Rapid induction onto extended-release injectable buprenorphine following opioid overdose: A case series

Highlights

• •Emergency departments can help expand opioid use disorder treatment access.
• •We examined rapid induction onto injectable extended-release buprenorphine.
• •Induction initiated within 7 days of opioid-related overdose.
• •No precipitated withdrawal or serious adverse events observed during induction.
• •No repeat overdoses, deaths in patients inducted onto injectable buprenorphine.

Abstract

Background

Buprenorphine treatment has been associated with reduced non-prescribed opioid use and opioid related overdose (OD). We evaluated initial outcomes of rapid induction onto extended-release injectable buprenorphine (BUP-XR) within 7 days of emergency department presentation for unintentional OD.

Methods

Between February 2019-February 2021, N = 19 patients with opioid use disorder received buprenorphine/naloxone (4/1 mg), followed by BUP-XR (300 mg) at induction and continued BUP-XR outpatient for 6 months. Primary outcomes included adverse events, repeat OD, and death.

Results

For patients who received at least one dose of BUP-XR, there were no treatment related serious adverse events or symptoms of precipitated withdrawal. In addition, there were no repeat visits for ODs or deaths within 6 months of the initial OD.

Discussion

These preliminary findings support the need for larger controlled clinical trials to examine the safety and efficacy of rapid induction of BUP-XR in patients with opioid use disorder at high risk of opioid OD. Rapid induction onto long-lasting injectable buprenorphine may be a promising and protective treatment approach in the future.

1. Introduction

The pervasiveness of fentanyl, fentanyl analogs and other novel synthetic opioids has resulted in an unprecedented number of overdoses (OD)s, reinforcing the need for expanded access to medications for opioid use disorder (MOUD) (Althoff et al., 2020; Centers for Disease Control and Prevention, 2022; Kharti et al., 2021; Soares et al., 2021). Consequently, emergency department (ED) visits for ODs have surged in recent years (Soares et al., 2021), and between 2011 and 2015, an estimated 5.5% of patients died within a year after admission to the ED for an OD (Weiner et al., 2020). Although retrospective and observational investigations have shown clear associations of MOUD on reduced rates of all-cause mortality and ODs, there remains a substantial gap in treatment engagement among individuals with opioid use disorder (OUD), particularly those seen in the ED for non-fatal OD (Hawk et al., 2021; Ochalek et al., 2020).

Due to the abundance of patients with OUD who present for symptoms of withdrawal or OD, EDs offer an ideal setting to address these issues and related health sequelae (D'Onofrio et al., 2017; Hawk et al., 2021; Soares et al., 2021). Patients who have initiated buprenorphine/naloxone (BUP-SL) in the ED have demonstrated opioid treatment enrollment, reductions in non-prescription opioid use, and decreased incidence of OD (Chen et al., 2020; D'Onofrio et al., 2017; Hawk et al., 2021).

Injectable formulations of buprenorphine demonstrated similar efficacy to BUP-SL in reduced non-prescribed opioid use, treatment engagement, and improved quality of life among patients with OUD (Farrell et al., 2022; Ling et al., 2020). Two open-label pilot studies that examined one-day induction onto BUP-XR after a single BUP-SL dose reported reduced opioid craving and withdrawal symptoms, and overall clinical safety of the rapid induction protocol (Hassman et al., 2022; Mariani et al., 2021).

Since BUP-XR has not yet been investigated among the ED or recent OD patient populations, this project examined initial safety of rapid BUP-XR induction protocol within 7-days of opioid OD in a case series of 19 patients.

2. Material and methods

2.1. Selection and recruitment of patients

Recruitment for this single-arm, open-label trial (ClinicalTrials.gov, NCT03818399) occurred between February 2019-February 2021 at an urban healthcare system in Richmond, Virginia, and study medication (Sublocade®) was provided by Indivior, PLC. Due to COVID-19 safety guidelines, staffing of research personnel in the ED was limited, and the study was terminated in February 2021 by Indivior, PLC for not reaching targeted enrollment. This decision was not related to adverse events or safety of the study medication.

Potential study candidates were identified via an electronic health record data pipeline described in previous work by our team (Ochalek et al., 2020). The study team reviewed these EHR cases to determine whether they met initial eligibility criteria, which included overdoses that were: 1. opioid-related, as defined by an improvement in symptoms after administration of naloxone, and 2. unintentional/not considered a suicide attempt. Following informed consent, patients completed screening for study eligibility. Patients were included if they were ≥18 years of age, met DSM-5 criteria for moderate or severe OUD, were clinically stable, and agreed to take only study-administered buprenorphine products. Patients were excluded if they had a diagnosis other than OUD requiring chronic opioid treatment, active suicidal ideation, uncontrolled current illness, abnormal liver function tests, history of Long QT syndrome, or were lactating, pregnant, or planning to become pregnant. They were also excluded if they had an allergy or hypersensitivity to buprenorphine and/or naloxone, were currently receiving MOUD, received methadone within the past 30 days, and used long-acting opioids within the prior 48–72 h. Those with a court order for treatment or pending legal action that could affect participation were excluded. Also excluded were those with benzodiazepine or alcohol intoxication or withdrawal, or DSM-5 diagnosis for severe sedative or alcohol use disorders.

The Virginia Commonwealth University Institutional Review Board reviewed and approved the study and written informed consent was obtained for participation in this trial.

2.2. Schedule of events and measures

The induction visit took place in the ED, ED observation unit, inpatient unit, or affiliated outpatient treatment clinic within 7 days of the index OD. Clinical Opioid Withdrawal Scale (COWS) and adverse events (AEs) were assessed prior to administration of BUP-SL and again 30 min post-BUP-SL. After an additional 30 min, if patients displayed no hypersensitivity or allergic reaction to the BUP-SL, they then received 300 mg BUP-XR subcutaneously. COWS and AEs assessments were repeated one-hour post-BUP-XR. The induction was two hours in duration, with an optional added hour for those who self-reported incarceration in the previous 30 days; however, no patients met this criterion.

Given that buprenorphine plasma concentrations decreased to a plateau of approximately 2 ng/mL within 4 to 5 days after the first 300 mg injection (Nasser et al., 2014; Laffont et al., 2022), we administered the second 300 mg BUP-XR dose on day 8. This rationale was based on evidence suggesting that higher buprenorphine plasma levels may offer additional protection against respiratory depression induced by high potency opioids such as fentanyl (most recent evidence published by Moss et al., 2022). Subsequent BUP-XR doses were administered monthly, for 7 total injections (each 300 mg). This dosing regimen was selected based on data indicating that plasma buprenorphine concentrations ≥ 2–3 ng/mL would achieve ≥ 70% brain mu-opioid receptor occupancy (Haight et al., 2019; Laffont et al., 2016). These concentrations have been shown to adequately control opioid withdrawal symptoms and craving, and block exogenously administered opioid liking (Haight et al., 2019; Laffont et al., 2022; Nasser et al., 2014). BUP-XR induction occurred in the ED (N = 8; 42%), ED observation unit (N = 3, 16%), inpatient unit after ED admission (N = 4; 21%), or outpatient clinic (N = 4; 21%). The median time between the index OD visit and the initial BUP-XR injection was 24.1 ± 57.8 h.

Information regarding number of repeat opioid-related overdoses resulting in ED admission within 6 months of the index overdose visit was abstracted from the EHR. All-cause mortality cases within 6 months of the index overdose were also obtained from EHR, which was regularly updated from the Virginia Department of Health Death Registry and the federal Social Security Death Index.

2.3. Statistical analyses

Descriptive statistics were conducted for baseline sociodemographic characteristics. COWS scores at the induction visit were compared between the three timepoints using individual paired samples t-tests. Data were analyzed using IBM SPSS Version 29.0.

3. Results

3.1. Baseline sociodemographic characteristics

Between February 2019 to February 2021, N = 732 unintentional, non-fatal OD cases presented to the ED, and N = 37 patients were approached, provided informed consent, and completed baseline assessments (Fig. 1). Nineteen patients were enrolled and received initial doses of BUP-SL and BUP-XR. Of the N = 19, a majority were Black (N = 18, 95%), male (N = 17, 89%), Non-Hispanic, Spanish, or Latinx (N = 17, 89%), had a mean age of 46.4 ± 12.1 and a mean of 11.6 ± 2.2 years of education. Also, N = 9 (47%) were never married or single and N = 12 (63%) were unemployed.

Fig. 1.

Enrollment flow diagram.

Schematic diagram representing patient selection and flow in the BUP-XR group (white boxes). Enrolled (N = 19) is defined as patients who received at least one dose of BUP-XR. Completers (N = 5) indicates patients who received all 7 BUP-XR doses. The N = 695 non-fatal, opioid related overdose cases presenting to the ED that were not approached or consented to participate in the study may have met more than one of the listed exclusionary criterion (gray box).

3.2. Primary outcomes

During the 6-month study, N = 11 (58%) of the BUP-XR group patients reported at least one AE, with constipation (N = 4, 20%) and injection site pain (N = 3, 15%) as the most common experienced. Two SAEs occurred that were both unrelated to the study medication and resolved.

Mean COWS scores decreased significantly from pre-(6.3 ± 4.7) to post-(2.2 ± 1.8) BUP-SL and to post-BUP-XR (1.7 ± 1.7) (p's<0.001). COWS scores following BUP-SL and BUP-XR did not differ significantly (p = 0.11). Of the three AEs reported at induction, two (injection site pain and mild sedation) were reported after BUP-XR, both of which were mild intensity and related to the BUP-XR. No patients experienced precipitated withdrawal during induction.

Among the N = 19 who received at least one dose of BUP-XR, none (0%) presented to the ED with repeat opioid OD or died from any cause in the 6-months following their index OD. Treatment engagement in VCU's outpatient buprenorphine treatment clinic was high in those who received at least one dose of BUP-XR, with N = 15 (79%) attending at least one outpatient visit after induction onto BUP-XR. The group mean number of outpatient visits attended across the 6-month period after BUP-XR induction was 13.3 ± 9.8.

Regarding retention, N = 9 (47%) received one of seven BUP-XR doses, N = 2 (11%) received two of seven, N = 2 (11%) received four of seven, N = 1 (5%) received five of seven, and N = 5 (26%) received all seven doses. Among patients who received just the initial BUP-XR dose (N = 9) but were not retained on BUP-XR, one patient preferred to switch to BUP-SL due to a reported AE of subjective drowsiness after the initial BUP-XR injection.

4. Discussion

Overall, study findings demonstrated initial safety of extended-release injectable buprenorphine administered within 7 days of presenting to the ED for an OD, and some preliminary evidence of providing protection from repeat OD and all-cause mortality in this clinical case series. Importantly, of the 9 patients who received only a single dose of BUP-XR, no repeat ED visits for OD or deaths were observed, illustrating the potential protective utility of this long-lasting buprenorphine formulation.

In contrast, an analysis of N = 540 patients seen in our ED during the same time period who were seen after regular outpatient clinic hours or were unable to be reached by staff and thus did not receive rapid induction onto BUP-XR, N = 97 (18%) presented to the ED with a repeat OD and N = 33 (6%) died within 6-months of their index OD, which is a similar rate to previously published data (Weiner et al., 2020). This suggests that early pharmacological intervention after OD may enhance treatment engagement generally and minimize risks of untreated OUD. These positive findings are especially salient given that 68% of the sample was enrolled during the height of the COVID-19 pandemic and its associated wave of ODs (Centers for Disease Control, 2021; Kharti et al., 2021; Ochalek et al., 2020; Soares et al., 2021).

Despite our promising initial findings, several limitations are worth noting. First, the small sample size recruited limits external validity and generality of these results. Although approximately 24 h elapsed between the index OD and induction, and while most inductions occurred in the ED or ED observation unit (57%), others occurred elsewhere, which may confound safety and withdrawal data. Since we did not collect data from other EDs or ODs outside the hospital setting (e.g., residence, EMS without transport to the ED), the number of repeat ODs may be underreported. Finally, the primary barrier to recruitment was that many OD cases presented after typical outpatient clinic hours; however, this supports the compatibility of a 24/7 ED setting for MOUD initiation (D'Onofrio et al., 2017; Hawk et al., 2021 ). Of the 17 ineligible patients, 35% withdrew before medication induction, which underscores the need to better address the barriers to treatment engagement among this vulnerable patient population.

Despite these limitations, neither the BUP-SL or BUP-XR produced precipitated withdrawal or treatment related serious adverse events, which is consistent with investigations of open-label BUP-XR on non-OD patients (Farrell et al., 2022; Mariani et al., 2021). In contrast, Hassman et al. (2022) observed precipitated withdrawal with BUP-XR in N = 2 (8%) of the sample, but noted that induction onto BUP-XR following a single 4 mg BUP-SL dose was generally well-tolerated. Our lack of urine drug screen data at the index ED visit limits interpretation of the precipitated withdrawal results in our sample. Given recent reports indicating that fentanyl is associated with protracted clearance, and precipitated withdrawal and difficult inductions onto buprenorphine (Antoine et al., 2021; Huhn et al., 2020), further studies in larger samples are warranted to provide better understanding around feasibility and safety of induction protocols onto BUP-XR. Finally, in our study, most patients were Black (95%), illustrating the large racial and ethnic disparities in ODs and treatment access that others have highlighted (Althoff et al., 2020; Kharti et al., 2021; Ochalek et al., 2020).

Given the dramatic rise in opioid ODs, it is important to consider expanding rapid initiation treatment modalities for OUD, with prioritization of patients at highest risk of an overdose. Larger investigations on safety and efficacy of BUP-XR as an option for treatment initiation in the ED or rapidly after ED visits are needed to reduce the burden of the opioid epidemic.

CRediT authorship contribution statement

FGM, LKM, BKW, and KLC conceptualized the study. TAO, FGM, and RTS drafted the manuscript. KJR, TTD, TAO, and TSG were responsible for data collection, acquisition, preparation. RTS and TAO performed statistical data analyses. RTS, TAO, CEM, BKW, LKM, KLC, and FGM contributed to data interpretation and manuscript writing. All authors contributed to critical revisions and approved a final version of the manuscript. RTS, TAO, and FGM have full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Declaration of Competing Interest

Dr. F. Gerard Moeller consults for Boehringer Ingelheim and AstraZeneca. He received past grant support from Indivior and Nektar and was a past consultant for Indivior and Astellas. No other disclosures were reported.