Medication for OUD (MOUD) is a first-line treatment for OUD and improves outcomes in
mortality, retention in treatment, and non-prescribed opioid use. Buprenorphine/naloxone
is the only MOUD of the three FDA-approved medications for OUD available in the
telehealth setting, as methadone and injectable naltrexone must be managed in an
in-person setting. Buprenorphine/naloxone, also referred to as brand name Suboxone, is
administered by placing a film strip under the tongue. Buprenorphine acts as a partial
agonist with a high binding affinity at the mu-opioid receptor; clearance of the pure
opioid agonist must occur before a full dose of buprenorphine is administered, as
buprenorphine will displace opioid agonists with lower binding affinity at the receptor
and cause rapid-onset "precipitated withdrawal." During traditional induction, patients
must abstain from opioids prior to starting buprenorphine/naloxone and thus endure
mild-to-moderate opioid withdrawal before initiating buprenorphine (to avoid precipitated
withdrawal). Barriers to traditional induction include the required withdrawal period,
fear of precipitated withdrawal (particularly with increased fentanyl in the opioid
supply, which is lipophilic and thus remains in the body longer after last use), and an
intolerable withdrawal period (which increases the risk of a patient leaving treatment to
return to non-prescribed opioid use). In addition, there are patients who are not ready
to stop their opioid but are ready to start treatment.
First described in the literature as the Bernese Method in 2016, microdosing induction
was developed to overcome these barriers. Microdosing induction requires the
administration of small but escalating doses of buprenorphine/naloxone over a period of
several days to weeks, such that the buprenorphine slowly overcomes the effect of the
opioid agonist at the receptor. This technique does not require a period of withdrawal
prior to starting treatment. Various microdosing induction protocols have been described
primarily in inpatient settings in case reports, case series, and literature reviews. No
published research studies exist that systematically evaluate the effectiveness and
safety of microdosing induction, particularly in a telehealth setting.
Using a quasi-experimental design for evaluating MOUD induction strategies in a
telehealth setting, the investigators will estimate the effect of microdosing induction
on patient completion of successful induction with mild withdrawal, adjusted maximum
withdrawal score, and adverse events. The investigators hypothesize that microdosing
induction patients will have higher odds of completing a successful induction with mild
withdrawal, lower maximum withdrawal scores, and a similar number of adverse events
compared to traditional induction patients.
Study Details:
The proposed study will follow a quasi-experimental design with a comparison group to
evaluate the effectiveness and safety of microdosing induction versus traditional
induction of buprenorphine/naloxone in telehealth patients at Bicycle Health. Bicycle
Health is a digital health company that provides biopsychosocial treatment of OUD via
telehealth. With guidance from the research team, participating medical providers at
Bicycle Health will recruit patients at intake who meet eligibility criteria (see
Participant Population section below). Based on sample size calculations under different
scenarios, and feasibility given current intake rates at Bicycle Health, the study will
enroll at least 85 patients in the microdosing induction group, and at least 85 patients
in the comparison group.
The study period will take place during the induction period of treatment. All enrolled
patients will undergo assessment by a participating provider through a visit at days one,
four, seven, and ten, which will include a modified-clinical opiate withdrawal scale
(M-COWS) and a clinical interview. Day one for microdosing induction patients will be the
first day they begin taking buprenorphine/naloxone. Day one for the traditional induction
study arm will be the first day without opioids. Surveys will be completed by the
providers during each visit. The patient will also undergo daily self-assessments for 10
days, which will include subjective opiate withdrawal scale (SOWS), presence of cravings,
self-reported continued opioid use, and patient satisfaction.
After the induction period, two urine drug screens will be conducted to monitor opioid
use in early treatment. Patients at Bicycle Health receive four urine drug screen cups
and four fentanyl dip cards in the mail about 1 week after their first appointment. The
first urine drug screen is expected to be completed when it is delivered to the patient's
residence, and it will primarily be used to ensure patients are taking buprenorphine. The
second urine drug screen is expected to be completed between 14-21 days after the first
test is completed. This urine drug screening will be used to collect objective data on
opioid use after initiation of buprenorphine. Retention in treatment will be measured at
day 10 and day 30.
Primary outcomes assess effectiveness and safety:
Completion of induction with no/mild withdrawal: receiving ≥ 8 mg of
buprenorphine/naloxone with no concurrent self-reported use of opioids by the end of
induction and M-COWS score remains in mild withdrawal range defined as ≤ 12 points
throughout induction
Maximum M-COWS score minus baseline M-COWS
Average and median M-COWS scores at day 1,4,7,10
Average and median SOWS scores ≤12 daily
All adverse events, defined as:
An untoward medical occurrence as a study participant that was administered a study
intervention, which does not necessarily have a causal relationship with this
intervention
An untoward medical occurrence meeting one of the following criteria at any dose -
results in death, is life-threatening, requires inpatient hospitalization, results
in persistent or significant disability or incapacity
Secondary outcomes include:
Treatment retention: defined as patient attendance at visit with a participating
provider on day 10 (+5) and day 30 (+7)
Self-reported return to opioid use after induction
Opioid appearance in drug screens
Self-reported cravings
Patient satisfaction
The investigators will use a multilevel logistic regression model to estimate the odds of
completing a successful induction with mild withdrawal. The investigators will use a
multilevel cox proportional hazards regression model for retention analysis. All models
will adjust for covariates. Covariates may include age, sex, payment method, baseline
M-COWS score. Additional covariates collected through patient intake form will be
considered, including history of unsuccessful induction, history of precipitated
withdrawal, and history of experience with buprenorphine. A difference-in-difference
analysis using multilevel linear regression will be used to assess maximum M-COWS score
minus baseline M-COWS score. Covariates will be adjusted for in the model. Covariates may
include age, sex, payment method, baseline M-COWS score, history of unsuccessful
induction, history of precipitated withdrawal, and history of experience with
buprenorphine. Average and median M-COWS and SOWS will be calculated at each data
collection timepoint. Adverse events will be reported as a percentage of enrolled
patients who experienced an adverse event. For secondary outcomes, level of
craving/withdrawal symptoms and patient satisfaction, the investigators will calculate
the mean and median scores for outcomes at each measurement time point.