Rapid Initiation of Injection Naltrexone for Opioid Use Disorder: A Stepped-Wedge Cluster Randomized Clinical Trial.

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.

PrEP for people who use opioids: A NIDA clinical trials network survey study in Southern U.S. cities where HIV incidence is high.

BACKGROUND: People who use opioids (PWUO) are at increased risk for HIV. Pre-exposure prophylaxis (PrEP) is effective but underutilized as HIV prevention among PWUO. This study examined predictors of willingness to take daily oral PrEP and long-acting injectable (LAI) PrEP among PWUO across eight Southern urban cities with high HIV incidence. METHODS: HIV-negative PWUO (N = 308) seeking services in community-based programs participated in this cross-sectional survey study. Measures included demographics, sexual risk behavior, substance use frequency, and awareness of and willingness to take oral and injectable PrEP. Data were analyzed using mixed-effects models. RESULTS: Willingness to take daily oral and LAI PrEP was moderately high (69.16% and 62.02%, respectively). Half had heard of PrEP, but only 4% had ever taken it. Only education and condomless vaginal sex predicted willingness to take oral PrEP. Only education predicted willingness to take LAI PrEP. Polysubstance use was prevalent, with substantial proportions of PWUO reporting frequent use of injection drugs (opioids or stimulants, 79.5%), non-injection opioids (73.3%), non-injection stimulants (71.1%), cannabis (62.6%), and hazardous drinking (29.6%). About 20% reported past-year condomless anal sex, and one-third reported past-year condomless vaginal sex. CONCLUSIONS: PWUO in this study were amenable to PrEP, particularly in light of education and condomless vaginal sex. Careful consideration for matching PrEP messaging to the PWUO audience is needed. PrEP promotion should expand beyond men who have sex with men to include groups such as these predominantly heterosexual, polysubstance-using PWUO with HIV risk who were open to both formulations of PrEP.

Subthreshold opioid use disorder prevention (STOP) trial: a cluster randomized clinical trial: study design and methods.

BACKGROUND: Preventing progression to moderate or severe opioid use disorder (OUD) among people who exhibit risky opioid use behavior that does not meet criteria for treatment with opioid agonists or antagonists (subthreshold OUD) is poorly understood. The Subthreshold Opioid Use Disorder Prevention (STOP) Trial is designed to study the efficacy of a collaborative care intervention to reduce risky opioid use and to prevent progression to moderate or severe OUD in adult primary care patients with subthreshold OUD. METHODS: The STOP trial is a cluster randomized controlled trial, randomized at the PCP level, conducted in 5 distinct geographic sites. STOP tests the efficacy of the STOP intervention in comparison to enhanced usual care (EUC) in adult primary care patients with risky opioid use that does not meet criteria for moderate-severe OUD. The STOP intervention consists of (1) a practice-embedded nurse care manager (NCM) who provides patient participant education and supports primary care providers (PCPs) in engaging and monitoring patient-participants; (2) brief advice, delivered to patient participants by their PCP and/or prerecorded video message, about health risks of opioid misuse; and (3) up to 6 sessions of telephone health coaching to motivate and support behavior change. EUC consists of primary care treatment as usual, plus printed overdose prevention educational materials and an educational video on cancer screening. The primary outcome measure is self-reported number of days of risky (illicit or nonmedical) opioid use over 180 days, assessed monthly via text message using items from the Addiction Severity Index and the Current Opioid Misuse Measure. Secondary outcomes assess other substance use, mental health, quality of life, and healthcare utilization as well as PCP prescribing and monitoring behaviors. A mixed effects negative binomial model with a log link will be fit to estimate the difference in means between treatment and control groups using an intent-to-treat population. DISCUSSION: Given a growing interest in interventions for the management of patients with risky opioid use, and the need for primary care-based interventions, this study potentially offers a blueprint for a feasible and effective approach to improving outcomes in this population. TRIAL REGISTRATION: Clinicaltrials.gov, identifier NCT04218201, January 6, 2020.

Surmounting Withdrawal to Initiate Fast Treatment with Naltrexone (SWIFT): A stepped wedge hybrid type 1 effectiveness-implementation study.

BACKGROUND: 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. METHODS: 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. DISCUSSION: 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: NCT04762537 Registered February 21, 2021.

Clinical documentation of patient-reported medical cannabis use in primary care: Toward scalable extraction using natural language processing methods.

Background: Most states have legalized medical cannabis, yet little is known about how medical cannabis use is documented in patients' electronic health records (EHRs). We used natural language processing (NLP) to calculate the prevalence of clinician-documented medical cannabis use among adults in an integrated health system in Washington State where medical and recreational use are legal. Methods: We analyzed EHRs of patients ≥18 years old screened for past-year cannabis use (November 1, 2017-October 31, 2018), to identify clinician-documented medical cannabis use. We defined medical use as any documentation of cannabis that was recommended by a clinician or described by the clinician or patient as intended to manage health conditions or symptoms. We developed and applied an NLP system that included NLP-assisted manual review to identify such documentation in encounter notes. Results: Medical cannabis use was documented for 16,684 (5.6%) of 299,597 outpatient encounters with routine screening for cannabis use among 203,489 patients seeing 1,274 clinicians. The validated NLP system identified 54% of documentation and NLP-assisted manual review the remainder. Language documenting reasons for cannabis use included 125 terms indicating medical use, 28 terms indicating non-medical use and 41 ambiguous terms. Implicit documentation of medical use (e.g., "edible THC nightly for lumbar pain") was more common than explicit (e.g., "continues medical cannabis use"). Conclusions: Clinicians use diverse and often ambiguous language to document patients' reasons for cannabis use. Automating extraction of documentation about patients' cannabis use could facilitate clinical decision support and epidemiological investigation but will require large amounts of gold standard training data.

HIV clinic-based extended-release naltrexone versus treatment as usual for people with HIV and opioid use disorder: a non-blinded, randomized non-inferiority trial.

BACKGROUND AND AIM: Opioid agonist medications for treatment of opioid use disorder (OUD) can improve human immunodeficiency virus (HIV) outcomes and reduce opioid use. We tested whether outpatient antagonist treatment with naltrexone could achieve similar results. DESIGN: Open-label, non-inferiority randomized trial. SETTING: Six US HIV primary care clinics. PARTICIPANTS: A total of 114 participants with untreated HIV and OUD (62% male; 56% black, 12% Hispanic; positive for fentanyl (62%), other opioids (47%) and cocaine (60%) at baseline). Enrollment halted early due to slow recruitment. INTERVENTION: HIV clinic-based extended-release naltrexone (XR-NTX; n = 55) versus treatment as usual (TAU) with buprenorphine or methadone (TAU; n = 59). MEASUREMENTS: Treatment group differences were compared for the primary outcome of viral suppression (HIV RNA ≤ 200 copies/ml) at 24 weeks and secondary outcomes included past 30-day use of opioids at 24 weeks. FINDINGS: Fewer XR-NTX participants initiated medication compared with TAU participants (47 versus 73%). The primary outcome of viral suppression was comparable for XR-NTX (52.7%) and TAU (49.2%) [risk ratio (RR) = 1.064; 95% confidence interval (CI) = 0.748, 1.514] at 24 weeks. Non-inferiority could not be demonstrated, as the lower confidence limit of the RR did not exceed the pre-specified margin of 0.75 in intention-to-treat (ITT) analysis. The main secondary outcome of past 30-day opioid use was comparable for XR-NTX versus TAU (11.7 versus 14.8 days; mean difference = -3.1; 95% CI = -8.7, 1.1) in ITT analysis. Among those initiating medication, XR-NTX resulted in fewer days of opioid use compared with TAU in the past 30 days (6.0 versus 13.6, mean difference = -7.6; 95% CI = -13.8, -0.2). CONCLUSIONS: A randomized controlled trial found supportive, but not conclusive, evidence that human immunodeficiency virus clinic-based extended-release naltrexone is not inferior to treatment as usual for facilitating human immunodeficiency virus viral suppression. Participants who initiated extended-release naltrexone used fewer opioids than those who received treatment as usual.

Care Facilitation Advances Movement Along the Hepatitis C Care Continuum for Persons With Human Immunodeficiency Virus, Hepatitis C, and Substance Use: A Randomized Clinical Trial (CTN-0064).

BACKGROUND: Direct-acting antivirals can cure hepatitis C virus (HCV). Persons with HCV/HIV and living with substance use are disadvantaged in benefiting from advances in HCV treatment. METHODS: In this randomized controlled trial, participants with HCV/HIV were randomized between February 2016 and January 2017 to either care facilitation or control. Twelve-month follow-up assessments were completed in January 2018.Care facilitation group participants received motivation and strengths-based case management addressing retrieval of HCV viral load results, engagement in HCV/HIV care, and medication adherence. Control group participants received referral to HCV evaluation and an offer of assistance in making care appointments. Primary outcome was number of steps achieved along a series of 8 clinical steps (eg, receiving HCV results, initiating treatment, sustained virologic response [SVR]) of the HCV/HIV care continuum over 12 months postrandomization. RESULTS: Three hundred eighty-one individuals were screened and 113 randomized. Median age was 51 years; 58.4% of participants were male and 72.6% were Black/African American. Median HIV-1 viral load was 27 209 copies/mL, with 69% having a detectable viral load. Mean number of steps completed was statistically significantly higher in the intervention group vs controls (2.44 vs 1.68 steps; χ 2 [1] = 7.36, P = .0067). Men in the intervention group completed a statistically significantly higher number of steps than controls. Eleven participants achieved SVR with no difference by treatment group. CONCLUSIONS: The care facilitation intervention increased progress along the HCV/HIV care continuum, as observed for men and not women. Study findings also highlight continued challenges to achieve individual-patient SVR and population-level HCV elimination. CLINICAL TRIALS REGISTRATION: NCT02641158.

Use of single IRBs for multi-site studies: A case report and commentary from a National Drug Abuse Treatment Clinical Trials Network study.

Recent NIH policy stipulates that multi-site studies must use a single or IRB (Institutional Review Board) in order to streamline the review process while maintaining standards for human subjects protection. The Western States Node of the Clinical Trials Network (CTN) used a single IRB for protocol CTN-0067, a clinical trial testing the use of an opioid antagonist (extended-release naltrexone) versus opioid agonists (buprenorphine or methadone) for opioid use disorders among individuals living with HIV. This case study discusses the processes and challenges associated with use of a single IRB. These lessons are also informed by other single IRB experiences within the CTN. The intention of the NIH single IRB policy is to facilitate efficient IRB processes. Advanced planning and transparent communication, however, are critical to avoid stalling IRB approval and protocol implementation. Research teams need to account for local IRB willingness to cede to a single IRB and understand the variations in interpretations of abbreviated reviews. In order to facilitate the effective use of single IRBs, recommendations include assigning staff at each study site for IRB submission coordination and interaction with the lead site IRB staff, training investigators and key regulatory staff on expectations for working with single IRBs, dedicating a regulatory specialist at the lead site to manage the process, developing a communication plan, and supporting the development of strong working relationships with local regulatory staff and the single IRB. The CTN experiences with single IRBs may provide insights for other investigators.

Validation of the TAPS-1: A Four-Item Screening Tool to Identify Unhealthy Substance Use in Primary Care.

BACKGROUND: The Tobacco, Alcohol, Prescription Medication, and Other Substance use (TAPS) tool is a combined two-part screening and brief assessment developed for adult primary care patients. The tool's first-stage screening component (TAPS-1) consists of four items asking about past 12-month use for four substance categories, with response options of never, less than monthly, monthly, weekly, and daily or almost daily. OBJECTIVE: To validate the TAPS-1 in primary care patients. DESIGN: Participants completed the TAPS tool in self- and interviewer-administered formats, in random order. In this secondary analysis, the TAPS-1 was evaluated against DSM-5 substance use disorder (SUD) criteria to determine optimal cut-points for identifying unhealthy substance use at three severity levels (problem use, mild SUD, and moderate-to-severe SUD). PARTICIPANTS: Two thousand adult patients at five primary care sites. MAIN MEASURES: DSM-5 SUD criteria were determined via the modified Composite International Diagnostic Interview. Oral fluid was used as a biomarker of recent drug use. KEY RESULTS: Optimal frequency-of-use cut-points on the self-administered TAPS-1 for identifying SUDs were ≥ monthly use for tobacco and alcohol (sensitivity = 0.92 and 0.71, specificity = 0.80 and 0.85, AUC = 0.86 and 0.78, respectively) and any reported use for illicit drugs and prescription medication misuse (sensitivity = 0.93 and 0.89, specificity = 0.85 and 0.91, AUC = 0.89 and 0.90, respectively). The performance of the interviewer-administered format was similar. When administered first, the self-administered format yielded higher disclosure rates for past 12-month alcohol use, illicit drug use, and prescription medication misuse. Frequency of use alone did not provide sufficient information to discriminate between gradations of substance use problem severity. Among those who denied drug use on the TAPS-1, less than 4% had a drug-positive biomarker. CONCLUSIONS: The TAPS-1 can identify unhealthy substance use in primary care patients with a high level of accuracy, and may have utility in primary care for rapid triage.

Long-term outcomes after randomization to buprenorphine/naloxone versus methadone in a multi-site trial.

AIMS: To compare long-term outcomes among participants randomized to buprenorphine or methadone. DESIGN, SETTING AND PARTICIPANTS: Follow-up was conducted in 2011-14 of 1080 opioid-dependent participants entering seven opioid treatment programs in the United States between 2006 and 2009 and randomized (within each program) to receive open-label buprenorphine/naloxone or methadone for up to 24 weeks; 795 participants completed in-person interviews (~74% follow-up interview rate) covering on average 4.5 years. MEASUREMENTS: Outcomes were indicated by mortality and opioid use. Covariates included demographics, site, cocaine use and treatment experiences. FINDINGS: Mortality was not different between the two randomized conditions, with 23 (3.6%) of 630 participants randomized to buprenorphine having died versus 26 (5.8%) of 450 participants randomized to methadone. Opioid use at follow-up was higher among participants randomized to buprenorphine relative to methadone [42.8 versus 31.7% positive opioid urine specimens, P < 0.01, effect size (h) = 0.23 (0.09, 0.38); 5.8 days versus 4.4 days of past 30-day heroin use, P < 0.05, effect size (d) = 0.14 (0.00, 0.28)]. Opioid use during the follow-up period by randomization condition was also significant (F(7,39,600) = 3.16; P < 0.001) due mainly to less treatment participation among participants randomized to buprenorphine than methadone. Less opioid use was associated with both buprenorphine and methadone treatment (relative to no treatment); no difference was found between the two treatments. Individuals who are white or used cocaine at baseline responded better to methadone than to buprenorphine. CONCLUSIONS: There are few differences in long-term outcomes between buprenorphine and methadone treatment for opioid dependence, and treatment with each medication is associated with a strong reduction in opioid use.