Guest Editorial: Rapid Initiation of Injectable Extended-Release Naltrexone for Opioid Use Disorder: A Time for Paradigm Shift in Treatment Protocols

Matisyahu Shulman, MD 
Edward V. Nunes, MD 
Adam Bisaga, MD 

The opioid crisis remains a critical public health issue in the United States, contributing to over 80,000 opioid overdose deaths in 2023 alone. Addressing this problem necessitates effective treatment options for individuals with opioid use disorder (OUD) that reduce the risk of relapse and overdose. Injectable extended-release (XR)-naltrexone is an FDA-approved treatment for OUD, particularly for populations less inclined towards agonist-based therapies such as methadone or buprenorphine, and otherwise attempting to remain abstinent without the help of medications. However, the conventional approach to initiate XR-naltrexone poses a significant hurdle due to the necessity of an extended opioid-free period to avoid precipitated withdrawal. This approach is often not practical and has a low rate of success, leading to discouragement among both providers and patients from trying this treatment option. 

A recent study by Shulman et al. evaluated an alternative, rapid procedure (RP) for initiating XR-naltrexone, comparing it to the standard procedure (SP) in a stepped-wedge cluster randomized trial across six community-based inpatient addiction treatment units. We would like to explore the implications of these findings, which suggest that the RP could significantly enhance the accessibility and effectiveness of XR-naltrexone, despite certain limitations. 

The standard protocol for initiating XR-naltrexone, as outlined in the packet insert for the XR-naltrexone preparation Vivitrol, involves a 5-day buprenorphine taper followed by a 7- to 10-day opioid-free period before administering XR-naltrexone. This approach, while effective in preventing precipitated withdrawal, requires patients to endure an extended period without opioid treatment, increasing their vulnerability to withdrawal symptoms, cravings, and potential dropout from the treatment program and subsequent heightened risk of relapse and overdose. 

The RP, as investigated in the Surmounting Withdrawal to Initiate Fast Treatment with Naltrexone (SWIFT) trial, aimed to shorten this process. The RP involved just one day of buprenorphine at the minimum necessary dose to provide comfort, followed by a single opioid-free day, and then the administration of ascending low doses of oral naltrexone along with adjunctive medications to manage withdrawal symptoms. This approach reduced the XR-naltrexone initiation period to 5-7 days, potentially increasing patient retention and adherence to treatment. 

The SWIFT trial enrolled 415 participants with OUD who presented to community programs and were interested in initiating relapse prevention treatment with XR-naltrexone. The trial was not designed as a traditional randomized controlled trial with individual patients randomized to one of two induction approaches. Instead, the trial assigned entire units to implement the more rapid approach, with a new unit randomized to be added every 14 weeks. This “stepped wedge” design mirrored the reality of real-world implementation of a new approach in preparing staff before the rollout date and providing the same intervention to everyone entering treatment on the unit. 

The results were compelling: 62.7% of participants in the RP group successfully initiated XR-naltrexone compared to just 35.8% in the SP group. Along with this greater likelihood of induction, the trial showed that severity of opioid withdrawal in both arms was comparable.   

However, the study also highlighted safety concerns associated with the RP. While the RP was noninferior and even superior in terms of initiation success, the number of targeted safety events (TSEs), such as falls and vomiting, observed in inpatients undergoing induction was greater in the more rapid approach. Overall, the frequency of TSEs was rare, and 5.3% of participants in the RP group experienced TSEs compared to 2.1% in the SP group. These findings suggest that while the RP can expedite treatment initiation, it requires more intensive medical management and safety monitoring to minimize the impact of potential medical complications. 

The rapid initiation of XR-naltrexone offers a promising solution to some of the barriers inherent in the traditional approach. By reducing the time required for initiation, the RP can provide relief from withdrawal and improve patient retention by lowering the risk of dropout during the vulnerable opioid-free period. However, the increased incidence of TSEs and serious adverse events (SAEs) necessitates careful consideration and robust safety protocols to mitigate these risks. To harness the full potential of the RP, addiction treatment programs must invest in enhanced medical supervision and clinician training to manage the unique challenges posed by the RP. Furthermore, additional research is needed to refine the RP and perhaps develop an even faster approach, while assuring minimization of adverse events. 

Questions still remain after the trial, including most importantly, those related to broader issues in the field of OUD treatment choice. The place of the opioid receptor antagonist among available treatment options remains a question. The trial screened every patient entering treatment on inpatient units for trial participation. Only about 10% of all patients screened requested treatment with XR-naltrexone, with many starting buprenorphine, but a great number of patients chose not to start any medication for OUD. How to increase engagement in medication-based treatment in the high-risk population that seeks treatment in medically supervised withdrawal management units but chooses to forego medication is one of the vital questions facing the field. It is not clear how many patients that are not interested in agonist maintenance treatment might choose to initiate relapse-prevention treatment with XR-naltrexone if offered an opportunity of a rapid and comfortable treatment initiation. Another important challenge raised by the trial is the problem of poor retention on XR-naltrexone treatment. The trial did not provide intervention to increase XR-naltrexone engagement after induction, and only about 20% of all participants received all three XR-naltrexone injections offered during the trial, highlighting the pressing need for interventions that can increase retention on XR-naltrexone for OUD. 

In conclusion, the findings of the SWIFT trial represent a significant step forward in the treatment of OUD with XR-naltrexone. The RP holds promise for increasing the accessibility and effectiveness of this treatment, particularly for the population presenting to inpatient units for opioid withdrawal management but choosing not to initiate opioid agonist treatment. However, the training of providers in managing safety concerns highlighted in the study must be addressed to ensure that this approach can be implemented effectively and safely. By balancing the benefits of rapid initiation with comprehensive safety measures, we can make meaningful progress in combating the opioid epidemic and improving outcomes for individuals with OUD. 

Matisyahu Shulman, MD, is an assistant professor of clinical psychiatry at Columbia University Irving Medical Center with a research focus on opioid use disorders clinical trials and the use of technology to enhance implementation, quality improvement, and treatment delivery. 

Edward V. Nunes, MD, is a professor of psychiatry at Columbia University Irving Medical Center. He is an internationally recognized leader in research on treatments for opioid use disorder and other substance use disorders, and on co-occurring psychiatric and substance use disorders. 

Adam Bisaga, MD, is a professor of psychiatry at the Columbia University Irving Medical Center. His NIDA-funded research is focused on development and implementation of new medications and treatment protocols to treat opioid and other substance use disorders. 

The SWIFT trial was supported by the NIH HEAL Initiative UG1 DA013035-19 from the National Institute on Drug Abuse (NIDA) and conducted in the NIDA Clinical Trials Network (CTN).