Randomized Trial of Buprenorphine Microdose Inductions During Hospitalization
Phase: PHASE4
Conditions: Substance Use Disorders, Opioid-use Disorder, Chronic Pain
Sponsor: Montefiore Medical Center

Study Title:  Randomized Trial of Buprenorphine Microdose 
Inductions During Hospitalization (Micro-bupe)
Protocol ID:  2021-13311
IRB Approval Date:  12/02/2022
NCT05118204

Microdose Bupe V.2.0 4-20-22
SECTION E: PROJECT 3: RANDOMIZED TRIAL OF BUPRENORPHINE MICRODOSE INDUCTIONS 
DURING HOSPITALIZATION
A. SPECIFIC AIMS
Our goal is to increase buprenorphine (BUP) treatment initiation among patients with chronic pain (CP) and
opioid misuse or opioid use disorder (OUD). Of 2 million Americans with OUD, between 1/3 – 2/3 have ≥1 CP 
condition.1 Eleven million Americans misuse opioid analgesics with 62% reporting pain as the primary reason 
for their misuse.2 There are >700,000 opioid-related hospitalizations annually.3 During hospitalization, OUD 
and other medical conditions are rarely managed together leading to suboptimal treatment outcomes.4,5 
Initiating BUP treatment could prevent re-hospitalizations while improving pain and opioid-related outcomes. 
BUP reduces opioid misuse and overdose in people with OUD and is an approved CP treatment making it 
ideal for people with OUD and CP.6,7 As a partial mu opioid receptor agonist, BUP avoids the opioid-induced 
hyperalgesia that limits long-term use of full opioid agonists for CP; however, transitioning from full agonists to 
BUP can be difficult due to BUP’s pharmacology.8 Standard approaches to initiating BUP (i.e. “induction”) 
require stopping opioids for >24-72 hours, which leads to withdrawal and fear of escalating pain.9-12 Avoiding 
withdrawal could increase BUP initiation, especially for patients taking long-term opioid therapy. 
Our multidisciplinary team will test a BUP microdosing protocol where patients start very low doses of BUP 
without stopping other full opioid agonists. We hypothesize that microdosing will increase BUP uptake by (1) 
avoiding the 24-72 hour period of withdrawal required for standard inductions and (2) reducing the risk of 
precipitating withdrawal.13 BUP binds mu opioid receptors with higher affinity than other opioids but provides 
only partial agonism. Therefore, if full agonists occupy mu opioid receptors when patients take normal BUP 
doses, they will experience the relative reduction in agonism as “precipitated” withdrawal. During standard 
inductions, patients avoid displacing full agonists by waiting to take BUP until they are in moderate opioid 
withdrawal. BUP “microdoses” do not displace enough full agonist to precipitate withdrawal; therefore, patients 
can start and gradually increase BUP doses without stopping other opioids. Case studies suggest that BUP 
microdosing is feasible and minimizes withdrawal,14  but no clinical trials have established safety and efficacy.15 
Targeting hospitalized patients will allow us to reach people at high-risk for opioid-related harms who are 
not already connected to outpatient care.16 Hospitalization is a critical “touchpoint” that often preceeds opioid 
overdose.17 Even when pain consultants are available, they rarely have experience managing both CP and 
opioid misuse or OUD. Evidence supports starting BUP during hospitalization to increase linkage to outpatient 
OUD treatment,18,19 but microdosing could change clinical practice by improving BUP treatment uptake. Our 
premise is that microdosing will improve long-term pain outcomes and reduce unnecessary hospitalizations 
specifically by facilitating initiation of BUP treatment in a non-treatment-seeking population.  
     We propose to test BUP microdosing vs. treatment as usual (TAU), meaning standard BUP 
induction. We will conduct a hybrid type 1 effectiveness-implementation study, using a pragmatic, open-label, 
randomized controlled trial (RCT). We will randomize 270 hospitalized patients with (a) CP and (b) opioid 
misuse or OUD to a 4-day microdosing protocol (without stopping full agonists) or 2-day standard induction 
(with stopping full agonists), and link them to outpatient BUP treatment. Study assessment visits will occur at 
baseline, 1 week, and 1, 3, and 6 months. The primary outcome will be BUP treatment uptake (taking BUP 7 
days after baseline). Secondary OUD outcomes will be illicit opioid use and retention in care at 1, 3, and 6 
months. Secondary pain outcomes will be pain intensity, pain interference, and quality of life at 3 months. 
Changes in pain and quality of life will be mediated by BUP treatment uptake and retention. During induction 
and 3-months of follow-up, we will also collect data for Ecological Momentary Assessment (EMA) of opioid 
withdrawal, craving, pain, and anxiety (“opioid- and pain-related symptoms”). These EMA data will allow us to 
assess whether BUP microdosing’s targets of engagement—opioid- and pain-related symptoms—mediate 
OUD outcomes. Exploratory analyses will also examine pain as a trigger for opioid relapse. 
     Aim 1: To test the effectiveness of microdosing (vs. TAU) on OUD outcomes. 
H1: The microdosing arm (vs. TAU) will have better BUP treatment uptake and retention, and less illicit opioid 
use. H2: Improvements in H1 will be mediated by opioid- and pain-related symptoms.
     Aim 2: To test the effectiveness of microdosing (vs. TAU) on pain outcomes. 
H3: The microdosing arm (vs. TAU) will have less pain intensity and interference, and improved quality of life. 
H4: Improvements in H3 will be mediated by OUD outcomes.
Aim 3: To inform future implementation and dissemination efforts, we will: 3a) Examine factors 
influencing reach, adoption, implementation, and maintenance of BUP microdosing. We will use 
qualitative and quantitative methods to describe multi-level factors influencing these domains; 3b) Calculate 
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Microdose Bupe V.2.0 4-20-22
the cost and examine cost-effectiveness of BUP microdosing. H5: Compared with TAU, BUP microdosing 
will be cost-effective from a societal and a health sector perspective.
B. SIGNIFICANCE
B.1 Opioid use disorder (OUD) and chronic pain (CP). There is a complex bidirectional relationship
between CP and OUD.20 Chronic pain (i.e., pain lasting ≥3 months) is common among people with OUD; long-
term opioid use may worsen CP.21 Depending on the medical setting, between 1/3 and 2/3 of patients with 
OUD have CP conditions.1,22,23 CP etiologies may precede development of OUD. The 2015 National Survey on 
Drug Use and Health estimates that 62% of the 11.5 million Americans who misuse prescription opioids do so 
to control pain.2,12 A substantial percentage (1-8%) of patients who start prescription opioids for CP develop 
incident OUD.21,24 Patients with CP and psychiatric co-morbidity are likely at increased risk for developing OUD 
when taking prescription opioids.25 Chronic pain may also stem from OUD-related conditions, such as HIV or 
HCV, and following accidents or trauma related to OUD.26 Alternatively, the pharmacologic effects of full opioid 
agonists can worsen CP through opioid-induced hyperalgesia, in which pain sensitization is enhanced despite 
opioid therapy.27 Ultimately, preventing OUD-related harms will require better management of CP.
B.2 Buprenorphine (BUP) may be the ideal medication for OUD and CP. BUP treatment (i.e,
buprenorphine or buprenorphine-naloxone) for OUD reduces illicit opioid use, HIV risk and opioid overdose 
mortality.28-30 BUP is also US Food and Drug Administration approved for CP treatment.7,31 Approved BUP 
formulations differ for OUD and CP, but the medication itself remains the same.32 As a partial opioid agonist at 
mu opioid receptors with high affinity binding and slow dissociation, BUP can prevent opioid withdrawal, reduce 
opioid craving, and block the effects of other misused opioids without causing euphoria in people with 
physiologic dependence to opioids (“opioid-dependent”).33-35 Despite being a partial agonist, BUP’s analgesic 
efficacy is comparable to that of morphine and other full agonists.34,36,37 Though the mechanism is incompletely 
understood, long-term BUP use likely results in less opioid-induced hyperalgesia than full opioid agonists, 
which can lead to improvements in pain and functioning.34,38-41 Because BUP has a ceiling effect, where doses 
above a threshold (probably 24-32 mg) do not cause additional respiratory depression, overdoses are less 
frequent with BUP than other prescription opioids.42-44 Studies that examine pain outcomes in patients taking 
BUP for OUD demonstrate reductions in pain, even without other pain-focused treatments.45-47 Nonetheless, 
work is needed to increase BUP treatment uptake - only 20% of 2 million Americans with OUD receive 
evidence-based treatment annually.48,49 Improving pathways to enter BUP treatment could prevent OUD-
related harms and improve pain. Figure E-1 demonstrates how our microdosing strategy is proposed to 
improve OUD outcomes, which will in-turn improve pain outcomes. 
B.3 Fear of withdrawal prevents people from initiating BUP. Needing to transition to BUP from opioid
agonists (i.e. heroin or prescription opioids) prevents people with opioid misuse or OUD from starting BUP. 
There are two challenges: 1) patients must typically avoid opioids for 24-72 
hours before starting BUP; and 2) precipitated or persistent withdrawal 
during BUP induction can lead to early treatment cessation. If BUP is taken 
too soon after full opioid agonists, opioid-dependent people will experience 
precipated withdrawal when BUP displaces other opioids at mu opioid 
receptors while providing only partial agonism. Relative reduction in opioid 
agonist activity is experienced as withdrawal,44,50,51 which can reduce 
interest in BUP treatment.52,53 People taking prescribed opioids express fear 
of stopping opioids due to worsening pain and withdrawal.9,10,54-57  Two early 
studies that attempted to transition patients with CP and likely OUD from 
prescription opioids to BUP highlight induction challenges. In one trial, 21 
patients consented to transition from prescription opioids to BUP, but only 
12 took BUP and 4 successfully completed induction.58 In a retrospective 
pain clinic study, only 104 of 271 patients receiving prescription opioids who 
were offered BUP successfully transitioned to BUP.8 One study of 76 CP 
patients with opioid misuse used an inpatient protocol to transition to BUP; 
the protocol included conversion to intravenous opioids and giving small 
doses of intramuscular or sublingual BUP.59 This worked, but elective 
hospitalization for BUP induction is too resource intensive to be 
generalizable. Even when BUP induction is successful, as many as 28% of 
patients drop-out during the first week of treatment, likely due to 
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uncontrolled craving and withdrawal.60-64 Improved BUP induction protocols are needed.
B.4 Hospitalization is an important “touch-point” to reach people who misuse opioids. People with 
opioid misuse or OUD are frequently hospitalized for reasons other than opioid overdose.65 As the number of 
Americans experiencing overdoses has skyrocketed, hospitalization rates for other opioid-related conditions, 
such as cellulitis or psychosis, have increased in parallel.65-67 People with OUD and CP are also frequently 
hospitalized for trauma and surgical procedures.68 A common scenario is that a hospitalized patient with opioid 
misuse or OUD has opioids started or increased to control pain, but uncertainty about opioid tapering prolongs 
hospitalization. In our hospital system, patients with an opioid positive urine test have a 1.6 day longer length 
of stay (7.6 days vs. 6.0 days) than patients with urine drug tests that are positive for other substances or 
negative for illicit substances (unpublished data). Opioid analgesics may be stopped abruptly to facilitate 
discharge, which could lead to pain, withdrawal and re-admission. Patients with OUD who are not receiving 
OUD treatment when hospitalized very rarely newly initiate OUD medications.69 Following hospitalization for 
OUD-related infections, patients are 50 times more likely to die from opioid overdose than the general 
population.17 Though BUP microdosing protocols could be used in many treatment settings, hospitalization is a  
particularly important time to initiate BUP treatment.
B.5 Microdosing as a strategy to facilitate BUP treatment induction. When BUP displaces opioid 
agonists, opioid-dependent patients experience precipitated withdrawal from the relative change in agonism. 
Microdosing starts low BUP doses (0.5 mg) 
that do not precipitate withdrawal, and then 
gradually increases dosage while continuing 
a full opioid agonist, thereby avoiding 
withdrawal and pain that occurs during 
standard inductions (see Figure E-2, Table 
E-2).13,15 Interest in microdosing has grown 
tremendously outpacing evidence of 
effectiveness. A recent meta-analysis of 
published data on BUP microdosing included 
20 studies, but all are case series and 
include 57 total participants.70 One series 
examined BUP microdosing for 8 CP 
patients taking high-dose prescription opioids and demonstrated success with 6 transitioning to BUP.71 Our 
group has developed BUP microdosing protocols (see D.2.7), which warrant testing in a rigorous clinical trial. 
B.6 Evaluating opioid- and pain-related symptoms during BUP induction. Understanding patients’ 
experiences with BUP induction could contribute to other interventions that facilitate treatment initiation and 
improve clinical practice. Persistent and precipitated withdrawal are relatively common experiences during 
induction.72-74 In BUP clinical trials, where participants are selected based on their willingness to undergo 
withdrawal before induction, standard inductions are highly successful (>94%), but elevated levels of opioid 
craving and withdrawal are reported for weeks following induction.64,75 Additionally, patients with CP may be 
ambivalent about stopping opioid analgesics. Collecting detailed qualitative and quantitative data regarding 
opioid- and pain-related symptoms will help identify how successful participants cope with these symptoms.  
B.7 Ecological momentary assessment (EMA) to evaluate pain as a trigger for illicit opioid relapse. 
During the trial, we will collect EMA data to examine the relationship between opioid- and pain-related 
symptoms with OUD outcomes. Analyses will clarify how these symptoms differ between arms and affect BUP 
uptake during the induction and other OUD outcomes during follow-up. Thus, the BUP microdosing targets of 
engagement will be measured using EMA data (i.e., opioid- and pain-related symptoms). In a clinical trial 
where BUP was maintained for 12 weeks and then tapered for 4 weeks among people with OUD and CP, high 
and fluctuating pain scores during maintenance BUP treatment were associated with relapse to illicit opioid use 
during the taper phase.76 Other studies document CP as a predictor of illicit substance use.41,77-80 Interestingly, 
a few studies that have examined pain and illicit opioid use outcomes among patients taking maintenance BUP 
or methadone did not report an association between pain and illicit opioid use.46,81,82 
EMA is a method for collecting electronic, real-time data that captures subjective states (e.g., pain) and 
occurrences of specific behaviors (e.g., illicit opioid use) as individuals go about their day.83 EMA overcomes 
limitations of in person assessments and other real-time sampling methods that use written reports (e.g., daily 
diaries), including retrospective bias and poor compliance.84 All EMA technologies tag participant inputs with a 
time/date stamp and record failures to respond to prompts.83 Thus, while people who misuse prescription 
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opioids report pain as the reason for their use, we will collect detailed data regarding opioid- and pain-related 
symptoms, and examine if these symptoms mediate the relationship between study arm and OUD outcomes. 
B.8 Implementation and dissemination promise and challenges. A key implementation challenge is 
engaging low-income Black and Hispanic patients in BUP treatment.85 Barriers include access to BUP and 
stigma of OUD treatment. We will collaborate with people with lived experience and the Stakeholder Board to 
minimize stigma, for example, with messaging that frames positive aspects of BUP treatment. Microdosing 
dissemination challenges include engaging hospital clinicians who have not had extensive training in addiction 
medicine. We will conduct qualitative interviews with clinical staff who support our research team in conducting 
the RCT to understand strategies for maintaining microdosing protocols once the study has been completed. 
B.9 Expanding evidence of BUP cost-effectiveness. CP is associated with greater estimated costs than 
cancer, cardiovascular disease, and diabetes.86 Total annual costs range from $560 billion to $635 billion 
annually in direct health expenditures and lost productivity. Hospitalization costs are also increasing. In a 
national sample, from 2011 to 2015, average costs per hospitalization for patients with OUD and CP increased 
from $37,029 to $47,480 even though length of stay remained stable between 5.74-5.82 days.68 BUP treatment 
is known to be cost-effective, and has the potential to reduce hospital length of stay and re-hospitalization.87 
However, the 5-day microdosing protocol could also delay discharges. Examining how hospital-based 
microdosing affects re-hospitalization, acute care utilization and other health system or social costs would 
provide additional incentives for wide-spread implementation and dissemination of BUP microdosing.  
B.10 Summary. CP and OUD can be effectively managed together with BUP. Helping out-of-treatment 
patients with CP and opioid misuse or OUD to start BUP during hospitalization would be beneficial in 
preventing opioid-related harms, improving pain, and potentially lowering health system costs. Microdosing is a 
promising approach to facilitate BUP induction – particularly for people with CP who fear stopping opioids – but 
rigorous clinical trials are necessary to demonstrate benefits in comparison to standard inductions. With high 
rates of opioid use and uncontrolled pain in the US, improving BUP treatment utilization will be highly impactful.  
C. INNOVATION
     C.1 First RCT of BUP microdosing. The first case study proposing BUP microdosing was published in 
2016.13 Since then there have been more than 20 microdosing case reports/series and much enthusiasm 
about the approach. However, no RCTs have demonstrated safety and efficacy in generalizable samples. 
Additionally, studies have not fully evaluated microdosing for people with opioid misuse or OUD and CP. 
     C.2 Rigorous assessment of BUP for opioid misuse or OUD and CP. Some data support use of BUP 
for controlling pain in people with OUD, but because different formulations are approved for OUD treatment 
and CP, few experimental studies examine both outcomes concomitantly. We will recruit hospitalized patients 
with opioid misuse or OUD, prescribe the buprenorphine/naloxone formulation used for OUD treatment, and 
rigorously study pain outcomes and the OUD treatment cascade of care over a 6-month follow-up period.  
     C.3 Ecological momentary assessment (EMA) will allow us to collect information in real-time, 
investigating relationships between BUP microdosing, opioid- and pain-related symptoms, and OUD outcomes. 
We will have detailed information about opioid withdrawal, opioid craving, pain, and anxiety during induction 
and follow-up, which can help elucidate reasons for suboptimal OUD outcomes. Follow-up data collection over 
1-week periods will also allow us to investigate opioid- and pain-related symptoms during different aspects of 
participants’ lives (e.g., during work vs. weekends) and contextual events that may lead to opioid use. We will 
provide participants with cell phones so that EMA data can be collected in a socioeconomically diverse sample.
D. APPROACH
     D.1 Preliminary studies: For over 15 years, our research group has been at the forefront of BUP 
treatment and innovation in primary care and community settings.88-96 We have developed a large primary 
care-based BUP treatment network (H97HA03793) and are conducting an RCT of BUP treatment initiation at 
syringe services programs (R01DA044878, PI: Fox). We have studied numerous BUP innovations, including 
home inductions, community-based referrals (R34DA031066), group medical visits (R34DA039041, PI: Fox), 
and “low-threshold” treatment.11,72,97-103 Our team also includes early-stage investigators trained in qualitative 
research and longitudinal data analysis. With 3 hospitals, 20 community health centers, and 5 opioid 
treatment programs in the Bronx, Montefiore provides the optimal setting for answering clinical questions 
about BUP. We have treated >1300 patients with BUP, ~1000 patients are hospitalized annually with OUD 
and CP, and we have conducted numerous NIH-funded BUP clinical trials. 
     D.1.1 OUD and chronic pain: In an observational cohort, we studied 82 patients with OUD who initiated 
BUP treatment in primary care and found that 60% had significant pain at baseline before starting BUP (i.e., 
pain ≥ 5 out of 10 using the Brief Pain Inventory) and 38% had persistent pain over 6 months (i.e., pain scores 
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≥ 5 at 1, 3 and 6-month follow-up visits). The average pain score for patients with baseline pain was 7.3 and 
decreased to 6.0 at the 6-month follow-up visit.46 These data suggest that out-of-treatment patients with OUD 
and CP will have clinically meaningful improvements in pain and will be retained in BUP treatment. 
     D.1.2 Failure to initiate BUP: Qualitative and quantitative data suggest that fear of withdrawal is a barrier 
to initiating BUP among people with opioid misuse or OUD and CP. In a qualitative study with people using 
illicit BUP, those who had experienced precipitated withdrawal when taking BUP were reluctant to consider 
formal BUP treatment.53 We have also documented CP patients’ fear of worsening pain with stoppage of 
prescription opioids.57 Among 324 patients who inquired about our outpatient BUP treatment program, only 
56% started treatment, demonstrating the need to improve the process of initiating BUP treatment.93   
     D.1.3 Inductions complicated by withdrawal symptoms are common: Our research has demonstrated 
that complicated BUP inductions (i.e. precipitated withdrawal after taking BUP) are regular occurrences 
happening in at least 17% of inductions.72 In addition, patients who have complicated inductions are less likely 
to remain in BUP treatment at 30-days than those who do not.11 
     D.1.4 BUP microdosing: Based on the literature, our group has developed outpatient and inpatient BUP 
microdosing protocols. Since 2020, we have used these protocols with 18 patients. Among the 18 patients who 
attempted microdosing induction, 11 were successful in initiating and continuing BUP treatment (unpublished 
data). Only 1 of 5 patients who were taking methadone treatment at the time of microdosing were successful 
with the transition. Therefore, we will exclude participants who are enrolled in methadone treatment programs.
     D.1.5 Previous EMA research: We have expertise in conducting research and collecting substance use 
data via EMA, including analysis of complex longitudinal studies with repeated measures. Using hand-held 
devices including smartphones, we have conducted NIH-funded research studies in which approximately 180 
data points have been successfully collected from each study participant.104-106     
     D.1.6 Previous research for costs-effectiveness analysis. Our team also has expertise in assessing 
costs and cost effectiveness of substance use interventions using data from EHR, clinical tracking systems, 
and claims. Our health economists leads the cost analysis in an ongoing HEAL initiative project 
(UF1MH121944) to test collaborative care approaches to co-existing OUD and mental health conditions in 
primary care. We will also be supported by the CHERISH Center, a NIDA-funded Center of Excellence, with 
outstanding resources for economic evaluations alongside clinical trials (see letter of support).
     D.1.7 Summary: Taken together these studies demonstrate our ability to conduct clinical trials with BUP, as 
well as, EMA and cost-effectiveness methods; the feasibility and acceptability of microdosing; likelihood of 
improved pain with BUP treatment; and the high volume of admissions to our hospital system for CP and OUD.  
D.2 Research Design and Methods:
D.2.1 Overview of study approach: We will conduct a hybrid type 1 effectiveness-implementation study, 
using a pragmatic, open label RCT. We will recruit 270 hospitalized patients with (a) CP and (b) opioid misuse 
or OUD, randomize them 1:1 to BUP microdosing or TAU, and link them to outpatient BUP treatment. We will 
assess BUP treatment uptake (primary outcome) and other OUD and pain outcomes. The microdosing arm will 
use a 5-day BUP microdosing protocol (see Figure E-2 and Table E-2) – BUP doses will be gradually 
increased while a full opioid agonist is continued. In the TAU arm, participants will stop other opioids and wait 
until they are in moderate opioid withdrawal before starting BUP. Both arms will receive follow-up care at 
Montefiore clinics to continue BUP treatment (with buprenorphine-naloxone) and manage CP. Assessment 
visits will occur at baseline, 1 week, and 1, 3, and 6-months. We will use EMA to assess opioid- and pain-
related symptoms during induction and three 1-week periods over 3 months. We will also collect detailed 
information on microdosing implementation and cost-effectiveness. 
D.2.2 Setting. We briefly describe study sites below and details are provided in the Facilities section. 
Montefiore Medical Center is the largest healthcare provider in The Bronx. The neighborhoods served by 
Montefiore are representative of low-income urban areas: over 65% of patients have public insurance, 57% 
Hispanic and 39% Non-Hispanic Black, and neighborhoods have been devastated by drug use. There are 
three Montefiore hospitals in the Bronx. Hospitalized medical patients are typically cared for by hospitalists with 
the availability of pain, addiction medicine, and psychiatry consultants. Montefiore also has 20 community 
health centers, the BUP Treatment Network (situated in 7 community clinics), and 5 opioid treatment programs. 
In outpatient settings, patients receive BUP treatment integrated with primary care services.   
D.2.3 Participant Eligibility: We will enroll hospitalized patients with CP and opioid misuse or OUD who 
are taking opioids and eligible for BUP treatment. Opioid misuse will be defined as heroin use or prescription 
opioid misuse (defined as: 1) use without a prescription; 2) use in greater amounts, or more often than 
prescribed  3) running out of prescription pain medication early).107 CP will be defined as pain that is chronic 
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(on most or all days for ≥ 3 months) and at least moderate intensity and interference (score >4 on Pain, 
Enjoyment of Life and General Activity scale [PEG]).108,109 We will exclude patients who are currently receiving 
any OUD treatment (see Table E-1).
D.2.4 Recruitment: 
We will actively and passively recruit hospitalized patients. Clinicians in the hospital, including pain and 
addiction consultants, will be informed about the study. Study information will be posted electronically and in 
common areas (e.g., physicians’ lounges). Dr. Torres-Lockhart, Director of Montefiore’s Addiction Consult 
Service, and Dr. Shaparin, Director of the Pain Service, will oversee recruitment of patients on whom they are 
consulted. Hospital Medical Directors will also assist in recruitment. We will also have the Epidemiology 
Informatic Unit (EISMU) produce daily recruitment data lists with identifiable information about hospitalized 
patients who have opioid use disorder and at least one chronic pain condition. We will contact the attending 
physician for hospitalized patients before approaching the patient for study recruitment. If given permission by 
the attending physician, the research coordinator will approach the hospitalized patient for recruitment. 
Feasibility of recruitment: In 2019, 987 patients with OUD and CP diagnoses of back pain, arthritis, or 
neuropathy were hospitalized at Montefiore. Co-morbidities that would be exclusions for this RCT were: BUP 
treatment (7%), methadone treatment (31%), severe alcohol use disorder (8%), and severe benzodiazepine 
use disorder (2%). Removing patients with ≥1 exclusion leaves 640 potential participants. In a prior RCT of 
BUP treatment for hospitalized patients, 21% of eligible patients were enrolled.18 Using a more conservative 
estimate of enrolling 14% of eligible patients, enrolling 270 participants in 3 years will be feasible (640 
eligible/year x 14% enrollment rate x 3 years = 270 participants).   
D.2.5 Screening and Randomization: Initial screening and consent: Participants will be screened for 
eligibility and exclusion criteria by a trained research coordinator using a brief questionnaire. Participants will 
be informed of study procedures, risks and benefits of study participation, tested for their understanding, and 
they will provide written consent. During enrollment, female participants will have urine pregnancy tests.
Randomization will be unblinded, stratified, and blocked, with a 1:1 ratio across the two arms. To ensure 
balanced distribution between arms, we will stratify by OUD severity (misuse/mild vs. moderate/severe), heroin 
use (past 30 days, yes vs. no), and mood disorders (yes vs. no). We will randomize in blocks of 4-8 to ensure 
comparison groups of equal size. To ensure concealment of allocation, a centrally-located data manager will 
generate allocation sequences (with SAS Proc Plan) and store sequences in a password-protected file. 
D.2.6 Participant tracking: We will use procedures that we have developed to retain people who use 
drugs in previous research, in which we have had an 84% retention rate over 6-month-follow-up.110  
Participants will complete locator forms at enrollment and update them at all research visits. Information will 
include: 1) participants' addresses, phone numbers, and social security numbers; 2) contact information of 
family or friends; 3) contact information of participants' community-based organizations and case managers; 
and 4) participants’ "hang out" locations.
Table E-1: Inclusion and Exclusion Criteria
Inclusion Criteria
Exclusion Criteria
Age > 18 years
Opioid misuse or OUD (see D.2.3)
Chronic pain (see D.2.3)
Currently taking opioids 
Fluency in English or Spanish
Planned hospitalization for ≥ 48 hours
Current OUD treatment (BUP, methadone, naltrexone)
Severe alcohol or benzodiazepine use disorder
Hypersensitivity to BUP or naloxone
Pain due to malignancy
Severe untreated mental illness (suicidality, psychosis)
presence of an acute or chronic medical condition that 
would make participation medically hazardous
Resting respiratory rate >20 or O2 saturation <92%
Pregnancy
Unable to consent due to pain or cognitive impairment
Table E-2. Microdosing Initiation Dosing Schedule
Day
Microdosing
Standard Induction
Full 
agonist
BUP 
Daily 
Total
Full 
agonist
BUP
Daily 
Total
1
Full dose
0.5 mg 
q12
1 mg
STOP
--
--
2
Full dose 
1 mg q8
3 mg
--
2 mg q4 h 
8 mg
3
Full dose
2 mg q8
6 mg
--
8 mg BID
16 mg
4
Full dose
4 mg q8
12 mg
--
8 mg BID
16 mg
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D.2.7 Clinical Protocols: Microdosing 
(Experimental arm): 
Participants randomized to 
microdosing will start low-
dose BUP while continuing 
a full opioid agonist 
according to a 4-day 
protocol (see Figure E-2 
&Table E-2). Participants 
will be assessed for opioid 
withdrawal using the 
clinical opioid withdrawal 
scale (COWS) before the 
first BUP dose and 30 
minutes after each 
administered dose while 
hospitalized.111 A full opioid 
agonist will be continued 
until day 5 of the 
protocol.112,113 If patients 
are planned for discharge 
before completing 
microdosing, they will receive at the time of discharge pre-packed medication clearly marked with the timing for 
each dose, instructions on how to take the medication and when to stop full agonist opioids. Opioid withdrawal 
will be assessed with the Subjective Opioid Withdrawal Scale (SOWS) via telephone.
Rationale for 5-day protocol: Published microdosing protocols range from 3 to 7 days or more. From 2012-
2016, the mean length of stay for patients at Montefiore Medical Center with an opioid positive urine drug test 
was 7.62 days (95% CI: 7.44-7.80). Some evidence suggests that rapid titration to maintenance BUP treatment 
dosages prevents drop-out,114 but rapid titration could increase precipitated withdrawal risk, therefore, we 
developed our protocol in the middle of the published range.
TAU (Control arm): Participants randomized to TAU will receive a standard BUP induction following clinical 
guidelines. Full opioid agonists will be stopped and a clinician will assess for withdrawal using the COWS 
scale. If participants have a COWS score of ≥8 they will be eligible to receive a 2 mg BUP dose. Participants 
will be reassessed for withdrawal 30 minutes after receiving their first BUP dose.  
Withdrawal management: Participants with COWS score increases of ≥50% or an absolute increase of 4 or 
more will be considered to have precipitated withdrawal. If this occurs, induction will be postponed to the 
following day. Clinicians can administer non-opioid adjunctive medications (i.e., clonidine, loperamide) during 
induction based on hospital protocols. Medication use will be considered a covariate in analyses with 
withdrawal symptoms as an outcome.
Intervention fidelity: Study clinicians will be trained in the study protocol for microdosing and TAU and 
follow a check-list for induction procedures. All BUP doses administered will be recorded in medical records. 
     Follow-up BUP treatment: Participants will be discharged with 1 week of BUP and scheduled for clinical 
visits at Montefiore within 1 week. During clinical visits, participants will be assessed for BUP adherence, illicit 
opioid use, and opioid craving. All BUP prescriptions will be buprenorphine-naloxone film or tablet formulations.
Maintenance dosing: For both arms, the target BUP dose will be 16 mg daily at discharge, consistent with 
the mean BUP dose for patients treated at Montefiore and standard clinical dosing goals for OUD.115 As per 
standard procedures, clinical visits will occur weekly during the first month. BUP dosage may be increased if 
needed (based on opioid use or uncontrolled pain). 
Psychosocial counseling and support: At clinical visits, clinicians will provide 15 minutes of standardized 
counseling directed toward medical management.116 Counseling will include discussion of current substance 
use, BUP adherence, and psychoeducation about avoiding relapse. End of study: At 6-months, all participants 
will have the option to continue clinical care at a Montefiore clinic, including those without insurance.  
D.2.8 Assessment Visits: A research assistant (RA) will meet with all participants at baseline, 1 week, 
and 1, 3 and 6 months (see Table E-3). Research visits will occur in the hospital or at a Montefiore clinic, and 
participants will receive $50 compensation at visits for the week 1, month 1 and month 3 visits and they will 
5
STOP
8 mg BID
16 mg
--
8 mg BID
16 mg
BUP = buprenorphine dosage; q4 = every 4 hours; BID = twice daily
Table E-3: Summary of Assessments and Schedule
Construct
Measure
Assessment period
0
1w 1m
3m
6m
Opioid Outcome Measures for Aim 1
BUP uptake
BUP medication administration, prescriptions 
X
BUP retention
BUP prescriptions
X
X
X
Illicit opioid use
Addiction Severity Illness (ASI), urine drug test
X
X
X
X
X
Pain Outcome Measures for Aim 1
Pain intensity
BPI pain severity subscale
X
X
X
X
X
Pain interference
BPI pain interference subscale  
X
X
X
X
X
Quality of life
PROMIS-Preference (PROP-Pr) Scoring System
X
X
X
X
Physical functioning
PROMIS Physical Function short form
X
X
X
X
X
Additional Mediators/Moderators and Covariates
Sociodemographics
Demographics questionnaire
X
Opioid withdrawal
Clinic Opioid Withdrawal Scale (COWS)
X
X
Opioid craving
Medication Craving Scale
X
X
X
X
Pain treatments
Prescriptions, pain-related visits/procedures
X
X
X
X
Mood symptoms
Patient Health Questionnaire (PHQ-9)
Generalized Anxiety Disorder–7 (GAD-7)
X
X
X
X
Substance use
PROMIS alcohol use, ASI, urine drug test
X
X
X
X
X
Prior OUD treatment
NIDA JCOIN harmonized questionnaire
X
**Additional measures will be included as required by the RFA, IMPOWR Coordination and 
Dissemination Center, and IMPOWR-ME Stakeholder Board.
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receive $100 for the baseline and month 6 visits. 
Questionnaires and urine drug tests will be 
completed at each study visit. Additionally, data will 
be collected using EMA in the hospital during 
induction and in between assessment visits (see 
below). To limit participant burden, EMA data will be 
collected only during induction over 2 weeks and 
then in three 1-week bursts during follow-up. 
D.2.9 Data Sources and Measures for Aims 1 
and 2 are presented in Tables E-3 and E-4.   
Questionnaires: Questionnaires will be 
administered in English or Spanish using REDCap, a well-established, HIPAA-compliant, web-based surveying 
platform and database that allows flexible instrument design, ease of contacting potential respondents, and 
reliable data collection and storage with error control. Additionally, items can be self- or interviewer-
administered. Our team has transitioned to online evaluations due to the COVID-19 pandemic and all 
instruments can be filled out online. Therefore, questionnaires can be administered at a Montefiore clinical site 
or virtually. 
Medical Records: We will abstract medical record data from the electronic health record (EHR), including 
administration of BUP during hospitalizations, BUP prescriptions and outpatient BUP visits. We will also 
abstract adjunctive medications administered in the hospital for managing opioid withdrawal and pain, and any 
pain medications prescribed in the outpatient setting during follow-up. We will abstract other pain-focused visits 
or interventions during the follow-up period (e.g., physical therapy). 
Urine Drug Testing will occur at each study visit using enzyme-multiplied immunoassay (EIA) technique 
for opiates, oxycodone, fentanyl, methadone, BUP, amphetamines, benzodiazepines, cocaine, and 
cannabinoids, and urine creatinine concentration to ensure validity.
Study logs: We will use study logs to examine the number of potential participants screened, consented, 
and reasons for declining consent. Study clinicians will document the amount of time that they spend during 
BUP induction using the microdosing or TAU protocol following a check-list of steps.
Ecological momentary assessment (EMA): We will use EMA to examine opioid and pain-related 
symptoms (opioid withdrawal and craving, pain, anxiety), along with illicit opioid use, BUP dose taken, and pain 
treatments. Using smartphone mobile technology, participants will receive time-scheduled prompts to report 
symptoms, ecological conditions (e.g., current activities), and behaviors. We will record assessments in two 
periods: the first 2 weeks (induction) and 3-month follow-up. During induction, participants will report opioid- 
and pain-related symptoms at random times during 5 daily blocks. The relatively long period of data collection 
oriented to induction will allow EMA data collection in the hospital and after participants return home to resume 
normal activities. During follow-up, we will collect data during three additional 1-week “bursts” to complement 
data from in-person study visits. Bursts will be separated by at least 2 weeks and no more than 6 weeks over 3 
months. Prompts will inquire about opioid- and pain-related symptoms, and context, such as physical activity, 
which may affect these symptoms and OUD or pain outcomes. As with our current studies, research staff will 
assist in downloading the secure customized EMA technology (www.Ilumivu.com) onto participant smart 
phones, and provide training to use the technology.106 Participants without smart phones will be provided one. 
Each report will take 1-2 minutes to complete. Based on the lack of significant reactivity effects found in past 
research, 5 standard EMA random reports will be prompted daily.117,118 EMA measures are summarized in 
Table E-4. 
Adherence to EMA: Participants will receive $0.20 for each set of assessments completed. If they complete 
more than 90% of assessments weekly, they will receive a bonus of $10. Feedback regarding EMA adherence 
will be provided with reminders about compensation. Total compensation can be $17 per EMA week. 
E.2.10 Key Outcomes for Aims 1 and 2: 
The primary outcome will be BUP uptake, defined as receiving BUP 7 days after the baseline visit using 
EHR data on hospital medication administration or prescription (dichotomous, yes/no). 
Secondary OUD outcomes include illicit opioid use and BUP retention. Illicit opioid use will be examined 
as the number of days of illicit opioid use (defined as self-reported use of heroin, fentanyl, or non-prescribed 
opioid analgesics) in the prior 30 days based on the Addiction Severity Index (continuous).119 Because urine 
drug testing (UDT) only captures opioid use in the prior 24-72 hours, it is a less sensitive measure of 
substance use over time; however, UDT results will be a secondary outcome measure. BUP retention will be 
Table E-4. Ecological Momentary Assessment (EMA) Measures
Construct
Measure
EMA opioid- and pain-related symptoms
Opioid withdrawal
Subjective Opioid Withdrawal Scale (SOWS)
Opioid craving
Visual analog scale
Pain intensity
Adapted BPI pain severity subscale
Anxiety
Generalized Anxiety Disorder–7 (GAD-7)
Exploratory EMA outcomes
Illicit opioid use
Self-report
BUP dose
Self-report
Pain treatment
Self-report
*All measures will occur at bursts 1 & 2 weeks, and 1, 2, & 3 months
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defined as having a BUP prescription written the following number of days after baseline: 30-60 days (1-month 
retention); 90-120 days (3-month retention); and 180-210 days (6-month retention). To be retained at 3 and 6-
months, participants will be required to have been retained at previous time points.46 All OUD outcomes are 
consistent with elements of the Opioid Use Disorder Cascade of Care.120    
Secondary pain outcomes include pain intensity, pain interference, and quality of life. Pain intensity will 
be measured using the Brief Pain Inventory (BPI).121 We will use the mean of 4 items that assess pain intensity 
over the past 24 hours on a scale of 1-10 (1=minimal pain, 10=intense pain). We will use the mean of these 4 
items. Pain interference will be measured using the pain interference scale from the BPI, which is a 7-item 
instrument measuring the impact of pain on daily activities and physical functioning. It is rated on a scale of 1-
10 (1=minimal interference, 10=high interference). We will use the mean of these 7 items. Quality of life will be 
measured using the PROMIS-Preference Scoring System (PROP-Pr), which is described in detail as part of 
the cost-effectiveness analyses below (see D.4.1).122-124 In our main analyses, we will examine changes from 
baseline to 3 months for all pain outcomes; in additional analyses, we will examine sustainability at 6 months. 
Other covariates: We will include covariates that may be associated with study outcomes including: 
sociodemographic characteristics (age, race/ethnicity, sex, employment, housing, insurance), opioid 
withdrawal and craving,111,125 adjunctive withdrawal medications (e.g., clonidine, loperamide), pain treatments 
including medications (e.g., NSAIDs, gabapentin) and other forms of treatment (e.g., physical therapy, steroid 
injections, surgery), mood symptoms (anxiety and depression),126-128 and prior OUD treatment. We will also 
include holistic outcome measures developed by the IMPOWR Coordination and Dissemination Center with 
people with lived experience (RFA-DA-21-029) and collaborate with the IMPOWR-ME Stakeholder Board to 
ensure we include other measures important to them. 
  D.2.11 Analytic plan Aims 1 and 2: Main analyses will be completed using an intention-to-treat approach.
Preliminary analyses. We will first review and summarize data using descriptive summaries and graphical 
analyses to ensure that values are within appropriate ranges, to check for outliers and abnormal values, and to 
verify that the distributions of measures meet the assumptions of the statistical tests that are planned as 
described below. We will also explore whether the microdosing and TAU groups are equivalent on potential 
confounding variables (age, sex, race/ethnicity, baseline substance use, and mood symptoms). 
Missing data. For missing data, we will use multivariate multiple imputation using the fully conditional 
specification method.129 We will repeat imputations five times, and then we will compare statistical results using 
datasets that include imputed values and the dataset that drops missing values. This will guide interpretation of 
our assessment of the impact of missing data, as well as, our interpretation of overall results.
Aim 1: To test the effectiveness of microdosing (vs. TAU) on OUD outcomes. 
H1: The microdosing arm (vs. TAU) will have better BUP treatment uptake and retention, and less illicit 
opioid use. Our primary analysis will be a logistic regression comparing the proportion of participants in each 
study arm who meet our definition of BUP uptake (see D.2.10). Secondary analyses will examine BUP 
retention and illicit opioid use as secondary outcomes. We will use a mixed effects logistic regression model to 
examine BUP retention at 1, 3, and 6 months and a mixed effects linear regression model to examine number 
of days of illicit opioid use (over 30 days) at 1, 3, and 6 months. Study arm will be considered a fixed effect, 
and participant and time (months) will be considered random effects. Additional analyses will include key 
variables mentioned above as covariates and potential confounders if they differ by study arm.
H2: Improvements in H1 will be mediated by opioid- and pain-related symptoms. Based on the model 
described in Figure E-3, we will use structural equation modeling to 
determine whether improvements in OUD outcomes are due to 
improvements in opioid- and pain-related symptoms. We will use 
EMA data (5 random reports per day) and data from in-person visits 
at baseline, 1 week, 1, 3, and 6 months. For example, when the 
dependent variable is BUP uptake, we will calculate the 
standardized total effect from the intervention (BUP microdosing) to 
BUP uptake, as well as the standardized mediational (i.e., indirect) 
effect of opioid- and pain-related symptoms (e.g., withdrawal). The mediational effect is calculated as the 
product of the effect from intervention to the mediator, and the effect from the mediator to the outcome. To 
account for the influence of the baseline measures (e.g., sociodemographic characteristics) on the outcome 
and the mediator, we will use a partial correlation matrix as the input matrix. This will be created by statistically 
parsing out the effects of the baseline measures cited above on the mediator and the outcome variable. Our 
proposed model will be estimated using Mplus.130 Overall model fit will be assessed by: (1) the root mean 
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square error of approximation (RMSEA), (2) Bentler’s comparative fit index (CFI),131 and (3) the standardized 
root mean square residual (SRMR). To account for non-normal distribution of the model variables (e.g., BUP 
uptake), we will use Mplus’s maximum likelihood with robust standard errors (MLR) as the estimator.
Aim 2: To test the effectiveness of microdosing (vs. TAU) on pain outcomes. 
H3: The microdosing arm (vs. TAU) will have less pain intensity and interference, and improved quality of 
life. We will use separate mixed effects linear regression models to compare each pain outcome from baseline 
to 3 months. Main analyses will use data from in-person visits at baseline, 1 week, 1 and 3 months. Study arm 
will be considered a fixed effect, and participant and time will be considered random effects. In additional 
analyses, we will include key variables mentioned above as covariates and potential confounders if they differ 
by study arm. We will also examine sustainability of outcomes at 6 months.
H4: Improvements in H3 will be mediated by OUD outcomes. Based on the model described in Figure E-4 
and similar to the analyses for H2 (see above), we will use 
structural equation modeling to determine whether improvements 
in pain outcomes are due to improvements in OUD outcomes. 
For example, when the dependent variable is pain intensity, we 
will calculate the standardized total effect from the intervention 
(BUP microdosing) to pain reduction at 3 months, as well as the 
standardized mediational (i.e., indirect) effect of BUP uptake, 
BUP retention, and illicit opioid use. For these analyses, our 
primary mediator is BUP retention. We will use both the EMA 
data (5 random reports per day) and data from in-person visits at baseline, 1 week, 1 and 3 months. 
     Sex as a biological variable. For Aims 1 and 2, we will examine sex as a biological variable by conducting 
stratified analyses by sex. In addition, we will conduct exploratory analyses to test whether there is a two-way 
interaction between OUD and pain outcomes and sex. 
Exploratory analysis: E1: During induction, opioid withdrawal and pain will be lower in the microdosing (vs. 
TAU) arm. We will use EMA data (5 random reports per day: within-individuals, repeated data) to examine if 
those in the microdosing arm report less opioid withdrawal and pain. Multilevel models will be used where 
random reports that record changes in opioid withdrawal and pain are assessed within individuals (level 1), and 
study arm is assessed between individuals (level 2). For example, study arm (level 2: microdosing vs. TAU) will 
be regressed onto opioid withdrawal (level 1). A significant coefficient for study arm indicates significant 
differences in overall levels of opioid withdrawal across study arms. We will also describe daily changes (linear 
or curvilinear) in opioid withdrawal and pain over time by including time (days since the beginning of induction) 
in the models above. Subsequently, a treatment x time interaction term will be included in models to examine if 
the trajectory (rates of changes over time) of opioid withdrawal and pain differ across study arms. Separate 
models will examine opioid withdrawal and pain, and separate models will examine induction (weeks 1, 2) and 
follow-up (1, 2, 3 months).
E2: Increases in pain intensity will be associated with illicit opioid use in follow-up. We will use EMA data (5 
random reports per day: the within-individuals, repeated data) to examine whether increases in pain are 
associated with illicit opioid use during the follow-up period (three 1-week bursts). We will use multilevel 
models to prospectively examine whether pain level at time 1 (T1) predicts illicit self-reported opioid use 
between T1 & T2, controlling for the previous pain level (T0), age, sex, and use of other pain treatments. In 
addition, we will include a pain x BUP initiation interaction term to test whether the relationships between pain 
and subsequent illicit opioid use differ across participants who do and do not initiate BUP treatment. 
D.2.12 Power and Sample Size: We will power the study based on the primary outcome of BUP uptake. 
We plan to enroll 135 participants in each arm. While published case studies report high levels of success with 
microdosing (nearly 100%), we will use a more conservative estimate of 
treatment uptake from our experience with microdosing (61%). In a 
controlled trial of standard induction to transition patients with CP from full 
opioid agonists to BUP, only 24% were successful with BUP uptake.58 To 
detect a difference of this size in BUP uptake, we would only need 27 
participants in each arm to assure 80% power. However, we will recruit a 
larger sample to account for the possibility that uptake will be greater than 
24% in the TAU arm (see Table E-5). Even with study attrition, we will be 
able to assess BUP uptake for all participants based on medical record extraction,  
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     For pain outcomes, we based our 
power calculations on expected 
changes in pain intensity from baseline 
to 3 months. Our pilot data (see D.1.1) 
suggests that mean (SD) pain intensity 
score will be 7.3 (±1.6) at baseline for 
all participants. With a sample of 270 
participants (135 per arm), the 
minimum effect size (Cohen’s d) that 
can be detected with power of 80% is 
0.34. This effect size corresponds to a 
difference between arms (microdosing 
vs. TAU) of 8.4% for participants’ 
reduction in pain scores (assuming that the SD of change is 1.8). Note that the SD for the pain score change is 
greater than that of the pain intensity score at each time point due to the intra-participant correlation in pain 
intensity over time. Because pain reduction is only considered for participants with BUP uptake, attrition is 
already incorporated into these estimates.   
D.3 Aim 3a) Examine factors influencing reach, adoption, implementation, and maintenance of the 
microdosing protocol. 
      D.3.1 Overview and hypotheses. In this hybrid type 1 effectiveness-implementation trial, we will use RE-
AIM and CFIR frameworks to guide Aim 3a, in which we will use qualitative and quantitative methods to 
describe multi-level factors influencing reach, adoption, implementation, and maintenance of BUP microdosing. 
D.3.2 RE-AIM and CFIR frameworks. The RE-AIM framework allows us to quantify implementation 
processes of Reach, Effectiveness, Adoption, Implementation, and Maintenance. We will determine how 
completely hospitals can deliver microdosing and whether protocols are continued at study sites 3 months after 
completing the RCT. Because RE-AIM may be less well-suited to explore how broader factors influence 
implementation, we will also apply the CFIR framework, which is comprehensive, widely used in substance use 
research, and explains how environmental context shapes implementation.132,133 CFIR’s 5 domains include: 
interventions, outer setting, inner setting, individuals involved, and process. RE-AIM will be used to construct 
quantifiable measures; complementary qualitative methods guided by CFIR will be applied to understand the 
factors that influence these measures. Both frameworks will allow us to better disseminate the BUP 
microdosing protocol, which will allow for greater transparency, reproducibility, and scientific contribution. 
D.3.3 Quantitative methods. Using RE-AIM, we will first define reach, adoption, implementation, and 
maintenance measures (Table E-6) derived from program logs and EHR data. The primary implementation 
measure will be the % of participants in each arm who complete induction (defined as receiving ≥ 1 BUP dose 
on induction day). Quantitative implementation benchmarks: We anticipate that 14% of screened patients with 
CP and OUD will enroll in the RCT,18 that > 95% of enrolled participants will be assessed for BUP induction, 
and that >70% of participants who initiate BUP will be linked to outpatient BUP treatment.18 If we are unable to 
meet these benchmarks annually, then we will retrain study coordinators and clinical staff in recruitment, 
pharmacy, and referral procedures.
D.3.4 Qualitative data collection: Dr. Hayes (early-stage investigator) or an RA will conduct 45-60 minute 
semi-structured interviews with participants and hospital providers. We will sample 20-30 participants in the 
microdosing arm, including those who do and do not initiate BUP. Participant interviews will occur after BUP 
induction. We will also interview 10 hospital providers who care for study participants. After completing 
interviews, if new themes continue to emerge, we will randomly select additional participants until thematic 
saturation is achieved. Patient interviews: We will develop a semi-structured interview guide with input from 
people with lived experience that asks open-ended questions about patients’ experiences with induction, 
particularly acceptability and reasons for BUP initiation or lack of initiation, and whether BUP helps with pain. 
Provider interviews will elicit information about factors associated with achieving RE-AIM outcomes (reach, 
effectiveness, adoption, implementation, and maintenance). The interview guide will be informed by CFIR 
domains regarding implementation of induction and referral procedures at the hospitals. Using the 5 CFIR 
domains, we will probe how various factors enable or hinder implementing the microdosing protocol. This 
includes ease of initiating BUP (e.g., feasibility), inner organization (e.g., fit and acceptability within hospitals), 
outer setting (e.g., social factors influencing clinical practice), perceptions of individuals involved (e.g., BUP 
Table E-6: Aim 3a Implementation Measures
Construct
Quantitative Measures
Qualitative Assessment
Reach
# and % of pts with CP and OUD screened
# and % of pts with CP and OUD enrolled
# and % of pts with CP and OUD ineligible
Rates of enrollment at each hospital
Log of verbatim reasons 
patients stated for declining 
enrollment
Adoption
# and % of participants assessed for induction
# and % of participant completing induction
# and % of participants referred for outpatient 
BUP treatment
# and % of participants linked to outpatient 
BUP treatment
Interviews with participants 
about their experience, 
including barriers and 
facilitators to treatment 
initiation and linkage
Implementation # and % of participants who receive ≥1 dose of 
BUP within assigned induction protocol 
Intervention fidelity check-list
Interviews with providers 
about barriers and facilitators 
to implementation
Maintenance
# of hospitals (of 3) conducting microdosing 
3m after grant
Interviews with providers 
about current practices 
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perceived benefits), and implementation processes (e.g., protocol adaptation). Questions will identify barriers, 
such as provider stigma about OUD, and facilitators, such as leadership endorsement of protocols.
     D.3.5 Analytic Plan: Interviews will be audio-recorded, digitally stored on an encrypted password protected 
computer, and professionally transcribed without participant identifiers. We will use thematic analysis to identify 
key themes relating to BUP initiation and implementation. Initial review of data: In an iterative process, Dr. 
Hayes and team will read all interview transcripts and record concepts that emerge upon repeated readings. 
Developing a coding scheme: The coding scheme will be based on the interview data and the goals of this 
project. The codebook will be discussed and agreed upon by the entire research team. Any necessary 
changes will be made by consensus. Coding: Using the codebook, two research team members will code data 
independently. The research team will meet, discuss codes, and, if there are any inconsistencies, will come to 
a consensus agreement as to application of codes for each transcript. Using Dedoose software (SocioCultural 
Research Consultants, Los Angeles CA), codes will be applied to the dataset and data will be organized by 
code. Sorting: After data are sorted and main themes are identified, the research team will meet again to 
ensure that all concepts are properly represented and that thematic saturation has occurred. Member-
checking: Identified themes will be presented to study participants to elicit interpretation and additional insight. 
D.4 Aim 3b: To calculate costs and examine cost-effectiveness of the BUP microdosing protocol 
H5: Compared with TAU, microdosing will be cost-effective from a societal and a health sector perspective. 
Following recommendations of the Second Panel on Cost-effectiveness in Health and Medicine,134 we will take 
two reference case perspectives: a health care sector perspective and a societal perspective, over a 6-month 
time horizon. We will use quality-adjusted life years (QALYs), a key indicator for patient wellbeing, as the 
effectiveness measure.134 Health Related Quality of Life (HRQoL) at discrete time points will be measured 
using a utility score resulting from the PROMIS-Preference (PROPr) system.123 
D.4.1 Measures:  Health-related quality of life (HRQoL) will be measured with the Patient-Reported 
Outcomes Measurement Information System (PROMIS).135,136 The PROMIS-Preference (PROPr) scoring 
system uses the respondent’s scores for each of 7 PROMIS domains to calculate a health utility index value 
that represents the general US population’s preference for the respondent’s current health state: Cognitive 
Function–Abilities, Depression, Fatigue, Pain Interference, Physical Function, Sleep Disturbance, and Ability to 
Participate in Social Roles and Activities.122,137 Construct validity for PROPr has been demonstrated using the 
EQ-5D-5L, the HUI, and two large datasets from the general US population.124 The health-utility value is then 
used to calculate QALYs, as investigators from CHERISH, and many others have done in similar studies.138-142
Measures of employment status, work hours and hourly wage rates: At baseline, 1,3, and 6-months, we will 
collect data on employment status, and if employed, number of hours typically worked in a week and hourly   
wage rates, by adapting instruments developed and tested by CHERISH researchers in previous OUD studies. 
  Measures of criminal activities: At baseline, 1,3, and 6-months, we will collect data on criminal activities (in 
the past 3 months) in order to assess related societal costs, including criminal justice system-related costs 
(policing, prosecution, incarceration, etc.) and tangible and intangible costs to the victims. We will collect self-
reported data on crimes committed for each major type of crime frequently reported by people with OUD.143  
  Measures of health care utilization outside the intervention: At baseline, 1,3, and 6-month health care 
utilization outside the intervention (including inpatient, outpatient, emergency services, and medications) during 
the past 3 months will be self-reported using a Non-Study Resources Form customized for this study. Use of 
non-medical resources (e.g., travel time to medical care) will also be self-reported and collected. 
     Table E-7 outlines the cost categories we will take into account when assessing incremental costs in each 
of the two reference case perspectives. We excluded cost categories not relevant to the timeframe of this study 
(e.g., impact on educational achievements). Because buprenorphine microdosing will occur during the index 
hospitalization only, we will not consider costs of patient time attending the intervention. The research team will 
have access to health insurance claims data for 40-50% of patients to be enrolled because their health plans 
make claims available to Montefiore for care management and research. For health care service costs, in 
addition to patient self-reports using validated questionnaires (see above) we will conduct a secondary analysis 
with these patients using the claims data, which are not subject to recall biases and not prone to missing data.   
Table E-7. Cost components for the two reference case perspectives
Cost Category
Health Care
Societal 
Source(s) of Data
Unit Cost/Monetary Conversion Factor
Costs of intervention 
delivery
Yes
Yes
Medical records, micro-induction-
protocol, and length of stay in hospital for 
the index hospitalization
Cost per night of hospital stay
Costs of other health 
care services 
Yes
Yes
Non-Study Resources Form (see D.4.1)
Various sources144 (e.g., Medicare/ Medicaid 
data, Kaiser Family Foundation)
Productivity – labor 
market earnings
No
Yes
Self-reports (see D.4.1)
Hourly wage rates reported at research 
interviews
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Criminal Justice 
involvement
No
Yes
Criminal Activities Form (see D.4.1)
Unit societal cost estimates for various types of 
crime145
      For each reference case perspective, to estimate the incremental HRQoL and costs associated with the 
intervention – BUP microdosing vs. TAU – we will use intent-to-treat design and estimate a mixed Generalized 
Linear Model of the HRQoL/costs at the patient-level and at each assessment point as a function of patient 
assignment to microdosing (vs TAU), site fixed effects, and patient characteristics bearing implications for the 
outcomes but possibly not balanced at baseline, with random effects at patient and site levels.146 The method 
of recycled predictions will be used to obtain predicted mean values for HRQoL and each cost category, by 
study arm. QALYs gained will be estimated using the area under the curve methodology.147-149  Predicted costs 
from different cost categories will be summed and tested according to relevant perspectives.149 We will derive 
predicted incremental costs for intervention vs TAU for each individual patient based on the estimated models. 
  Cost-effectiveness analysis (CEA) will estimate an incremental cost-effectiveness ratio (ICER) associated 
with BUP microdosing vs. TAU. The ICER will be calculated by dividing (mean) incremental cost associated 
with microdosing vs TAU by (mean) incremental effectiveness. Sampling uncertainty in the estimated ICER will 
be taken into account by bootstrapping the study sample of the individual-level incremental cost and 
incremental effectiveness estimates and deriving non-parametric confidence intervals. We will further construct 
ICER acceptability curves for both reference case perspectives.  Acceptability curves display the probability 
that an ICER would fall below a given willingness to pay for an incremental unit of the desired outcome and 
thus be considered a good value (that is, cost-effective).150,151          
D.5 Design considerations and limitations:
     Limitations: This study is designed as a pragmatic clinical trial to maximize generalizability. We will not be 
able to compare BUP vs. full opioid agonists regarding pain control; however, it would be unethical to prescribe 
opioid analgesics to participants with OUD. It is possible that some participants may receive prescription 
opioids from other prescribers,152 and we will be able to determine medications prescribed using the EHR. If a 
participant transfers care to an out-of-state facility, or receives treatment with BUP or methadone at a program 
that directly dispenses medication, this information will not be available in our EHR. Nonetheless, participants 
will self-report whether they received medication from outside facilities.
     Consideration of other approaches: Why not integrate additional pain-focused interventions? We 
hypothesize that pain relief will stem from BUP. This study complements two others proposed in IMPOWR-ME. 
One proposed study will integrate Acceptance and Commitment Therapy and electronic care coordination into 
outpatient BUP treatment to improve pain outcomes. The other will study integration of yoga and physical 
therapy into outpatient opioid treatment programs. Together these studies will improve care for patients with 
CP and opioid misuse or OUD along a spectrum by evaluating strategies for initiating BUP treatment and then 
integrating OUD treatment and behavioral and physical interventions in two different outpatient settings.  
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