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Aims: To estimate the effectiveness of different thresholds for administering opioid withdrawal medications (clonidine and clonazepam) on the probability of successfully initiating extended-release naltrexone (XR-NTX) among participants with opioid use disorder (OUD) during medically managed withdrawal.
Design: Secondary analysis of a multisite clinical trial comparing a rapid vs. standard approach for XR-NTX initiation, 2021–2022.
Setting: Six community inpatient addiction treatment units in the United States.
Participants: English-speaking adults seeking treatment for DSM-5 OUD and expressing interest in XR-NTX treatment (n = 415).
Measurements: We estimated the extent to which the following thresholds for adjunctive medication administration would affect the probability of initiating XR-NTX over time: 1) where adjunctive medications were given in response to at mild-to-moderate withdrawal symptoms or greater [Clinical Opiate Withdrawal Scale (COWS) score ≥ 5), 2) where adjunctive medications were given in response to minimal withdrawal symptoms or greater (COWS score ≥ 3) and 3) where adjunctive medications were given regardless of withdrawal symptoms. Using a longitudinal sequentially doubly robust estimator, we estimated the cumulative probability of XR-NTX initiation under each of these three treatment regimes while accounting for dropout and initiation of other medications as competing events.
Findings: The estimated probability of initiating XR-NTX by day 14 was 50.4% [95% confidence interval (CI) = 41.8–58.9) under the no-threshold regime, 43.9% (95% CI = 39.1–48.7) under the regime of waiting for minimal withdrawal symptoms and 38.5% (95% CI = 34.3–42.6) under the regime of waiting for mild-to-moderate withdrawal symptoms. Probability of XR-NTX initiation was a statistically significant 11.9 percentage points higher (95% CI = 3.6–20.2) under the no-threshold regime versus the mild-to-moderate threshold regime, and a non-statistically significant 6.4 percentage points (95% CI = −0.8 to 13.7) higher under the no-threshold regime versus the minimal threshold regime.
Conclusions: Providing clonidine and clonazepam daily during the first five days of medically managed opioid withdrawal appears to statistically significantly increase the likelihood of initiating extended-release naltrexone treatment compared with waiting for mild-to-moderate withdrawal symptoms to administer adjunctive medications. To improve initiation rates, providers may consider lowering the threshold at which they provide adjunctive medications, giving these medications preemptively or to manage even minimal withdrawal symptoms.
Related protocols: CTN-0097
Background: The National Institute on Drug Abuse (NIDA) Clinical Trials Network (CTN) has supported clinical trials of substance use disorder (SUD) interventions for 25 years. This review describes the use of implementation outcomes across CTN trials, characterizes outcomes included, and identifies gaps and potential opportunities to strengthen implementation research within the CTN and the field of SUD treatment.
Methods: This systematic review included active or completed studies listed on the CTN Dissemination Library webpage as of August 18, 2021, and approved by the CTN for development by January 1, 2022. Study summaries and protocols were reviewed if they: 1) measured at least one implementation outcome and 2) examined a practice change, intervention, or process. Extracted data elements included trial design characteristics, implementation frameworks, and outcome assessment domains informed by the RE-AIM and Proctor Implementation Outcomes Frameworks.
Results: 114 protocols were considered, 42 full-text protocols were screened, and 25 were included for data extraction. Start dates of trials spanned a 20-year period (2004–2024) with latter studies including more implementation outcomes. Fidelity (n = 29) and reach/penetration (n = 26) were the most included implementation outcomes. Equity was not identified in any protocols. Methods of defining, capturing, and evaluating outcomes data varied across trials and outcomes.
Conclusions: The inclusion of implementation outcomes increased over time, perhaps reflecting a growing emphasis on implementation research. Incorporating measures of equity could advance knowledge about differential receipt or effectiveness of SUD interventions. Future research should seek to improve the consistency and comprehensiveness in descriptions of implementation science elements.
Related protocols: CTN-0016, CTN-0056, CTN-0062-Ot, CTN-0064, CTN-0065, CTN-0069, CTN-0074, CTN-0074-A-1, CTN-0075, CTN-0076-Ot, CTN-0079, CTN-0079-A-1, CTN-0088, CTN-0090, CTN-0091, CTN-0095, CTN-0096, CTN-0097, CTN-0098, CTN-0099, CTN-0102, CTN-0103, CTN-0107, CTN-0116, CTN-0121
This is the primary outcomes article for CTN-0097.
Importance: Injectable extended-release (XR)-naltrexone is an effective treatment option for opioid use disorder (OUD), but the need to withdraw patients from opioid treatment prior to initiation is a barrier to implementation.
Objective: To compare the effectiveness of the standard procedure (SP) with the rapid procedure (RP) for XR-naltrexone initiation.
Design, setting, and participants: The Surmounting Withdrawal to Initiate Fast Treatment with Naltrexone study was an optimized stepped-wedge cluster randomized trial conducted at 6 community-based inpatient addiction treatment units. Units using the SP were randomly assigned at 14-week intervals to implement the RP. Participants admitted with OUD received the procedure the unit was delivering at the time of their admission. Participant recruitment took place between March 16, 2021, and July 18, 2022. The last visit was September 21, 2022.
Interventions: Standard procedure, based on the XR-naltrexone package insert (approximately 5-day buprenorphine taper followed by a 7- to 10-day opioid-free period and RP, defined as 1 day of buprenorphine at minimum necessary dose, 1 opioid-free day, and ascending low doses of oral naltrexone and adjunctive medications (eg, clonidine, clonazepam, antiemetics) for opioid withdrawal.
Main outcomes and measures: Receipt of XR-naltrexone injection prior to inpatient discharge (primary outcome). Secondary outcomes included opioid withdrawal scores and targeted safety events and serious adverse events. All analyses were intention-to-treat.
Results: A total of 415 participants with OUD were enrolled (mean [SD] age, 33.6 [8.48] years; 205 [49.4%] identified sex as male); 54 [13.0%] individuals identified as Black, 91 [21.9%] as Hispanic, 290 [69.9%] as White, and 22 [5.3%] as multiracial. Rates of successful initiation of XR-naltrexone among the RP group (141 of 225 [62.7%]) were noninferior to those of the SP group (68 of 190 [35.8%]) (odds ratio [OR], 3.60; 95% CI, 2.12-6.10). Withdrawal did not differ significantly between conditions (proportion of days with a moderate or greater maximum Clinical Opiate Withdrawal Scale score (>12) for RP vs SP: OR, 1.25; 95% CI, 0.62-2.50). Targeted safety events (RP: 12 [5.3%]; SP: 4 [2.1%]) and serious adverse events (RP: 15 [6.7%]; SP: 3 [1.6%]) were infrequent but occurred more often with RP than SP.
Conclusions: In this trial, the RP of XR-naltrexone initiation was noninferior to the standard approach and saved time, although it required more intensive medical management and safety monitoring. The results of this trial suggest that rapid initiation could make XR-naltrexone a more viable treatment for patients with OUD.
Related protocols: CTN-0097
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 NIDA 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: This is one of the first community-based, hybrid effectiveness-implementation trials of an inpatient procedure to initiate injectable naltrexone for opioid use disorder relapse prevention treatment. 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.
Related protocols: CTN-0097