseline than those with less successful outcomes (nonabstainers). Differences in cocaine use were not evident in the 1st baseline visit or week, but the abstainers used significantly less cocaine in the last visit and week of baseline compared with the nonabstainers. Cocaine use during baseline provided critical predictors of response to the experimental treatment.

Automated measurement of motor activity in human subjects: effects of repeated testing and d-amphetamine.

Repeated exposure to a test setting decreases, and amphetamine increases, motor activity in animals. To evaluate whether these effects also occur in human subjects, we recorded motor activity levels from 12 subjects during a double-blind oral drug discrimination (placebo vs. 75 mg tripelennamine) study. Before each 4-h session, activity monitors were attached to the subject's wrist and ankle. During each session, subjects rated their drug effects hourly (task periods), and could freely choose among leisure activities during intertask intervals (recreational periods). Habituation was evaluated by comparing activity response during initial (training phase) vs. later (discrimination phase) placebo sessions. During later sessions the two training drugs, as well as diazepam (2.5, 5 mg P.O.) and d-amphetamine (5, 10 mg P.O.) were administered. Consistent with animal studies, repeated exposure to the test environment significantly decreased, and d-amphetamine significantly and selectively increased, wrist motor activity. These data indicate that human motor activity is sensitive to environmental factors (task, time), drug class, and d-amphetamine dose. Activity measures may, therefore, be useful in evaluating environment/psychostimulant interactions in humans.

Assessment of cocaine use with quantitative urinalysis and estimation of new uses.

Qualitative urinalysis methods of monitoring cocaine use may over-detect frequency of use, possibly decreasing the ability of clinical trials to detect effective treatments. Quantitative urinalysis and newly developed criteria for identifying new cocaine use were evaluated as alternative measures of cocaine use. Urine specimens collected in a cocaine dosing study in non-treatment-seeking subjects (n = 5) and a cocaine treatment trial (n = 37) were analyzed for the cocaine metabolite, benzoylecgonine, with qualitative and quantitative methods. Pharmacokinetic criteria ('New Use' rules) were applied to quantitative data to identify occasions of new cocaine use. Results were compared to known cocaine administrations in the laboratory study and to self-reported drug use and qualitative urinalysis for subjects in the clinical trial. New Use criteria correctly identified cocaine administrations in the cocaine dosing study in all but a small number of specimens. In the clinical trial, quantitative urinalysis and estimated New Uses provided more information about patterns and frequency of use than qualitative urinalysis in the different treatment conditions in the clinical trial. Interpretation of quantitative urinalysis with New Use rules appears to be a useful method for monitoring treatment outcome and may be more accurate than traditional qualitative urinalysis in estimating frequency of cocaine use.

Comparison of self-reported drug use with quantitative and qualitative urinalysis for assessment of drug use in treatment studies.

The effectiveness of substance abuse treatment programs can be monitored by self-reported drug use and objectively measured by qualitative and quantitative urinalysis. The advantages and disadvantages of each of these three methods of assessing drug use are reviewed. Data collected in a clinical trial of a behavioral treatment for cocaine abuse are used to evaluate the relationships among qualitative and quantitative urinalysis for cocaine metabolite and self-reported cocaine use. Qualitative and quantitative urine testing showed greater rates of drug use than that shown by self-report, though there were significant correlations between self-reported use and urine toxicology results. Benzoylecgonine concentrations in urine specimens supported the suggestions that rates of drug use as determined by qualitative urinalysis are artificially high due to carryover and were informative about subjects' patterns of use.

Increasing opiate abstinence through voucher-based reinforcement therapy.

Heroin dependence remains a serious and costly public health problem, even in patients receiving methadone maintenance treatment. This study used a within-subject reversal design to assess the effectiveness of voucher-based abstinence reinforcement in reducing opiate use in patients receiving methadone maintenance treatment in an inner-city program. Throughout the study subjects received standard methadone maintenance treatment involving methadone, counseling, and urine monitoring (three times per week). Thirteen patients who continued to use opiates regularly during a 5-week baseline period were exposed to a 12-week program in which they received a voucher for each opiate-free urine sample provided: the vouchers had monetary values that increased as the number of consecutive opiate-free urines increased. Subjects continued receiving standard methadone maintenance for 8 weeks after discontinuation of the voucher program (return-to-baseline). Tukey's posthoc contrasts showed that the percentage of urine specimens that were positive for opiates decreased significantly when the voucher program was instituted. (P < or = 0.01) and then increased significantly when the voucher program was discontinued during the return-to-baseline condition (P < or = 0.01). Rates of opiate positive urines in the return-to-baseline condition remained significantly below the rates observed in the initial baseline period (P < or = 0.01). Overall, the study shows that voucher-based reinforcement contingencies can decrease opiate use in heroin dependent patients receiving methadone maintenance treatment.

Sustained cocaine abstinence in methadone maintenance patients through voucher-based reinforcement therapy.

BACKGROUND: Chronic cocaine abuse remains a serious and costly public health problem. This study assessed the effectiveness of a voucher-based reinforcement contingency in producing sustained cocaine abstinence. METHODS: A randomized controlled trial compared voucher-based reinforcement of cocaine abstinence to noncontingent voucher presentation. Patients were selected from 52 consecutively admitted injecting heroin abusers in a methadone maintenance treatment program. Patients with heavy cocaine use during baseline period (N = 37) participated. Except where otherwise indicated, the term cocaine abuse is used in this article in a generic sense and not according to the DSM-III-R definition. Patients exposed to abstinence reinforcement received a voucher for each cocaine-free urine sample (ie, negative for benzoylecgonine) provided three times per week throughout a 12-week period; the vouchers had monetary values that increased as the number of consecutive cocaine-free urine samples increased. Control patients received noncontingent vouchers that were matched in pattern and amount to the vouchers received by patients in the abstinence reinforcement group. RESULTS: Patients receiving vouchers for cocaine-free urine samples achieved significantly more weeks of cocaine abstinence (P = .007) and significantly longer durations of sustained cocaine abstinence (P = .001) than controls. Nine patients (47%) receiving vouchers for cocaine-free urine samples achieved between 7 and 12 weeks of sustained cocaine abstinence; only one control patient (6%) achieved more than 2 weeks of sustained abstinence. Among patients receiving vouchers for cocaine-free urine samples, those who achieved sustained abstinence ( > or = 5 weeks) had significantly lower concentrations of benzoylecgonine in baseline urine samples than those who did not achieve sustained abstinence (P < or = .01). Patients receiving voucher reinforcement rated the overall treatment quality significantly higher than controls (P = .002). CONCLUSION: Voucher-based reinforcement contingencies can produce sustained cocaine abstinence in injecting polydrug abusers.

Effects of phentermine and cocaine on fenfluramine-induced depletion of serotonin in mouse brain.

The combined administration of phentermine and fenfluramine (PHEN/FEN) has been used as a treatment for obesity. Recent evidence suggests that this drug mixture may also be an effective medication for substance abuse disorders, including cocaine dependence. It is well-established that repeated high-dose fenfluramine causes serotonin (5-HT) terminal degeneration in laboratory animals, and no studies have addressed possible interactions between phentermine and fenfluramine. The purpose of the present work was to examine the effect of phentermine coadministration on fenfluramine-induced depletion of 5-HT in mouse forebrain. In addition, because of the potential for cocaine abuse in drug addicts taking PHEN/FEN as a medication, we examined the effects of PHEN/FEN on forebrain 5-HT levels in the presence or absence of cocaine. Fenfluramine (0, 3, 10, 30 mg/kg, s.c. twice daily for 4 days) caused a dose-dependent reduction in forebrain 5-HT without affecting dopamine or norepinephrine. Phentermine coadministration (7 mg/kg, s.c. twice daily for 4 days) did not significantly alter the 5-HT-depleting effect of fenfluramine. Likewise, cocaine (10 mg/kg, i.p.), administered 60 min prior to or 60 min after PHEN/FEN, had no effect on the PHEN/FEN-induced decrease in central 5-HT. The present results indicate that doses of phentermine far above those typically administered to humans do not potentiate the 5-HT-depleting effect of repeated high-dose fenfluramine. Moreover, exposure to cocaine does not significantly alter the long-term neurochemical actions of the PHEN/FEN mixture.