Inpatient Low Dose Transitions from Full Agonist Opioids Including Methadone onto Long Acting Depot Buprenorphine: Case Series from a Multicenter Clinical Trial

Abstract

Objectives:

Persons with opioid use disorder (OUD) suffer disproportionately from morbidity and mortality related to serious addiction-related infections requiring hospitalization. Long-acting buprenorphine (LAB) is an underutilized medication for OUD that may facilitate linkage to care and treatment retention when administered prior to hospital discharge. Transition onto buprenorphine in the inpatient setting is often complicated by pain, active infection management, potential surgical interventions, and risk of opioid withdrawal in transition from full agonists to a partial agonist.

Methods:

The COMMIT trial is a randomized controlled trial evaluating LAB administered by Infectious Disease physicians and hospitalists compared to treatment as usual for persons with OUD hospitalized with infections. We report a case series of participants on full agonist opioids including methadone who were transitioned to sublingual buprenorphine using low dose (“microdosing”) strategies followed by LAB injection.

Results:

Seven participants with current opioid use disorder and life-threatening infections, all with significant concurrent pain and many requiring surgical intervention, underwent low dose transitions starting at buccal buprenorphine doses ranging from 225 mcg to 300 mcg TID on the first day. All were well tolerated with average time to LAB injection of 7.5 days (range: 5 to 10 days).

Conclusions:

Inpatient low dose buprenorphine transition from full agonist opioids including methadone onto LAB is feasible even in those with complex hospitalizations for concurrent infections and/or surgery. This strategy facilitates dosing of LAB prior to hospital discharge when risk of opioid relapse and overdose are significant.

Introduction

The US opioid epidemic has been accelerating, with over 1 million total overdose deaths since 2001 and overdose deaths spiking to levels previously unseen now in the context of the COVID-19 pandemic.¹ In addition to overdose deaths, the morbidity and mortality due to opioid use disorder (OUD) includes infections from intravenous use and subsequent infection-related hospitalizations that have also risen dramatically in the past two decades.^2,3 Current trends highlight the urgency of identifying novel treatments and models of care to treat opioid use disorder and its associated comorbidities.

The inpatient setting is a unique underutilized setting to intervene, treat infections related to injection drug use, and initiate medications for opioid use disorder (MOUD). While the hospital setting is a ‘reachable moment’ for initiating MOUD, there exist a number of logistical barriers in this setting such as illness severity, pain control, surgical interventions, and management of opioid withdrawal during transition from high dose illicit opioids and/or prescribed pain medications to MOUD formulations.

For patients who are receiving full opioid agonists (e.g. morphine, hydromorphone, oxycodone, methadone), low dose or so called “microdose” strategies have been used to facilitate the transition onto the partial agonist buprenorphine, if this is the desired MOUD of choice, though this has been demonstrated largely in outpatient settings⁴. Newer long-acting injectable buprenorphine (LAB) formulations allow for a one-month duration of therapeutic blood levels.^5,6 Potential advantages of LAB include low dosing frequency (circumventing problems with adherence to daily dosing) and lack of diversion potential. A particular advantage of LAB for hospitalized patients with OUD is that it provides protection from relapse and overdose during hospitalization⁷ and across the first month after hospital discharge, a time when risk is elevated and transition to stable long term MOUD care is a challenge in part due to numerous competing needs that may preclude immediate linkage to care.

The COMMIT Trial (Coordinated medical treatment of opioid use disorder and infectious disease; NCT# NCT04180020) is a multisite randomized controlled trial testing a new model of care (ID/LAB) in which opioid use disorder (OUD) is managed by infectious disease (ID) specialists and hospitalists using LAB concurrent with management of associated infections. We present a case series of participants from the COMMIT Trial hospitalized with OUD and concurrent infections who underwent transition from full agonist opioids, including methadone, to LAB via low dose transition strategies.

Methods

The COMMIT study protocol and detailed methods have been previously published⁸. Enrollment occurred at the three designated clinical sites: Yale New Haven Hospital (New Haven, CT), PRISMA Health Greenville (Greenville, SC), and Penn State-Hershey (Hershey, PA). Trial enrollment began on August 19, 2020 and continues to date. Participants were adults with moderate to severe active OUD and a concurrent active or suspected infection. All study procedures were reviewed and approved by the single IRB of record at the Medical University of South Carolina. The study is registered on ClinicalTrials.gov (NCT04180020). Inclusion criteria were defined as: 1) Age > 18, English or Spanish speaking, 2) hospitalization with any suspected or confirmed infection, 3) current DSM-5 moderate to severe OUD, and 4) willingness to participate in a clinical trial.

Exclusion were as follows: 1) Severe medical or psychiatric disability making participation unsafe at the discretion of local site PIs, 2) pregnancy, planning conception, or breast-feeding for female participants, 3) allergy, hypersensitivity, or medical contraindication to buprenorphine, 4) moderate to severe liver impairment, 5) preexisting enrollment on methadone or buprenorphine and desire to continue post discharge, and 6) inability or unwillingness to give informed consent.

Informed consent was completed by study personnel for those participants who were interested and eligible. Randomization occurred 1:1 to the ID/LAB arm versus treatment as usual (TAU). Those in the ID/LAB arm were assigned to receive three study provided doses of LAB with referral as soon as able to community substance use providers for continued MOUD prescribing per patient preference. The LAB formulation used in this study was Sublocade^® (Indivior Inc., North Chesterfield, VA), FDA approved in 2017 for treatment of moderate to severe OUD⁹ –the 300 mg dose was used for all three study provided doses as it has been associated with better opioid abstinence outcomes for those with intravenous opioid use.¹⁰ The TAU arm consisted of formal diagnosis of OUD, recommendation to the primary clinical team for treatment with MOUD as per standard of care, and any addiction and/or infectious disease treatment per the clinical team’s discretion. Study participation lasted for 6 months. Other resources provided to both study arms included naloxone distribution, overdose education, linkage to outpatient care, and standardized scheduled Medical Management¹¹ phone calls.

Inpatient buprenorphine inductions were performed by hospital clinicians with the support of study personnel. Addiction Medicine consultation was available at two of the research sites (Yale, Penn State) at the start of study enrollment, and consultants participated in inductions if requested by the primary hospital clinical team. Research clinicians ordered the study Sublocade^® for all participants in the LAB arm in collaboration with the inpatient care team. Due in part to the receipt of an IND by the FDA, clearance was granted for accelerated induction from sublingual (SL) buprenorphine onto Sublocade^® more rapidly than the 7 days delineated in the package insert, supported by published data on safety and feasibility of rapid initiation.¹²

Case Definition

Persons were included in this cohort if they met the following case definition criteria:

1. Enrollment in the COMMIT Trial (active OUD, at least moderate/severe)

2. Receipt of full agonist opioids including methadone in the hospital at time of study randomization

3. Transition onto SL buprenorphine followed by LAB utilizing a low dose transition (e.g. buprenorphine with concurrent full agonist dosing; initial buprenorphine doses as low as 2 mg or less, as low as 0.5 mg)

   Patients with ‘classical’ or standard guideline-based buprenorphine transitions (e.g., agonist medications were halted and buprenorphine was started after a brief abstinence period) were not included in this case series.

Patient data was sufficiently deidentified prior to case series inclusion such that no additional consent was deemed necessary by the Principal Investigators.

Method of transfer onto buprenorphine was decided based on clinical care team discretion, research team input, and patient-centered decision making based on risks and benefits. Transitions onto SL buprenorphine were generally consistent with the Modified Bernese method¹³ utilizing buccal buprenorphine (Belbuca^®; Collegium Pharmaceutical Inc., Stoughton, MA), in which 225 mcg was used as the first day dose. The 225 mcg dose (roughly equivalent to 0.5 mg SL buprenorphine) is comprised of a 75 mcg film + 150 mcg film and has the added advantage of not requiring film or tablet cutting. Doses were generally doubled each day – by day 6 a target dose of 12 mg SL buprenorphine was achieved at which point most mu opioid receptors are occupied by buprenorphine with displacement of any other agonist opioid due to high receptor affinity of buprenorphine.^14,15 Full dose agonists were continued without taper and were discontinued in full by day 7, typically with continued up-titration of SL buprenorphine. Clinical Opioid Withdrawal Scale (COWS¹⁶) scores were performed immediately before Sublocade^® dosing and in 30 minute intervals afterwards for up to two hours per study protocol.

Results

Seven patients met case definition criteria as shown in Table 1. Six of the patients were recruited at the Yale site, and one at the Penn State Hershey site. Of note, the PRISMA Greenville site did not have low dose buprenorphine formulations on formulary until June 9, 2021.

Table 1:

Patient Characteristics

Case	Patient	Substance Use Dx per MINI	Day of Randomization and Length of Stay	Infectious Syndrome	Surgery	Preceding Opioid Regimens
1	35 y/o female	Severe OUD, severe cocaine UD	Day 6 of hospitalization LOS: 42d	Enterococcal aortic valve/mitral valve prosthetic endocarditis	Redo aortic valve/mitral valve replacement (d8) pacemaker placement (d11)	MOUD Prior: none (remote buprenorphine) Substance use: IV heroin+fentanyl, non-prescribed methadone (oral); smoked methamphetamine At time of randomization: Methadone 10 mg bid Before transition: methadone of 45 mg (15 mg tid po)
2	31 y/o female	Severe OUD Prescribed benzodiazepine and dextroamphetamine use	Day 29 of hospitalization LOS: 43d	MSSA native tricuspid valve endocarditis	Tricuspid valve replacement + pacemaker placement (d10)	MOUD prior: Intermittent SL buprenorphine / naloxone Substance use: IV heroin + smoked crack cocaine At time of randomization: Po hydromorphone 4 mg q4h + SL buprenorphine / naloxone 8 mg bid Before transition: Po hydromorphone 6 mg q3h + MS Contin® 30 mg IR
3	39 y/o male	Severe OUD	Day 7 of hospitalization LOS: 17d	MSSA bacteremia + chronic ulnar osteomyelitis	n/a	MOUD prior: None (remote buprenorphine / naloxone) Substance use: IV heroin+fentanyl, IV cocaine At time of randomization: methadone 60 mg (started during hospitalization) +oxycodone 10–15 mg q4h prn Before transition: methadone 60 mg qday (started during hospitalization) +oxycodone 10–15 mg q4h prn
4	35 y/o male	Severe OUD, severe benzodiazepine UD	Day 7 of hospitalization LOS: 15d	Bilateral upper extremity abscesses	n/a	MOUD prior: Methadone 115 mg qday Substance use: IV heroin and fentanyl; smoked crack-cocaine At time of randomization: Methadone 115 mg + mid low dose transition Before transition: Methadone 115 mg
5	67 y/o male	Severe OUD	Day 8 of hospitalization LOS: 16d (premature discharge)	MRSA septic arthritis of knee	knee arthroscopic irrigation and debridement (d2)	MOUD prior: none Substance use: IV heroin and fentanyl; IV cocaine At time of randomization: Methadone 30 mg qday (started in hospital) + oxycodone 15 mg q4h prn Before transition: Methadone 30 mg qday (started in hospital) + oxycodone 15 mg q4h prn
6	44 y/o male	Severe OUD Severe cocaine UD	Day 2 of hospitalization LOS: 8d	Severe covid 19 pneumonia	n/a	MOUD prior: Methadone 60 mg qday Substance Use: Smoked heroin and crack-cocaine At time of randomization: Methadone 60 mg Before transition: Methadone 60 mg
7	29 y/o male	Severe methamphetamine UD, severe OUD, severe cocaine UD, severe cannabis UD	Day 5 of hospitalization LOS: 13d	Polymicrobial mitral native valve endocarditis	Mitral valve replacement (d2)	MOUD prior: none Substance use: IV heroin, oral oxycodone; IV methamphetamine At time of randomization: IV hydromorphone + po oxycodone Before transition: IV hydromorphone + po oxycodone

Key : COWS = Clinical Opioid Withdrawal Scale; d/c = discharge; IV = intravenous; IR = Immediate release; LAB = Long-acting buprenorphine; LOS = Length of Stay; MINI = Mini-International Neuropsychiatric Interview; MOUD = Medications for opioid use disorder; MRSA = Methicillin Resistant Staphylococcus Aureus; MSSA = Methicillin Susceptible Staphylococcus Aureus; MS-ER = morphine sulfate extended-release; po = By mouth; q day = Each day; UD = Use disorder (e.g. OUD = opioid use disorder); WD = withdrawal

All hospitalization days (e.g. d1, d2) given in terms of day of hospitalization

Background characteristics

Ages ranged from 29 to 67 years old with a mean age of 40 years. Five participants identified as male and two identified as female. Six of the participants were White/Caucasian and one participant was Black/African American. All had a diagnosis of severe OUD as assessed by the Mini-International Neuropsychiatric Interview (MINI¹⁷). Comorbid substance use disorder diagnoses were seen in over half of the group. Three of the seven participants had cocaine use disorder, one with benzodiazepine use disorder, and one had current methamphetamine use disorder. All patients reported some form of stimulant use in the month preceding hospitalization.

Admissions

The average length of stay per participant for the index hospitalization was 22 days. All persons were admitted for infectious syndromes. Three had endocarditis, two with bone/joint infections, one with abscesses/skin and skin structure infections and one with severe COVID19 pneumonia. Four out of seven persons required surgical interventions. All but one infection was deemed to be secondary to injection drug use complications. Pain at enrollment was assessed via the Pain, Enjoyment of Life and General Activity, or PEG scale¹⁸ from 0 to 10 for ‘past week pain’ and pain at time of questioning, with scores in the 3 to 7 range reflecting moderate to severe pain. The average score in the past week was rated 8.2 (range: 5 to 10) and average at time of questioning was rated 5.7 (range: 3 to 7).

Four participants were not on any form of MOUD prior to the index hospitalization. For those who had been prescribed a form of MOUD prior to the hospitalization: one endorsed intermittent adherence to sublingual (SL) buprenorphine, another was started on methadone in the week prior to hospitalization with the desire for buprenorphine therapy, and the last was on methadone with intent of switching off the medication by the time of admission.

Prior to transition initiation, five of seven participants had methadone as a component of their full agonist opioid regimen. Three of these persons were initiated onto methadone on admission, typically for acute opioid withdrawal management in the context of acute pain needs, upcoming surgery and/or sepsis.

Transitions were initiated on average on day 10 of hospitalization. For those who required surgical intervention, all low dose transitions began after surgery. Opioid regimens per day of transition are shown in Table 2. The low dose transition period was defined as the number of days from first buprenorphine initiation to either a) the day of cessation of the full opioid agonist in question, in keeping with definitions in the published literature, or b) the dosing of LAB, if given prior to cessation of full opioid agonists. The average time in transition was 6.7 days. While the buccal Modified Bernese method was most commonly used, there were minor variations. In cases #5 and #6, a more rapid protocol was utilized in which the starting dose was a) 225 mg bid Belbuca^® (Case #5; SL equivalent 0.5 mg bid) and b) 225 mg tid Belbuca^® (Case #6; SL equivalent 0.5 mg tid). For both transitions, buprenorphine dosing was increased more rapidly per day, with transition completion by day 6 and day 5, respectively. More rapid transitions were opted for based on patient-centered decision-making and to optimize hospital discharge date. One participant had their buprenorphine transition dosing held stable for one day due to withdrawal symptoms as their methadone dose was erroneously discontinued prematurely. Withdrawal symptoms were managed with clonidine and the induction was able to continue as planned the next day. The participant with the more rapid transition (Case #5) did not have any precipitated withdrawal during their low dose transition.

Table 2:

Case Buprenorphine Inductions

Day	Case
	#1	#2	#3	#4	#5	#6	#7
1	225 mcg buccal buprenorphine × 1 Methadone 15 mg tid po Hydromorphone 4–6 mg po prn	225 mcg buccal buprenorphine × 1 MS-ER 30 po bid + HM po q4h prn + HM 1 mg IV q6h prn	225 mcg buccal buprenorphine × 1 methadone 60 mg oxycodone 10–15 mg q4h prn	225 mcg buccal buprenorphine × 1 Methadone 115 mg qday	225 mg bid buccal buprenorphine Methadone 30 mg qday oxycodone 15 mg q4h prn	300 mg TID buccal buprenorphine Methadone 60 mg qday	225 mcg buccal buprenorphine × 1 Hydromorphone 0.2 mg q 4 prn Oxycodone IR 10 mg q 4 prn
2	225 mcg buccal buprenorphine bid Methadone 15 mg tid po Hydromorphone 4–6 mg po prn	225 mcg buccal buprenorphine bid MS-ER 30 po bid + HM po q4h prn + HM 1 mg IV q6h prn	225 mcg buccal buprenorphine bid methadone 60 mg oxycodone 10–15 mg q4h prn	225 mcg buccal buprenorphine bid Methadone 115 mg qday	225 mg buccal buprenorphine in AM + 450 twice in PM Methadone 30 mg qday oxycodone 15 mg q4h prn	450 mg TID buccal buprenorphine Methadone 60 mg qday	225 mcg buccal buprenorphine bid Oxycodone IR 10 mg q 4 prn
3	450 mcg buccal buprenorphine bid Methadone 15 mg tid po Hydromorphone 4–6 mg po prn	450 mcg buccal buprenorphine bid MS-ER 30 po bid + HM po q4h prn + HM 1 mg IV q6h prn	450 mcg buccal buprenorphine bid methadone 60 mg oxycodone 10–15 mg q4h prn	450 mcg buccal buprenorphine bid Methadone 115 mg qday	450 mcg buccal buprenorphine in AM and 2 mg SL BID in PM Methadone 30 mg qday oxycodone 15 mg q4h prn	2 mg SL bup/nx TID Methadone 60 mg qday	450 mcg buccal buprenorphine bid Oxycodone IR 10 mg q 4 prn Oxycodone IR 5 mg q 4 prn
4	2 mg SL bup/nx BID Methadone 15 mg tid po Hydromorphone 4–6 mg po prn	2 mg SL bup/nx BID MS-ER 30 po bid + HM po q4h prn + HM 1 mg IV q6h prn	2 mg SL bup/nx BID methadone 60 mg oxycodone 10–15 mg q4h prn	2 mg SL bup/nx BID Methadone 115 mg qday	4 mg SL bup/nx BID Methadone 30 mg qday oxycodone 15 mg q4h prn	4 mg SL bup/nx TID Methadone 60 mg qday	2 mg SL bup/nx bid Oxycodone IR 10 mg q 4 prn Oxycodone IR 5 mg q 4 prn
5	4 mg SL bup/nx BID Methadone 15 mg tid po Hydromorphone 4–6 mg po prn	4 mg SL bup/nx BID MS-ER 30 mg po bid + HM 4mg Q4h po prn + 1 mg IV q8h prn	4 mg SL bup/nx BID methadone 60 mg oxycodone 10–15 mg q4h prn	4 mg SL bup/nx BID Methadone 115 mg qday	4 mg SLbup/nx TID Methadone 30 mg qday oxycodone 15 mg q4h prn	8 mg SL bup/nx bid	4 mg SL bup/nx bid Oxycodone IR 10 mg q 4 prn Oxycodone IR 5 mg q 4 prn
6	4 mg SL bup/nx BID Methadone 15 mg tid po Hydromorphone 4–6 mg po prn	4 mg SL bup/nx TID MS-ER 30 mg po bid HM 4mg Q4h po prn + 1 mg IV q8h prn	4 mg SL bup/nx TID methadone 60 mg oxycodone 20 mg q4h prn	4 mg SL bup/nx TID Methadone 115 mg qday	8 mg SL bid	300 mg LAB	4 mg SL bup/nx bid Oxycodone IR 10 mg q 4 prn Oxycodone IR 5 mg q 4 prn
7	4 mg SL bup/nx TID Methadone 15 mg tid po Hydromorphone 4–6 mg po prn	8 mg SL bup/nx BID HM 4mg Q4h po prn + 1 mg IV bid prn	8 mg SL bup/nx BID oxycodone 10–15 mg q4h prn	8 mg SL bup/nx BID	8 mg SL bid		8 mg SL bup/nx (in AM) 300 mg LAB Oxycodone IR 10 mg q 4 prn Oxycodone IR 5 mg q 4 prn
8	8 mg SL bup/nx BID Hydromorphone 4–6 mg po prn	8 mg SL bup/nx BID HM 4mg Q4h po prn + 1 mg IV bid prn	8 mg SL bup/nx BID HM 4mg q6h prn	8 mg SL bup/nx BID	300 mg LAB
9	8 mg SL bup/nx BID Hydromorphone 4–6 mg po prn	8 mg SL bup/nx BID HM 4mg Q6h po prn + 1 mg IV qday	300 mg LAB HM 4mg q6h prn	300 mg LAB
10	8 mg SL bup/nx BID Hydromorphone 4–6 mg po prn	300mg LAB HM 4mg Q6h po prn
11	8 mg SL bup/nx (in AM) 300 mg LAB Hydromorphone 4–6 mg po prn

Key : BID = twice a day; bup/nx = buprenorphine with naloxone; HM = hydromorphone; IV = intravenous; IR = Immediate release; LAB = Long-acting buprenorphine; LOS = Length of Stay; MINI = Mini-International Neuropsychiatric Interview; MOUD = Medications for opioid use disorder; MS-ER = morphine sulfate extended-release; po = By mouth; prn = as needed; q day = Each day; TID = thrice a day

LAB (Sublocade^®) was dosed on average 7.5 days (range 5 to 10 days) after the beginning of the low dose transition – in two participants it was dosed 6 days after transition initiation. In cases in which methadone was stopped after low dose transition, on average 3.2 days elapsed between last methadone dosing and Sublocade^® administration. As shown in Table 3, there were no COWS scores that exceeded five throughout this monitoring duration for any participant. The highest recorded COWS score was two for the daily COWS monitoring the day after LAB initiation until time of discharge. One participant (Case #5) received Sublocade^® after an unplanned hospital discharge in the community without issue.

Table 3:

Case Buprenorphine Induction Details

Case	Induction	LAB Dosing	COWS at LAB Injection	Days from Buprenorphine Initiation to LAB Dosing	Induction Comments
1	8 day transition starting d16 with continued methadone Methadone last dosed d21, final SL buprenorphine / naloxone dose 8 mg bid	Sublocade® 300 mg Day 25 of hospitalization	1 – immediately prior 0 – immediately after 0 – q30 mins for 2 hours	10 days 4 days between last methadone dose and LAB	Opioid WD symptoms on day 6 of transition (AM methadone dose missed), 4 mg bid buprenorphine / naloxone dose retained × 1 day and clonidine given. Symptoms resolved within 12 hours with treatment Continued hydromorphone 4–6 mg po q3h prn Sublocade® dosed one day later due to Federal Holiday
2	7 day transition starting d22 with continued 30 MS-ER po bid + hydromorphone 1 mg IV q6h prn and 4 mg po prn MS-ER last dosed d27	Sublocade® 300 mg Day 31 of hospitalization	1 – immediately prior 0 – immediately after 0 to 1 – q30 mins for 2 hours	9 days 4 days between last MS-ER dose and LAB	One dose 225 mcg Belbuca® given (d19) w/ mild sweating and patient c/f opioid WD Induction restarted d22 with scheduled clonidine 0.1 mg TID Concurrent tapering of prn hydromorphone regimen
3	7 day transition starting d8 with continued 60 mg methadone plus oxycodone → hydromorphone po Methadone last dosed d12	Sublocade® 300 mg Day 15 of hospitalization	1 – immediately prior 1 – immediately after 0 to 1 – q30 mins for 2 hours	8 days 3 days between last methadone dose and LAB	Switched from oxycodone 10–20 mg q4h to hydromorphone po 4 mg po q6h for wound analgesia over course of buprenorphine induction, no opioid WD symptoms during induction 48 hours between last methadone dose and Sublocade®
4	7 day transition starting d5 with continued methadone Methadone last dosed d10	Sublocade® 300 mg on Day 13 of hospitalization	1 – immediately prior 3 – immediately after 1 – q30 mins for 2 hours	8 days 3 days between last methadone dose and LAB	Concurrent benzodiazepine taper
5	6 day transition starting d11 with continued Methadone + oxycodone prn Methadone last dosed d15	Sublocade® 300 mg on Day 18 from admission (post-hospitalization)	1- immediately prior 1- immediately after 0 to 1- q30 mins for 2 hours	7 days 3 days between last methadone dose and LAB	Protocol accelerated as follows: Day 1– 225 mg bid Belbuca® Day 2– 225 mg in AM + 450 twice in PM Day 3 – 450 mcg in AM and 2 mg SL bid in PM Day 4 – 4 mg SL bid Day 5 – 4 mg SL tid Day 6 – 8 mg SL bid Patient had unplanned discharge on day 6 of induction – 8 mg Suboxone® bid continued as outpatient and Sublocade® given in research offices two days later
6	5 day transition starting d3 with continued methadone Methadone last dosed d6	Sublocade® 300 mg on Day 8 of admission	4- immediately prior 2- immediately after 0–1 – q30 mins for 2 hours	5 days 2 days between last methadone dose and LAB	Protocol accelerated as follows: Day 1– 300 mg TID Belbuca® Day 2– 450 mg TID Belbuca® Day 3 – 2 mg SL TID Day 4 – 4 mg SL TID Day 5 – 8 mg SL bid Opioid induced constipation with vomiting of methadone dose on d6 of hospitalization. Potential mild opioid WD, patient declining non-agonist treatment. Symptoms resolved on day of Sublocade® dosing
7	7 day transition starting d5 with continued hydromorphone 0.2 mg IV q6h + oxycodone	Sublocade® 300 mg on Day 11 of hospitalization	2 – immediately after and q30 mins for 2 hours	6 days	IV hydromorphone tapered off during induction

Key : COWS = Clinical Opioid Withdrawal Scale; d/c = discharge; IV = intravenous; IR = Immediate release; LAB = Long-acting buprenorphine; LOS = Length of Stay; MINI = Mini-International Neuropsychiatric Interview; MOUD = Medications for opioid use disorder; MRSA = Methicillin Resistant Staphylococcus Aureus; MSSA = Methicillin Susceptible Staphylococcus Aureus; MS-ER = morphine sulfate extended-release; po = By mouth; qday = Each day; UD = Use disorder (e.g. OUD = opioid use disorder); WD = withdrawal

All hospitalization days (e.g. d1, d2) given in terms of day of hospitalization

All participants received at least one subsequent study provided Sublocade^® dose in the outpatient setting. At the week 12 timepoint, five out of seven participants had switched to sublingual buprenorphine. Of those that switched, four cited patient preference though had access to insurance processed Sublocade^® if they so desired; one cited transportation issues as a barrier to further Sublocade^® use.

Discussion

This case series is the first to report complex transitions from long-acting opioids onto buprenorphine in severely ill medical inpatients via a ‘microdosing’ procedure starting with low dose buccal buprenorphine followed by gradual up-titration and injection of LAB. These transitions were all performed in a highly comorbid population with concurrent severe bacterial and viral infections in the context of a clinical trial protocol.

Induction onto buprenorphine utilizing guideline-based strategies requires cessation of all opioids (illicit or prescribed) followed by development of at least mild opioid withdrawal symptoms before sublingual buprenorphine is given at a starting dose of 2 to 4 mg. Persons with OUD hospitalized with serious infections can have a number of barriers that preclude use of these standard induction strategies. Initiation of buprenorphine in patients regularly taking full opioid agonists can produce precipitated withdrawal if buprenorphine is given too soon, or at too high a dose, after cessation of full agonists. Precipitated withdrawal, which is more likely to occur when full dose agonists are taken at high doses, is becoming more common due to the widespread presence of fentanyl in the drug supply^19–21; this is thought to be from the lipophilic nature of fentanyl which results in fat deposition and atypical pharmacokinetics with prolonged detectable levels. Withdrawal of any type (intentional or precipitated) can be a severe stress to the system - this is an even greater concern among patients with severe medical comorbidity in the inpatient setting. Finally, persons with OUD who are hospitalized often have conditions that are either painful or require surgeries that cause significant pain; as this patient population requires more opioid analgesia than others due to physiologic opioid tolerance, it is often not feasible for analgesia to be held. Low-dose buprenorphine induction presents as an alternate strategy that can theoretically avoid any type of withdrawal or immediate opioid cessation.

The first report of low-dose buprenorphine induction was published as a dual patient case series in 2016²², and since then there has been growing real world experience in both the inpatient and outpatient setting of its use, with numerous case series, a retrospective analysis²³, and reviews⁴ having been published – there has been no randomized data or data from trials thus far. The pivotal trials evaluating the efficacy of LAB excluded participants with severe medical or psychiatric comorbidity and were conducted in outpatient settings with 7 days of stable buprenorphine dosing prior to injection⁵. A Scottish case series²⁴, to our knowledge the only other published cohort with transitions from long acting opioids to LAB, also was limited to participants who were managed exclusively in the outpatient setting with no reported major comorbidities. This dearth of inpatient LAB data despite the Sublocade^® formulation being FDA approved since 2017 is likely due to its limited commercial availability on inpatient formularies – Sublocade^® in this case series was available prior to discharge as part of the clinical trial protocol. This case series adds to the current literature to show feasibility of long LAB in the inpatient setting after low-dose transitions occur.

There was no precipitated withdrawal upon dosing of LAB as measured by COWS assessment up to two hours after injection. The Sublocade^® package insert describes a 7 day period of stability on SL buprenorphine prior to dosing²⁵ - our novel dosing strategy was performed in the context of a clinical trial with FDA IND approval for rapid LAB initiation. In one case, Sublocade^® was administered on day 6 of the low dose transition, the shortest in this case series, and was tolerated well without precipitated withdrawal or adverse effects. The Scottish case series²⁴ had an average time duration between induction initiation and LAB dosing of 13 to 14 days on average. In this series the average time was 8 days in a patient population that was hospitalized with high degree of comorbidity (and critically ill at times during their hospitalization). Average time from admission date to LAB dosing was 17.3 days. In general, inductions and LAB dosing were performed after any required surgeries and once a patient was less acutely ill and nearing discharge. In some cases, LAB was dosed relatively soon after surgical intervention without issue. Buprenorphine transitions prior to surgery are feasible despite common misconceptions of buprenorphine contraindications in the perioperative period,²⁶ and it is conceivable that the time frame between admission to LAB dosing could be even further reduced when clinically appropriate.

There are limitations to the findings in this case series. The sample included was limited in size, and larger cohorts are needed to more inclusively capture patient experiences undergoing these complex opioid transitions, further understand tolerability, safety, and protocol refinement. More data and experience are needed, particularly from randomized studies to better evaluate transitions from full agonist opioids onto SL buprenorphine utilizing the modified Bernese method. This should include better identification of patients that would benefit from novel induction methods as opposed to conventional strategies. The modified Bernese method is just one of many buprenorphine transition strategies that exist – gathering information on tolerability with other formulations such as the buprenorphine patch (Butrans^®; Purdue Pharma, Stamford, CT) leading to LAB dosing will be important. More rapid transitions onto therapeutic SL buprenorphine doses also exist²⁷ – further study in this regard can yield additional benefit by decreasing length of hospital stay if tolerated well. Of note, all patients had some form of concurrent stimulant use preceding hospitalization, tracking with current trends in US national substance use trends and highlighting the need for comprehensive addiction care management. Finally, these participants had their inductions and LAB dosing performed in the context of a clinical trial protocol; there remain limitations in availability for LAB both in the inpatient setting prior to discharge and in the community.

Conclusions

Initiation of MOUD in the hospital setting is a crucial strategy in the multi-pronged approach necessary to combat morbidity and mortality related to OUD. Our study shows the feasibility of low dose transitions onto long-acting injection buprenorphine for patients with serious comorbidities in a manner that is safe, well tolerated and expedited such that it complements and does not excessively prolong hospitalization. As OUD treatment options and strategies expand, clinical infrastructure should evolve to meet these growing needs. Hospital pharmacies should prioritize the importance of including LAB formulations on inpatient formularies in addition to outpatient settings. While infections may be the immediate reason for hospitalization, OUD is often the root cause – integrating treatment of addiction and infectious diseases with strategies such as the one described here are imperative to reduce morbidity and mortality from all aspects of the opioid epidemic.