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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:

Extended-release naltrexone (XR-NTX) is an effective maintenance treatment for opioid use disorder, but induction from active opioid use is a challenge as individuals must complete detoxification before induction. In this study, researchers aimed to determine whether use of methadone or buprenorphine, long acting agonist opioids commonly used for detoxification, were associated with decreased likelihood of induction onto XR-NTX.

Researchers performed a secondary analysis of a large open-label randomized trial of buprenorphine versus XR-NTX for treatment of individuals with opioid use disorder recruited from eight short term residential (detoxification) units (CTN-0051, X:BOT). This analysis only included individuals randomized to the XR-NTX arm of the trial (N = 283). The method of detoxification varied according to usual practices at each inpatient program. Logistic regression models estimating the log-odds of induction onto XR-NTX were fit, with detoxification regimen received as the predictor.

In the unadjusted logistic regression model, detoxification drug received (either methadone or buprenorphine) was significantly associated with decreased likelihood of induction onto XR-NTX compared to receiving non-opioid detoxification (Overall: P < 0.001); buprenorphine vs non-opioid detoxification: OR (95% CI) = 0.32 (0.15–0.67); methadone vs non-opioid detoxification: OR (95% CI) = 0.23 (0.11–0.46). After controlling for site as a random effect, the association of detoxification drug with induction success lost statistical significance.

Conclusions: Use of agonist medication during detoxification was associated with XR-NTX induction failure. Medication choice was determined by each site’s clinical practice and therefore this association could not be separated from other site level variables.

Related protocols: CTN-0051

Abstract:

This article examines age differences across genders in clinical characteristics in emerging adult (25 years or less) vs. older adult patients (26 years or older) with opioid use disorder (OUD). Participants included 570 people (30% female) entering a comparative effectiveness medication trial of buprenorphine vs. extended-release naltrexone (CTN-0051, X:BOT).

Analysis revealed similar differences across genders in clinical characteristics in emerging adult vs. older participants. However, women who were 26 years old or older reported more mental health problems compared with women 25 years old or younger, while men 25 or younger reported more mental health problems compared with men 26 or older.

Conclusions: Different strategies for emerging adult and older patients seeking OUD treatment may be necessary to address psychiatric comorbidities that differ across genders in this population. Comprehensive psychiatric assessment should be systematically included in OUD treatment for all genders. Treatment should focus on the emerging adult development phase when appropriate, with psychiatric treatment tailored for women and men, separately, across the lifespan.

Related protocols: CTN-0051

Abstract:

Addressing opioid use disorder (OUD), heroin and fentanyl use, and escalating rates of overdose deaths in the United States is a top priority. FDA-approved medications to treat OUD include methadone, buprenorphine, and naltrexone. Both naltrexone and buprenorphine have short- and long-acting formulations, and, unlike methadone, which can be dispensed only from approved facilities, naltrexone and buprenorphine can be prescribed in office-based settings by physicians or other prescribing providers. As new evidence regarding the effectiveness and cost-effectiveness of these treatment is established, providers, payers, and other stakeholders need to understand the resources and associated costs of implementation and ongoing provision of different treatment models.

This study describes the approach and results of a comprehensive multisite cost analysis of the first head-to-head randomized clinical trial in the U.S. of extended-release injectable naltrexone (XR-NTX) and buprenorphine-naloxone (BUP-NX) for preventing opioid relapse (NIDA Clinical Trials Network study CTN-0051). Cost data were collected for 3 intervention phases: program start-up, inpatient detoxification, and up to 24 weeks of medication induction and management visits (post detoxification). Cost analyses were from the healthcare sector perspective (2015 US$); patient costs are also reported. Site visits were conducted, with a cost survey administered to each of the 8 participating treatment programs, and study data on medication and services utilization were analyzed. Nationally representative sources were used to estimate unit costs. Uncertainty was evaluated in sensitivity analyses.

Analysis revealed that mean start-up costs were $1071 per program for XR-NTX and $828 per program for BUP-NX. Mean costs per participant were $5416 for XR-NTX (57% detoxification, 37% medication, 3% provider, 3% patient) and $4148 for BUP-NX (64% detoxification, 12% medication, 10% provider, 14% patient). Total cost per participant ranged by site from $2979 to $8963 for XR-NTX and from $2521 to $6486 for BUP-NX.

Conclusions: For treatment providers, offering XR-NTX and/or BUP-NX as part of existing detoxification treatment modalities generates modest costs in addition to the costs of detoxification, which vary substantially among the 8 sites. From the patient’s perspective, the costs associated with medication management visits may be a barrier for some individuals considering these treatments.

Related protocols: CTN-0051

Abstract:

The multi-site Prescription Opioid Addiction Treatment Study (POATS), conducted by the NIDA Clinical Trials Network, was the largest clinical trial yet conducted with patients dependent on prescription opioids (N=653). In addition to main trial results, the study yielded numerous secondary analyses, and included a 3.5-year follow-up study, the first of its kind with this population. This paper summarizes the POATS design, main outcomes, predictors of outcome, subgroup analyses, the predictive power of early treatment response, and the long-term follow-up study.

POATS examined combinations of buprenorphine-naloxone of varying duration and counseling of varying intensity. The primary outcome analysis showed no overall benefit to adding drug counseling to buprenorphine-naloxone and weekly medical management. Only 7% of patients achieved a successful outcome (abstinence or near-abstinence from opioids) during a 4-week taper and 8-week follow-up; by comparison, 49% of patients achieved success while subsequently stabilized on buprenorphine-naloxone.

Long-term follow-up results were more encouraging, with higher abstinence rates than in the main trial. Patients receiving opioid agonist treatment at the time of follow-up were more likely to have better outcomes, though a sizeable number of patients succeeded without agonist treatment. Some patients initiated risky use patterns, including heroin use and drug injection. A limitation of the long-term follow-up study was the low follow-up rate.

Conclusions: POATS was the first large-scale study of the treatment of prescription opioid dependence; its findings can influence both treatment guidelines and future. In particular, the results of POATS suggest support for an individualized approach to behavioral interventions in the context of buprenorphine-naloxone treatment of prescription opioid use disorders. The fact that some patients benefited from counseling (heroin users who attended sessions regularly, for example) suggests that some patients would do well with just medical management and others should receive additional counseling.

Related protocols: CTN-0030

Abstract:

This is the third of a series of discussions pertaining to CTN collaborations with CSAT. This webinar will consist of three presentations on Pregnant and Parenting Women with SUD.

The webinar’s agenda was as follows:

12:00 – 12:10 pm:
CSAT’s Director, Dr. Kimberly Johnson will speak on the Pregnant and Parenting Women Program at CSAT. [view slides]

12:10 – 12:35 pm:
Dr. Hendrée Jones, Professor in the Department of Obstetrics and Gynecology, School of Medicine, University of North Carolina, Chapel Hill, will review State of the Science on Pregnant and Parenting Women with SUD. [view slides]

12:35 – 1:00 pm:
Dr. Julia Frew and Dr. Daisy Goodman of the Geisel School of Medicine, and Dr. Steven Chapman, Dartmouth-Hitchcock Medical Center will describe the Dartmouth-Hitchcock Moms in Recovery Program. [view slides]

1:00 – 1:30 pm:
Questions and answers.

Abstract:

The combination of prescription opioid dependence and chronic pain is increasingly prevalent and hazardous to public health. Variability in pain may explain poor prescription opioid addiction treatment outcomes in persons with chronic pain. This secondary analysis of Phase 2 of the NIDA Clinical Trials Network’s multisite “Prescription Opioid Addiction Treatment Study” (POATS), examined pain trajectories and pain volatility in patients with chronic pain receiving treatment for prescription opioid addiction.

Secondary analyses of adults with chronic pain (n=149) who received buprenorphine/naloxone (BUP/NLX) and counseling for 12 weeks in POATS were conducted. Good treatment outcome was defined as urine-verified abstinence from opioids at treatment endpoint (week 12) and during at least 2 of the previous 3 weeks. Pain severity significantly declined over time during treatment (b = -0.36, p < .001). Patients with greater pain volatility were less likely to have a good treatment outcome (odds ratio = 0.55, p < .05), controlling for baseline pain severity and rate of change in pain over time. 1 standard deviation increase in pain volatility was associated with a 44% reduction in the probability of endpoint abstinence.

Conclusions: The significant reduction in subjective pain during treatment provides observational support for the analgesic effects of BUP/NLX in patients with chronic pain and opioid dependence. Patients with greater volatility in subjective pain during treatment have increased risk of returning to opioid use by the conclusion of an intensive treatment with BUP/NLX and counseling. Clinicians providing treatment for co-occurring prescription opioid addiction and chronic pain may want to consider monitoring pain volatility to monitor for risk for poor treatment outcomes and adjust treatment regimens accordingly. Future research should examine underlying mechanisms of pain volatility and identify related therapeutic targets to optimize interventions for prescription opioid addiction and co-occurring chronic pain.

Related protocols: CTN-0030

Abstract:

This is the Results Article for CTN-0030-A-3.

Despite the growing prevalence of prescription opioid dependence, longitudinal studies have not examined long-term treatment response. The current study examined outcomes over 42 months in the National Drug Abuse Treatment Clinical Trials Network Prescription Opioid Addiction Treatment Study (POATS, CTN-0030). POATS was a multi-site clinical trial lasting up to 9 months, examining different durations of buprenorphine-naloxone plus standard medical management for prescription opioid dependence, with participants randomized to receive or not receive additional opioid drug counseling. A subset of participants (N=375 of 653) enrolled in a follow-up study. Telephone interviews were administered approximately 18, 30, and 42 months after main-trial enrollment. Comparison of baseline characteristics by follow-up participation suggested few differences.

Results found that at Month 42, much improvement was seen: 31.7% were abstinent from opioids and not on agonist therapy; 29.4% were receiving opioid agonist therapy, but met no symptom criteria for current opioid dependence; 7.5% were using illicit opioids while on agonist therapy; and the remaining 31.4% were using opioids without agonist therapy. Participants reporting a lifetime history of heroin use at baseline were more likely to meet DSM-IV criteria for opioid dependence at Month 42. Engagement in agonist therapy was associated with a greater likelihood of illicit-opioid abstinence. Eight percent (n = 27/338) used heroin for the first time during follow-up; 10.1% reported first-time injection heroin use.

Conclusions: This was the first study to examine long-term treatment outcomes of patients with prescription opioid dependence, and results were more encouraging than short-term outcomes from POATS suggested they might be. Long-term outcomes for those dependent on prescription opioids demonstrated clear improvement from baseline. These results are consistent with research on heroin dependence in supporting the value of opioid agonist therapy for prescription opioid dependence; however, half of the follow-up participants reported good outcomes without agonist therapy as well. Additionally, a subset exhibited a worsening course, by initiating heroin use and/or injection opioid use. These data underscore the importance of longer-term follow-up in understanding the course of this increasingly prevalent substance use disorder.

Related protocols: CTN-0030, CTN-0030-A-3

Abstract:

Given the growing prevalence of prescription opioid dependence and the considerable rates of additional psychopathology in drug dependence, this study examined the association between the presence of a co-occurring Axis I psychiatric disorder and sociodemographic and clinical characteristics in this secondary analysis of patients entering a treatment study for dependence on prescription opioids. Treatment outcomes were also compared. Patients dependent on prescription opioids participated in a multi-site, two-phase, randomized, controlled trial to assess different lengths of buprenorphine-naloxone pharmacotherapy and different intensities of counseling (National Drug Abuse Treatment Clinical Trials Network protocol CTN-0030, Prescription Opioid Addiction Treatment Study (POATS)). Among the 653 participants entering the first phase of the trial, 360 entered the second phase, receiving 12 weeks of buprenorphine-naloxone treatment; they are reported here. Half of those participants (180/360) had a current co-occurring psychiatric disorder in addition to substance dependence. Sociodemographic characteristics were similar overall between those with and without a co-occurring psychiatric disorder, but women were 1.6 times more likely than men to have a co-occurring disorder. On several clinical indicators at baseline, participants with a co-occurring disorder had greater impairment. However, they had better opioid use outcomes at the conclusion of 12 weeks of buprenorphine-naloxone stabilization than did participants without a co-occurring disorder.

Conclusions: Prescription opioid-dependent patients with a co-occurring psychiatric disorder had a better response to buprenorphine-naloxone treatment despite demonstrating greater impairment at baseline. This finding emphasizes the importance of conducting psychiatric assessments in substance dependence treatment settings so that clinicians are best able to understand and serve patients. Additional research is needed to determine the mechanism of this finding and to adapt treatments to address this population.

Related protocols: CTN-0030

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:

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:

This study aimed to quantify the relations between craving and withdrawal symptoms and time to first opioid use among prescription opioid (PO) abusers undergoing buprenorphine detoxification. Higher indicators of craving and withdrawal at the outset of the taper were hypothesized to predict earlier user. Data from 653 PO-dependent individuals initiating a 14-day taper from buprenorphine/naloxone, recruited for the National Drug Abuse Treatment Clinical Trials Network protocol CTN-0030, were analyzed using survival analysis to explore time to first use as a function of opioid craving and withdrawal. Participants were collapsed across condition and measurements taken at the start of the taper were used. Participants were followed for 10 weeks after the taper began. PO craving was measured by 3 items on the Visual Analog Scale (VAS; e.g. “How much do you currently crave opiates?”) and opioid withdrawal was measured by the Clinical Opiate Withdrawal Scale and 1 item on the VAS. Withdrawal significantly predicted time to first use, such that each withdrawal unit increase led to a 1.0% decrease in time to first use. Craving items significantly predicted time to first use. Each unit increase on the craving item response scales was associated with a 1.7% to 1.9% decrease in time to first use, depending on the item. Further analyses revealed differences among individuals who terminated study involvement after the first taper and those willing to take part in a second taper.

Conclusions: Higher reports of withdrawal and craving at the outset of a buprenorphine taper are important clinical indicators of earlier lapse to opioids. Novel therapies to attenuate these effects are needed.

Related protocols: CTN-0030

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:

Although gender differences in substance use disorders have been identified, few studies have examined gender differences in prescription drug dependence. This study aimed to examine gender differences in clinical characteristics and treatment outcomes in a large clinical trial for prescription opioid dependence, National Drug Abuse Treatment Clinical Trials Network protocol CTN-0030, “Prescription Opioid Addiction Treatment Study (POATS).” Despite no pre-treatment differences in opioid dependence severity, women reported significantly greater functional impairment, greater psychiatric severity, and high likelihood of using opioids to cope with negative affect and pain than men. Women were also more likely than men to have first obtained opioids via a legitimate prescription and to use opioids via the intended route of administration. Men reported significantly more alcohol problems than women. There were no significant gender differences in medication dose, treatment retention, or opioid outcomes. Thus, despite the presence of pre-treatment gender differences in this population, once the study treatment was initiated, women and men exhibited similar opioid use outcomes.

Conclusions: These findings underscore the importance of careful assessment of prescription opioid misuse in women, as traditional markers of opioid misuse and need for treatment (e.g. using the drug via a non-recommended route) were less common in women. Though the severity of prescription opioid dependence was similar among men and women in this sample, the functional impairment associated with this disorder appears to be more severe for women, and rates of treatment success were low regardless of gender. Efforts to improve overall outcome are needed.

Abstract:

Prescription opioid dependence is a growing problem, but little research exists on its treatment, including patient characteristics that predict treatment outcome. A secondary analysis from a large, multisite, randomized clinical trial, the National Drug Abuse Treatment Clinical Trials Network (CTN) Prescription Opioid Addiction Treatment Study (POATS, CTN-0030), was undertaken to examine baseline patient characteristics (N=360) associated with success during 12-week buprenorphine/naloxone treatment for prescription opioid dependence. Baseline predictor variables included self-reported demographic and opioid use history information, diagnoses assessed via the Composite International Diagnostic Interview, and historical opioid use and related information from the Pain and Opioid Analgesic Use History. In bivariate analyses, pre-treatment characteristics associated with successful opioid use outcome included older age, past-year or lifetime diagnosis of major depressive disorder, initially obtaining opioids with a medical prescription to relieve pain, having only used opioids by swallowing or sublingual administration, never having used heroin, using an opioid other than extended-release oxycodone most frequently, and no prior opioid dependence treatment. In multivariate analysis, age, lifetime major depressive disorder, having only used opioids by swallowing or sublingual administration, and receiving no prior opioid dependence treatment remained as significant predictors of successful outcome.

Conclusions: This is the first study to examine characteristics associated with treatment outcome in patients dependent exclusively on prescription opioids. Characteristics associated with successful outcome after 12 weeks of buprenorphine/naloxone treatment include some that have been previously found to predict heroin-dependent patients’ response to methadone treatment and some specific to prescription opioid-dependent patients receiving buprenorphine-naloxone. It is hoped that knowledge about patient characteristics associated with successful (and unsuccessful) outcome from the current study can be used to help develop more effective treatments for this patient population.

Related protocols: CTN-0030