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Abstract: Recent studies indicate that sex-based differences exist in co-occurring psychiatric symptoms and disorders among individuals with opioid use disorders (OUD). Whether these associations are present in adolescent samples and change during OUD treatment is poorly understood. In this study, researchers examined sex-based differences in psychiatric symptoms and relationships among sex, psychiatric symptoms, and opioid use outcomes in youth with OUD receiving buprenorphine/naloxone (Bup/Nal) and psychosocial treatment. The study randomly assigned 152 youth (15-21 years old) diagnosed with OUD to either 12 weeks of treatment with Bup/Nal or up to 2 weeks of Bup/Nal detoxification with both treatment arms receiving weekly drug counseling as part of a multisite clinical trial (CTN-0010). Researchers compared psychiatric symptoms, assessed via the Youth Self Report (YSR) at baseline and week 12, across male and female OUD participants. The study used logistic regression models to identify sex and psychiatric symptom variables that were predictors of opioid positive urine (OPU) at week 12. Compared to males, females with OUD had higher mean psychiatric symptom scores at baseline across broad-band and narrow-band symptom domains. The study observed significant reductions in psychiatric symptoms scores in both males and females during treatment, and by week 12, females only differed from males on anxious-depressive symptom scores. Females, in general, and youth of both sexes presenting to treatment with higher anxious depression scores were less likely to have a week-12 OPU. Conclusions: Clinically significant sex-based differences in psychiatric symptoms are present at baseline among youth with OUD receiving Bup/Nal-assisted treatment and mostly resolve during treatment. Related protocols: CTN-0010

Abstract:

Evidence-based interventions for treating opioid use disorder (OUD) in youth are limited and little is known about specific and general mechanisms of OUD treatments and how they promote abstinence. This study used data from the CTN-0010 trial to evaluate the mediating effects of psychosocial treatment-related variables (therapy dose and therapeutic alliance) on end-of-treatment opioid abstinence in a sample of youth with OUD (n=152, 40% female, mean age=19.7 years) randomized to receive either 12 weeks of treatment with Bup/Nal (“Bup-Nal”) or up to 2 weeks of Bup/Nal detoxification (“Detox”) with both treatment arms receiving weekly individual and group drug counseling +/- family therapy.

Participants in the Bup-Nal group attended more therapy sessions (16 vs 6 sessions), had increased therapeutic alliance at week 4, and had less opioid use by week 12 compared to those in the Detox group. In both treatment arms, youth who attended more therapy sessions were less likely to have a week 12 opioid positive urine. In a multiple mediator model, therapy dose mediated the association between treatment arm and opioid abstinence.

Conclusions: These findings provide preliminary support for a “dose-response” effect of addiction-focused therapy on abstinence in youth OUD. Further, the results identified a mediating effect of therapy dose on the relationship between treatment assignment and opioid treatment outcomes, suggesting that extended Bup-Nal treatment may enhance abstinence, in part, through a mechanism of therapy facilitation, by increasing therapy dose during treatment.

Related protocols: CTN-0010

Abstract:

This study aimed to evaluate buprenorphine-naloxone’s effects on the QTc in youth with opioid dependence (the QTc, or “corrected QT interval,” is a measure of the duration of electrical activation and recovery of the ventricular muscle). Prolongation of the QTc increases the risk for torsades de pointes (TdP), an uncommon variant of polymorphic ventricular tachycardia, that can result in syncope, ventricular fibrillation, and sudden death. Buprenorphine is a partial agonist that is an effective treatment for opioid dependence. Compared with methadone, it has a lower risk of QTc prolongation in adults, and may also reduce the risk of TdP, but it is less studied in youth. This study involved a secondary analysis of the electrocardiogram data from 95 individuals who participated in a multi-site trial for youth with opioid dependence (CTN-0010). The participants were randomized to a 2-week (DETOX) or a 12-week course of buprenorphine-naloxone (BUP). At baseline, 12-lead electrocardiograms were done at weeks 4 and 12, and QTc intervals were hand-measured and calculated using Bazett formula. Increases above 60 milliseconds were considered clinically significant, and readings above 450 milliseconds (in men) and 470 milliseconds (in women) indicated a prolonged QTc.

Results found that mean QTc intervals were higher for BUP than for DETOX participants at baseline, week 4, and week 12 (p=0.045), and women had longer mean QTc intervals than men (p<0.0005). Variations in the QTc intervals were observed in some; however, none were above 500 milliseconds — the level at which risk for TdP becomes more significant. The few QTc prolongations that occurred were among participants who were receiving psychotropic medications that are known to prolong the QTc, and indicate a need for further evaluation of potential interactions between buprenorphine-naloxone and SSRIs, or other commonly used psychotropic medications.

Conclusions: In this randomized trial, the mean QTc at baseline, before randomization, was higher in BUP than in DETOX patients. Minimal changes in the QTc were seen at 4 and 12 weeks in a few patients in both groups. There was no evidence that buprenorphine-naloxone alone increased the QTc to a level that increased the risk for TdP. These results add to the known safety data on buprenorphine-naloxone among adults, and could add to the literature that buprenorphine-naloxone is a safe and effective treatment for opioid-dependent young adults with clinically significant QTc prolongations, or who are at risk for developing it.

Related protocols: CTN-0010

Abstract:

Cannabis use is common among opioid-dependent patients, but studies of its association with treatment outcome are mixed. In this secondary analysis of National Drug Abuse Treatment Clinical Trials Network protocol CTN-0010 (“Buprenorphine/Naloxone-Facilitated Rehabilitation for Opioid Dependent Adolescents/Young Adults”), the association of cannabis use with opioid treatment outcomes is assessed. In the main study, participants (N=152) aged 15-21 years were randomized to receive psychosocial treatments and either a 12-week course of buprenorphine/naloxone with a dose taper to zero in weeks 9-12, or a 2-week detoxification with buprenorphine/naloxone. Drug use was assessed by self-report and urine drug screen at baseline and during study weeks 1-12. The association between cannabis and opioid use at weeks 4, 8, and 12 was examined using logistic regression models. Participants reported a median of 3 days (range=0-30) cannabis use in the past month; half (50.3%, n=77) reported occasional use; one-third reported no use (33.1%, n=50), and one-sixth reported daily cannabis use (16.6%, n=25). Median lifetime cannabis use was 4.0 years (range=0-11) and median age of initiation of use was 15 years (range 9-21). Neither past cannabis use (age of initiation and use in the month prior to baseline), nor concurrent use, was associated with level of opioid use.

Conclusions: Overall, cannabis use had no association with opioid use over 12 weeks in this sample of opioid-dependent youth. While cannabis use remains potentially harmful, it was not a predictor of poor opioid treatment outcome, as measured by opioid urine drug screens, in this sample.

Related protocols: CTN-0010

Abstract:

Objective measures of drug use are very important in treatment outcome studies of persons with substance use disorders, but obtaining and interpreting them can be challenging and not always practical. Thus, it is important to determine if, and when, drug use self-reports are valid. To this end we explored the relationships between urine drug screen results and self-reported substance use among adolescents and young adults with opioid dependence participating in a clinical trial of buprenorphine-naloxone. In this study (National Drug Abuse Treatment protocol CTN-0010), 152 individuals seeking treatment for opioid dependence were randomized to a 2-week detoxification with buprenorphine-naloxone (DETOX) or 12 weeks buprenorphine-naloxone (BUP), each with weekly individual and group drug counseling. Urine drug screens and self-reported frequency of drug use were obtained weekly, and patients were paid $5 for completing weekly assessments. At weeks 4, 8, and 12, more extensive assessments were done, and participants were reimbursed $75. Self-report data were dichotomized (positive vs. negative), and for each major drug class the kappa statistic and the sensitivity, specificity, positive predictive value were computed, as well as the negative predictive value of self-report using urine drug screens as the “gold standard.” Generalized linear mixed models were used to explore the effect of treatment group assignment, compensation amounts, and participant characteristics on self-report.

Conclusions: In general, findings support the use of self-report of drug use as a valid outcome measure in treatment studies of adolescents and young adults with opioid use disorders. However, those in the BUP group were more likely to under-report cocaine and opioid use. Therefore, if used alone, self-report would have magnified the treatment effect of the BUP condition. Future studies could further define the predictors of greater or lower probability of over- and under-reporting, so that interpretations of treatment studies using self-report as primary outcome measures can be more accurate.

Related protocols: CTN-0010

Abstract:

Cannabis use is common among opioid-dependent patients, but studies of its association with treatment outcome are mixed. In this secondary analysis of data, the association of cannabis use with opioid treatment outcome is assessed. In the main study, National Drug Abuse Treatment Clinical Trials Network protocol CTN-0010, participants (n=152) aged 15-21 years were randomized to receive psychosocial treatments and either a 12-week course of buprenorphine-naloxone with a dose taper to zero in weeks 9-12, or a 2-week detoxification with buprenorphine-naloxone. Drug use was assessed by self-report and urine drug screen at baseline and during study weeks 1-12. The association between cannabis and opioid use at weeks 4, 8, and 12 was examined using logistic regression models. Participants reported a median of 3 days (range=0-30) cannabis use in the past month; half reported occasional use, one-third reported no use, and one-sixth reported daily cannabis use. Median lifetime cannabis use was 4 years (range=0-11) and median age of initiation of use was 15 years (range 9-21). Neither past cannabis use (age of initiation and use in the month prior to baseline) nor concurrent use was associated with level of opioid use.

Conclusions: Overall, cannabis use had no association with opioid use over 12 weeks in this sample of opioid-dependent youth. While cannabis use remains potentially harmful, it was not a predictor of poor opioid treatment outcome. These results add to the growing literature on the effects of cannabis use during treatment for another substance use disorder.

Related protocols: CTN-0010

Abstract:

In opioid dependent youth there is substantial attrition from medication-assisted treatment. If youth at risk for attrition can be identified at treatment entry or early in treatment, they can be targeted for interventions to help retain them in treatment. In this study, part of CTN-0010 (“Buprenorphine/Naloxone-Facilitated Rehabilitation for Opioid Dependent Adolescents/Young Adults”), opioid dependent adolescents and young adults (n=152), aged 15-21, were randomized to 12 weeks (BUP, n=74) or 2 weeks of detoxification (DETOX, n=78) with buprenorphine/naloxone (Bup/Nal), both in combination with 12 weeks of psychosocial treatment. Baseline and early treatment related predictors of treatment attrition were identified in each group using bivariate and multivariate logistic regression.

In the DETOX group, 36% left between weeks 2 and 4, at the end of the dose taper, while in the BUP group, only 8% left by week 4. In the BUP group, early adherence to Bup/Nal, early opioid negative urines, use of any medications in the month prior to treatment entry, and lifetime non-heroin opioid use were associated with retention while prior 30-day hallucinogen use was associated with attrition. In the DETOX group, only use of sleep medications was associated with retention. A broad range of other pretreatment characteristics were unrelated to attrition.

Conclusions: Prompt attention to those with early non-adherence to medication or an early opioid positive urine, markers available in the first two weeks of treatment, may improve treatment retention. Extended Bup/Nal treatment appears to be effective in improving treatment retention for youth with opioid dependence across a wide range of demographics and pre-treatment clinical characteristics.

Related protocols: CTN-0010

Abstract:

Attrition in studies of substance use disorder treatment is problematic, potentially introducing bias into data analysis. This secondary analysis of data from protocol CTN-0010 (Buprenorphine/Naloxone-Facilitated Rehabilitation for Opioid Dependent Adolescents/Young Adults) aimed to determine the effect of participant compensation amounts on rates of missing data and observed rates of drug use. In the study, treatment-seeking opioid-dependent subjects aged 15-21 were randomized to a 2-week detoxification with buprenorphine/naloxone (DETOX) or 12 weeks buprenorphine/naloxone (BUP). Participants were compensated $5 for weekly urine drug screens and self-reported drug use information and $75 for more extensive assignments at weeks 4, 8, and 12. Though BUP assignment decreased the likelihood of missing data, there were significantly less missing data at 4, 8, and 12 weeks than other weeks, and the effect of compensation on the probability of urine screens being positive was more pronounced in DETOX subjects.

Conclusions: These findings suggest that variations in the amount of compensation for completing assignments can differentially affect outcome measurements, depending on treatment group assignment. Adequate financial compensation may minimize bias when treatment condition is associated with differential dropout and may be a cost-effective way to reduce attrition. Moreover, active users may be more likely than non-active users to drop out if compensation is inadequate, especially in control groups or in groups who are not receiving active treatment.

Related protocols: CTN-0010

Abstract:

HIV continues to be a significant problem among substance users and their sexual partners in the United States. The National Drug Abuse Treatment Clinical Trials Network (CTN) offers a national platform for effectiveness trials of HIV interventions in community substance abuse treatment programs. This article presents the HIV-related activities of the CTN during its first 10 years. While emphasizing CTN HIV protocols, this article reviews the (1) HIV context for this work; (2) the collaborative process among providers, researchers, and National Institute on Drug Abuse CTN staff, on which CTN HIV work was based; (3) results of CTN HIV protocols and HIV secondary analyses in CTN non-HIV protocols; and (4) implications for future HIV intervention effectiveness research in community substance abuse treatment programs.

Conclusions: While the feasibility of engaging frontline providers in this research is highlighted, the limitations of small to medium effect sizes and weak adoption and sustainability in everyday practice are also discussed.

Related protocols: CTN-0010, CTN-0013, CTN-0015, CTN-0017, CTN-0018, CTN-0019, CTN-0032

Abstract:

Prescription opioids are second only to marijuana as the most commonly used illicit substances among high school seniors. Buprenorphine, a partial mu-agonist, has shown promise in treating opioid-dependent youth in two recent NIDA-funded studies, including a multisite trial in the National Drug Abuse Treatment Clinical Trials Network (CTN-0010, “Buprenorphine/Naloxone-Facilitated Rehabilitation for Opioid Dependent Adolescents/Young Adults”). This ancillary investigation of data from that study, which compared 12 weeks of extended buprenorphine/naloxone (Bup/Nal) therapy to 2 weeks of Bup/Nal detoxification in youth ages 15-21, aimed to examine predictors of opioid abstinence in Bup/Nal-assisted psychosocial treatment for opioid-dependent youth. Results found that youth presenting to treatment with previous 30-day injection drug use and more active medical/psychiatric problems were less likely to have a week-12 opioid-positive urine (OPU). Those with early treatment abstinence (i.e., weeks 1 and 2) and those who received additional nonstudy treatments during the study were less likely to have a week-12 OPU and those not completing 12 weeks of treatment were more likely to have an OPU.

Conclusions: Youth with advanced illness (i.e., reporting injection drug use and additional health problems) and those receiving ancillary treatments to augment study treatment were more likely to have lower opioid use. Treatment success in the first 2 weeks and completion of 12 weeks of treatment were associated with lower rates of opioid-positive urines. These findings suggest that youth with advanced illness respond well to Bup/Nal treatment and identify options for tailoring treatment for opioid-dependent youth presenting at community-based settings.

Related protocols: CTN-0010

Abstract:

The focus of this presentation is on the outcomes of medication studies in the CTN and how those outcomes can be applied to treatment in community-based settings. Medication studies in the CTN have included four studies on opioid dependence (buprenorphine vs. clonidine, buprenorphine taper, buprenorphine for adolescents, and the Prescription Opioid Addiction Treatment Study) and two studies on methylphenidate (methylphenidate for smokers with ADHD and methylphenidate for adolescents with ADHD and substance use disorder). Outcomes from each trial are presented, along with implications for community-based treatment providers. Overall, these protocols have demonstrated that medication studies — both straight-forward studies and highly complex ones — can be conducted safely and effectively in community drug abuse treatment programs. Staff members in these programs can be highly enthusiastic about the new therapies, something that aids in implementation, and evidence supports the fact that successful medication trials can lead to increased use of empirically validated pharmacotherapies.

The presentation ends with a look at ongoing and future medication research in the CTN, including buprenorphine for cocaine dependence, long-acting injectable naltrexone for opioid dependence, bupropion for smokers with stimulant dependence, buspirone for cocaine dependence, and treatments for cannabis dependence.

Related protocols: CTN-0001, CTN-0002, CTN-0003, CTN-0009, CTN-0010, CTN-0028, CTN-0030

Abstract:

The National Drug Abuse Treatment Clinical Trials Network (CTN) has faced many challenges over its first eleven years. This review explores some of these challenges and the paths the CTN took to meet these challenges, including: designing clinical trials that reflect the CTN’s mission and changing public health needs, finding the synergies in the varied expertise of clinical treatment providers and academic researchers, promoting evidence-based practices, and expanding the Network into mainstream medical practices to reach a broader patient population. Included in this exploration are specific examples from CTN clinical trials.

CTN studies have shown that quality clinical trials can be successfully implemented into practice settings unfamiliar with research logistics by taking clinicians’ practical needs and research knowledge level into account. The challenges yet to be faced in the CTN’s efforts to expand opportunities to offer existing treatments to the segment of the drug-abusing population that utilizes mainstream health care seem large, but not as large as the potential for improvements in public health.

Related protocols: CTN-0001, CTN-0002, CTN-0003, CTN-0004, CTN-0005, CTN-0006, CTN-0007, CTN-0009, CTN-0010, CTN-0011, CTN-0013, CTN-0014, CTN-0015, CTN-0017, CTN-0018, CTN-0019, CTN-0020, CTN-0021, CTN-0027, CTN-0028, CTN-0029, CTN-0030, CTN-0031, CTN-0032, CTN-0037, CTCN-0044, CTN-0047, CTN-0048, CTN-0049

Abstract:

This presentation from the “CTN Design & Analysis” workshop at the 2011 Steering Committee Meeting addresses the problem of missing data from CTN trials. The focus is mostly on primary outcomes data, which may be missing for a variety of reasons, including discontinuation of the study, outcomes undefined for some participants (such as quality of life measures after death), or attrition. Though CTN studies are focused on efficacy, not perfection (that is, it’s not “Does treatment work if perfectly delivered?” but instead “Is this a good treatment strategy?”), researchers should still strive to collect complete data from all participants, even those who do not complete the study, as results will never be believable, no matter how sophisticated the statistical method, if there is too much missing data. A variety of approaches for dealing with missing data are discussed, including ways to design trials to help minimize the likelihood of missing data. Ways to analyze missing data are also provided, including repeated-measure designs, linear and quadratic time trend or spline models, and the importance of sensitivity analysis. The presentation uses protocol CTN-0010 to provide a case study about ways to work with and around missing data.

Related protocols: CTN-0010

Abstract:

The objective of this study (ancillary protocol CTN-0010-A-1) was to estimate cost, net social cost, and cost-effectiveness in a clinical trial of buprenorphine-naloxone treatment versus brief detoxification in opioid-dependent youth (protocol CTN-0010). Patients were randomized to 12 weeks of buprenorphine-naloxone (BUP) or a 14-day buprenorphine taper (DETOX). All were offered twice-weekly drug counseling. The 12-week outpatient study treatment cost was $1514 higher for BUP relative to DETOX. However, one-year total direct medical cost was only $83 higher for BUP. The cost-effectiveness ratio of BUP relative to DETOX was $1376 in terms of 1-year direct medical costs per quality-adjusted life year (QALY) and $25,049 in terms of outpatient treatment program cost per QALY. The acceptability curve suggests that the cost-effectiveness ratio of BUP relative to DETOX has an 86% change of being accepted as cost-effective for a threshold of $100,000 per QALY.

In conclusion, extended buprenorphine-naloxone treatment relative to brief buprenorphine detoxification is cost-effective in the US health-care system for the outpatient treatment of opioid-dependent youth. Extended BUP treatment may result in greater social benefits than brief detoxification and be of more value to the insurer because the effectiveness of treatment results in medical cost offsets not captured by the treatment program itself. This suggests there is an incentive within health insurance plans to cover the provision of these services. Similarly, the apparent reduction in crime-related costs in the BUP group is a benefit to society not captured by the health-care system’s analyses. This finding suggests a role for public funding of effective treatment programs such as extended BUP treatment for opioid-dependent youth.

Related protocols: CTN-0010, CTN-0010-A-1

Abstract:

This ancillary investigation of data from protocol CTN-0010 (“Buprenorphine/Naloxone-Facilitated Rehabilitation for Opioid Dependent Adolescents/Young Adults”) examined the effect of monetary incentives on rates of missing data and observed rates of drug use among opioid dependent subjects aged 15-21 during participation in a randomized trial. Subjects seeking treatment for opioid dependence were randomized to 2 weeks of detoxification with buprenorphine/naloxone (DETOX) or 12 weeks of buprenorphine/naloxone (BUP), each with weekly individual and group drug counseling. At weeks 4, 8, and 12, extensive assessments were done and participants were given $75. At all other weeks, assessment was limited to urine drug screen and self-report of drug use, and compensation was only $5. A comparison of drug screens that were missing, positive for opioids, and negative for opioids in the high-reimbursement weeks versus the low-reimbursement rates found that rates of missing data were significantly lower for the high-reimbursement weeks than for the low ones.

This study demonstrated in quantitative terms the effect of participant compensation on rates of missing data and rates of documented drug use and abstinence. The results demonstrate the importance of adequate compensation to maintain follow-up rates, and suggest that the higher compensation rates preferentially enhanced follow-up rates among those who were using opioids.

Related protocols: CTN-0010