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Abstract: The co-occurrence of substance use disorders (SUD) and trauma-exposure is a risk factor for suicidal thoughts and behaviors (STB). However, traditional methods of measurement for suicidal thoughts and behaviors are limited by an overreliance on dichotomous (i.e., yes or no) and averaged/summed scale score measurements. Further, among trauma-exposed individuals with SUD, it remains unclear which specific demographic factors, types of SUDs, and trauma sequelae (e.g., posttraumatic stress disorder [PTSD] symptom clusters) may be associated with elevated STB. The present study utilized item response theory to (a) generate empirically derived STB severity scores and, (b) examine which demographic factors, SUD diagnoses, and DSM-IV PTSD symptom clusters are associated with suicidality in a trauma-exposed sample with SUDs. Female trauma-exposed participants with SUDs (N=544) were recruited from community substance use treatment facilities in the NIDA Clinical Trials Network (CTN). Clinician-administered interviews assessed STB, SUDs, and PTSD symptoms. Results indicated that the unidimensional item response theory (IRT) model used to estimate latent STB severity scores fit well, with strong local reliability and higher levels of latent STB severity. Regression predictors of elevated STB severity included younger age, opioid dependence, and higher PTSD reexperiencing symptoms. Conclusions: Despite the critical importance of understanding, assessing, and identifying STB in trauma-exposed populations with SUDs, research methodologies that measure these variables are limited. This study used an innovative statistical analytic methodology to examine STB in a way that mirrors the weighting of various factors in suicide risk assessment. The findings highlight that trauma-exposed women with substance dependence who are younger, have opioid dependence, and/or have higher reexperiencing symptoms may warrant focused suicide risk assessment and management strategies. Clinicians are advised to screen for and target opioid use disorders and reexperiencing symptoms when addressing suicidal thoughts and behavior in trauma-exposed individuals with SUDs. Future work to elucidate the mechanisms through which these relationships operate would be beneficial.

Abstract:

The CHOICES study (CTN-0055) randomized participants with HIV and opioid use disorder (OUD) to HIV clinic-based extended-release naltrexone (XR-NTX), which which requires complete cessation of opioid use, versus treatment-as-usual (i.e., buprenorphine, methadone). Study participants randomized to XR-NTX were interviewed to assess their experiences with successful and unsuccessful XR-NTX induction.

Semi-structured qualitative interviews were completed with a convenience sample of study participants with HIV and OUD (n=37) randomized to XR-NTX in five HIV clinics between 2018 and 2019. All participants approached agreed to be interviewed. Interviews were digitally recorded, professionally transcribed, and analyzed using thematic analysis.

Participants included women (43%), African Americans (62%) and Hispanics (16%), between 27 to 69 years of age. Individuals who completed XR-NTX induction (n=20) reported experiencing (1) readiness for change, (2) a supportive environment during withdrawal including comfort medications, and (3) caring interactions with staff. Four contrasting themes emerged among participants (n=17) who did not complete induction: (1) concern and anxiety about withdrawal including past negative experiences, (2) ambivalence about or reluctance to stop opioids, (3) concerns about XR-NTX effects, and (4) preferences for other medications.

Conclusions: The results highlight opportunities to improve initiation of XR-NTX in high-need groups. Addressing expectations regarding induction may enhance XR-NTX initiation rates.

Related protocols: CTN-0055

Abstract:

Opioid use disorder (OUD) in pregnant women has increased significantly in recent years. Maintaining these women on sublingual (SL) buprenorphine (BUP) is an evidence-based practice but BUP-SL is associated with several disadvantages that an extended-release (XR) BUP formulation could eliminate.

The National Drug Abuse Treatment Clinical Trials Network (CTN) is conducting an intent-to-treat, two-arm, open-label, pragmatic randomized controlled trial, Medication treatment for Opioid-dependent expectant Mothers (MOMs; CTN-0080), to compare mother and infant outcomes of pregnant women with OUD treated with BUP-XR, relative to BUP-SL. A second aim is to determine the relative economic value of utilizing BUP-XR.

Approximately 300 pregnant women with an estimated gestational age (EGA) of 6–30 weeks, recruited from 12 sites, will be randomized in a 1:1 ratio to BUP-XR or BUP-SL, balancing on site, EGA, and BUP-SL status (taking/not taking) at the time of randomization. Participants will be provided with study medication and attend weekly medication visits through 12 months postpartum. Participants will be invited to participate in two sub-studies to evaluate the: 1) mechanisms by which BUP-XR may improve mother and infant outcomes; and 2) effects of prenatal exposure to BUP-XR versus BUP-SL on infant neurodevelopment.

Conclusions: This paper describes the key design decisions for the main trial made during protocol development. This Investigational New Drug (IND) trial uniquely uses pragmatic features where feasible in order to maximize external validity, hence increasing the potential to inform clinical practice guidelines and address multiple knowledge gaps for treatment of this patient population.

Related protocols: CTN-0080

Abstract:

The U.S. experienced nearly 48,000 opioid overdose deaths in 2017. Treatment of opioid use disorder (OUD) with buprenorphine is a recommended part of primary care, yet little is known about current U.S. practices in this setting. This observational study reports the prevalence of documented OUD and OUD treatment with buprenorphine among primary care patients in six large health systems.

Adults with 2 or more primary care visits during a three-year period (October 1, 2013 to September 30, 2015) in six health systems were included. Data were obtained from electronic health record and claims data, with measures, assessed over the 3-year period, including indicators for documented OUD from ICD 9 and 10 codes and OUD treatment with buprenorphine. The prevalence of OUD treatment was adjusted for age, gender, race/ethnicity, and health system.

Among 1,368,604 primary care patients, 13,942 (1%) had documented OUD, and among those, 21% had OUD treatment with buprenorphine. For those with documented OUD, the adjusted prevalence of OUD treatment with buprenorphine varied across demographic and clinical subgroups. OUD treatment was lower among patients who were older, women, Black/African American and Hispanic (compared to white), non-commercially insured, and those with non-cancer pain, mental health disorders, greater comorbidity, and more opioid prescriptions, emergency department visits or hospitalizations.

Conclusions: This study has important strengths and findings and provides a stark picture of the gap in treatment for patients with OUD. Among primary care patients in six health systems, one in five with OUD were treated with buprenorphine with disparities across demographic and clinical characteristics. Less buprenorphine treatment among those with greater acute care utilization highlights an opportunity for systems-level changes to increase OUD treatment.

Related protocols: CTN-0074

Abstract:

To advance understanding of medication treatments for opioid use disorder (OUD), identification of distinct subgroups and factors associated with differential treatment response is critical. This study examined trajectories of opioid use for patients with OUD who were randomized to (but not in all cases inducted into) buprenorphine-naloxone (BUP-NX) or extended-release naltrexone (XR-NTX), and identified characteristics associated with each trajectory.

This secondary analysis of data from CTN-0051, Extended-Release Naltrexone vs. Buprenorphine for Opioid Treatment (X:BOT), used growth mixture models to identify distinct trajectories of days of opioid use among a subsample of 535 individuals with OUD who participated in the original 24-week randomized controlled trial of BUP-NX (n=281) or XR-NTX (n=254).

Four distinct opioid use trajectory classes were identified for BUP-NX (near abstinent/no use (59%); low use (13.2%); low use, increasing over time (15%); and moderate use, increasing over time (12.8%)). Three distinct opioid use trajectory classes were found for XR-NTX (near abstinent/no use (59.1%); low use (14.6%); and moderate use, increasing over time (26.4%)). Across both BUP-NX and XR-NTX, the near abstinent/no use class had the highest number of medical management visits. Within BUP-NX, the low use class had a greater proportion of individuals with a previous successful treatment history compared with other classes. Within XR-NTX, the moderate use, increasing over time class had the highest proportion of Hispanic participants compared with other classes.

Conclusions: Findings highlight the significant heterogeneity of opioid use during a randomized controlled trial of BUP-NX and XR-NTX and several factors associated with longitudinal patterns of opioid use that can be effectively targeted in the context of active clinician monitoring and adaptive treatment strategies tailored to patient needs. Policies that increase access and adherence to medication treatment, alongside an understanding of the unique patterns of medication response and the factors that influence it, will be critical in reducing the current opioid crisis.

Related protocols: CTN-0051

Abstract:

Pharmacists are on the frontline caring for patients at risk of an opioid overdose and for patients with an opioid use disorder (OUD). Dispensing naloxone and medications for OUD and counseling patients about these medications are way pharmacists can provide care. Key to pharmacists’ involvement is their willingness to take on these practice responsibilities.

As part of NIDA Clinical Trials Network protocol CTN-0075, Physician-Pharmacist Collaboration in the Management of Patients with Opioid Use Disorder, this scoping review aimed to identify, evaluate, and summarize published literature describing pharmacists’ attitudes toward naloxone and medications for OUD, i.e., methadone, buprenorphine, and naltrexone. All searches were performed on December 7, 2015, in 5 databases: Embase.com, PubMed.gov, Cumulative Index to Nursing and Allied Health Literature (CINAHL) via EBSCOhost, Cochrane Central Register of Controlled Trials via Wiley, and Clarivate Web of Science. Articles included original research conducted in the United States, described attitude-related language toward naloxone and medications for OUD, and pharmacists.

A total of 1323 articles were retrieved, 7 were included. Five studies reported on pharmacists’ attitudes toward naloxone dispensing; 1 study reported on attitudes toward naloxone, buprenorphine, and buprenorphine/naloxone; and 1 reported on attitudes toward buprenorphine/naloxone. Respondents were diverse, including pharmacists from different practice specialties.

Studies found that pharmacists agreed with a naloxone standing order, believed that naloxone should be dispensed to individuals at risk of an opioid overdose, and were supportive of dispensing buprenorphine. A minority of pharmacists expressed negative attitudes. Barriers cited to implementation included education and training, workflow, and management support.

Conclusions: Pharmacists were positive in their attitudes toward increased practice responsibilities for patients at risk of an opioid overdose or with an OUD. Pharmacists must receive education and training to be current in their understanding of OUD medications, and they must be supported in order to provide effective care to this patient population.

Related protocols: CTN-0075

Abstract:

Efforts to address the opioid epidemic include increasing access to medications for opioid use disorder (OUD), particularly with buprenorphine. A poorly understood challenge is that among individuals with OUD who do receive buprenorphine, many do not adhere to the pharmacotherapy long enough to achieve sustained benefits. This study aimed to identify factors associated with buprenorphine treatment utilization over time.

Using random-intercept modeling, the authors identified factors associated with buprenorphine treatment utilization over 2 years after first follow-up of 789 individuals with OUD who had participated in a multi-site randomized clinical trial of buprenorphine compared to methadone. (CTN-0050). Key predictors were participants’ reports of buprenorphine treatment accessibility and acceptability (assessed at first follow-up) and their interaction effects, controlling for baseline randomization status, sociodemographics, and other covariates.

Results: Approximately 9.3–11.2% of participants utilized buprenorphine treatment over the 2 years of follow-up. Interaction effects indicated that individuals who perceived buprenorphine to be both accessible and acceptable were most likely to use buprenorphine during follow-up, controlling for other factors. In contrast, individuals who perceived buprenorphine to be unacceptable were least likely to use buprenorphine, regardless the level of perceived access to the medication. Buprenorphine treatment utilization was also negatively associated with Hispanic ethnicity, West coast context, and cumulative months receiving methadone treatment and incarceration during follow-up.

Conclusions: To engage more individuals with OUD in long-term treatment with buprenorphine, interventions should target buprenorphine treatment acceptability, in addition to increasing buprenorphine access, and tailor efforts to meet the needs of vulnerable populations.

Related protocols: CTN-0050

Abstract:

A critical strategy to address the opioid epidemic is increasing access to pharmacotherapy, particularly buprenorphine/naloxone (BUP). BUP is a partial agonist that has a superior safety profile than methadone (MET), a full agonist, in terms of overdose risk. Few studies have compared the long-term outcomes of participants randomized to BUP or MET treatment for opioid use disorder (OUD), however, and differences in treatment retention by medication type may translate into variation in criminal justice outcomes.

This study aimed to compare long-term criminal justice outcomes among opioid dependent individuals randomized to receive buprenorphine or methadone. Five-year follow-up was conducted in 2011-2014 of 303 opioid-dependent participants entering three opioid treatment programs in California in 2006-2009 (as part of CTN-0050, “Starting Treatment with Agonist Replacement Therapy (START)”) and randomized to receive either buprenorphine/naloxone or methadone.

Participants received BUP (n=179) or MET (n=124) for 24 weeks and then were tapered off their treatment over 8 weeks or less or referred for ongoing clinical treatment. Midway through the study, the randomization scheme was switched from 1:1 BUP:MET to 2:1 because of higher drop out in the BUP arm.

Study outcomes included arrests and self-reported incarceration. Predictors included randomization condition (BUP vs. MET), age, gender, race/ethnicity, use of cocaine, drug injection in the 30 days prior to baseline, and study site. Treatment status (BUP, MET, none) during follow-up was included as a time-varying covariate.

There was no significant difference by randomization condition in the proportion arrested (BUP: 55.3%, MET: 54%) or incarcerated (40.9%, 47.3%) during follow-up. Among methadone-randomized individuals, arrest was less likely with methadone treatment (0.50, 0.35-0.72) during follow-up (relative to no treatment) and switching to buprenorphine had a lower likely likelihood of arrest than those receiving no treatment (0.39, 0.18-0.87). Among buprenorphine-randomized individuals, arrest was less likely with receipt of buprenorphine (0.49, 0.33-0.75) during follow-up and switching to methadone had a similar likelihood of arrest as methadone-randomized individuals receiving no treatment. Likelihood of arrest was also negatively associated with older age (0.98, 0.96-1.00); it was positively associated with Hispanic ethnicity (1.63, 1.04-2.56), cocaine use (2.00, 1.33-3.03), injection drug use (2.19, 1.26-3.83), and study site.

Conclusions: In a US sample of people treated for opioid use disorder, continued treatment with either buprenorphine or methadone was associated with a reduction in arrests relative to no treatment. Cocaine use, injection drug use, Hispanic ethnicity, and younger age were associated with higher likelihood of arrest.

Related protocols: CTN-0050

Abstract:

The natural course of prescription opioid use disorder has not been examined in longitudinal studies. This study examined correlates of opioid abstinence over time after completing a treatment trial for prescription opioid dependence.

The multi-site Prescription Opioid Addiction Treatment Study (POATS) examined different durations of buprenorphine-naloxone and different intensities of counseling to treat prescription opioid dependence. Following the clinical trial, a longitudinal study was conducted from March 2009-January 2013. At 18, 30, and 42 months after treatment entry, telephone interviews were conducted (N=375). In this exploratory, naturalistic study, logistic regression analyses examined the association between treatment modality (including formal treatment and mutual help (i.e., 12-step programs)) and opioid abstinence rates at the follow-up assessments.

At the three follow-up assessments, approximately half of the participants reported engaging in current substance use disorder treatment (47-50%). The most common treatments were buprenorphine maintenance (27-35%) and mutual-help group attendance (27-30%), followed by outpatient counseling (18-23%) and methadone maintenance (4%).

In adjusted analyses, current opioid agonist treatment showed the strongest association with current opioid abstinence (ORs=5.4, 4.6, and 2.8 at the three assessments), followed by current mutual-help attendance (ORs=2.2, 2.7, and 1.9); current outpatient counseling was not significantly associated with abstinence in the adjusted models.

Conclusions: This study, using long-term follow-up data from the largest randomized trial of treatment for prescription opioid dependence to date, found that ongoing treatment was strongly associated with odds of opioid abstinence up to 42 months following the trial. Although current opioid agonist treatment had the strongest association with abstinence, mutual-help attendance was also significantly associated with abstinence. Critically, mutual-help attendance was associated with an additive benefit among those receiving opioid agonist treatment and was also associated with abstinence in those not receiving agonist treatment. Adults with prescription opioid dependence appear to benefit from continued medication and mutual-help participation as part of long-term, ongoing care.

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

Abstract:

Prescription Drug Monitoring Programs (PDMPs) are intended to help reduce prescription drug misuse and opioid overdose, yet little is known about the longitudinal patterns of opioid prescribing that may be associated with mortality. This study investigated longitudinal opioid prescribing patterns among patients with opioid use disorder (OUD) and without OUD in relation to mortality using PDMP data.

Growth modeling was used to examine opioid prescription data from the California PDMP for a 4-year period before death or a comparable period ending in 2014 for those remaining from a sample of 7728 patients (2576 with OUD, and 5152 matched non-OUD controls) treated in a large healthcare system.

Compared to controls, individuals with OUD (alive and deceased) had received significantly more opioid prescriptions, greater number of days’ supply, and steeper increases of opioid dosages over time. For morphine equivalents (ME, in grams) the interaction of OUD and mortality was significant at both intercept and slope; deceased OUD patients demonstrated the sharpest increase (an average yearly increment of 7.84 grams over alive patients without OUD) and ended with the highest level of opioids prescribed before they died (20.2 grams higher). Older age, public health insurance, cancer, and chronic pain were associated with higher number and dose of opioid prescriptions.

Conclusions: Prescription Drug Monitoring Programs offer important resources useful for monitoring physician and patient behaviors to determine potentially unsafe prescription and usage patterns. The database can also be used to identify patients at risk for misuse and related adverse consequences based on prescriptions received for opioids and other drugs. In addition to high levels of opioid prescriptions, clinicians need to pay special attention to escalating patterns of prescription dosage, which can be a critical warning signal for heightened mortality risks, particularly among OUD patients.

Abstract:

Not enough evidence exists to compare buprenorphine-naloxone with extended-release naltrexone for treating opioid use disorder. This study evaluated the cost-effectiveness of these two medications using data from NIDA Clinical Trials Network protocol CTN-0051, which examined their effectiveness for opioid use disorder treatment in inpatient detoxification or short-term residential treatment programs.

Costs were evaluated from health care system and societal perspectives over the 24-week intervention and the 36-week observation period. Researchers estimated economic and clinical effectiveness outcomes (Quality-Adjusted Life-Years (QALYs) and abstinent years) and compared incremental costs to incremental effectiveness. Sensitivity analyses included assuming a higher cost of XR-NTX ($1,309/injection vs. $704), and excluding participants who were not successfully initiated on their randomized treatment (i.e., per protocol).

Results found that the mean cost, per participant, of XR-NTX exceeded that of BUP-NX, including $427 greater study-provided detoxification cost and $1,250 greater study-provided medication/therapy cost, but the only statistically significant difference was from the health care system perspective at 24 weeks. Differences in effectiveness were not significant. Considering costs and effectiveness together, BUP-NX was preferred.

Conclusions: Data from this clinical trial indicate that BUP-NX is less costly from the health care system perspective and has similar effectiveness compared to XR-NTX; higher detoxification and medication costs for XR-NTX were not offset by savings in other costs. The inclusion of additional society perspective costs (criminal justice, productivity, and patient time and travel) introduced more uncertainty. Per protocol results were similar, indicating that among those initiating treatment, XR-NTX detoxification and medication costs remain important economic concerns.

Related protocols: CTN-0051

Abstract:

Current data suggest that opioid misuse or opioid use disorder (OUD) may be over-represented among tobacco users. However, this association remains understudied in primary care settings. A better understanding of the extent of heterogeneity in opioid misuse among primary care patients who use tobacco may have implications for improved primary care-based screening, prevention, and intervention approaches. This study assessed the prevalence of opioid misuse and OUD by sociodemographic characteristics and past-year polysubstance use among a sample of 2000 adult (aged 18+) primary care patients across 5 distinct clinics (CTN-0059: the TAP Tool study). Latent class analysis (LCA) was used to identify heterogeneous subgroups of tobacco users according to past-year polysubstance use patterns. Multinomial logistic regression was used to examine variables associated with LCA-defined class membership.

Results found that past-year tobacco use was reported by >84% of participants who reported past-year opioid misuse or OUD. Among those reporting past-year tobacco use, the prevalence of past-year opioid misuse and OUD was 14% and 9.5%, respectively. The prevalence of opioid misuse or OUD was highest among tobacco users who were male or unemployed. Three LCA-defined classes among tobacco users were identified including a tobacco-minimal drug use group (78%), a tobacco-cannabis group (10.1%), and a tobacco-opioid/polydrug use group (11.9%). Class membership differed by sociodemographic characteristics.

Conclusions: Results from this study support the benefit of more comprehensive assessment of and/or monitoring for opioid misuse among primary care patients who use tobacco, particularly for those who are male, unemployed, or polydrug users. Primary care providers should not only recognize the association between tobacco use and opioid misuse, but also the differential liability of misuse among some patient subgroups, which may be used to inform prevention or early intervention groups.

Related protocols: CTN-0059

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:

This study describes the approach and results of a comprehensive cost analysis of NIDA Clinical Trials Network protocol CTN-0051, Extended-Release Naltrexone vs. Buprenorphine for Opioid Treatment (X:BOT), 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. The objective was to provide rigorous estimates of the costs of training, inpatient detoxification, and medication management visits, highlighting the variation in these costs across sites and settings. Results found that providing XR-NTX and BUP-NX to patients receiving inpatient detoxification generates relatively modest costs to the healthcare provider. The average costs per patient were $5,416 for XR-NTX and $4,148 for BUP-NX. Results of the X:BOT cost analysis study provide current practical information on the types of costs incurred by providers, payers, and patients for XR-NTX and BUP-NX, but continued research is needed to understand the costs of medication-assisted treatment as the system continues to evolve.

Abstract:

This ancillary investigation of data from NIDA Clinical Trials Network protocol CTN-0051, a randomized, controlled trial comparing extended-release naltrexone to buprenorphine, examined baseline gender differences in individuals with opioid use disorder (OUD) receiving inpatient services. Participants (N=570) provided demographic, substance use, and psychiatric history information.

Women were significantly younger; more likely to identify as bisexual, live with a sexual partner, and be financially dependent on someone else; and less likely to be employed. Women also reported significantly greater psychiatric comorbidity and risk behaviors, and had shorter duration, but similar age of onset, of opioid use.

Conclusions: Findings underscore economic, psychiatric, and infection vulnerability among women with OUD, which may complicate treatment initiation, retention, and recovery. Gender-specific interventions focused on these areas of disparity for women with OUD should be considered, including integration of OUD care with treatment for co-occurring psychiatric disorders and trauma, couples-based risk reduction interventions which address relational dynamics, and interventions that address the unique needs of sexual minority women.

Related protocols: CTN-0051