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. Author manuscript; available in PMC: 2025 Mar 1.
Published in final edited form as: J Subst Use Addict Treat. 2023 Dec 14;158:209261. doi: 10.1016/j.josat.2023.209261

Low-Dose Buprenorphine Initiation and Treatment Continuation Among Hospitalized Patients with Opioid Dependence: A Retrospective Cohort Study

Benjamin T Hayes 1, Phoebe Li 1, Tess Nienaltow 1, Kristine Torres-Lockhart 1, Laila Khalid 1, Aaron D Fox 1
PMCID: PMC10947892  NIHMSID: NIHMS1953563  PMID: 38103838

Abstract

Background:

Buprenorphine is an effective treatment for both opioid use disorder (OUD) and chronic pain, but buprenorphine’s pharmacology complicates treatment initiation for some patients. Low-dose buprenorphine initiation is a novel strategy that may reduce precipitated withdrawal. Few studies describe what patient populations benefit most from low-dose initiations and the clinical parameters that impact treatment continuation. This study aimed to 1) describe experiences with low-dose buprenorphine initiation, including both successes and failures among hospitalized patients in an urban underserved community; 2) identify patient- and treatment-related characteristics associated with unsuccessful initiation and treatment discontinuation; and 3) assess buprenorphine treatment continuation after discharge.

Methods:

This is a retrospective cohort study with opioid-dependent (meaning OUD or receiving long-term opioid therapy for chronic pain) patients who underwent low-dose buprenorphine initiation during hospital admission from October 2021 through April 2022. The primary outcome was successful completion of low-dose initiation. Bivariate analysis identified patient- and treatment-related factors associated with unsuccessful initiation. Secondary outcomes were buprenorphine treatment discontinuation at post-discharge follow-up, 30- and 90-days.

Results:

Of 28 patients who underwent low-dose buprenorphine initiation, 68% successfully completed initiation. Unsuccessful initiation was associated with receipt of methadone during admission and higher morphine milligram equivalents (MME) of supplemental opioids. Of 22 patients with OUD, the percent receiving a buprenorphine prescription at a follow-up visit, 30 days, and 90 days, respectively, was 46%, 36%, and 36%. Of 6 patients with chronic pain, the percent receiving a buprenorphine prescription at a follow-up visit, 30 days, and 90 days, respectively, was 100%, 100%, and 83%.

Conclusion:

Low-dose buprenorphine initiation can be successful in opioid-dependent hospitalized patients. Patients taking methadone or requiring higher MME of supplemental opioids may have more difficulty with the low-dose buprenorphine initiation approach, but these findings should be replicated in larger studies. This study suggests patient- and treatment-related factors that clinicians could consider when determining the optimal treatment strategy for patients wishing to transition to buprenorphine.

Keywords: Buprenorphine, Low-dose initiation, Microdosing, Opioid use disorder, Addiction Consult Service

1.1. Introduction.

Buprenorphine is a first-line treatment for opioid use disorder (OUD) that both generalist and specialist practitioners in the United States (US) with DEA licensure can prescribe; however, during an ongoing overdose crisis, where 80,816 people died from opioid-involved overdoses in 2021, only a small fraction of those who could benefit from buprenorphine treatment actually receive it (Center for Behavioral Health Statistics and Quality, 2015; National Center for Health Statistics, 2022; Sordo et al., 2017). Buprenorphine is also approved for chronic pain treatment, yet it is underutilized compared to other opioids despite the lower risk of overdose with buprenorphine treatment (Bart, 2012; Gudin & Fudin, 2020; Neumann et al., 2013; Pade et al., 2012). Numerous factors, including stigma, costs, insurance coverage, and systemic racism, limit buprenorphine treatment uptake, but buprenorphine’s pharmacology also makes it difficult for persons with OUD to start treatment (Barry & Huskamp, 2011; Cunningham et al., 1993; Hansen et al., 2016; Sohler et al., 2013; Van Boekel et al., 2013). New strategies for initiating buprenorphine treatment are a key area for innovation.

Buprenorphine, a partial opioid agonist, has a higher binding affinity and lower intrinsic activity at mu opioid receptors than other opioids; therefore, if buprenorphine displaces other opioids that occupy opioid receptors in physically dependent persons, it can precipitate opioid withdrawal (Walsh & Eissenberg, 2003). Symptoms of precipitated withdrawal, including myalgias, gastrointestinal symptoms, anxiety and opioid craving, contribute to early buprenorphine treatment cessation (Soyka et al., 2008; Walsh & Eissenberg, 2003). The increasing presence of fentanyl in supplies of non-prescribed opioids in most areas of the US may also contribute to precipitated withdrawal and failed buprenorphine initiations among people with OUD (Antoine et al., 2021; Silverstein et al., 2019; Varshneya et al., 2022). To avoid precipitating withdrawal, standard approaches to buprenorphine initiation require patients to stop other opioids for 24–48 hours until the onset of moderate withdrawal; however, just the fear of withdrawal may reduce patients’ interest in buprenorphine treatment (Cunningham et al., 2020; Hayes et al., 2021; Lee et al., 2014; Silverstein et al., 2020; Whitley et al., 2010). Similarly, uncontrolled pain may contribute to anxiety and cravings and lead people to discontinue treatment or dissuade people with chronic pain from trying buprenorphine (Buonora et al., 2020; Eklund et al., 1997; Frank et al., 2016). Thus, many patients would prefer to completely avoid opioid withdrawal during buprenorphine treatment initiation.

A low-dose buprenorphine initiation strategy avoids any planned withdrawal and may also reduce the incidence of precipitated withdrawal. Though the literature describes different low-dose buprenorphine initiation strategies, typically, patients start buprenorphine at low doses (0.5 mg) that are unlikely to precipitate withdrawal if taken soon after other opioids. Patients then take gradually higher buprenorphine doses while continuing a full opioid agonist, thereby avoiding the expected withdrawal during standard initiation (Hämmig et al., 2016; Wong et al., 2021). Studies report low-dose intitiation outcomes among both patients with OUD and patients with chronic pain who take opioids (Adams et al., 2021; Ahmed et al., 2021). Early findings suggest that patients can successfully initiate buprenorphine treatment with the low-dose strategy, but small sample sizes and missing clinical information limit utility for clinical practice (Moe et al., 2021). In particular, few publications have described initiation failures, complications during initiation, and factors that impact treatment outcomes. Clinicians need data describing what patient populations benefit most from low-dose initiations and the clinical parameters that impact long-term treatment outcomes.

One important unknown is the incidence at which low-dose initiation attempts are unsuccessful. Among three reviews of published case studies, only three individal patients were reported as not meeting criteria for successful initiation (Adams et al., 2021; Ahmed et al., 2021; Moe et al., 2021). Subsequently, two observational cohort studies reported low-dose buprenorphine initiation outcomes among hospitalized patients with OUD. One study (N = 68) reported that 26% of patients did not complete low-dose buprenorphine initiation, and a second study (N = 62) found that 18% did not complete buprenorphine initiation (Bhatraju et al., 2022; Button et al., 2022). More research that describes when low-dose initiation works – and when it does not – will benefit clinical practice.

There are other gaps in the low-dose buprenorphine initiation literature. Very few studies report complications during initiation. Opioid withdrawal and worsening pain can complicate low-dose initiations, particularly among people using non-prescribed opioids. In one meta-analysis, only six of 22 studies ascertained withdrawal and only three reported episodes of precipitated withdrawal (Moe et al., 2021). Two other studies provided insufficient clinical information to determine whether withdrawal-like symptoms were due to precipated withdrawal (Bhatraju et al., 2022; Button et al., 2022). Studies also incompletely describe patient factors associated with treatment outcomes. One cohort study found that older age, withdrawal symptoms during initiation, and starting buprenorphine to facilitate post-hospital placement were associated with unsuccessful initiation (Bhatraju et al., 2022). Other patient-related factors could impact treatment success, including sociodemographics, OUD treatment history, comorbid mental health conditions, or other substance use (Alford et al., 2011; Damian et al., 2017; Ferri et al., 2014; Hser et al., 2014; Saal & Lee, 2020; Samples et al., 2018; Weinstein et al., 2017). Characteristics of low-dose initiation protocols, such as the speed of buprenorphine titration, whether patients complete initiation during hospitalization, how clinicians use supplemental opioids, or how clinicians treat withdrawal symptoms with adjuvant medications, may also influence initiation success. Research that identifies the patient- and treatment-related factors associated with initiation outcomes will help improve patient outcomes.

Finally, few studies have reported follow-up outcomes after low-dose initiation. Research that follows treatment continuation beyond the initiation period is valuable for several reasons. First, early treatment retention is an important predictor of long-term treatment outcomes, such as long-term retention, substance use, overdose, and mortality (Cunningham et al., 2013; Fine et al., 2021; Glanz et al., 2023; Manhapra et al., 2018; Soyka et al., 2008). Second, early treatment drop-out has consequences for future treatment, as patients who drop out in the first 30 days may not return to treatment for 12 months or more (Hui et al., 2017). Therefore, both short- and long-term retention are valuable indicators for initiation success and treatment stability.

This study’s objectives were to: 1) describe experiences with low-dose buprenorphine initiation, including both successes and failures among hospitalized patients in an urban underserved community; identify patient- and treatment-related characteristics associated with unsuccessful initiation and treatment discontinuation; and 3) assess buprenorphine treatment continuation after discharge.

2. Materials and Methods

2.1. Setting and Study Design

This retrospective cohort study examined hospitalized patients at an academic hospital in the Bronx, NY. Addiction medicine physicians who supervised internal medicine residents and medical students made all clinical decisions. In New York City, the Bronx is the borough most impacted by substance use disorders. In 2021 there were 70.6 deaths from drug overdose per 100,000 residents, the highest rate in the city and the largest absolute increase since 2020 (Askari et al., January 2023). The Albert Einstein College of Medicine institutional review board approved all study procedures.

2.2. Sample Selection

Eligible participants were adults (≥ 18) who attempted low-dose buprenorphine initiation during hospitalizations between October 2021 and April 2022 with the Addiction Medicine Consult (ACS) service. The ACS team provides clinical consults regarding buprenorphine treatment for patients with OUD or those with chronic pain transitioning from other opioids to buprenorphine. ACS physicians maintained a registry of patients undergoing low-dose buprenorphine initiation. Researchers queried the electronic medical record (EMR) for all inpatient orders during the study period for buccal buprenorphine, which is the buprenorphine formulation used in this hospital for buprenorphine doses lower than what is available in sublingual (SL) formulations (the pharmacy does not divide SL films or tablets). Researchers reviewed all other buprenorphine orders to confirm low-dose buprenorphine initiation episodes. At least one research team member manually reviewed medical records to assure that identified patients had undergone a low-dose buprenorphine initiation.

2.3. Low dose initiation procedure

The hospital’s low-dose buprenorphine initiation protocols differed for patients who were taking short-acting and long-acting opioids (Table 1a, b). The protocols follow other published examples (Klaire et al., 2019; Terasaki et al., 2019; Weimer et al., 2021). The initial dose was 225 mcg of buccal buprenorphine (equivalent to 0.5 mg SL buprenorphine) once on the first day with gradually increasing dosage over either four or seven days. Physicians offered low-dose initiation when they thought patients might benefit based on clinical circumstances, such as prior challenges initiating buprenorphine, history of precipitated withdrawal, dependence on long-acting opioids (e.g., methadone), severe pain requiring continuous opioids, or patient preference. Physicians prescribed full opioid agonists to manage withdrawal or pain until the patient reached a therapeutic buprenorphine dose, at which time they discontinued or tapered other opioids. Typically, the goal dosage was 8/2–16/4 mg SL buprenorphine/naloxone (hereafter, referred to as buprenorphine); however, physicians tailored dosages to patients’ clinical needs and preferences. Nursing staff documented clinical opioid withdrawal scores (COWS) at clinician-directed intervals, typically every 4 hours.

Table 1a:

Dosing protocol for short-acting opioids

Day Buprenorphine dose Full opioid agonist
Buccal buprenorphine film dose SL bup-nx film dose Total equivalent dose
1 225 mcg q6h (maximum 4 doses per day) max 2 mg Full dose
2 450 mcg q6h (max 4 doses per day) max 4 mg Full dose
3 2 mg q6h max 8 mg Full dose
4 Total dose of day prior plus 2–4 mg q4h PRN STOP
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SL, sublingual; bup-nx, buprenorphine-naloxone; q4h, every 4 hours; q6h, every 6 hours

Table 1b:

Dosing protocol for long-acting opioids

Day Buprenorphine dose Full opioid agonist
Buccal buprenorphine film dose SL bup-nx film dose Total equivalent dose
1 225 mcg once 0.5 mg Full dose
2 225 mcg BID 1 mg Full dose
3 450 mcg BID 2 mg Full dose
4 2 mg BID 4 mg Full dose
5 4 mg BID 8 mg Full dose
6 4 mg TID 12 mg Full dose
7 12 mg in the AM, 2–4 mg Q4H PRN ≥12mg STOP
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SL, sublingual; bup-nx, buprenorphine-naloxone; BID, twice daily; TID, 3 times daily

2.4. Data Collection and Analysis

Researchers manually abstracted EMR data using a form designed for this study. Addiction Medicine physicians used a standard template during clinical consultations to document substance use and social factors that may affect clinical outcomes. Researchers identified follow-up prescriptions using the EMR and New York State Prescription Drug Monitoring Program (PDMP).

The primary outcome was successful low-dose initiation, defined as the patient having (a) received a total dose of 8 mg or greater of buprenorphine and no other opioids within a 24-hour period; and (b) a documented COWS score of 12 or less; or if the physician documented in the EMR that the initiation was successfully completed (Button et al., 2022; Wong et al., 2021). If a patient was discharged prior to completing the protocol, then researchers ascertained successful completion from outpatient notes and the PDMP. If patients discontinued buprenorphine prior to reaching a specified endpoint, the outcome was considered an initiation failure. The primary outcome for patients with OUD and those with chronic pain was the same, despite potential differences between these groups in social or behavioral circumstances, because interactions between buprenorphine and other medications are most likely to determine successful initiation.

Secondary outcomes were buprenorphine treatment continuation at three different time points: post-discharge follow-up, 30 days, and 90 days. Buprenorphine continuation at post-discharge follow-up was defined as documentation that the patient had a buprenorphine prescription written within the first 30 days of discharge from the hospital. Continuation at 30 days was defined as the patient having a buprenorphine prescription written 30 days or more after completing initiation without a gap in prescriptions of greater than 14 days. Continuation at 90 days was defined as having the patient having an active buprenorphine prescription at 90 days post-initiation without a gap in prescriptions of greater than 30 consecutive days. Other treatment retention studies define these endpoints with broader windows (e.g. 30–60 days for 1 month retention and 90–120 days for 3 month retention) (Cunningham et al., 2013; Jakubowski et al., 2020), but the definitions above better captures treatment discontinuation after the low-dose initiation and differentiates treatment continuation from a new treatment episodes. Patients needed to meet the criteria for successful low-dose initiation to meet subsequent continuation endpoints. Because patients with OUD and those with chronic pain may have different social and behavioral circumstances impacting treatment continuation, these outcomes were disaggregated for patients with OUD and chronic pain only.

Covariates included patient- and treatment-associated variables based on previously published literature and internal discussions among the research team, (Bhatraju et al., 2022; Button et al., 2022). Patient characteristics included age at initiation, gender, race, ethnicity, insurance type, housing (homeless (street or shelter) or unstably housed (temporary stay with family/acquaintance) vs stably housed), mental health diagnosis (yes/no), substance use disorder (SUD) diagnoses, prior buprenorphine prescription (yes/no), history of precipitated withdrawal from buprenorphine (yes/no), fentanyl exposure (positive fentanyl on urine drug test), primary opioid used (self-report), enrollment in methadone treatment for OUD at admission (yes/no), record of confirmed methadone dose (mg), reason for opioid use (OUD and/or chronic pain), lifetime overdose history (yes/no), and history of intravenous drug use (IVDU) (yes/no). Hospital admission treatment-related characteristics included whether patients were hospitalized for treatment of opioid overdose or withdrawal (yes/no), number of days admitted to the hospital, and whether methadone was administered during hospitalization (yes/no). Low-dose initiation treatment-related characteristics included reason for low-dose initiation, setting of successful completion (inpatient/outpatient), whether the patient left the hospital prior to completing initiation (yes/no), number of days for initiation, COWS scores during initiation, precipitated withdrawal during initiation (yes/no), opioids administered during hospitalization 24 hours prior to buprenorphine initiation, and supplemental opioids received during low-dose initiation (reported in morphine milligram equivalents (MME) using the MdCalc calculator (MDCalc ©)).

2.5. Statistical Analysis

Descriptive analyses use means and standard deviations or median and interquartile range for continuous variables and proportions for categorical variables. Bivariate analyses examined associations between the primary outcomes and other variables using t-tests or Mann-Whitney rank-sum and chi-square or Fisher’s exact tests. All statistical analyses used a cutoff of p < 0.05 to establish significant associations between covariates and successful initiation or retention.

3. Results

3.1. Sample characteristics

Table 2 presents the characteristics of the study sample. A total of 28 patients received buccal buprenorphine during admission from October 2021 through April 2022; all 28 patients started low-dose buprenorphine initiation. Participants were mostly men (57%), white (79%), Latino/a/x (57%; all identified as white), middle aged (median age 50.5 years, IQR 40.0, 60), stably housed (75%), had Medicaid insurance (64%) and had at least one mental health diagnosis (61%).

Table 2.

Characteristics Associated with Low-dose Bup Initiation Success at Follow-up, N=28

Successful Initiation n = 19 Unsuccessful Initiation n = 9 p-value
Patient-related characteristics
Age: median (IQR) 53.0 (40.0, 59.0) 45 (40, 60) NS
Gender (man) 10 (52.6) 6 (66.7) NS
Race white (vs. Black) 14 (73.7) 8 (88.9) NS
Race (Black) 5 (26.3) 1 (11.1)
Ethnicity Latino/a/x (yes)* 9 (47.4) 7 (77.8) NS
Insurance Type NS
 Medicaid 13 (68.4) 5 (55.6)
 Medicare 4 (21.1) 3 (33.3)
 Private 1 (5.3) 0 (0)
 None 1 (5.3) 1 (11.1)
Stably Housed (yes) 15 (79.0) 6 (66.7) NS
Mental Health Diagnosis (yes) 12 (63.2) 5 (55.6) NS
OUD Diagnosis
 OUD only 5 (26.3) 6 (66.7) NS
 OUD + other SUD 8(42.1) 3 (33.3) NS
 None 6 (31.6) 0 (0) NS
Prior bup rx (yes) 9 (47.4) 4 (44.4) NS
History of precipitated withdrawal (yes) 2 (10.5) 3 (33.3) NS
Fentanyl exposure (yes)** 2 (12.5) 1 (11.1) NS
Primary Opioid Used
 Rx opioids 9 (47.4) 4 (44.4) NS
 Heroin and/or fentanyl 9 (47.4) 4 (44.4) NS
 Methadone 1 (5.3) 1 (11.1) NS
Enrolled in methadone treatment at admission (yes) 2 (10.5) 4 (44.4) NS
 Preadmission methadone treatment dose (mg): median (IQR) 30 (30, 30) 65 (60, 113) NS
Opioids Used For
 OUD only 10 (52.6) 6 (66.7) NS
 Pain only 6 (31.6) 0 (0) NS
 Both 3 (15.8) 3 (33.3) NS
Lifetime overdose history (yes) 5 (26.3) 4 (44.4) NS
History of IVDU (yes) 6 (31.6) 3 (33.3) NS
Admission diagnosis drug overdose or withdrawal (yes) 13 (68.4) 8 (88.9) NS
Methadone during admission (yes) 9 (47.4) 8 (88.9) 0.049
 Continued from pre-admission 2 (10.5) 4 (44.4) NS
 Started during admission 7 (36.8) 4 (44.4) NS
Treatment-related characteristics
Days admitted to hospital: median (IQR) 14.5 (10.3, 20.3) 8 (4,14) NS
Reason for low-dose initiation
 Transition off methadone 8(42.1) 6 (66.7) NS
 Transition off opioid analgesics 9 (47.4) 1 (11.1) NS
 History of precipitated withdrawal 2 (10.5) 3 (33.3) NS
Low-dose initiation days: median (IQR) 6 (4, 7) 3 (2, 6) NS
Highest COWS: median (IQR) 1 (0, 2) 5(1, 12) NS
Precipitated withdrawal (yes) 2 (10.5) 2 (22.2) NS
Left hospital prior to completion (yes) 4 (21.1) 4 (44.4) NS
Initiation completed as inpatient (yes) 15 (79.0) 4 (21.1) -
Opioids taken in 24 hrs prior
 Methadone 7 (36.8) 7 (77.8) NS
 Other opioids 9 (47.4) 1 (11.1) NS
 None 3 (15.8) 1 (11.1) NS
Overlapping opioid
 Methadone 7 (36.8) 7 (77.8) NS
 Other opioids 10 (52.6) 2 (22.2) NS
 None 2 (10.5) 0 (0) NS
Supplemental opioid MME: median (IQR) 182 (24.0, 1480.0) 1800 (363, 4600) 0.04
Adjuvant medications (yes) 12 (63.2) 7 (77.8) NS
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*

All Latino/a/x individuals identified themselves as white.

**

Based on urine drug test, 7 participants missing data

Bup, buprenorphine; IQR, interquartile range; SUD, substance use disorder; OUD, opioid use disorder; SUD, substance use disorder; rx, prescription; mg, milligram; IVDU, intravenous drug use; COWS, Clinical Opiate Withdrawal Score; Bolded = statistically significant

3.2. Opioid and substance use history

Most patients had opioid use disorder (OUD) (79%): 39% were diagnosed with OUD only, 39% with OUD and another substance use disorder, and 21% had no OUD diagnosis. Less than half of patients had previously received buprenorphine prescriptions (46%) and 18% had previously experienced precipitated withdrawal. At admission, 11% of patients had fentanyl detected in urine drug testing. Before admission, patients primarily used prescription opioid analgesics (46%), heroin and/or fentanyl (46%), or methadone (7%). Six patients with OUD (27%) were enrolled in a methadone treatment prior to admission; median dose was 60.0 mg (IQ range 30 to 70 mg).

3.3. Hospital admission treatment-related characteristics

Patients were admitted to the hospital for a median of 12 days (IQ range 6 to 18 days). Most patients (75%) were admitted for reasons related to opioid use (either overdose or withdrawal treatment). Most patients received methadone during their admission (61%).

3.4. Low-dose initiation treatment-related characteristics

Provider-documented reasons for low-dose initiation were to: transition from methadone to buprenorphine (50%), transition patients with pain from full opioid agonists to buprenorphine (36%) or avoid precipitated withdrawal among those with a prior history (17%). Low-dose buprenorphine initiation attempts lasted a median of 6 days (IQ range 4 to 7 days). Three patients received 20mcg/hour buprenorphine transdermal patch before initiating the standard low-dose buccal protocol. Few patients (25%) experienced a COWS equal to or greater than 7 and 14% experienced precipitated withdrawal. In the 24 hours prior to low-dose initiation, opioids administered in the hospital were: methadone (50%), other opioid analgesics (36%), and none (14%). During initiation, supplemental opioids administered were methadone (50%), other opioids (43%), and none (7%). The median MME for supplemental opioids during initiation was 530 (IQ range 67, 2127). Most patients (63%) also received at least one adjuvant medication during initiation (clonidine, hydroxyzine, loperamide, ondansetron, NSAIDS, acetaminophen, or gabapentin).

3.5. Treatment outcomes

Table 2 shows the low-dose buprenorphine initiation outcomes. Of 28 patients who started low-dose initiation, 68% successfully completed initiation; their median highest COWS was 1 (IQ range 0, 2). Patients who did not successfully complete low-dose buprenorphine initiation had a median highest COWS of 5 (IQR 1, 12). Reasons for unsuccessful initiation were: the patient was discharged prior to completion without a follow-up appointment (44%) and patient experienced precipitated withdrawal leading to either discontinuation of buprenorphine or opting for standard induction (22%). Receiving any methadone during admission (p=0.049) and higher MME values of supplemental opioids (p=0.04) were significantly associated with unsuccessful initiation.

Table A.1 displays treatment continuation outcomes by patient and treatment characteristics for patients with OUD. The percent of patients with OUD continuing buprenorphine treatment at a post-hospitalization follow-up visit, 30-days, and 90-days, respectfully, was 46%, 36%, and 36%. Patients with an OUD diagnosis who received lower MME values of supplemental opioids were more likely than those with higher MME to receive a buprenorphine prescription at post-hospitalization follow-up (p = 0.01), at 30-day follow-up (p = 0.02), and at 90-day follow-up (p = 0.02).

Patients with chronic pain only were more likely than those with OUD to continue treatment at a post-hospitalization follow-up visit (p = 0.02) and at 30-day follow up (p = 0.02) (see Table A.2). Among the six patients with only chronic pain, 100% received a buprenorphine prescription at follow-up after hospital discharge and at 30-day follow-up; 83.3% (n=5) received a buprenorphine prescription at 90-day follow-up (see Table A.3). The one patient with chronic pain only who did not continue buprenorphine at 90 days had a treatment plan with their outpatient provider to taper off buprenorphine and stop all opioids.

4. Discussion

This retrospective cohort study reinforces existing literature by demonstrating that opioid-dependent people can successfully transition to buprenorphine with minimal withdrawal symptoms through low-dose buprenorphine initiation. Two-thirds of all patients successfully completed buprenorphine initiation, but fewer than one third of patients with OUD continued to receive buprenorphine prescriptions at 90 days. Our study provides a detailed assessment of patient and treatment-related characteristics that predict initiation success or failure.

The buprenorphine initiation success rate was lower than those in prior observational cohort studies (64% vs 69–82%) (Bhatraju et al., 2022; Button et al., 2022). Variations in clinical practices, such as using different low-dose initiation strategies, supplemental opioids, or adjunctive medications to treat withdrawal could influence these outcomes. For example, Bhatraju et al. (2022) studied patients who received a single seven-day protocol using only sublingual buprenorphine-naloxone, and Button et al. (2022) described three different low-dose initiation strategies (a standard protocol, a protocol for acute pain, and a protocol for transitioning off methadone), using buprenorphine transdermal patches and sublingual buprenorphine-naloxone. However, neither study provides details on adjuvant medications. Thus, future research should compare how different low-dose strategies and other management decisions affect treatment outcomes.

Characteristics associated with initiation failure also differed from other cohort studies. In the current study, receiving methadone during admission and receiving higher doses of supplemental opioids were associated with initiation failure. Though not significant, unsuccessful patients had higher median COWS than successful patients. Bhatraju et al. (2022) found that older age, withdrawal symptoms during transition, and switching to buprenorphine to facilitate post-hospital placement were associated with initiation failure. Bhatraju et al. (2022) concluded that patient motivation and confidence in the process are important predictors of success. Findings from the current study provide a broader picture, adding that treatment decisions may also be important determinants of success.

The finding that methadone complicated low-dose initiation has important clinical implications because clinicians often choose the low-dose initiation strategy to avoid precipitating withdrawal in patients taking methadone treatment. Methadone has a longer half-life than other opioids increasing the risk of precipitated withdrawal with the standard buprenorphine initiation approach (Lintzeris et al., 2022; Rosado et al., 2007). Although this is the first study to report a statistically significant association with treatment failure, another case series noted treatment failures among patients taking methadone (Moe et al., 2021). The high proportion of patients who were transitioning from methadone to buprenorphine in the current study may have contributed to the significant findings.

There are several clinical factors that might explain the association between receiving methadone and initiation failure. First, it is possible that patients still experienced withdrawal with the low-dose initiation method. Patients who received methadone in the hospital had higher COWS than those who did not (see appendix, Table A.4). In previous case reports of low-dose initiation, only patients who received methadone experienced precipitated withdrawal (Moe et al., 2021). The length of initiation in the current study (IQR 4–7 days) was slightly shorter than other similar studies (Adams et al., 2021; Bhatraju et al., 2022); therefore, the more rapid dose titration may have increased precipitated withdrawal risk and negatively impacted outcomes for patients receiving methadone. To lower precipitated withdrawal risk, some experts suggest that patients taking methadone may need a slower initiation (e.g., weeks instead of days) (Button et al., 2022; Hill et al., 2022). If patients transition from methadone to short-acting opioids before initiating buprenorphine they may also avoid opioid withdrawal while giving more time for patients to metabolize methadone (Callan et al., 2020). Second, prior methadone treatment could represent a marker for more severe OUD, which has been associated with buprenorphine treatment discontinuation (Ker et al., 2021; Zhu et al., 2018). Clinicians often prefer methadone treatment for patients who have not found success with other OUD treatments, have high opioid tolerance, or need directly observed medication administration or additional psychosocial support (Cunningham et al., 2020; Srivastava et al., 2017; Whelan & Remski, 2012). Lastly, some people with OUD may prefer methadone to buprenorphine and the unsuccessful initiation could reflect dissatisfaction with buprenorphine (Yarborough et al., 2016). Future studies should confirm whether methadone treatment consistently predicts difficulty with the low-dose initiation method.

Receiving higher doses of supplemental opioids during initiation was also associated with unsuccessful initiation. Other studies have not found this relationship, and the data from the current study cannot fully explain the mechanism. However, because clinicians may choose the low-dose initiation method for patients taking high doses of opioid analgesics, the finding could have important implications. For example, if methadone and high-dose opioids are most likely to precipitate withdrawal symptoms, then clinical adjustments, such as titrating to lower opioid doses before transition or using slow low-dose initiation protocols may be necessary (Breen et al., 2003; Foran et al., 2022; Hill et al., 2022). However, clinical trials or comparative effectiveness research are needed to answer questions about the ideal approach to low-dose initiation.

The current study also had lower buprenorphine treatment continuation at 30-days (36.4%) and 90 days (36.4%) for patients with OUD than others studies of buprenorphine treatment for hospitalized patients with OUD, where 30-day and 90-day retention ranges from 39–64% and 27–56%, respectively (Kessler et al., 2022; Liebschutz et al., 2014; Trowbridge et al., 2017; Wakeman et al., 2017). One other cohort study of low-dose buprenorphine initiation reported 64% of patients with OUD continued buprenorphine at 30 days (Bhatraju et al., 2022). Another study of emergency department-based buprenorphine initiation demonstrated 30-day follow-up rates that were similar for patients receiving low-dose (32%) and standard (24%) methods (Moe et al., 2020). The drop-off between treatment initiation success and post-hospitalization treatment continuation should be a target for future quality improvement initiatives.

The finding that patients with OUD had lower buprenorphine treatment continuation than patients without OUD also highlights that follow-up can be difficult after hospital discharge. Evidence-based interventions that could be paired with a low-dose initiation strategy to improve buprenorphine treatment retention, include dedicated addiction consult services (Englander et al., 2019; Wakeman et al., 2017), peer navigation or recovery coaches (Byrne et al., 2020; Magidson et al., 2021; Summers et al., 2020), and post-discharge bridge clinics (Taylor et al., 2023; Wakeman et al., 2022). Assuring that patients who initiate buprenorphine in the hospital have support in following-up post-discharge could prevent treatment discontinuation.

Limitations

The study has limitations. Retrospectively reviewing EMR data may result in missing or inaccurate data. However, addiction specialists systematically recorded clinical data in their notes, which may improve reliability. There also may be selection bias in the sample due to clinicians’ judgement in deciding who received low-dose initiations. If clinicians recommended the novel strategy to patients deemed most likely to continue buprenorphine treatment, findings regarding initiation success and follow-up outcomes may not generalize to other patients. The small sample size limited statistical power and made multivariable analyses infeasible. Larger prospective clinical trials could address these shortcomings. Future studies reporting patient perspectives on what led to success or failure, including qualitative methods, would also deepen study findings. Pain scores during and after buprenorphine initiation were inconsistently recorded in the EMR and could not be included in analyses.

5. Conclusions

Low-dose buprenorphine initiation can be successful for hospitalized patients with opioid dependence, including those with OUD. Characteristics that might make low-dose initiation less successful include receiving methadone or higher MME of supplemental opioids during initiation. Findings from this study can assist clinicians and patients in deciding the optimal buprenorphine initiation strategy and anticipating potential treatment challenges. Further research should prospectively examine determinants of initiation success as well as patient perspectives on the low-dose initiation process.

Highlights:

  • Low-dose buprenorphine initiation can succeed during hospitalization for patients with OUD.

  • Success may be more difficult to attain when taking methadone or higher MME of opioids.

  • Chronic pain patients (vs OUD) were more likely to continue buprenorphine post-hospitalization.

Funding

The research described was supported by National Institutes of Health Grant Number K23DA055933. Dr. Fox is supported by the National Institutes of Health under Grant R01DA044878.

APPENDIX

Table A.1.

Participant Characteristics and Bup Treatment Continuation at Post-hospital Follow-up, 30 days and 90 days* Among Patients with OUD, N = 22

Patient-related characteristics
Bupe rx at follow-up n = 10 No bupe rx at followup n = 12 p-value Bupe rx 30 days n = 8 No bupe rx 30 days n = 14 p-value Bupe rx 90 days n = 8 No bupe rx 90 days n = 14 p-value
Age: median (IQR) 56 (46, 59) 44 (40, 61) NS 57 (66, 47) 46 (40, 60) NS 57 (47, 66) 46 (40, 60) NS
Gender (man) 5 (50.0) 7 (58.3) NS 5 (62.5) 7 (50.0) NS 5 (62.5) 7 (50.0) NS
Race (white) 7 (70.0) 11 (91.7) NS 7 (87.5) 11 (78.6) NS 7 (87.5) 11 (78.6) NS
Ethnicity Latino/a/x (yes) 6 (60.0) 4 (33.3) NS 4 (50.0) 8(57.1) NS 4 (50.0) 8(57.1) NS
Insurance Type Medicaid 6 (60.0) 7 (58.3) NS 4 (50.0) 9 (64.3) NS 4 (50.0) 9 (64.3) NS
Stably Housed (yes) 7 (70.0) 8 (66.7) NS 7 (87.5) 8(57.1) NS 7 (87.5) 8(57.1) NS
Mental Health Diagnosis (yes) 7 (70.0) 7 (58.3) NS 6 (75.0) 8(57.1) NS 6 (75.0) 8(57.1) NS
Prior bupe rx (yes) 7 (70.0) 5 (41.7) NS 5 (62.5) 7 (50.0) NS 5 (62.5) 7 (50.0) NS
History of Precipitated Withdrawal (yes) 2 (20.0) 3 (25.0) NS 2 (25.0) 3 (21.4) NS 2 (25.0) 3 (21.4) NS
Primary Opioid Used
 Rx opioids 3 (30.0) 4 (33.3) NS 3 (37.5) 4 (28.6) NS 3 (37.5) 4 (28.6) NS
 Heroin and/or fentanyl 6 (60.0) 7 (58.3) NS 4 (50.0) 9 (64.3) NS 4 (50.0) 9 (64.3) NS
 Methadone 1 (10.0) 1 (8.3) NS 1 (12.5) 1 (7.1) NS 1 (12.5) 1 (7.1) NS
Enrolled in methadone treatment (yes) 3 (25.0) 3 (30.0) NS 2 (22.2) 4 (30.8) NS 2 (25.0) 4 (28.6) NS
 Preadmission methadone treatment dose (mg): median (IQR) 30 (30, 70) 60 (60, 155) NS 30 (30, 30) 65 (60, 113) NS 30 (30, 30) 65 (60, 113) NS
Lifetime overdose history (yes) 3 (30.0) 6 (50.0) NS 1 (12.5) 8(57.1) NS 1 (12.5) 8(57.1) NS
Methadone During Admission (yes) 7 (70.0) 10 (83.3) NS 5 (62.5) 12 (85.7) NS 5 (62.5) 12 (85.7) NS
 Continued from pre-admission 3 (25) 3 (30) NS 2 (22.2) 4 (30.8) NS 2 (25.0) 4 (28.6) NS
 Started during admission 6 (50.0) 5 (50.0) NS 4 (44.4) 7 (53.9) NS 3 (37.5) 8(57.1) NS
Treatment-related characteristics
Days admitted to hospital: median (IQR) 12.5 (5.5,17.5) 11 (5, 28.5) NS 12.5 (5, 17) 11 (6, 18) NS 11 (5, 17) 13 (6, 21) NS
Reason for low-dose initiation
 Transition off methadone 6 (60.0) 8 (66.7) NS 4 (50.0) 10 (71.4) NS 4 (50.0) 10 (71.4) NS
 Transition off opioid analgesics 2 (20.0) 2 (16.7) NS 2 (25.0) 2 (14.3) NS 2 (25.0) 2 (14.3) NS
 History of precipitated withdrawal 2 (20.0) 3 (25.0) NS 2 (25.0) 3 (21.4) NS 2 (25.0) 2 (14.3) NS
Low-dose initiation days: median (IQR) 4.5 (4, 6) 5 (2.5, 7.5) NS 4.5 (3, 6) 5 (3, 7) NS 5 (3, 6) 5 (3, 7) NS
Highest COWS: median (IQR) 1 (0, 8) 1.5 (0, 9) NS 1 (1, 8) 1.5 (0, 6) NS 2 (1, 8) 2 (0, 6) NS
Precipitated withdrawal (yes) 2 (20.0) 2 (16.7) NS 2 (25.0) 2 (14.3) NS 2 (25.0) 2 (14.3) NS
Left hospital prior to completion (yes) 4 (40.0) 4 (33.3) NS 4 (50) 4 (28.6) NS 4 (50.0) 4 (28.6) NS
Initiation completed as inpatient (yes) 6 (60.0) 3 (100) NS 4 (50.0) 0 (0) NS 4 (50.0) 5 (100.0) NS
Opioids taken in 24 hrs prior
 Methadone 5 (50.0) 9 (75.0) NS 3 (37.5) 11 (78.6) NS 3 (37.5) 11 (78.6) NS
 Other opioids 2 (20.0) 2 (16.7) NS 2 (25.0) 2 (14.3) NS 2 (25.0) 2 (14.3) NS
 None 3 (30.0) 1 (8.3) NS 3 (37.5) 1 (7.1) NS 3 (37.5) 1 (7.1) NS
Overlapping opioid
 Methadone 5 (50.0) 9 (75.0) NS 3 (21.4) 11 (78.6) NS 3 (37.5) 11 (78.6) NS
 Other opioids 3 (30.0) 3 (25.0) NS 3 (37.5) 3 (21.4) NS 3 (37.5) 3 (21.4) NS
 None 2 (20.0) 0 (0) NS 2 (25.0) 0 (0) NS 2 (25.0) 0 (0) NS
Supplemental opioid MME: median (IQR) 111 (8, 800) 1907 (872, 3548) 0.01 96 (3.8, 720) 1640 (363, 2496) 0.02 96 (4, 720) 1640 (363, 2496) 0.02
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Bup, buprenorphine; IQR, interquartile range; SUD, substance use disorder; OUD, opioid use disorder; rx, prescription; COWS, Clinical Opiate Withdrawal Score; Bolded = statistically significant

Table A.2.

Bup Rx at Follow-up Visits Among Patients with OUD versus Chronic Pain Only, N = 28

Bupe rx at follow up n=16 No bupe rx at follow up n=12 p-value Bupe rx 30 days n=14 No bupe rx 30 days n=14 p-value Bupe rx 90 days n=13 No bupe rx 90 days n=15 p-value
OUD* 10 (62.5) 12 (100) 0.02 8 (57.1) 14 (100) 0.02 8 (61.5) 14 (93.3) 0.07
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OUD, opioid use disorder;

*

reference group = patient with chronic pain only

Table A.3.

Characteristics Associated with Low-dose Bup Initiation Success and Bup Rx at Follow-up Visits Among Patients with Chronic Pain Only, N = 6

Bupe rx at first follow-up and at 30 days, n = 6 Bupe rx 90 days n=5 No bupe rx 90 days n=1 p-value
Patient-related characteristics
Age: median (IQR) 42 (30, 53) 48 (30, 53 35 NS
Gender (man) 4 (66.7) 3 (60.0) 1 (100) NS
Race white (vs. Black) 4 (66.7) 3 (60.0) 1 (100) NS
Race (Black) 2 (33.3) 2 (40.0) 0 NS
Ethnicity Latino/a/x (yes)* 4 (66.7) 3 (60.0) 1 (100) NS
Insurance Type
 Medicaid 5(83.3) 4 (80.0) 1 (100) NS
 Medicare 1 (16.7) 1 (20.0) 0 NS
 Private 0 0 0 --
 None 0 0 0 --
Stably Housed (yes) 6 (100.0) 5 (100) 1 (100) --
Mental Health Diagnosis (yes) 3 (50.0) 3 (60.0) 1 (100)
Prior bup rx (yes) 1 (16.7) 1 (20.0) 0 NS
History of precipitated withdrawal (yes) 0 0 0 --
Lifetime overdose history (yes) 0 0 0 --
History of IVDU (yes) 0 0 0 --
Admission diagnosis drug overdose or withdrawal (yes) 0 0 0 --
Methadone during admission (yes) 0 0 0 --
 Continued from pre-admission 0 0 0 --
 Started during admission 6 (100.0) 5 (100) 1 (100) --
Treatment-related characteristics
Days admitted to hospital: median (IQR) 19 (17, 22) 17 (17, 22) 21 NS
Reason for low-dose initiation
 Transition off opioid analgesics 6 (100) 5 (100) 1 (100) --
Low-dose initiation days: median (IQR) 7 (6, 8) 7 (6, 8) 7 NS
Highest COWS: median (IQR) 0 (0, 2) 0 (0, 2) 0 (0, 0) NS
Precipitated withdrawal (yes) 0 0 0 --
Left hospital prior to completion (yes) 0 0 0 --
Initiation completed as inpatient (yes) 6 (100) 5 (100) 1 (100) --
Opioids taken in 24 hrs prior
 Opioids other than bup or methadone 6 (100) 5 (100) 1 (100) --
Overlapping opioid
 Opioids other than bup or methadone 6 (100) 5 (100) 1 (100) --
Supplemental opioid MME: median (IQR) 142 (88, 419) 124 (88, 160) 419 NS
Adjuvant meds (yes) 5(83.3) 4 (80.0) 1 (100) NS
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*

All individuals identified as Latino/a/x and white.

Bup, buprenorphine; IQR, interquartile range; SUD, substance use disorder; OUD, opioid use disorder; rx, prescription; IVDU, intravenous drug use; COWS, Clinical Opiate Withdrawal Score; Bolded = statistically significant

Table A.4.

Highest COWS (mean (95% CI)) by Methadone During Admission

Methadone during admission n = 17 No Methadone during admission n = 11 p-value
COWS, Mean (CI) 5.4 (2.3, 8.5) 1.2 (−0.22, 2.6) 0.04
Successful Initiation n = 9 Unsuccessful Initiation n = 8 p-value Successful Initiation n = 10 Unsuccessful Initiation n = 1 p-value
COWS, Mean (CI) 4.0 (−0.4, 8.4) 6.9 (1.6, 12.2) NS 1.2 (−0.4, 2.8) - -
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COWS, Clinical Opiate Withdrawal Score; CI, Confidence interval

Footnotes

Declarations of interest: none

This manuscript has not been previously published and is not under consideration in any other peer-reviewed media.

CRediT roles:

Benjamin T. Hayes: Conceptualization, Methodology, Project administration, Formal analysis, Funding acquisition; Writing – original draft

Phoebe Li: Investigation; Data curation; Writing – Reviewing and Editing

Tess Nienaltow: Writing – Reviewing and Editing

Kristine Torres-Lockhart: Conceptualization; Investigation; Writing – Reviewing and Editing

Laila Khalid: Conceptualization; Writing – Reviewing and Editing

Aaron D. Fox: Conceptualization; Supervision; Writing – Reviewing and Editing

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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