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Abstract: High levels of missing outcome data for biologically confirmed substance use (BCSU) threaten the validity of substance use disorder (SUD) clinical trials. Underlying attributes of clinical trials could explain BCSU missingness and identify targets for improved trial design. We reviewed 21 clinical trials funded by the NIDA National Drug Abuse Treatment Clinical Trials Network (CTN) and published from 2005 to 2018 that examined pharmacologic and psychosocial interventions for SUD. We used configurational analysis-a Boolean algebra approach that identifies an attribute or combination of attributes predictive of an outcome-to identify trial design features and participant characteristics associated with high levels of BCSU missingness. Associations were identified by configuration complexity, consistency, coverage, and robustness. We limited results using a consistency threshold of 0.75 and summarized model fit using the product of consistency and coverage. For trial design features, the final solution consisted of two pathways: psychosocial treatment as a trial intervention OR larger trial arm size (complexity=2, consistency=0.79, coverage=0.93, robustness score=0.71). For participant characteristics, the final solution consisted of two pathways: interventions targeting individuals with poly- or nonspecific substance use OR younger age (complexity=2, consistency=0.75, coverage=0.86, robustness score=1.00). Conclusions: Psychosocial treatments, larger trial arm size, interventions targeting individuals with poly- or nonspecific substance use, and younger age among trial participants were predictive of missing BCSU data in SUD clinical trials. Interventions to mitigate missing data that focus on these attributes may reduce threats to validity and improve utility of SUD clinical trials. Related protocols: CTN-0002, CTN-0003, CTN-0004, CTN-0006, CTN-0007, CTN-0009. CTN-0013, CTN-0014, CTN-0015, CTN-0017, CTN-0021, CTN-0029, CTN-0030, CTN-0031, CTN-0037, CTN-0044, CTN-0046, CTN-0048, CTN-0051, CTN-0053

Abstract:

Sleep disturbance may play a role in cocaine use outcomes and, hence, may be a potential therapeutic target for cocaine use disorder (CUD). Research in this area, which has largely relied on resource-intensive polysomnography, would be facilitated by identifying a self-report sleep measure predictive of CUD outcomes and by a better understanding of the mechanisms by which sleep may impact CUD outcomes.

This study, a secondary analysis of CTN-0046 (Smoking Cessation and Stimulant Treatment), tested the predictive validity of the Pittsburgh Sleep Quality Index (PSQI), a self-report assessment of past-month sleep quality. To better understand potential mechanisms, mediation models relating sleep disturbance to CUD outcomes were evaluated.

The PSQI was collected at baseline; the outcomes of interest were cocaine and drug abstinence at end-of-treatment (weeks 9-10). Potential mediators, measured in weeks 1-8, were: cocaine craving (Brief Substance Craving Scale); and anxiety and depression symptoms (Hospital Anxiety and Depression Scale). Mediation techniques were used to evaluate mediation effects separately and jointly.

The majority of participants (58.3%) had baseline sleep disturbance. Sleep disturbance was not a significant predictor of end-of-treatment abstinence when regressed without consideration of mediators. Cocaine craving, anxiety, and depression were significant mediators, both separately and jointly, of an effect of baseline sleep disturbance on end-of-treatment abstinence.

Conclusions: This exploratory analysis suggests that there may be an indirect relationship between self-reported sleep quality and substance use outcomes in cocaine-dependent patients, mediated by craving, anxiety, and depression.

Related protocols: CTN-0046

Abstract:

The purpose of this study was to estimate obesity prevalence among drug-dependent individuals and to compare prevalence across different types of drug dependence.

1596 opioid- and/or stimulant-dependent participants were extracted from six clinical trials within the National Drug Abuse Treatment Clinical Trials Network of the National Institute on Drug Abuse (NIDA CTN) to estimate obesity prevalence among drug-dependent users. Age-, sex-, and race-matched National Health and Nutrition Examination Survey (NHANES) samples were used as a general population reference. Standardized prevalence ratios (SPRs) were calculated to compare the CTN sample to NHANES as well as to compare within the CTN sample. Logistic regression estimated associations between the type of drug dependence and obesity.

The standardized obesity prevalence among the drug-dependent CTN trial participants was 67% of expected for age-, sex- and race-matched NIHANES participants (SPR = 0.67, 95% CI: 0.60-0.74). Obesity was least prevalent among opioid-dependent-only participants (SPR = 0.36, 95% CI: 0.27-0.46 compared to the NHANES, and SPR = 0.33, 95% CI: 0.23-0.46 compared to the stimulant-dependent-only participants). Compared to stimulant-dependent-only users (p < 0.0001), the odds of obesity were 67% lower among opioid-dependent-only users (adjusted odds ratio [AOR] = 0.33, 95% CI: 0.23-0.46) and 33% lower among opioid and stimulant-co-dependent users (AOR = 0.67, 95%CI: 0.49-0.90) after controlling for age, sex, race, education and employment pattern.

Conclusions: The prevalence of obesity among drug-dependent clinical trial participants was lower than the general population, and lowest among opioid-dependent-only users, suggesting an inverse relationship between obesity prevalence and drug dependence, most notable among opioid-dependent-only users.

Related protocols: CTN-0001, CTN-0002, CTN-0003, CTN-0037, CTN-0046, CTN-0048

Abstract:

Smoking prevalence is high among substance abusers, making it important to understand when nicotine abstinence will aid, impair, or not affect abstinence from other substances. This study tested novel hypotheses about the coupling of nicotine and stimulant craving over time during stimulant dependence treatment. Adults (N=538) with cocaine and/or methamphetamine dependence completed a 10-week randomized controlled trial of substance use treatment with or without smoking cessation treatment (NIDA Clinical Trials protocol CTN-0046, Smoking Cessation and Stimulant Treatment, S-CAST). Participants reported nicotine and stimulant craving weekly and use twice per week. Latent change score modeling tested the association between weekly increases in nicotine craving and subsequent weekly changes in stimulant craving. Interestingly, results revealed a “substitution” effect: increases in nicotine craving predicted subsequent decreases in stimulant craving. Additionally, increases in nicotine craving predicted subsequent increases in nicotine use, and decreases in stimulant use. As expected, the substitution effect between nicotine and stimulant craving was stronger when stimulants were administered through the same route as nicotine (i.e., smoking), versus other routes. Finally, smoking cessation treatment eliminated the coupling between nicotine craving and stimulant craving.

Conclusions: Contrary to concerns about nicotine abstinence during substance dependence treatment, increases in nicotine craving may be associated with later reductions in stimulant craving and use, and unrelated when smoking cessation treatment is introduced. Weekly changes in nicotine craving convey information that can help clinicians to predict and understand shifts in stimulant craving and use during substance use disorder treatment. This research improves the understanding of how the ebb and flow of craving relates across substances and holds promise for treatments that harness these interrelationships to improve abstinence from co-occurring substance use problems.

Related protocols: CTN-0046

Abstract:

Smoking is highly prevalent in substance dependence, but smoking-cessation treatment (SCT) is more challenging in this population. To increase the success of smoking cessation services, it is important to understand potential therapeutic targets, like nicotine craving, that have meaningful but highly variable relationships with smoking outcomes. This secondary analysis of data from National Drug Abuse Treatment Clinical Trials Network protocol CTN-0046 (Smoking Cessation and Stimulant Treatment) characterized the presence, magnitude, and specificity of nicotine craving as a mediator of the relationship between SCT and smoking abstinence in the context of stimulant-dependence treatment. The original trial was a randomized, 10-week study conducted at 12 outpatient substance use disorder (SUD) treatment programs. Adults with cocaine and/or methamphetamine dependence (n=538) were randomized to SUD treatment as usual (TAU) or TAU+SCT. Participants reported nicotine craving, nicotine withdrawal symptoms, and substance use in the week following a uniform quit attempt of the TAU+SCT group, and self-reported smoking 7-day point prevalence abstinence (verified by carbon monoxide) at end-of-treatment.

Bootstrapped regression models indicated that, as expected, nicotine craving in the week following a quit attempt was a significant mediator between SCT and smoking abstinence, accounting for 14% of the total effect. Nicotine withdrawal symptoms and substance use were not significant mediators. This pattern held for separate examinations of cocaine and methamphetamine dependence.

Conclusions: Nicotine craving accounts for a small but meaningful portion of the relationship between smoking-cessation treatment and smoking-abstinence during SUD treatment. Nicotine craving, particularly during the week following a quit attempt, may be a useful therapeutic target for increasing the effectiveness of smoking-cessation treatment in substance dependence. This timing is useful for clinicians and researchers attempting to predict outcomes within SUD treatment, as the increased variability and intensity of craving after a quit attempt may produce a clearer relationship between craving and nicotine outcomes.

Related protocols: CTN-0046

Abstract:

This is the primary outcomes article for CTN-0046.

The purpose of this study, National Drug Abuse Treatment Clinical Trials Network protocol CTN-0046, was to evaluate the impact of concurrent treatments for substance use disorder and nicotine-dependence for stimulant-dependent patients. It was a randomized, 10-week trial with follow-up at 3 and 6 months after smoking quit date, conducted at 12 substance use disorder treatment programs between February 2010 and July 2012. Adults meeting DSM-IV-TR criteria for cocaine and/or methamphetamine dependence and interested in quitting smoking were randomized to treatment as usual (TAU) (n=271) or TAU with smoking-cessation treatment (n=267). All participants received TAU for substance use disorder treatment. Participants assigned to TAU with concurrent smoking-cessation treatment received weekly individual smoking cessation counseling and extended-release bupropion (300mg/d) during weeks 1-10. During post-quit treatment (weeks 4-10), participants assigned to TAU with smoking-cessation treatment received a nicotine inhaler and contingency management for smoking abstinence. The primary outcome was weekly proportion of stimulant-abstinent participants during the treatment phase, as assessed by urine drug screens and self-report. Secondary measures included other substance/nicotine use outcomes and treatment attendance.

There were no significant treatment effects on stimulant-use outcomes, as measured by the primary outcome and stimulant-free days, on drug-abstinence, or on attendance. Overall, participants assigned to treatment as usual with smoking-cessation treatment averaged 77.2% stimulant-abstinent weeks compared to 78.1% stimulant-abstinent weeks for participants assigned to treatment as usual. There was a similar lack of significant treatment effect on stimulant abstinence at 3-month and 6-month follow-ups. Participants receiving TAU with smoking cessation treatment, relative to those receiving TAU alone, however, had significantly better outcomes on smoking point-prevalence abstinence. Additionally, participants receiving TAU with smoking cessation treatment, relative to those receiving TAU alone, had significantly better outcomes for drug-free days (abstinence from all illicit substances, not just stimulants) at 6-month follow-up.

Conclusions: Providing smoking-cessation treatment to cocaine- and/or methamphetamine-dependent patients in outpatient substance use disorder treatment had no effect on stimulant-use outcomes or treatment attendance, but significantly improved smoking-abstinence outcomes and outcomes for drug-free days at 6-month follow-up. Concurrent smoking-cessation and substance use disorder treatment can significantly improve smoking-abstinence outcomes and do not negatively impact non-nicotine outcomes.

Related protocols: CTN-0046

Abstract:

Past research suggests that a significant relationship exists between cigarette smoking and illicit-stimulant abuse. The present study, a secondary analysis of the National Drug Abuse Treatment Clinical Trials Network protocol CTN-0046 (Smoking Cessation and Stimulant Treatment (S-CAST)), evaluated the association between achieving smoking abstinence in response to smoking-cessation treatment (SCT) and illicit-stimulant abstinence in cocaine- and/or methamphetamine-dependent participants.

Two hundred and sixty-seven adults meeting DSM-IV-TR criteria for cocaine- and/or methamphetamine-dependence and interested in quitting smoking were randomized to SUD treatment-as-usual plus SCT consisting of weekly individual smoking cessation counseling, extended-release (XL) bupropion (300 mg/day), nicotine inhaler, and contingency management for smoking abstinence. Smoking abstinence was assessed via self-report and carbon monoxide levels. The analysis found a significant effect for the cocaine-dependent subsample (n=147) in which participants who stopped smoking were abstinent for illicit stimulants an average of 78.2% of the post-smoking-quit weeks (weeks 4-10) relative to 63.6% in participants who continued smoking. No significant effects were found for the sample as a whole (n=249) or for the methamphetamine-dependent subsample (n=102).

Conclusions: The present results suggest that cocaine-dependent patients achieving smoking abstinence in response to smoking-cessation treatment might evidence not only improved smoking outcomes but improved cocaine use outcomes as well. Because the prevalence of smoking in cocaine-dependent patients is 75-80%, and cigarette smoking itself is deadly, using smoking-cessation treatment to intervene with both cocaine use and cigarette smoking would impact two important public health issues. Future research to replicate this finding appears warranted.

Related protocols: CTN-0046

Abstract:

Research suggests that mentholated cigarettes may play a role in cocaine dependence. The purpose of this study was to expand upon the research on mentholated cigarettes and cocaine dependence and to evaluate the role of mentholated cigarettes in methamphetamine dependence. Data for the analysis came from National Drug Abuse Treatment Clinical Trials Network protocol CTN-0046, a multisite, randomized trial evaluating the impact of smoking cessation treatment in stimulant-dependent outpatients. Participants’ reasons for concurrent use of cigarettes and illicit stimulants were assessed via self-report. Stimulant-abstinence was measured by self-report and urine drug screens. Smoking cessation was assessed via self-report and carbon monoxide levels. Of the 301 cocaine-dependent participants, 201 (67%) were menthol and 100 (33%) were non-menthol cigarette smokers. Cocaine-dependent participants who smoked menthol, compared to non-menthol, cigarettes were significantly more likely to report that cigarettes prolong their cocaine high and were less likely to be stimulant abstinent during active treatment, at 3 month follow-up, and at 6 month follow-up. No parallel differences were found between menthol and non-menthol methamphetamine-dependent smokers. The prevalence of Caucasian menthol smokers was significantly greater in the cocaine-dependent participants (37.2%) than in the methamphetamine-dependent participants. Smoking cessation was not significantly associated with cigarette type for either cocaine- or methamphetamine-dependent participants.

Conclusions: The present results suggest that mentholated cigarettes play a role in cocaine, but not methamphetamine, dependence. Cocaine clinical trialists should assess whether participants smoke mentholated cigarettes, since these results suggest that this easily-assessed variable is associated with cocaine use outcomes. Additionally, the results suggest that concurrent use of mentholated cigarettes with cocaine is associated with more severe cocaine dependence. This potential negative impact on public health should be considered when weighing the potential costs and benefits of banning metholated cigarettes.

Related protocols: CTN-0046

Abstract:

Cigarette smoking is prevalent in cocaine/methamphetamine-dependent patients and associated with significant morbidity and mortality, yet the provision of smoking cessation treatment in conjunction with substance use disorder (SUD) treatment is not standard practice. This is due, in part, to clinician concern that combining smoking cessation treatment with SUD treatment could lead to poorer SUD outcomes. The National Drug Abuse Treatment Clinical Trials Network is conducting a 10-week, two-group, randomized trial to evaluate the impact of providing smoking cessation treatment (SCT) with SUD treatment as usual (TAU), compared to TAU alone, in smokers who are in outpatient treatment for cocaine or methamphetamine dependence (protocol CTN-0046, S-CAST). Approximately 528 participants recruited from 12 community treatment programs will be randomized into the trial. This paper describes key design decisions make during protocol development. The trial is designed to evaluate the relationship between cigarette smoking and stimulant use, which prior research suggests is linked, and should contribute to our understanding of how best to address the co-occurring problems of nicotine dependence and cocaine/methamphetamine-dependence.

Unique aspects of the trial include the primary question of interest, which concerns the impact of providing SCT on SUD outcomes rather than on smoking outcomes, and the intensity of the SCT chosen, which includes bupropion, nicotine replacement, and two psychosocial interventions. S-CAST is designed to answer questions of interest to clinicians as well as more basic researchers and should contribute significantly to our understanding of how best to address the co-occurring problems of nicotine and cocaine/methamphetamine dependence.

Related protocols: CTN-0046

Abstract:

The National Drug Abuse Clinical Trials Network (CTN) collaborates with community treatment programs to conduct clinical trials testing the effectiveness of emerging pharmacological and behavioral therapies for alcohol and drug use disorders. Each community treatment program is unique and variation in organizational and workforce characteristics may contribute to variation in patient outcomes. A clinical trial completed within the CTN (CTN-0017), for example, found that distance between detoxification and outpatient clinics was the strongest influence on entering outpatient care following detoxification (Campbell et al, 2010). An interesting and potentially influential workforce characteristic is staff commitment toward implementation of the study intervention. Variation in goal commitment may affect the quality of implementation of a clinical trial intervention and contribute to variation between study sites in patient outcomes.

For this study, goal commitment was assessed prior to the implementation of three CTN trials (CTN-0031 (STAGE-12), CTN-0046 (S-CAST), and CTN-0044 (Web Delivery)) to assess variation between protocols and variation between study site within protocols. The analysis found that both protocol type and job title/job role were associated with variation in goal commitment in the three trials.

Related protocols: CTN-0031, CTN-0044, CTN-0046

Abstract:

This brochure, intended for participants thinking about joining the CTN-0046 (Smoking Cessation and Stimulant Treatment Study (S-CAST)) protocol, provides an overview of the project and answers any questions participants might have. This study will compare participating clinics’ treatment as usual for stimulant dependence with a combination of treatment for stimulant dependence and smoking cessation to discover the latter’s impact on stimulant-use outcomes, outcomes for other drugs of abuse, and smoking outcomes. Research shows that rates of smoking in cocaine and methamphetamine users are 3-4 times greater than in the general population; it is hoped that this combined approach will be effective for reducing both smoking and stimulant use in participants.

Related protocols: CTN-0046