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Abstract: Aims: To estimate the effectiveness of different thresholds for administering opioid withdrawal medications (clonidine and clonazepam) on the probability of successfully initiating extended-release naltrexone (XR-NTX) among participants with opioid use disorder (OUD) during medically managed withdrawal. Design: Secondary analysis of a multisite clinical trial comparing a rapid vs. standard approach for XR-NTX initiation, 2021–2022. Setting: Six community inpatient addiction treatment units in the United States. Participants: English-speaking adults seeking treatment for DSM-5 OUD and expressing interest in XR-NTX treatment (n = 415). Measurements: We estimated the extent to which the following thresholds for adjunctive medication administration would affect the probability of initiating XR-NTX over time: 1) where adjunctive medications were given in response to at mild-to-moderate withdrawal symptoms or greater [Clinical Opiate Withdrawal Scale (COWS) score ≥ 5), 2) where adjunctive medications were given in response to minimal withdrawal symptoms or greater (COWS score ≥ 3) and 3) where adjunctive medications were given regardless of withdrawal symptoms. Using a longitudinal sequentially doubly robust estimator, we estimated the cumulative probability of XR-NTX initiation under each of these three treatment regimes while accounting for dropout and initiation of other medications as competing events. Findings: The estimated probability of initiating XR-NTX by day 14 was 50.4% [95% confidence interval (CI) = 41.8–58.9) under the no-threshold regime, 43.9% (95% CI = 39.1–48.7) under the regime of waiting for minimal withdrawal symptoms and 38.5% (95% CI = 34.3–42.6) under the regime of waiting for mild-to-moderate withdrawal symptoms. Probability of XR-NTX initiation was a statistically significant 11.9 percentage points higher (95% CI = 3.6–20.2) under the no-threshold regime versus the mild-to-moderate threshold regime, and a non-statistically significant 6.4 percentage points (95% CI = −0.8 to 13.7) higher under the no-threshold regime versus the minimal threshold regime. Conclusions: Providing clonidine and clonazepam daily during the first five days of medically managed opioid withdrawal appears to statistically significantly increase the likelihood of initiating extended-release naltrexone treatment compared with waiting for mild-to-moderate withdrawal symptoms to administer adjunctive medications. To improve initiation rates, providers may consider lowering the threshold at which they provide adjunctive medications, giving these medications preemptively or to manage even minimal withdrawal symptoms. Related protocols: CTN-0097

Abstract:

Opioid use disorder (OUD) represents a significant public health challenge. Identifying variations in the severity of opioid withdrawal that can predict treatment success and may help improve the process of aligning patients with appropriate therapies could help improve outcomes. This study was a secondary latent class growth analysis (LCGA) of data from a randomized controlled trial that involved individuals seeking treatment for OUD (CTN-0051). Participants were 474 adults (270 taking buprenorphine, 204 on extended-release naltrexone (XR-NTX)) in a 24-week trial for OUD. Withdrawal was measured weekly using the Subjective Opioid Withdrawal Scale. Analysis found that a two-class model (high sustained withdrawal and low withdrawal classes) was most parsimonious among patients in both treatment arms. The experience of withdrawal was more intense in the high withdrawal class of the BUP arm when compared to the XTR arm (average M=22.9 vs. M=12.4 respectively). No differences were evident regarding age, sex, race, or ethnicity. There were significant differences in history of anxiety and history of depression.

Related protocols: CTN-0051

Abstract:

This study aimed to estimate health state utility values (HSUVs) for the key health states found in opioid use disorder (OUD) cost-effectiveness models in the published literature. Data were obtained from six trials representing 1,777 individuals with OUD in the NIDA Clinical Trials Network (CTN-0001, -0002, -0009. -0030, -0049, and -0051). Researchers implemented mapping algorithms to harmonize data from different measures of quality of life (the SF-12 Versions 1 and 2 and the EQ-5D-3 L). They performed a regression analysis to quantify the relationship between HSUVs and the following variables: days of extra-medical opioid use in the past 30 days, injecting behaviors, treatment with medications for OUD, HIV status, and age. A secondary analysis explored the impact of opioid withdrawal symptoms.

There were statistically significant reductions in HSUVs associated with extra-medical opioid use (-0.002 (95% CI [-0.003,-0.0001]) to -0.003 (95% CI [-0.005,-0.002]) per additional day of heroin or other opiate use, respectively), drug injecting compared to not injecting (-0.043 (95% CI [-0.079,-0.006])), HIV-positive diagnosis compared to no diagnosis (-0.074 (95% CI [-0.143,-0.005])), and age (-0.001 per year (95% CI [-0.003,-0.0002])). Parameters associated with medications for OUD treatment were not statistically significant after controlling for extra-medical opioid use (0.0131 (95% CI [-0.0479,0.0769])), in line with prior studies. The secondary analysis revealed that withdrawal symptoms are a fundamental driver of HSUVs, with predictions of 0.817 (95% CI [0.768, 0.858]), 0.705 (95% CI [0.607, 0.786]), and 0.367 (95% CI [0.180, 0.575]) for moderate, severe, and worst level of symptoms, respectively.
Conclusions: Researchers for this study observed HSUVs for OUD that were higher than those from previous studies that had been conducted without input from people living with the condition.

Related protocols: CTN-0001, CTN-0002, CTN-0009, CTN-0030, CTN-0049, CTN-0051

Abstract:

Buprenorphine is an effective yet underused treatment for opioid use disorder (OUD). The goal of this study, part of CTN-0099 (Emergency Department-INitiated bupreNOrphine and VAlidaTIOn Network Trial: ED-INNOVATION), was to evaluate the feasibility (acceptability, tolerability, and safety) of 7-day injectable extended-release buprenorphine in patients with minimal to mild opioid withdrawal.

This nonrandomized trial comprising 4 emergency departments in the Northeast, mid-Atlantic, and Pacific geographic areas of the US included adults aged 18 years or older with moderate to severe OUD and Clinical Opiate Withdrawal Scale (COWS) scores less than 8 (minimal to mild), in which scores range from 0 to 7, with higher scores indicating increasing withdrawal. Exclusion criteria included methadone-positive urine, pregnancy, overdose, or required admission. Outcomes were assessed at baseline, daily for 7 days by telephone surveys, and in person at 7 days. Patient recruitment occurred between July 13, 2020, and May 25, 2023.

The intervention was injection of a 24-mg dose of a weekly extended-release formulation of buprenorphine (CAM2038) and referral for ongoing OUD care. Primary feasibility outcomes included the number of patients who (1) experienced a 5-point or greater increase in the COWS score or (2) transitioned to moderate or greater withdrawal (COWS score =13) within 4 hours of extended-release buprenorphine or (3) experienced precipitated withdrawal within 1 hour of extended-release buprenorphine. Secondary outcomes included injection pain, satisfaction, craving, use of nonprescribed opioids, adverse events, and engagement in OUD treatment.

A total of 100 adult patients were enrolled (mean [SD] age, 36.5 [8.7] years; 72% male). Among the patients, 10 (10.0% [95% CI, 4.9%-17.6%]) experienced a 5-point or greater increase in COWS and 7 (7.0% [95% CI, 2.9%-13.9%]) transitioned to moderate or greater withdrawal within 4 hours, and 2 (2.0% [95% CI, 0.2%-7.0%]) experienced precipitated withdrawal within 1 hour of extended-release buprenorphine. A total of 7 patients (7.0% [95% CI, 2.9%-13.9%]) experienced precipitated withdrawal within 4 hours of extended-release buprenorphine, which included 2 of 63 (3.2%) with a COWS score of 4 to 7 and 5 of 37 (13.5%) with a COWS score of 0 to 3. Site pain scores (based on a total pain score of 10, in which 0 indicated no pain and 10 was the worst possible pain) after injection were low immediately (median, 2.0; range, 0-10.0) and after 4 hours (median, 0; range, 0-10.0). On any given day among those who responded, between 29 (33%) and 31 (43%) patients reported no cravings and between 59 (78%) and 75 (85%) reported no use of opioids; 57 patients (60%) reported no days of opioid use. Improving privacy (62%) and not requiring daily medication (67%) were deemed extremely important. Seventy-three patients (73%) were engaged in OUD treatment on day 7. Five serious adverse events occurred that required hospitalization, of which 2 were associated with medication.

Conclusions: This nonrandomized trial of the feasibility of a 7-day buprenorphine injectable in patients with minimal to mild opioid withdrawal (COWS scores, 0-7) found the formulation to be acceptable, well tolerated, and safe in those with COWS scores of 4 to 7. This new medication formulation could substantially increase the number of patients with OUD receiving buprenorphine.

Related protocols: CTN-0099

Abstract:

This is the primary outcomes article for CTN-0097.

Importance: Injectable extended-release (XR)-naltrexone is an effective treatment option for opioid use disorder (OUD), but the need to withdraw patients from opioid treatment prior to initiation is a barrier to implementation.

Objective: To compare the effectiveness of the standard procedure (SP) with the rapid procedure (RP) for XR-naltrexone initiation.

Design, setting, and participants: The Surmounting Withdrawal to Initiate Fast Treatment with Naltrexone study was an optimized stepped-wedge cluster randomized trial conducted at 6 community-based inpatient addiction treatment units. Units using the SP were randomly assigned at 14-week intervals to implement the RP. Participants admitted with OUD received the procedure the unit was delivering at the time of their admission. Participant recruitment took place between March 16, 2021, and July 18, 2022. The last visit was September 21, 2022.

Interventions: Standard procedure, based on the XR-naltrexone package insert (approximately 5-day buprenorphine taper followed by a 7- to 10-day opioid-free period and RP, defined as 1 day of buprenorphine at minimum necessary dose, 1 opioid-free day, and ascending low doses of oral naltrexone and adjunctive medications (eg, clonidine, clonazepam, antiemetics) for opioid withdrawal.

Main outcomes and measures: Receipt of XR-naltrexone injection prior to inpatient discharge (primary outcome). Secondary outcomes included opioid withdrawal scores and targeted safety events and serious adverse events. All analyses were intention-to-treat.

Results: A total of 415 participants with OUD were enrolled (mean [SD] age, 33.6 [8.48] years; 205 [49.4%] identified sex as male); 54 [13.0%] individuals identified as Black, 91 [21.9%] as Hispanic, 290 [69.9%] as White, and 22 [5.3%] as multiracial. Rates of successful initiation of XR-naltrexone among the RP group (141 of 225 [62.7%]) were noninferior to those of the SP group (68 of 190 [35.8%]) (odds ratio [OR], 3.60; 95% CI, 2.12-6.10). Withdrawal did not differ significantly between conditions (proportion of days with a moderate or greater maximum Clinical Opiate Withdrawal Scale score (>12) for RP vs SP: OR, 1.25; 95% CI, 0.62-2.50). Targeted safety events (RP: 12 [5.3%]; SP: 4 [2.1%]) and serious adverse events (RP: 15 [6.7%]; SP: 3 [1.6%]) were infrequent but occurred more often with RP than SP.

Conclusions: In this trial, the RP of XR-naltrexone initiation was noninferior to the standard approach and saved time, although it required more intensive medical management and safety monitoring. The results of this trial suggest that rapid initiation could make XR-naltrexone a more viable treatment for patients with OUD.

Related protocols: CTN-0097

Abstract:

The Clinical Opiate Withdrawal Scale (COWS) is used to assess withdrawal in clinical trials and practice. The aims of this study were to examine the inter-item correlations and factor structure of the COWS in opioid-dependent men and women. This is a secondary data analysis of the National Drug Abuse Treatment Clinical Trials Network study CTN-0003, a randomized clinical trial that compared buprenorphine/naloxone tapering strategies. The trial included 11 sites in 10 US cities. Participants were opioid-dependent individuals (n=516) that had data on the COWS. The COWS at study baseline was analyzed in the study. Inter-item correlations showed weak to moderate relationships between the items. A 1-factor model did not fit the data for men, where resting pulse rate was not related to withdrawal for men, and yawning and gooseflesh skin was not related to withdrawal for women. A reduced model comprised of only the 8 items that were significantly related to the construct of withdrawal in both men and women, and an exploratory 2-factor model, were also assessed but not retained due to inconsistencies across gender.

Conclusions: This study failed to find a single model where all items were related to the construct of withdrawal (i.e., statistically significant meaningful factor loadings) for men and women in mild withdrawal. Further research testing the hypothesized factor structure in other opioid-dependent samples, particularly in samples with greater variation in COWS scores and for those in moderate opioid withdrawal, is needed. The COWS was developed to rate severity within each item because that corresponds with clinical severity within the individual on each item; that may not be necessarily the case across items. The composite score simply acknowledges that some individual will show more, or less, withdrawal symptoms within certain physiological systems and may therefore not assess a single construct of withdrawal. Further research testing the hypothesized factor structure in other opioid-dependent samples is needed.

Related protocols: CTN-0003

Abstract:

This secondary analysis of data from the National Drug Abuse Institute Clinical Trials Network study CTN-0030 (Prescription Opioid Addiction Treatment Study (POATS)) aimed to compare induction experiences among participants who self-reported using one of the four most commonly reported prescription opioids (POs) and examine factors associated with difficult buprenorphine-naloxone (bup-nx) induction. The Prescription Opioid Addiction Treatment Study was a multi-site, randomized clinical trial using a two-phase adaptive treatment research design. This analysis examined bup-nx induction of participants who self-reported primary PO use of methadone, ER-oxycodone, IR-oxycodone, and hydrocodone (n=569). Analyses examined characteristics associated with difficult induction, defined as increased withdrawal symptoms measured by the Clinical Opiate Withdrawal Scale (COWS) after the first bup-nx dose with higher scores denoting greater withdrawal symptoms/severity. Contrary to the study’s hypothesis, difficult induction experiences did not differ by primary PO type. Those who experienced a post-induction increase in COWS score had lower pre-dose COWS scores compared to those who did not experience a post-induction increase in COWS score (10.09 vs. 12.77). Demographics characteristics, depression, and pain history did not predict a difficult induction.

Conclusions: Difficult bup-nx inductions were not associated with participants’ primary PO. Severity of withdrawal, measured with the COWS, was an important variable, reminding clinicians that bup-nx should not be commenced prior to evidence of moderate opioid withdrawal. These findings add to the evidence that with careful procedures, bup-nx can be used with few difficulties in PO-dependent patients.

Related protocols: CTN-0030

Abstract:

The Adjective Rating Scale for Withdrawal (ARSW) is commonly used to assess opiate withdrawal in clinical practice and research. This study aimed to examine the factor structure of the ARSW, test measurement invariance across gender and treatment groups, and assess longitudinal measurement invariance across the clinical trial. Secondary data analysis of National Drug Abuse Treatment Clinical Trials Network protocol CTN-0003, a randomized clinical trial comparing two tapering strategies for buprenorphine/naloxone, was performed. The ARSW was analyzed at baseline, end of taper, and 1-month follow-up (n=515 opioid-dependent individuals). A 1-factor model of the ARSW fit the data and demonstrated acceptable reliability. Measurement invariance was supported across gender and taper groups. Longitudinal measurement invariance was not found across the course of the trial, with baseline assessment contributing to the lack of invariance.

Conclusions: The ARSW appears to be measuring withdrawal equivalently across gender and buprenorphine/naloxone taper periods in opioid-dependent individuals. The authors recommend that researchers and clinicians using this tool analyze ARSW total scores across groups at each time point separately. If changeover time is of interest, change from post-treatment through follow-up may offer the most valid comparison; pre-treatment ARSW values may not be assessing withdrawal in the same way as post-treatment and follow-up values. Future research is needed to replicate these findings in other trials, in various clinical settings, and across other demographic groups in order to fully assess the measurement properties of the ARSW.

Related protocols: CTN-0003

 

Abstract:

This CTN ancillary investigation aimed to address an urgent need for screening of substance use problems in medical settings by examining substance-specific dependence criteria as potential brief screeners for the detection of patients with a substance use disorder (SUD). Researchers examined data from intake assessments of substance use disorders completed by 920 opioid dependent adults from outpatient treatment settings at 11 programs in 10 U.S. cities (part of protocol CTN-0003, which investigated taper schedules for buprenorphine/naloxone dosing). Data were analyzed by factor analysis, item response theory (IRT), sensitivity, and specificity procedures. Across all substances (alcohol, amphetamines, cannabis, cocaine, sedatives), “withdrawal” was among the least prevalent symptoms, while “taking large amounts” and “inability to cut down” were among the more prevalent. Items closely related to the latent trait of a substance use disorder showed good-to-high values of area under the receiver operating characteristic curve in identifying cases of SUD; IRT-defined severe and less discriminative items exhibited low sensitivity in identifying cases of SUD (“withdrawal” for all substances; “time using” for alcohol and sedatives; “giving up activities” for sedatives).

Conclusions: Study results suggest that “withdrawal” and “time using” are much less reliable indicators for a substance use disorder than “taking larger amounts than intended” and “inability to cut down,” and that the latter two items should be studied further for consideration in developing a simplified tool for screening patients for SUD in medical settings. These findings have implications for the use of common health indicators in electronic health records systems to improve patient care. This study also demonstrates the unique value of IRT analysis in determining the underlying trait of a set of measures and elucidating item-level psychometric information to help interpret results of sensitivity and specificity; researchers should consider incorporating IRT approaches into their analysis plans to support the psychometric quality of patient-reported items.

Supported by the Duke Clinical Research Institute (CTN DSC 1).

Related protocols: CTN-0003

Abstract:

Clinical parameters for determining buprenorphine dose have not been adequately examined in treatment outcome research. This study is a secondary analysis of data collected from National Drug Abuse Treatment Clinical Trials Network (CTN) protocol CTN-0003, a recently completed comparison of buprenorphine taper schedules designed to assess whether participant baseline characteristics are associated with buprenorphine dose. For this ancillary investigation, 516 participants were categorized by dose provided in the final dosing week after 3 weeks of flexible dosing (9.3% received a final week dose of 8 mg buprenorphine, 27.3% received 16 mg, and 63.4% received 24 mg). Findings show that final week dose groups differed in baseline demographic and drug use characteristics including education, heroin use, route of drug administration, withdrawal symptoms, and craving. These groups also differed in opioid use during the four dosing weeks, with the lowest use in the 8 mg group and highest use in the 24 mg group (p < .0001). A significant association was also found between final week dose group and withdrawal and craving. Participants with greater withdrawal symptoms and craving scores had larger final week doses.

Conclusions: Final week dose groups in this investigation differed in demographic and drug use characteristics, and the group receiving the largest final week dose had the highest rate of continued opioid use. These findings may contribute to the development of clinical guidelines regarding buprenorphine dose in the treatment of opioid dependence; however, further investigations that include random assignment to dose by baseline characteristics are needed. Methods for determining optimal buprenorphine dose will be extremely helpful in clinical settings in which physicians currently have no formal tools for determining appropriate dosages.

Related protocols: CTN-0003

Abstract:

Previous work suggests that opioid users have lower health-related quality of life (HRQOL) than patients with more prevalent chronic illnesses such as hypertension or diabetes. Although comparisons with population norms are informative, studies of the correlates of HRQOL for opioid users are needed to plan clinical services. This article reports on a study that tested a conceptual model of the pathways between physiologic factors and symptoms in relation to HRQOL among 344 opioid users participating in the National Drug Abuse Treatment Clinical Trials Network (CTN) studies about buprenorphine (protocols CTN-0001 and CTN-0002). Physical and mental HRQOL were measured by the Short-Form (SF)-36; withdrawal signs, symptoms, and functioning were also measured with validated instruments. Using structural equation modeling, the authors tested hypotheses that medical history directly predicts withdrawal signs and symptoms, and that medical history, withdrawal signs and symptoms, and functioning predict the physical and mental HRQOL latent variables of the SF-36. The study’s results found most hypothesized relationships to be significant, with good model fit. The model explained 34% of the variance in physical HRQOL. In conclusion, the conceptual framework appears valid for explaining variation in the physical and mental HRQOL of opioid users undergoing medically managed withdrawal. Future work should assess whether opioid dependence treatments that are informed by effects of treatment on HRQOL lead to better outcomes, including increases in patients’ motivation to engage in longer-term rehabilitation efforts.

Related protocols: CTN-0001, CTN-0002

Abstract:

This two-hour course, produced by the National Drug Abuse Treatment Clinical Trials Network (CTN) Clinical Coordinating Center for CTN members and the public, provides an overview of important information about drugs of abuse, including intoxication and withdrawal syndromes of various drug classes, DMS-IV substance abuse and dependence criteria, and commonly used methods and procedures used to evaluate substance use, abuse, and dependence measures.

The target audience is CTN members and members of the public interested in learning the basics about drug abuse and the identification of addiction.

Presented by Gloria M. Miele, PhD (Columbia University, GNY Node).

Additional Resources:

Download slides (pptx)

Abstract:

The occurrence of craving and withdrawal symptoms may contribute to relapse to drug use during treatment episodes and recovery efforts. Craving compels drug seeking behavior and withdrawal symptoms are a barrier to sustained abstinence. The current study examines indices of craving intensity and withdrawal symptom severity across time in a detoxification program, and addresses the association between craving and withdrawal symptom severity and drug use. The study analyzed data collected as part of protocol CTN-0003, a 28-day taper trial, using the Visual Analog Scale (VAS) to collect information on self-reported craving intensity and the Clinical Opiate Withdrawal Scale (COWS) to collect clinically observed withdrawal symptoms from 516 opiate-dependent study participants. Results demonstrate that patterns of craving and withdrawal occurred in parallel across the four weeks, with a sharp reduction in both craving and withdrawal symptoms from week 1 to week 2, followed by a slower reduction from week 2 to week 3. Both craving and withdrawal symptoms leveled out from week 3 to week 4. Understanding changes in craving and withdrawal across time in a detoxification program is useful in guiding clinical treatment plans, such as scheduled clinic visits and number of weekly behavioral sessions.

Related protocols: CTN-0003

Abstract:

For individuals dependent on opioids, recovery efforts begin with a period of withdrawal that typically includes discomfort from symptoms, possibly precipitating a return to drug use. The study described here, a secondary analysis of individuals enrolled in the National Drug Abuse Treatment Clinical Trials Network study CTN-0002 (“Buprenorphine/Naloxone versus Clonidine for Outpatient Opiate Detoxification”), investigated whether the provision of ancillary medications for opioid withdrawal symptoms affected treatment outcomes in 139 participants receiving buprenorphine in a 13-day detoxification trial. Outcomes measures include the number of opioid-free urine samples collected and retention in treatment. Ancillary medications were provided to 70% of participants: 59% received medication for insomnia, 45% for anxiety, 40% for bone pain, 35% for nausea, and 28% for diarrhea.

Findings indicate no difference in the number of opioid-free urine samples between the group receiving ancillary medication and the group who did not, although tests of specific ancillary medications indicate that those who received diarrhea medication had fewer opioid-free urines than those who did not (P = .004). Results also indicate that participants attended fewer days of treatment if they received anxiety, nausea, or diarrhea medication compared to no medication (all P values < .05). Clinicians treating individuals dependent on opioids should consider high rates of craving and withdrawal symptoms and the need for ancillary medications as a red flag for further monitoring and assessment. Practice changes that may be required include adjusting buprenorphine dose, increasing provision of ancillary medications, switching to another pharmacotherapy, or providing alternatives to medication for treating withdrawal symptoms, and monitoring patients to ensure they are taking buprenorphine as instructed.

Related protocols: CTN-0002

Abstract:

This article reports on an ancillary investigation of protocol CTN-0010 (“Buprenorphine/Naloxone-Facilitated Rehabilitation for Opioid Dependent Adolescents/Young Adults”) examining baseline patient characteristics to predict dosing of buprenorphine-naloxone, a promising treatment for opioid addiction in youths. Outpatients aged 15-21 were randomized to a 12-week buprenorphine-naloxone dosing condition (including 4 weeks of taper) as part of CTN-0010. Predictors of dosing included sociodemographic characteristics (gender, race, age, and education), substance use (alcohol, cannabis, cocaine, and nicotine use), and clinical characteristics (pain and withdrawal severity). Most (75.4%) reported having either “some” (n=40, 58%) or “extreme” (n=12, 17.4%) pain on enrollment. Maximum daily dose of buprenorphine-naloxone (19.7mg) received by patients reporting “extreme” pain at baseline was significantly higher than the dose received by patients reporting “some” pain (15mg) and those without pain (12.8mg). In the adjusted analysis, only severity of pain and withdrawal significantly predicted dose. During the dosing period, there were no significant differences in opioid use, as measured by urinalysis, by level of pain.

These data suggest that the presence of pain in this population may be quite prevalent and also appears to predict buprenorphine-naloxone dose levels in opioid-dependent youth. Patients with pain have comparable opioid use outcomes to those without pain, but require higher buprenorphine-naloxone doses. Further research is needed to assess the clinical importance of pain preceding vs. following opioid use. This study further suggests that patients with pain respond to higher buprenorphine doses; hence, buprenorphine may have a role in managing pain in opioid-dependent youth.

Related protocols: CTN-0010