Guest Editorial: Injectable-Only Overlapping Buprenorphine Starting Protocol in a Low-Threshold Setting: Current State, Lessons Learned, and Future Direction

Background

Initiating buprenorphine for opioid use disorder (OUD) in outpatient settings is more difficult for patients using fentanyl. There are research and published literature supporting this trend.¹ Nearly as compelling is the concordant experience reported by patients and outpatient providers, many of whom have observed a significant decline in successful buprenorphine initiations since the widespread emergence of fentanyl. Novel buprenorphine initiation strategies are needed, especially in places serving high volumes of patients with OUD who are also experiencing homelessness and have other complex medical and social needs such as supportive housing programs, drop-in centers, street outreach teams, and community health centers. Traditional strategies for initiating sublingual (SL) buprenorphine preparations in the outpatient setting for these communities present multiple barriers including multi-step complexity of overlapping SL buprenorphine starting protocols,² the need to cease fentanyl use in withdrawal-first protocols,³ or deliberate precipitation of withdrawal in naloxone-assisted methods.⁴ In 2024 a novel buprenorphine initiation strategy utilizing only long-acting injectable buprenorphine (LAIB) was introduced to the Seattle area by the Downtown Emergency Service Center (DESC).⁵ The initial cohort of patients undergoing this initiation protocol demonstrated a 75% completion rate of the 3-injection series and 64% of these patients received a second monthly LAIB dose. Of the study population, 79% were experiencing homelessness or living in permanent supportive housing, indicating that this method may be an acceptable option for some with high social needs to start buprenorphine.

Second-generation injectable buprenorphine was approved by the US Food and Drug Administration in 2023 and comes in both weekly and monthly formulations. The slower onset of buprenorphine reduces the likelihood of the rapid displacement of fentanyl seen with SL preparations. The protocol utilized by DESC leverages these unique pharmacokinetics of second-generation injectable buprenorphine through sequential administration of LAIB doses administered over 3 days: an 8 mg weekly injection on day 1; a 16 mg weekly injection on day 2; and a monthly 128 mg or 300 mg injection on day 3, as long-term maintenance.

The DESC publication was not without limitations.⁶ The study encompasses a smaller sample size, lacks a control arm, has minimal narrative on the subjective experiences of those undergoing the initiations, and occurs in a health system not applicable to many institutions—eg, Medicaid coverage of LAIB, wraparound and outreach services for those undergoing the initiation, ability to have high frequency of visits on consecutive days. These limitations further emphasize the need for the continued development and application of injectable formulations in alternative, novel outpatient protocols especially for marginalized communities like those represented in the DESC study. Small case series are beginning to demonstrate the variability and applicability of protocols like the one utilized by DESC.⁷ Additionally, larger institutions like the Medication Use Improvement Committee for San Francisco Department of Public Health have published both 2- and 3-dose LAIB protocols for outpatient use.⁸ Furthermore, the evidence supporting the safety and efficacy of these formulations in pregnant patients continues to grow.⁹

Local Uptake, Lessons Learned, and the Future of LAIB

Local uptake and implementation of this novel initiation strategy has become increasingly common across the greater Seattle area, particularly within programs serving unhoused, primarily Medicaid-insured communities. This protocol has been implemented in a variety of settings including a low-threshold treatment program embedded in a drop-in center that also offers field-based OUD care in shelters and supportive housing, a hub and spoke model of integrated primary care and addiction medicine care housed within a federally qualified health center (FQHC), more traditional office-based opioid treatment (OBOT) clinics, and purely outreach-based models like street medicine programs and overdose response teams.

Like all MOUD strategies in the fentanyl era, unique challenges still exist with this injectable-only initiation protocol. Key points we have learned over the last several years include:

• The injectable-only protocol is best used as a strategy for individuals with active opioid use disorder who are unable or unwilling to discontinue unregulated full-agonist opioid use, and who have difficulty with sublingual overlapping buprenorphine approaches (low-dose initiations), whether due to complexity, preference, or other factors.
• As with sublingual overlapping protocols, continued full-agonist use is an assumed element of the protocol.
• Withdrawal occurs. It has yet to be studied rigorously, but local teams are seeing trends and adjusting accordingly. The most significant withdrawal experiences, anecdotally, have tended to be in individuals who stopped or reduced their unregulated use during the process—only further highlighting the importance of ongoing full-agonist use.
• Ancillary medications are often needed and should be encouraged. Coaching reasons for initiation, frequency of administration, and normalization of ongoing use for several days after completion of the series has been helpful.
• Nearly all individuals experience lower cravings and reduced use, based on clinical experience, after receiving the monthly injection (third day of the protocol). Ongoing use of SL buprenorphine, often 16–32 mg daily, on top of their monthly LAIB to help with cravings or protracted withdrawal is common, particularly while reaching steady state with these medications. Many continue supplemental SL buprenorphine indefinitely.
• The fear of buprenorphine-precipitated withdrawal with SL use even after receiving a monthly formulation is profound in many patients due to prior adverse experiences. Extensive coaching and support in these situations is important. There is no clear consensus on the optimal timing for discontinuing full-agonist opioid use and initiating sublingual buprenorphine for breakthrough symptoms after the first monthly injection. While most individuals will not experience precipitated withdrawal when waiting 8–12 hours, many prefer to wait until peak injection effect—up to 24 hours, depending on the formulation.
• On-demand access for these medications is critical. The groups doing this at scale have implemented pharmaceutical pathways, or partnerships, which allow same-day access to LAIB formulations. This is accomplished through same-day courier services, in-house 340B pharmacies with REMS certification, or buy and bill models.
• Washington state is fortunate to have Medicaid coverage for LAIB in all formulations without the need for prior authorization. As mentioned above, on-demand access for these medications is key for optimal implementation of this protocol.
• Alternative models of care are needed to best serve many of these patients. Examples include flexible clinic hours and appointment scheduling; access to transportation and incentive programs; field-based outreach with pharmacy-dispensed, patient-labeled medications; and administration of LAIB in patients' places of residence. These approaches have been effective in supporting vulnerable individuals who struggle with traditional clinic-based models.

The continued study and innovation of novel LAIB initiation protocols is needed. Future areas of focus could include:

• Continued expansion of emergency department and inpatient-based protocols
• The expansion of novel SL buprenorphine initiation strategies and LAIB protocols, including those utilizing ketamine-assisted protocols^10,11
• Use of full opioid agonists, like methadone, during the LAIB initiation process
• Ongoing advocacy efforts by state and national organizations to ensure coverage of LAIB formulations without prior authorization by state and private insurance plans
• Research and patient experience on ways to utilize LAIB with patients hoping to transition from methadone
• Further data on the qualitative experiences of patients undergoing these protocols in order to better counsel patients on what to expect when making decisions in their care
• Further data on possible secondary impacts stabilization has on other, co-occurring substance use disorders and medical comorbidities.

Overall, injectable-only protocols have been transformative for people who use drugs in the greater Seattle area. In the fentanyl era, outpatient care teams have observed unprecedented levels of patient engagement and continuity of care. Most importantly, these approaches are expanding access to lifesaving medications, improving patients' quality of life, and supporting greater autonomy as individuals navigate their substance use and recovery journeys.