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This study examines the demographic and clinical correlates and time course of depressive symptoms among abstinent adolescents with substance use disorders (SUD) during residential treatment. Fifty-six adolescents were administered the Beck Depression Inventory at Weeks 1, 3, and 5 of residential treatment for SUD. Clinically significant depression persisted in a substantial minority at the time of discharge. Shorter length of stay patients reported higher baseline scores and a significant decline by Week 3. Longer length of stay patients showed significant decline in scores only at Week 5. Females, Caucasians, and high frequency cocaine/opiates users had elevated depressive symptoms, while those with shorter duration of abstinence did not. [ABSTRACT FROM AUTHOR]

Recent reports describe alarming trends of adolescent drug use and a lack of treatment for substance use disorder symptoms. Early efforts in adolescent treatment relied on adult models that may not have considered the unique needs of adolescents. Recently, there has been an increased emphasis in developing intervention models designed specifically for adolescents. This article provides descriptions of current approaches to adolescent substance abuse treatment and summaries of research assessing the effectiveness of these models. [ABSTRACT FROM AUTHOR]

AbstractObjective: Adverse Childhood Events (ACEs) are associated with increased vulnerability for posttraumatic stress disorder (PTSD), but not everyone who experiences ACEs develops PTSD. Impulsivity has gained interest as a potential mediator between ACEs and PTSD, given that both PTSD and ACEs have been closely related to impulsivity. However, less is known about the relationship within the context of substance use disorder (SUD), a population highly vulnerable to co-occurring PTSD. This study examined whether impulsivity mediates the relationship between ACEs and PTSD symptoms in adults seeking residential treatment for substance use disorder (SUD). Methods: N = 134 consenting adults in residential treatment for SUD completed questionnaires measuring impulsivity (UPPS-P), ACEs (ACEs Scale), and PTSD symptoms (PCL-5). Regression models tested our hypotheses that ACEs would predict PTSD symptoms and that impulsivity would mediate this relationship. Results: Two-thirds of participants met the PCL-5 score threshold for a provisional diagnosis of PTSD. ACEs score and impulsivity were significant direct predictors of PTSD symptoms (coeff = 2.23, p < .001; coeff = 1.03, p < .001). Among UPPS-P subconstructs, only lack of premeditation emerged as a partial mediator (z = 2.14, p = 0.032). Conclusions: Individuals with SUD experience adverse and traumatic events at alarming rates and are at increased risk for PTSD. Our mediation finding suggests that impulsivity and especially lack of premeditation may be clinically relevant in the development or maintenance of PTSD symptoms among individuals with SUD. [ABSTRACT FROM AUTHOR]

The aim of this study is to determine if extended‐release, bioabsorbable, subcutaneous naltrexone (NTX) implants inhibit respiratory depression after an IV injection of fentanyl. Bioabsorbable implants fabricated from two different release‐controlling polymers, poly‐D‐L‐lactide (PDLLA) and polycaprolactone (PCL), alone (placebo) or containing NTX, were subcutaneously implanted in Sprague Dawley rats. After 3.5 months of implantation, the rodents were administered an IV bolus of fentanyl through the tail vein. The placebo implant rats received a dose of 4 micrograms (mcg) ‐ (10 mcg/kg/dose), while the NTX implanted animals received a dose of 8 mcg (20 mcg/kg/dose). The minimum active dose of fentanyl that caused a > 50 ± 2% depression in the respiration rate in the placebo implanted rodents was 4 mcg. The respiration rate of the placebo implanted rats dropped from 208 ± 14 breaths/minute at predose, to 84 ± 12 breaths/minute (p = 0.0003) at 2 min. In contrast, all NTX implanted animals easily tolerated twice the dose of 8 mcg of fentanyl without any significant reduction in respiration rate. The mean respiration rate = increased from 164 ± 22 breaths/minute at predose to 178 ± 17 breaths/minute (p = 0.24) at 2 min. The mean plasma concentrations of NTX, 3.5 months after implantation, ranged from 7.4 (±1.1) ng/mL to 80.3 (±37.5) ng/mL. Bioabsorbable implants containing NTX effectively blocked fentanyl‐induced respiratory depression in rodents as compared with placebo implants, 3.5 months after implantation. [ABSTRACT FROM AUTHOR]

Background and Objectives: Posttraumatic stress disorder (PTSD) is highly comorbid with substance use disorders (SUD) and can impede SUD recovery. Residential SUD treatment is a crucial opportunity to address PTSD. However, PTSD treatment is lacking in residential SUD care. Methods: We conducted a nonrandomized feasibility study of Written Exposure Therapy (WET), a brief, evidence‐based treatment for PTSD, with patients in residential SUD treatment. We assessed attitudes towards treatment (Credibility and Expectancy Questionnaire, Barriers to Treatment Participation Scale) and mental health indicators (PTSD Checklist for DSM‐5, Trauma Coping Self‐Efficacy, Difficulties in Emotion Regulation‐Short Form, and Brief Assessment of Recovery Capital). Results: Thirty of 49 eligible participants completed WET (61%) and 92% (n = 45) attended at least one WET session. Paired sample t‐tests revealed significant posttreatment improvement across all mental health indicators, with medium to large effect sizes. Discussion and Conclusions: Attendance and completion rates compared favorably to prior exposure‐based treatment for PTSD in SUD settings. Although causality cannot be inferred without a randomized controlled trial, mental health indicators, including PTSD, improved significantly following WET. Scientific Significance: These findings provide evidence that PTSD can be successfully treated in short‐term residential care using brief exposure‐based interventions, which is a crucial clinical need that has been minimally studied in the past. [ABSTRACT FROM AUTHOR]

This article presents behavioral interventions designed to enhance uptake and retention on medication for opioid use disorder (MOUD) among transition-age youth (16–25 years) enrolled in treatment services. The article describes three relationship-oriented interventions designed to address barriers to MOUD uptake, enhance MOUD adherence planning, and strengthen OUD recovery among youth: Relational Orientation; Medication Education and Decision-making Support, and Family Leadership and Ownership of Adherence to Treatment. These interventions are inter-connected can be delivered flexibly. The article concludes with three case examples that illustrate how these modular interventions can be tailored to meet the needs of diverse client profiles. [ABSTRACT FROM AUTHOR]

Background and Objectives: To inform clinical practice, we identified subgroups of adults based on levels of depression symptomatology over time during opioid use disorder (OUD) treatment. Methods: Participants were 474 adults in a 24‐week treatment trial for OUD. Depression symptoms were measured using the 17‐item Hamilton Depression Rating Scale (HAM‐D) at nine‐time points. This was a secondary analysis of the Clinical Trials Network Extended‐Release Naltrexone versus Buprenorphine for Opioid Treatment (XBOT) trial using a growth mixture model. Results: Three distinct depression trajectories were identified: Class 1 High Recurring—10% with high HAM‐D with initial partial reductions (of HAM‐D across time), Class 2 Persistently High—5% with persistently high HAM‐D, and Class 3 Low Declining—85% of the participants, with low HAM‐D with early sustained reductions. The majority (low declining) had levels of depression that improved in the first 4 weeks and then stabilized across the treatment period. In contrast, 15% (high recurring and persistently high) had high initial levels that were more variable across time. The persistently high class had higher rates of opioid relapse. Discussion and Conclusions: In this OUD sample, most depressive symptomatology was mild and improved after medication treatment for opioid use disorder (MOUD). Smaller subgroups had higher depressive symptoms that persisted or recurred after the initiation of MOUD. Depressive symptoms should be followed in patients initiating treatment for OUD, and when persistent, should prompt further evaluation and consideration of antidepressant treatment. Scientific Significance: This study is the first to identify three distinct depression trajectories among a large clinical sample of individuals in MOUD treatment. [ABSTRACT FROM AUTHOR]

Background and Objectives: Better understanding of predictors of opioid abstinence among patients with opioid use disorder (OUD) may help to inform interventions and personalize treatment plans. This analysis examined patient characteristics associated with opioid abstinence in the X:BOT (Extended-Release Naltrexone versus Buprenorphine for Opioid Treatment) trial. Methods: This post-hoc analysis examined factors associated with past-month opioid abstinence at the 36-week follow-up visit among participants in the X:BOT study. 428 participants (75% of original sample) attended the visit at 36 weeks. Logistic regression models were used to estimate the probability of opioid abstinence across various baseline sociodemographics, clinical characteristics, and treatment variables. Results: Of the 428 participants, 143 (33%) reported abstinence from non-prescribed opioids at the 36-week follow-up. Participants were more likely to be opioid abstinent if randomized to XR-NTX (compared to BUP-NX), were on XR-NTX at week 36 (compared to those off OUD pharmacotherapy), successfully inducted onto either study medication, had longer time on study medication, reported a greater number of abstinent weeks, or had longer time to relapse during the 24-week treatment trial. Participants were less likely to be abstinent if Hispanic, had a severe baseline Hamilton Depression Rating (HAM-D) score, or had baseline sedative use. Conclusions: A substantial proportion of participants was available at follow-up (75%), was on OUD pharmacotherapy (53%), and reported past-month opioid abstinence (33%) at 36 weeks. A minority of patients off medication for OUD reported abstinence and additional research is needed exploring patient characteristics that may be associated with successful treatment outcomes. [ABSTRACT FROM AUTHOR]

Extended-release naltrexone (XR-NTX) is an important treatment option for individuals with opioid use disorder (OUD) and/or alcohol use disorder (AUD). However, problems with retention are a major barrier to its overall effectiveness, and interventions to improve adherence are underdeveloped. The purpose of this study was to pilot test the MAT-PLUS intervention, which combines assertive outreach and involvement of a treatment significant other (TSO) to improve adherence to XR-NTX. Adults (N = 41) seeking treatment for OUD and/or AUD with XR-NTX were recruited from an inpatient addiction treatment center and randomized to the MAT-PLUS intervention or treatment as usual (TAU) for 16-weeks. TSOs (N = 19) of individuals in the MAT-PLUS condition were also enrolled. The primary outcome was the number of XR-NTX doses received and relapse to regular heavy use (opioid or alcohol) was a secondary outcome. Participants in the MAT-PLUS group received 3.4 doses compared to 2.5 in TAU, which was significant after controlling for SUD diagnosis (p < 0.05). Rates of receipts of all prescribed doses were 61.1 % in MAT-PLUS compared to 30.4 % in TAU, giving an NNT of 3.3. Relapse rates and days of heavy use did not vary by treatment group. This study demonstrates preliminary efficacy of the MAT-PLUS intervention for XR-NTX adherence. This study was limited by its small sample size and future research should broaden the intervention to apply across medications for SUD in larger samples. Family support with an emphasis on medication adherence has strong potential for improving addiction treatment outcomes. • The MAT-PLUS intervention increased adherence to extended-release naltrexone. • The MAT-PLUS intervention did not have an effect on relapse or days of heavy use. • The MAT-PLUS intervention demonstrates preliminary feasibility and efficacy. [ABSTRACT FROM AUTHOR]

Opioid use among youth is a public health concern in the United States, with >3300 overdose deaths occurring nationally each year. Unfortunately, youth in the United States are still prescribed medication for opioid use disorder (OUD) at a lower rate than their adult counterparts. From 10/2013 to 01/2018, adolescents (ages 15–17; n = 25) and young adults (ages 18–21; n = 263) with moderate to severe OUD enrolled in the parent trial of extended-release naltrexone (XR-NTX; n = 82) versus treatment-as-usual (TAU; either buprenorphine maintenance [ n = 94] or counseling without buprenorphine maintenance [ n = 112]). The study assessed opioid use outcomes for adolescents vs. young adults using timeline follow-back self-report procedures at baseline and 3-/6-month follow-up assessments. Mixed-effects longitudinal and clustered panel regression models compared treatment effects over time of XR-NTX and TAU on opioid use outcomes in this secondary analysis. Though adolescent participants reported significantly less opioid use at baseline relative to their young adult counterparts (p < 0.05), the two age groups reported similar rates of opioid use throughout the intervention period. Additionally, both adolescents and young adults receiving XR-NTX evidenced lower rates of opioid use than those receiving TAU at all time points, and adolescents on XR-NTX were the only group who reduced their opioid use at all time points. Mixed-effects models indicated adolescents receiving XR-NTX demonstrated a 48 % lower rate of opioid use days [Incidence Rate Ratio (IRR) = 0.52; p = 0.020], while young adults receiving XR-NTX reported an estimated 26 % lower rate (IRR = 0.74; p = 0.009). Results indicate that adolescents respond favorably to XR-NTX relative to TAU for treatment of OUD, demonstrating similar outcomes to young adults. • Opioid use outcomes for adolescents with OUD were compared with those of young adults. • Results analyzed on an "as received" bases. • Receipt of XR-NTX associated with lower opioid use at follow-up than TAU for both groups. • Adolescents responded favorably to XR-NTX with similar outcomes to young adults. [ABSTRACT FROM AUTHOR]

The opioid epidemic in the United States has not spared youth or young adults, as evidenced by a six-fold increase in opioid use disorder (OUD) diagnoses in the last two decades. Given this dramatic rise, a call for greater uptake and accessibility of medications for opioid use disorder (MOUDs) among youth and young adults has ensued, resulting in an increasing number of MOUD treatment pathways for this vulnerable population. This secondary data analysis seeks to characterize patient and provider preferences for MOUD treatment pathways, and test for associations between baseline MOUD treatment preferences and opioid use and treatment adherence outcomes. Participants included 288 youth and young adults (age 15–21 years), recruited from a residential treatment program in Maryland. The study assessed patient preferences at baseline (n = 253) and provider preferences at patient treatment discharge (n = 224). Mixed-effects negative binomial regression models were conducted for opioid use outcomes, and logistic regressions were conducted for treatment adherence outcomes. Results indicate that congruence of treatment with patients' (Incidence Rate Ratio [IRR] = 0.65) and providers' (IRR = 0.66) preferences was significantly associated with reduced self-reported days of opioid use in the past 90 days, but only for patients receiving extended-release naltrexone (XR-NTX). Results also indicated that patients were less likely to switch medication treatment pathways (e.g., from XR-NTX to buprenorphine, or vice versa) during follow-up if they received their preferred treatment at baseline, a finding which held true for both XR-NTX (Odds Ratio [ OR ] = 0.32) and buprenorphine (OR = 0.22). Receipt of MOUD congruent with patient and provider preferences was associated with reduced opioid use and greater treatment adherence in this sample of youth and young adults with OUD. • Patients were less likely to switch treatments if they received their preference. • This finding held for patients receiving either XR-NTX or buprenorphine. • Preference-receipt congruence reduced opioid use and improved adherence. [ABSTRACT FROM AUTHOR]

This article proposes a taxonomy of linkage facilitation services used to help persons with opioid use disorder access treatment and recovery resources. Linkage facilitation may be especially valuable for persons receiving medication for opioid use disorder (MOUD) given the considerable barriers to treatment access and initiation that have been identified. The science of linkage facilitation currently lacks both consistent communication about linkage facilitation practices and a conceptual framework for guiding research. To address this gap, this article presents a taxonomy derived from expert consensus that organizes the array of practitioners, goals, and activities associated with linkage services for OUD and related needs. Expert panelists first independently reviewed research reports and policy guidelines summarizing the science and practice of linkage facilitation for substance use disorders generally and OUD specifically, then met several times to vet the conceptual scheme and content of the taxonomy until they reached a final consensus. The derived taxonomy contains eight domains: facilitator identity , facilitator lived experience , linkage client , facilitator-client relationship , linkage activity , linkage method , linkage connectivity , and linkage goal. For each domain, the article defines basic domain categories, highlights research and practice themes in substance use and OUD care, and introduces innovations in linkage facilitation being tested in one of two NIDA-funded research networks: Justice Community Opioid Innovation Network (JCOIN) or Consortium on Addiction Recovery Science (CoARS). To accelerate consistent application of this taxonomy to diverse research and practice settings, the article concludes by naming several considerations for linkage facilitation workforce training and implementation. • Linkage facilitation (LF) is becoming commonplace in settings that serve persons with OUD. • A formal taxonomy is needed to promote consistent communication about LF standards and practices. • LF activities fall in eight domains, exemplified by research innovations from two federally funded networks. [ABSTRACT FROM AUTHOR]

Abstract Background Buprenorphine can be effective in a variety of community substance use treatment settings outside of methadone programs, including outpatient programs and medical practices. In these settings, it has been found to be effective in reducing opioid use and retaining patients in treatment. Despite its effectiveness and safety, it is rarely provided to individuals with opioid use disorders in probation and parole settings. Methods Male and female individuals under probation or parole supervision (N = 320) with histories of opioid use disorder will be enrolled in this randomized controlled trial. Participants will be randomized to one of two study arms: Buprenorphine Bridge Treatment (BBT): Participants will begin buprenorphine using the MedicaSafe dispensing device immediately after an on-site intake at a community supervision office and continue such treatment until they are transitioned to a community program; or Treatment as Usual (TAU): Participants will receive a referral to buprenorphine pharmacotherapy treatment in the community. Treatment outcomes will be: (a) illicit opioid oral saliva drug test results; and (b) treatment adherence (i. entered community based treatment; ii. number of days receiving opioid treatment). Results We describe the background and rationale for the study, its aims, hypotheses, and study design. Conclusions If shown to increase compliance rates with conditions of probation and parole, buprenorphine treatment co-located at community supervision field offices could have a major impact on delivery of buprenorphine treatment to the criminal justice population. The public health impact of the proposed study would be widespread because this intervention could be implemented throughout areas of the US. [ABSTRACT FROM AUTHOR]

Few studies have examined the cost of medication for opioid use disorder (MOUD) with counseling for the adolescent and young adult population. This study calculated the health care utilization and cost of MOUD treatment, other substance use disorder treatment, and general health care for adolescents and young adults receiving treatment for opioid use disorder. The study randomized youth ages 15 to 21 (N = 288) equally into the two study conditions: extended-release naltrexone (XR-NTX) or treatment as usual (TAU). While participants committed to treatment based on randomization the study observed considerable nonadherence to both randomized conditions. Instead of using the randomly assigned study conditions, we present descriptive costs by the type of MOUD treatment received: XR-NTX only, buprenorphine only, any other combination of MOUD treatments, and no MOUD. Health care use was aggregated over the 6-month period for each participant, and we calculated average/participant utilization for each treatment group. To determine participant costs, we multiplied the unit costs of health care services obtained from the literature by the reported amount of health care utilization for each participant. We then calculated the mean, standard error, median and IQR for MOUD costs, other substance use disorder treatment costs and general healthcare cost from the health care sector perspective. On average, participants in the XR-NTX only group received 2.6 doses of XR-NTX (equivalent to approximately 78 days of treatment). The buprenorphine only group had an average of 97 days of buprenorphine treatment. The XR-NTX only group had higher/patient costs compared to participants in the buprenorphine only group ($10,491 vs. $8765) and higher XR-NTX utilization would further increase costs. Participants in the any other MOUD combination group had the highest total costs ($14,627) while participants in the no MOUD group at the lowest ($3453). Our cost analysis calculates the real-world cost of MOUD treatment and, while not generalizable, provides policy makers an estimate of costs for adolescents and young adults. We found that participants in the XR-NTX only group received fewer days of medication compared to the buprenorphine only group, but their medication costs were higher due to the cost of XR-NTX injections. While the buprenorphine only group had the highest number of days of medication utilization of all the groups, the average number of days of medication utilization was considerably shorter than the six-month treatment period. • Calculated healthcare use and costs for adolescent and young adults with OUD • Significant participant non-adherence to both randomized conditions occurred. • Average utilization of XR-NTX and buprenorphine was well below the 6-month treatment period. • The cost of XR-NTX doses increased average cost despite low average XR-NTX utilization. [ABSTRACT FROM AUTHOR]

Background: Extended-release naltrexone (XR-NTX), an opioid antagonist, and sublingual buprenorphine-naloxone (BUP-NX), a partial opioid agonist, are pharmacologically and conceptually distinct interventions to prevent opioid relapse. We aimed to estimate the difference in opioid relapse-free survival between XR-NTX and BUP-NX.Methods: We initiated this 24 week, open-label, randomised controlled, comparative effectiveness trial at eight US community-based inpatient services and followed up participants as outpatients. Participants were 18 years or older, had Diagnostic and Statistical Manual of Mental Disorders-5 opioid use disorder, and had used non-prescribed opioids in the past 30 days. We stratified participants by treatment site and opioid use severity and used a web-based permuted block design with random equally weighted block sizes of four and six for randomisation (1:1) to receive XR-NTX or BUP-NX. XR-NTX was monthly intramuscular injections (Vivitrol; Alkermes) and BUP-NX was daily self-administered buprenorphine-naloxone sublingual film (Suboxone; Indivior). The primary outcome was opioid relapse-free survival during 24 weeks of outpatient treatment. Relapse was 4 consecutive weeks of any non-study opioid use by urine toxicology or self-report, or 7 consecutive days of self-reported use. This trial is registered with ClinicalTrials.gov, NCT02032433.Findings: Between Jan 30, 2014, and May 25, 2016, we randomly assigned 570 participants to receive XR-NTX (n=283) or BUP-NX (n=287). The last follow-up visit was Jan 31, 2017. As expected, XR-NTX had a substantial induction hurdle: fewer participants successfully initiated XR-NTX (204 [72%] of 283) than BUP-NX (270 [94%] of 287; p<0·0001). Among all participants who were randomly assigned (intention-to-treat population, n=570) 24 week relapse events were greater for XR-NTX (185 [65%] of 283) than for BUP-NX (163 [57%] of 287; hazard ratio [HR] 1·36, 95% CI 1·10-1·68), most or all of this difference accounted for by early relapse in nearly all (70 [89%] of 79) XR-NTX induction failures. Among participants successfully inducted (per-protocol population, n=474), 24 week relapse events were similar across study groups (p=0·44). Opioid-negative urine samples (p<0·0001) and opioid-abstinent days (p<0·0001) favoured BUP-NX compared with XR-NTX among the intention-to-treat population, but were similar across study groups among the per-protocol population. Self-reported opioid craving was initially less with XR-NTX than with BUP-NX (p=0·0012), then converged by week 24 (p=0·20). With the exception of mild-to-moderate XR-NTX injection site reactions, treatment-emergent adverse events including overdose did not differ between treatment groups. Five fatal overdoses occurred (two in the XR-NTX group and three in the BUP-NX group).Interpretation: In this population it is more difficult to initiate patients to XR-NTX than BUP-NX, and this negatively affected overall relapse. However, once initiated, both medications were equally safe and effective. Future work should focus on facilitating induction to XR-NTX and on improving treatment retention for both medications.Funding: NIDA Clinical Trials Network. [ABSTRACT FROM AUTHOR]

Extended-release injectable naltrexone (XR-NTX) is an effective treatment for opioid use disorder (OUD), but initiation remains a barrier to implementation. Standard practice requires a 10- to 15-day inpatient admission prior to XR-NTX initiation and involves a methadone or buprenorphine taper followed by a 7- to 10-day washout, as recommended in the Prescribing Information for XR-NTX. A 5- to 7-day rapid induction approach was developed that utilizes low-dose oral naltrexone and non-opioid medications. The CTN-0097 Surmounting Withdrawal to Initiate Fast Treatment with Naltrexone (SWIFT) study was a hybrid type I effectiveness-implementation trial that compared the effectiveness of the standard procedure (SP) to the rapid procedure (RP) for XR-NTX initiation across six community inpatient addiction treatment units, and evaluated the implementation process. Sites were randomized to RP every 14 weeks in an optimized stepped wedge design. Participants (target recruitment = 450) received the procedure (SP or RP) that the site was implementing at time of admission. The hypothesis was RP will be non-inferior to SP on proportion of inpatients who receive XR-NTX, with a shorter admission time for RP. Superiority testing of RP was planned if the null hypothesis of inferiority of RP to SP was rejected. If RP for XR-NTX initiation is shown to be effective, the shorter inpatient stay could make XR-NTX more feasible and have an important public health impact expanding access to OUD pharmacotherapy. Further, a better understanding of facilitators and barriers to RP implementation can help with future translatability and uptake to other community programs. Trial Registration: NCT 04762537 Registered February 21, 2021. • One of the first community, hybrid effectiveness-implementation trials for rapid initiation of injectable naltrexone. • Inpatient programs may adopt this rapid procedure and increase implementation of injectable naltrexone for OUD treatment. • An implementation facilitation package can support widespread dissemination of this rapid induction procedure. [ABSTRACT FROM AUTHOR]

We examine ethical challenges encountered in the design of an effectiveness trial (CTN-0051; X:BOT), comparing sublingual buprenorphine-naloxone (BUP-NX), an established treatment for opioid dependence, to the newer extended-release injectable naltrexone (XR-NTX). Ethical issues surrounded: 1) known poor effectiveness of one possible, commonly used treatment as usual control condition—detoxification followed by counseling without medication; 2) the role of patients' preferences for treatments, given that treatments were clinically approved and available to the population; 3) differences between the optimal “usual treatment” clinical settings for different treatments making it challenging to design a fair comparison; 4) vested interest groups favoring different treatments exerting potential influence on the design process; 5) potentially vulnerable populations of substance users and prisoners; 6) potential therapeutic misconception in the implementation of safety procedures; and 7) high cost of a large trial limiting questions that could be addressed. We examine how the design features underlying these ethical issues are characteristic of effectiveness trials, which are often large trials that compare treatments with varying degrees of existing effectiveness data and familiarity to patients and clinicians, in community-based treatment settings, with minimal exclusion criteria that could involve vulnerable populations. Hence, investigators designing effectiveness trials may wish to remain alert to the possibility of similar ethical issues. [ABSTRACT FROM AUTHOR]

Introduction For opioid-dependent patients in the US and elsewhere, detoxification and counseling-only aftercare are treatment mainstays. Long-term abstinence is rarely achieved; many patients relapse and overdose after detoxification. Methadone, buprenorphine-naloxone (BUP-NX) and extended-release naltrexone (XR-NTX) can prevent opioid relapse but are underutilized. This study is intended to develop an evidence-base to help patients and providers make informed choices and to foster wider adoption of relapse-prevention pharmacotherapies. Methods The National Institute on Drug Abuse's Clinical Trials Network (CTN) study CTN-0051, X:BOT, is a comparative effectiveness study of treatment for 24 weeks with XR-NTX, an opioid antagonist, versus BUP-NX, a high affinity partial opioid agonist, for opioid dependent patients initiating treatment at 8 short-term residential (detoxification) units and continuing care as outpatients. Up to 600 participants are randomized (1:1) to XR-NTX or BUP-NX. Results The primary outcome is time to opioid relapse (i.e., loss of persistent abstinence) across the 24-week treatment phase. Differences between arms in the distribution of time-to-relapse will be compared (construction of the asymptotic 95% CI for the hazard ratio of the difference between arms). Secondary outcomes include proportions retained in treatment, rates of opioid abstinence, adverse events, cigarette, alcohol, and other drug use, and HIV risk behaviors; opioid cravings, quality of life, cognitive function, genetic moderators, and cost effectiveness. Conclusions XR-NTX and BUP-NX differ considerably in their characteristics and clinical management; no studies to date have compared XR-NTX with buprenorphine maintenance. Study design choices and compromises inherent to a comparative effectiveness trial of distinct treatment regimens are reviewed. Clinical Trial Registration: NCT02032433 . [ABSTRACT FROM AUTHOR]

Background: Extended-release naltrexone, a sustained-release monthly injectable formulation of the full mu-opioid receptor antagonist, is effective for the prevention of relapse to opioid dependence. Data supporting its effectiveness in U.S. criminal justice populations are limited.Methods: In this five-site, open-label, randomized trial, we compared a 24-week course of extended-release naltrexone (Vivitrol) with usual treatment, consisting of brief counseling and referrals for community treatment programs, for the prevention of opioid relapse among adult criminal justice offenders (i.e., persons involved in the U.S. criminal justice system) who had a history of opioid dependence and a preference for opioid-free rather than opioid maintenance treatments and who were abstinent from opioids at the time of randomization. The primary outcome was the time to an opioid-relapse event, which was defined as 10 or more days of opioid use in a 28-day period as assessed by self-report or by testing of urine samples obtained every 2 weeks; a positive or missing sample was computed as 5 days of opioid use. Post-treatment follow-up occurred at weeks 27, 52, and 78.Results: A total of 153 participants were assigned to extended-release naltrexone and 155 to usual treatment. During the 24-week treatment phase, participants assigned to extended-release naltrexone had a longer median time to relapse than did those assigned to usual treatment (10.5 vs. 5.0 weeks, P<0.001; hazard ratio, 0.49; 95% confidence interval [CI], 0.36 to 0.68), a lower rate of relapse (43% vs. 64% of participants, P<0.001; odds ratio, 0.43; 95% CI, 0.28 to 0.65), and a higher rate of opioid-negative urine samples (74% vs. 56%, P<0.001; odds ratio, 2.30; 95% CI, 1.48 to 3.54). At week 78 (approximately 1 year after the end of the treatment phase), rates of opioid-negative urine samples were equal (46% in each group, P=0.91). The rates of other prespecified secondary outcome measures--self-reported cocaine, alcohol, and intravenous drug use, unsafe sex, and reincarceration--were not significantly lower with extended-release naltrexone than with usual treatment. Over the total 78 weeks observed, there were no overdose events in the extended-release naltrexone group and seven in the usual-treatment group (P=0.02).Conclusions: In this trial involving criminal justice offenders, extended-release naltrexone was associated with a rate of opioid relapse that was lower than that with usual treatment. Opioid-use prevention effects waned after treatment discontinuation. (Funded by the National Institute on Drug Abuse; ClinicalTrials.gov number, NCT00781898.). [ABSTRACT FROM AUTHOR]

Background Extended-release naltrexone (XR-NTX, Vivitrol®; Alkermes Inc.) is an injectable monthly sustained-release mu opioid receptor antagonist. XR-NTX is a potentially effective intervention for opioid use disorders and as relapse prevention among criminal justice system (CJS) populations. Methods This 5-site open-label randomized controlled effectiveness trial examines whether XR-NTX reduces opioid relapse compared with treatment as usual (TAU) among community dwelling, non-incarcerated volunteers with current or recent CJS involvement. The XR-NTX arm receives 6 monthly XR-NTX injections at Medical Management visits; the TAU group receives referrals to available community treatment options. Assessments occur every 2 weeks during a 24-week treatment phase and at 12- and 18-month follow-ups. The primary outcome is a relapse event, defined as either self-report or urine toxicology evidence of ≥ 10 days of opioid use in a 28-day (4 week) period, with a positive or missing urine test counted as 5 days of opioid use. Results We describe the rationale, specific aims, and design of the study. Alternative design considerations and extensive secondary aims and outcomes are discussed. Conclusions XR-NTX is a potentially important treatment and relapse prevention option among persons with opioid dependence and CJS involvement. ClinicalTrials.gov : NCT00781898 [ABSTRACT FROM AUTHOR]

Background: Although there is consensus that having a "high-enough" dose of buprenorphine (BUP-NX) or methadone is important for reducing relapse to opioid use, there is debate about what this dose is and how it should be attained. We estimated the extent to which different dosing strategies would affect risk of relapse over 12 weeks of treatment, separately for BUP-NX and methadone.Methods: This was a secondary analysis of three comparative effectiveness trials. We examined four dosing strategies: 1) increasing dose in response to participant-specific opioid use, 2) increasing dose weekly until some minimum dose (16 mg BUP, 100 mg methadone) was reached, 3) increasing dose weekly until some minimum and increasing dose in response to opioid use thereafter (referred to as the "hybrid strategy"), and 4) keeping dose constant after the first 2 weeks of treatment. We used a longitudinal sequentially doubly robust estimator to estimate contrasts between dosing strategies on risk of relapse.Results: For BUP-NX, increasing dose following the hybrid strategy resulted in the lowest risk of relapse. For methadone, holding dose constant resulted in greatest risk of relapse; the other three strategies performed similarly. For example, the hybrid strategy reduced week 12 relapse risk by 13 % (RR: 0.87, 95 %CI: 0.83-0.95) and by 20 % (RR: 0.80, 95 %CI: 0.71-0.90) for BUP-NX and methadone respectively, as compared to holding dose constant.Conclusions: Doses should be targeted toward minimum thresholds and, in the case of BUP-NX, raised when patients continue to use opioids. [ABSTRACT FROM AUTHOR]

Introduction: We know little about what youth with opioid use disorders (OUD) think about outpatient substance use treatment and 12-step meetings following discharge from residential substance use treatment. This study explores youths' preferences between intensive outpatient treatment (IOP) and community-based 12-step groups.Method: The study recruited youth (n = 35) from a larger randomized trial (N = 288) that examined the effectiveness of extended-release naltrexone versus treatment-as-usual. This study asked the youth to participate in semi-structured qualitative interviews at baseline, 3 months, and 6 months post-residential treatment discharge. Qualitative interviews probed youths' key decision points during the six-months following residential treatment for OUD, including medication and counseling, and 12-step continuation in the community.Results: Qualitative analyses revealed three overarching themes related to youths' preferences for either IOP or 12-step meetings: structure of recovery support, mechanisms of accountability, and relationships.Conclusion: Despite varying preferences, this analysis highlights the complexity of benefits that youth report receiving from each approach. Research has yet to determine the degree to which these approaches are complementary or supplementary for this population. [ABSTRACT FROM AUTHOR]

Abstract: Background: 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. Methods: Opioid dependent adolescents and young adults (n=152), aged 15–21, were randomized to 12weeks (BUP, n=74) or 2weeks of detoxification (DETOX, n=78) with buprenorphine/naloxone (Bup/Nal), both in combination with 12weeks of psychosocial treatment. Baseline and early treatment related predictors of treatment attrition were identified in each group using bivariate and multivariate logistic regression. Results: 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 although not an independent predictor. A broad range of other pre-treatment characteristics was 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 2weeks of treatment, may improve treatment retention. Extended Bup/Nal treatment appeared effective in improving treatment retention for youth with opioid dependence across a wide range of demographics, and pre-treatment clinical characteristics. [Copyright &y& Elsevier]

Objective: To examine predictors of opioid abstinence in buprenorphine/naloxone (Bup/Nal)-assisted psychosocial treatment for opioid-dependent youth.Method: Secondary analyses were performed of data from 152 youth (15-21 years old) randomly assigned to 12 weeks of extended Bup/Nal therapy or up to 2 weeks of Bup/Nal detoxification with weekly individual and group drug counseling. Logistic regression models were constructed to identify baseline and during-treatment predictors of opioid-positive urine (OPU) at week 12. Predictors were selected based on significance or trend toward significance (i.e., p < .1), and backward stepwise selection was used, controlling for treatment group, to produce final independent predictors at p ≤ .05.Results: 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 OPU. Those with early treatment opioid 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 OPU. 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.Clinical Trial Registration Information: Buprenorphine/Naloxone-Facilitated Rehabilitation for Opioid Dependent Adolescents; http://www.clinicaltrials.gov; NCT00078130. [ABSTRACT FROM AUTHOR]

The article presents a study examining the randomized controlled trial of osmotic-release methylphenidate (OROS-PHM) in adolescents with attention-deficit/hyperactivity disorder (ADHD) and substance use disorders (SUD). It evaluates the efficacy and safety of osmotic-release methylphenidate compared with placebo for ADHD and SUD. A 16-week randomized controlled multi-site trial of OROS-MPH has been conducted against placebo. OROS-MPH has been found with no greater efficacy than placebo for ADHD.

Background: 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.Objectives: In the current study, we 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.Methods: The study randomly assigned one hundred and fifty-two 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 (NIDA-CTN-0010). We 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.Results: 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 symptom 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. [ABSTRACT FROM AUTHOR]

Objective: To characterize baseline depressive symptoms among substance-abusing adolescents and determine their association with post residential treatment substance use outcomes.Method: In total, 153 adolescents (mean age 6.6 years, +/- 0.11) entering residential treatment were assessed at intake and at 3, 6, 9, and 12 months. Beck Depression Inventory (BDI) and Global Appraisal of Individual Needs were administered to assess depression, other risk factors, and substance use. A regression model was developed with 10 risk factors including BDI scores of >/=11 versus <11 to predict the outcome measure mean percentage of days in the past 90 days with any (nonnicotine) substance use.Results: At intake, 55% had BDI scores of >/=11. A baseline BDI score of >/=11 was significantly associated with greater mean percentage of days of substance use (27.5 +/- 3.8% versus 15.4 +/- 4.0% days, p <.01) across 1-year follow-up. Two other factors were significant: length of drug career >2 years and having an opioid use disorder.Conclusions: Results from this prospective study, although preliminary, suggest the association of depressive symptoms with poorer substance outcomes and the utility of the BDI as a prognostic tool. They highlight the need for interventions targeting co-occurring depressive symptoms that may improve adolescent substance treatment outcomes. [ABSTRACT FROM AUTHOR]

Aim: This report examined naturalistic opioid use outcomes and utilization of medications for opioid use disorder (MOUD) 36 weeks post-randomization in the National Drug Abuse Treatment Clinical Trials Network (CTN) Extended-Release Naltrexone (XR-NTX) versus Buprenorphine-Naloxone (BUP-NX) for Opioid Treatment trial (CTN-0051, X:BOT).Design: X:BOT was a multisite, randomized, 24-week comparative effectiveness trial of BUP-NX (N = 287) and XR-NTX (N = 283). Study medications were discontinued following treatment completion, relapse, or dropout. Participants were encouraged to continue MOUD. This report examined opioid use outcomes in 428 (75%) of the 570 participants who attended the 36-week follow-up visit.Setting and Participants: Adults with opioid use disorder recruited from 8 community treatment programs across the United States.Measurements: Outcomes included medication status (on/off MOUD), type of MOUD (BUP-NX, XR-NTX, or methadone), abstinence from non-prescribed opioids, opioid use days, relapse, and other substance use 30 days prior to the 36-week visit. Relapse was defined as opioid use for 4 consecutive weeks or 7 consecutive days in the past month. Baseline and clinical variables included opioid use severity, intravenous drug use, study medication assignment, and induction status.Findings: Of the 428 participants who completed the 36-week visit, 225 (53%) of participants were receiving MOUD and 203 (47%) were not. Compared to those off medication, participants on medication had fewer opioid use days (4.4 days (SD 9.0) versus 9.8 days (SD 12.1)), fewer met relapse criteria (37 (16.4%) versus 79 (38.9%)), and reported less stimulant use (34 (15.2%) versus 56 (27.7%)) and sedative use (14 (6.3%) versus 31 (15.3%)). There was no difference in abstinence rates between those on or off MOUD. A greater proportion of participants on XR-NTX (47 (53.4%) of 88 participants) were abstinent from non-prescribed opioids compared to those on buprenorphine (28 (23.3%) of 120 participants).Conclusions: Naturalistic outcomes data showed that despite potential barriers to continuing treatment in the community, about half of individuals were on opioid use disorder pharmacotherapy at follow-up and those on medication generally had better outcomes. Future research should explore barriers and facilitators to treatment retention in community settings; and developing interventions tailored to improve treatment engagement and adherence. [ABSTRACT FROM AUTHOR]

Background: Few published research studies have examined the effectiveness of extended-release naltrexone (XR-NTX) for the treatment of opioid use disorder (OUD) among adolescents and young adults.Methods: This two-group randomized controlled trial recruited 288 youth, ages 15-21, with moderate/severe OUD from a residential addiction treatment program in Baltimore, Maryland. The study randomized the youth within the first week of treatment entry to receive either XR-NTX or treatment-as-usual (TAU; either buprenorphine maintenance treatment or treatment without OUD medication following medically managed withdrawal) prior to discharge, with continued treatment in the community for 6 months. However, due to various reasons spanning patients' and caregivers' preferences and constraints, considerable participant nonadherence to randomized condition occurred (i.e., only 30% of the participants randomized to XR-NTX received an initial injection, while 27% of participants randomized to TAU received an XR-NTX injection at treatment discharge, instead of their assigned treatment). The study used generalized linear mixed modeling (GLiMM) to examine self-reported 90-day opioid, cocaine, marijuana, and alcohol use as well as DSM-5 OUD criteria on "intention-to-treat" (as randomized), "as-received" (XR-NTX vs. not XR-NTX), and "as-medicated" (XR-NTX vs. buprenorphine vs. no medication) bases.Results: The condition x time interactions in the intention-to-treat analyses failed to reach significance for past-90-day self-reported use of illicit opioids, cocaine, marijuana, or alcohol, or in meeting DSM-5 OUD criteria at 3 or 6 months [all ps > 0.05]. However, these findings are of limited interpretive value due to participant nonadherence to their randomized condition. When the study analyzed results by the treatment received at discharge, the "as-received" group x time interaction for illicit opioid use was significant [p = .003], with the XR-NTX group reporting less opioid use in the past 90 days at 3 and 6 months. Participants who received their first XR-NTX dose at inpatient discharge (n = 82) received, on average, 1.3 subsequent injections in the community over the 6-month study follow-up period. Only 2 of the 82 study participants received XR-NTX continuously through the 6-month postdischarge follow-up period. Twelve serious adverse events (SAEs) occurred during the study, but the study determined that only 1 was possibly study related (hepatitis C/elevated liver function test results).Conclusion: None of the condition x time interactions in the intention-to-treat analyses reached significance. Participants' nonadherence may have contributed to the failure to reject the null hypothesis. Irrespective of randomized condition, participants who received XR-NTX for OUD demonstrated low retention in treatment, receiving an average of only 1.3 subsequent injections, yet reported less opioid use at follow-up than participants who did not received XR-NTX. Treatment programs should consider XR-NTX as a treatment option for youth motivated to receive it. Future research should focus on building developmentally informed strategies to improve uptake of and adherence to relapse prevention medication in this population. [ABSTRACT FROM AUTHOR]

Background: We assess adverse events (AEs) following medication initiation for adolescents and young adults with opioid use disorder (OUD)., Methods: This is a secondary analysis of a clinical trial of long-acting injectable naltrexone (LAI-naltrexone) among youth with OUD aged 15 to 21 years. Participants were recruited from residential treatment and placed into 1 of 3 treatment groups based on medication receipt at time of discharge (no medication, sublingual buprenorphine-naloxone [buprenorphine], or LAI-naltrexone). Frequencies and percentages of AEs by body system were compared by medication group at the 1-month follow-up visit. Logistic regression was used to compare groups on their likelihood of reporting an AE, overall and excluding injection site reactions., Results: Of 199 participants, 71 (36%) received no medication, 59 (30%) buprenorphine, and 69 (35%) LAI-naltrexone at discharge. Participants who received LAI-naltrexone experienced more AEs, primarily due to injection site reactions (62%, accounting for 43% of all AEs among participants who received LAI-naltrexone). There were 6 reports of nonlethal overdose, 5 in the no medication, 1 in the buprenorphine, and none in the LAI-naltrexone group. Participants receiving LAI-naltrexone were more likely to report an AE compared to the other groups ( P  = .04), but this difference was no longer significant when excluding injection site reactions ( P  = .82)., Conclusions: Excluding injection site reactions, there were no significant differences in the likelihood of reporting an AE 1 month after receiving LAI-NTX, buprenorphine, and no medications. LAI-naltrexone should be among the medications offered for the treatment of OUD in youth., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Drs Terplan, Schwartz, Gryczynski, and Monico were investigators on a NIDA-funded study that received medication in-kind from Alkermes and Indivior. In addition, Dr Schwartz has consulted for Verily Life Sciences and Dr Gryczynski is part owner of COG Analytics. Dr Fishman has been a consultant for Alkermes, Verily Life Sciences, Drug Delivery LLC, and US World Meds, and has received research funding from Alkermes and US World Meds. Drs Mitchell and O’Grady report no conflicts.

Introduction: Opioid Use Disorder (OUD) is a catastrophic public health problem for young adults (YAs) and their families. While medication for OUD (MOUD) is safe, effective, and recognized as the standard of care, its' uptake and success have been limited in YAs compared to older adults., Methods: This narrative review summarizes the existing literature and highlights select studies regarding barriers to YA MOUD, potential explanations for those barriers, and strategies to overcome them., Results: Barriers are prominent along the entire cascade of care, including: treatment engagement and entry, MOUD initiation, and MOUD retention. Hypothesized explanations for barriers include: developmental vulnerability, inadequate treatment system capacity, stigma against MOUD, among others. Interventions to address barriers include: promotion of family involvement, increasing provider capacity, integration of MOUD into primary care, assertive outreach, and others., Conclusions: Integrating an adapted version of family coaching from the Community Reinforcement Approach and Family Training (CRAFT) and other models into YA MOUD treatment serves as an example of an emerging novel practice that holds promise for broadening the funnel of engagement in treatment and initiation of MOUD, and enhancing treatment outcomes. This and other developmentally-informed approaches should be evaluated as part of a high-priority clinical and research agenda for improving OUD treatment for YAs., Competing Interests: Declaration of competing interest Dr. Fishman has been a consultant for Indivior, Alkermes, Drug Delivery LLC, Nirsum Labs. Dr. Marsch is affiliated with Square2 Systems Inc. and is a consultant for Boehringer Ingelheim and Click Therapeutics. These relationships are managed by her employer, Dartmouth College. Dr. Wenzel, Dr. Subramaniam, Dr. Levy, Dr. Borodovsky, Gauthier, McLeman, Fredyma, and Murray, have no financial or personal interests to declare. This manuscript reflects the views of the authors and may not reflect the opinions, views, and official policy or position of the U.S. Department of Health and Human Services or any of its affiliated institutions or agencies. Dr. Subramaniam was substantially involved in this project, consistent with her role as Scientific Officer in the CTN grants. She has no financial or personal interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Medications for opioid use disorder (MOUD) are the most effective treatment for OUD. Many patients struggle with adherence, but young adults face unique developmental barriers and experience higher relapse rates. The Youth Opioid Recovery Support (YORS) intervention is a developmentally informed behavioral approach to increase medication adherence through assertive outreach, family involvement, low-barrier access to extended-release MOUD, and contingency management. Early studies have shown promising results, and a randomized controlled trial is underway. Here we describe the implementation of YORS using case examples, offer guidance on adapting YORS to real-world clinical settings, and explore future directions for research and practice., Competing Interests: Disclosure Dr M. Fishman has been a consultant for Alkermes, Inc, Indivior, Nirsum Labs and Drug Delivery LLC. Dr M. Fishman has received research grant funding from Alkermes. Dr M. Fishman and Dr K. Wenzel have received research grant funding from NIH. Other authors have nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Aim 1 of this cross-sectional, observational study with people in residential treatment for substance use disorders (SUDs) was to document stress exposure. Aim 2 was to assess potential sociodemographic and health differences based on probable posttraumatic stress disorder (PTSD) status. Aim 3 was to assess relative contributions of Diagnostic and Statistical Manual (DSM)-congruent versus DSM-incongruent stressors (Criterion A vs non-Criterion A) to mental and physical health. We hypothesized that both types of stressors would significantly contribute to impairment across indicators and that DSM-congruent stressor exposure would be more strongly associated with impairment than DSM-incongruent exposure., Methods: We assessed exposure to DSM-congruent traumatic stressors and DSM-incongruent life stressors, PTSD and depressive symptoms, emotion regulation difficulties, substance use recovery capital, and physical/mental health-related quality of life among 136 people in residential SUD treatment who were 64% men, 36% women; 49% white, 41% Black, 11% multiracial/another race; 18% lesbian, gay, or bisexual (LGB+); mean age = 39.82 (standard deviation = 12.24) years., Results: Participants reported experiencing a mean of 9.76 (SD = 6.11) DSM-congruent events. Those with probable PTSD were younger and more likely to be LGB+ than those without probable PTSD ( P  < .05). Experiencing higher numbers of DSM-congruent events was associated with more severe PTSD and depressive symptoms, emotion regulation difficulties, and lower physical health-related quality of life ( P  < .05). DSM-incongruent stressor exposure was not independently associated with any indicators. Recovery capital was not associated with either type of stress exposure., Conclusions: Stressful event exposure among people in residential SUD treatment is very high. Those who are younger or LGB+ in residential SUD treatment may be at greater risk of developing PTSD. DSM-congruent stressors are more consistently associated with mental health indicators than are DSM-incongruent stressors. Prioritizing treatment targets and identifying implementable treatment strategies can be challenging with this complex population., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The aim of this study is to determine if extended-release, bioabsorbable, subcutaneous naltrexone (NTX) implants can mitigate respiratory depression after an intravenous injection (IV) of fentanyl. Six different BIOabsorbable Polymeric Implant Naltrexone (BIOPIN) formulations, comprising combinations of Poly-d,l-Lactic Acid (PDLLA) and/or Polycaprolactone (PCL-1 or PCL-2), were used to create subcutaneous implants. Both placebo and naltrexone implants were implanted subcutaneously in male dogs. The active naltrexone implants consisted of two doses, 644 mg and 1288 mg. A challenge with IV fentanyl was performed in 33 male dogs at 97-100 days after implantation. Following the administration of a 30 μg/kg intravenous fentanyl dose, the placebo cohort manifested a swift and profound respiratory depression with a ~50% reduction in their pre-dose respiratory rate (RR). The BIOPIN NTX-implanted dogs were exposed to escalating doses of intravenous fentanyl (30 μg/kg, 60 μg/kg, 90 μg/kg, and 120 μg/kg). In contrast, the dogs implanted with the BIOPIN naltrexone implants tolerated doses up to 60 μg/kg without significant respiratory depression (<50%) but had severe respiratory depression with fentanyl doses of 90 μg/kg and especially at 120 μg/kg. Bioabsorbable, extended-release BIOPIN naltrexone implants are effective in mitigating fentanyl-induced respiratory depression in male canines at about 3 months after implantation. This technology may also have potential for mitigating fentanyl-induced respiratory depression in humans., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

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 and Relevance: 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., Trial Registration: ClinicalTrials.gov Identifier: NCT04762537.

Objective: This study evaluated the association between medication for opioid use disorder (MOUD) and health care utilization over time among a sample of treatment-seeking individuals with opioid use disorder. In contrast to previous studies, this study used a novel measure of MOUD adherence, more comprehensive utilization data, and analyses that controlled for detailed individual and social determinants of health., Methods: This study was a secondary analysis of a comparative effectiveness trial (N=570) of extended-release naltrexone versus buprenorphine-naloxone. The outcome of interest was usage of nonstudy acute care, inpatient and outpatient addiction services, and other outpatient services across 36 weeks of assessment. Adherence (percentage of days taking MOUD) was defined as low (<20%), medium (≥20% but <80%), or high (≥80%). A two-part model evaluated the probability of utilizing a resource and the quantity (utilization days) of the resource consumed. A time-varying approach was used to examine the effect of adherence in a given month on utilization in the same month, with analyses controlling for a wide range of person-level characteristics., Results: Participants with high adherence (vs. low) were significantly less likely to use inpatient addiction (p<0.001) and acute care (p<0.001) services and significantly more likely to engage in outpatient addiction (p=0.045) and other outpatient (p=0.042) services., Conclusions: These findings reinforce the understanding that greater MOUD adherence is associated with reduced usage of high-cost health services and increased usage of outpatient care. The results further suggest the need for enhanced access to MOUD and for interventions that improve adherence., Competing Interests: Dr. Fishman has served as a consultant for Alkermes, Drug Delivery LLC, Indivior, and Verily Life Sciences and has received research support from Alkermes. Dr. Rotrosen has received indirect research support from Alkermes, Braeburn, CHESS Health, Datacubed Health, Indivior, and Pear Therapeutics; he serves as a principal investigator for the New York Node of the NIDA CTN and as chair of the data and safety monitoring board for a U.S. Department of Veterans Affairs study; and he has served as chair of the data and safety monitoring board for a trial conducted by the Canadian Research Initiative in Substance Misuse. Dr. Nunes has received research support from Alkermes, Braeburn, Camurus, CHESS Health, Indivior, and Pear Therapeutics; he has served as a nonpaid consultant for Alkermes, Camurus, Indivior, and Pear Therapeutics; and he serves as a principal investigator for the New York Node of the NIDA CTN. Dr. Murphy has served on an advisory board for Indivior. The other authors report no financial relationships with commercial interests.

The use of fentanyl and its analogs is the primary driver of deaths related to the opioid overdose crisis. In fall 2021, the U.S. Drug Enforcement Administration issued its first public safety alert in 6 years to raise awareness of the escalating prevalence of fentanyl in counterfeit pills and in other opioids, such as heroin, and nonopioids, such as methamphetamine. In addition to increased public awareness, specific actions are needed to remediate the risk for fentanyl overdose. The authors endorse four principles to address the opioid overdose crisis and provide guidance for remediating its impacts: an incremental approach to behavior change or harm reduction; engagement strategies for individuals with substance use disorder; an integrated care approach to ensure better access to treatment programs and effective interventions; and vigilance among clinicians, program staff, and patients to the threat of fentanyl-adulterated drugs. The authors offer specific recommendations on how to apply these principles effectively within health care systems, communities, and law enforcement agencies across the United States., Competing Interests: Dr. Fishman has been a consultant for Alkermes, Indivior, and Drug Delivery L.L.C. The other authors report no financial relationships with commercial interests.

This article introduces the Relationship-Oriented Recovery System for Youth (RORSY) protocol, which is designed to increase uptake of Medications for Opioid Use Disorder (MOUD) and related services among adolescents and young adults. Youth exhibit alarmingly poor rates of MOUD initiation and adherence, OUD services involvement and long-term recovery success. RORSY attends to three developmentally unique recovery needs of this age group: assess and bolster youth recovery capital, prioritize involvement of concerned significant others, and use digital direct-to-consumer recovery supports. RORSY contains five evidence-informed intervention modules that can be flexibly tailored to meet the individual and relationship needs of a given youth: Relational Orientation, Youth Recovery Management Planning, Relational Recovery Management Planning, Relationship Skills Building, and Digital Recovery Support Planning. The article concludes with practice and policy recommendations for making relationship-building a top clinical priority for addressing youth OUD.

Introduction: Psychosocial support is recommended in conjunction with medication for opioid use disorder (MOUD), although optimal "dose," modality, and timing of participation is not established. This study comprised a secondary analysis of counseling and 12-Step attendance and subsequent opioid use in a MOUD randomized clinical trial., Methods: The parent study randomly assigned 570 participants to receive buprenorphine-naloxone (BUP-NX, n =287) or extended-release injectable naltrexone (XR-NTX, n =283). Mixed-effects logistic regression models were fit with opioid use as the response variable, and a counseling/12-Step attendance predictor. Differences by treatment assignment were examined., Results: Any counseling or 12-Step attendance was associated with reduced odds of opioid use at the subsequent visit, whether considered individually or aggregated across type. A continuous relationship was observed for 12-Step attendance (F(1,5083)=5.01, p =.025); with each additional hour associated with 13% (95% CI: 0.83, 0.90) reduction in odds of opioid use. The strength of this association grew over time. In the BUP-NX arm, group counseling was associated with a greater reduction in odds of opioid use than for XR-NTX, (OR=0.32 (95% CI: .22, 0.48) vs. OR=0.69 (95% CI: 0.43, 1.08)). For XR-NTX, 12-Step was associated with a greater reduction in odds of opioid use (OR=0.35 (95% CI: 0.22, 0.54) vs. OR=0.65 (95% CI: 0.47, 0.89) for BUP-NX))., Conclusions: Psychosocial engagement has a proximal association with opioid use, the strength of that association may grow with dose and time. Alternatively, more motivated individuals may both attend more counseling/12-Step and have better treatment outcomes, or the relationship may be reciprocal., Competing Interests: Declaration of Competing Interest Dr. Hefner has no conflict of interest to declare. Dr. Shmueli-Blumberg has no conflict of interest to declare. Dr. Campbell has no conflict of interest to declare. Dr. Pavlicova has no conflict of interest to declare. Dr. Fishman serves as a consultant for Alkermes, a consultant for Drug Delivery LLC, holds a research grant from Alkermes and a research grant from Medicasafe. Ms. Meyers-Ohki has no conflicts of interest to declare. Dr. Shulman has no conflicts of interest to declare. Dr. Greiner has no conflicts of interest to declare. Ms. Novo has no conflicts of interest to declare. Dr. Rotrosen has served as a Principal Investigator or a co-Investigator on studies for which support in the form of donated medication and/or funds has been, or is, provided by Indivior, Alkermes, and Braeburn, and apps provided by Pear Therapeutics, CHESS Health, and Data Cubed. Dr. Rotrosen recently served in a non-paid capacity as a member of an Alkermes study Steering Committee. Dr. Nunes has served as a Principal Investigator or co-Investigator on studies for which support in the form of donated medication and/or funds has been, or is, provided by Indivior, Alkermes, and Braeburn-Camurus, and digital therapeutics provided by Pear Therapeutics and CHESS Health, and has served as an unpaid consultant to Alkermes, Braeburn-Camurus and Pear Therapeutics.

Objective: The concept of "deaths of despair" (suicide, overdose, and alcohol-related liver disease) highlights the importance of detecting and understanding the course of co-occurring depression in patients with opioid use disorder (OUD)., Methods: In a 24-week trial of 570 patients with DSM-5 -defined OUD randomized to buprenorphine-naloxone (BUP-NX) or extended-release naltrexone (XR-NTX) from January 2014 to January 2017, the prevalence of depression (assessed with Hamilton Depression Rating Scale [HDRS]) was examined at baseline and after 4 weeks of treatment, and the association between depression and relapse to opioid use was explored using logistic regression., Results: Among 473 patients who initiated medication, 14.2% (67/473) had moderate/severe depression (HDRS ≥ 17) and 34.9% (165/473) had mild depression (8 ≤ HDRS ≤ 16) at baseline. Patients with moderate/severe depression had more frequent histories of anxiety disorders and suicidal ideation. After 4 weeks of treatment, approximately two-thirds of participants with depression either responded (HDRS reduced ≥ 50% from baseline) or remitted (HDRS ≤ 7), with no significant differences between medication treatment groups. Those with moderate/severe depression were less likely to remit (52.8%; 28/53) compared to those with mild depression (76%; 98/129) at week 4 (OR = 0.43, 95% CI = 0.21-0.89, P  = .02). Further, those who remitted at week 4 had lower, but not significantly different, risk of relapse to opioids compared to those who did not remit (OR = 0.55, 95% CI = 0.28-1.08, P  = .08)., Conclusions: Depression is common among patients with OUD and often remits after initiation of BUP-NX or XR-NTX, although when it does not remit it may be associated with worse opioid use outcome. Depression should be screened and followed during initiation of treatment and, when it does not remit, specific depression treatment should be considered., Trial Registration: ClinicalTrials.gov identifier: NCT02032433., (© Copyright 2022 Physicians Postgraduate Press, Inc.)