Keywords
opioid use disorder pregnancy - buprenorphine pregnancy - buprenorphine microdosing
pregnancy - microdosing buprenorphine
For pregnant persons, medications for opioid use disorder (MOUD) are the recommended
therapy and have been shown to improve pregnancy outcomes and save lives. Buprenorphine
is a partial agonist at the µ opioid receptor with high-binding affinity and slow
dissociation from the receptor. The partial agonist effect has significant safety
benefits when compared with full agonist opioids such as methadone. Buprenorphine
products are unlikely to cause respiratory arrest unless combined with other central
nervous system depressants.
Because buprenorphine has a higher binding affinity for the µ receptor than full agonist
opioids, immediately starting buprenorphine in a patient taking a full agonist will
abruptly displace the full agonist from the µ receptor, leading to precipitated withdrawal.
To avoid precipitated withdrawal during conventional buprenorphine inductions, patients
abstain from full agonist opioids until they experience mild-to-moderate opioid withdrawal.
This is a case presentation of a successful buprenorphine induction of a pregnant
patient on methadone maintenance, who desired induction onto buprenorphine to minimize
the risk of neonatal opioid withdrawal syndrome (NOWS), which severely affected her
prior child. Written consent to publish a report of the case has been obtained by
the patient.
Case Presentation
The patient is a 29-year-old G2P1001 at 18 2/7 weeks of gestation, who desired a switch
from methadone to buprenorphine to minimize NOWS in this pregnancy. The patient had
a history of IV drug use from 17 to 25 years of age. This pregnancy was complicated
by hepatitis C infection, a history of anxiety and depression, and tobacco use. Her
medications included a daily Prenatal vitamin (PNV) and methadone 68 mg daily. Her
prior pregnancy was 3 years earlier, a normal spontaneous vaginal delivery at 37 6/7
weeks of gestation of a female infant weighing 7 pounds 8 ounces, complicated by severe
NOWS with a prolonged hospitalization.
She was counseled that buprenorphine maintenance can also be associated with NOWS,
and that changes in neonatal treatment incorporating “eat, sleep, console” allow successful
newborn transition and significantly decrease the experience of neonatal withdrawal
symptoms and need for opioid medication.[1] She was also counseled regarding smoking cessation as a means to decrease the risk
of NOWS.[2] Despite these recommendations, the patient slowly weaned herself from 68 mg of methadone,
down to 30 mg daily, a decrease of 2 mg every other day. The methadone clinic instructed
her to abstain from methadone for at least 48 hours, until she experienced moderate
withdrawal symptoms before initiating the traditional buprenorphine induction.
The patient was counseled extensively regarding the possible risks and benefits of
microdosing. She desired to proceed with microdosing instead of the traditional buprenorphine
induction. The Prescription Monitoring Program was checked and the patient had no
other prescriptions for opiates recorded.
She continued to take her daily dose of methadone 30 mg, while increasing her daily
dose of buprenorphine according to the protocol used by Terasaki et al.[3] ([Table 1]).
Table 1
Buprenorphine microdosing protocol
|
Day
|
Buprenorphine dosage
|
Methadone dose
|
|
1
|
0.5 mg[a] SL once/day
|
Full dose
|
|
2
|
0.5 mg SL twice/day
|
Full dose
|
|
3
|
1 mg SL twice/day
|
Full dose
|
|
4
|
2 mg SL twice/day
|
Full dose
|
|
5
|
4 mg SL twice/day
|
Full dose
|
|
6
|
8 mg SL once/day
|
Full dose
|
|
7
|
8 mg SL in am, and 4 mg SL in pm
|
Full dose
|
|
8
|
12 mg SL/day
|
Stop
|
Abbreviation: SL, sublingually.
a For our buprenorphine formulation, one-quarter of a 2 mg sublingual strip/film was
used.
The patient did well during the week of buprenorphine microdosing, with no complaints
of withdrawal or cravings. She continued to be engaged in her prenatal care. She had
a normal fetal anatomy scan. Her dose of buprenorphine was increased to 8 mg twice
daily in the third trimester for some withdrawal symptoms in the evening consisting
of the new onset of nausea and vomiting. She had a normal follow-up growth ultrasound
at 32 weeks. She was down to 2 cigarettes a day.
The patient underwent an induction of labor at 39 weeks and had a spontaneous vaginal
delivery of a 3,340 gram male infant. Apgar scores were 8 and 9 after 1 and 5 minutes,
respectively. The cord blood toxicology screen was positive for tetrahydrocannabinol
(THC). The neonatal urine toxicology screen was positive for THC and buprenorphine.
The Finnegan Neonatal Abstinence Score peaked at 5 days of life. Only nonpharmacologic
interventions were used. He did not require any opioids for treatment. The patient
continued her daily dose of buprenorphine intrapartum and postpartum. Her pain was
adequately controlled with nonsteroidal anti-inflammatory drugs and Tylenol. She was
referred to gastrointestinal postpartum for treatment of hepatitis C.
Discussion
Provisional data from Centers for Disease Control and Prevention National Center for
Health Statistics indicate that there were an estimated 100,306 drug overdose deaths
in the United States during the 12-month period ending in April 2021, with 75,673
due to opioids.[4] Overdose deaths from synthetic opioids, primarily fentanyl, also increased during
that same time period. Opioid use in pregnancy has escalated dramatically, paralleling
the epidemic observed in the general population.
The increase in synthetic opioids such as fentanyl in the illicit drug market has
further complicated buprenorphine inductions.[5] Although fentanyl has a rapid onset and short duration of action, it is lipophilic,
resulting in distribution to the peripheral tissues in a manner that is not dose dependent.
Consequently, continuous and prolonged use of fentanyl can result in increased volume
of distribution systemically with slow dissipation overall. Correspondingly, there
appears to be an increased incidence of precipitated withdrawal during the induction
process of buprenorphine with fentanyl use. This occurs despite patients objectively
being in moderate-to-severe opioid withdrawal before starting the medication. This
is a barrier to treatment for both patients and providers and has been associated
with dissatisfaction and noncompliance.
Precipitated withdrawal occurs when there is a net decrease in opioid effect. Buprenorphine
is a partial opioid agonist that has a high affinity for the µ-receptor, but less
intrinsic opioid effect than a pure opioid agonist such as methadone or fentanyl.
When buprenorphine is given to a patient with an opioid agonist on board, the partial
agonist, buprenorphine, displaces the full agonist from the µ-receptor, and since
it activates the receptor to a lesser degree than a full-agonist, this results in
a net decrease in agonist effect, thereby precipitating withdrawal.[6]
Buprenorphine microdosing using the Bernese method, was first described by Hämmig
et al in 2016[7] and involved repetitive, low-dose exposure to buprenorphine over several days, such
that partial and full opioid agonists can be continued concurrently without precipitated
withdrawal. Buprenorphine induction using microdosing can improve the care of patients
with OUD by minimizing opioid withdrawal symptoms, reducing the dropout rate during
induction, and decreasing the fear of withdrawal. It can safely be performed in the
outpatient setting.[8]
MOUD is an approach to opioid use treatment that combines the use of U.S. Food and
Drug Administration-approved drugs with counseling and behavioral therapies for people
diagnosed with opioid use disorder (OUD). Both methadone and buprenorphine are medications
used to treat OUD. It is generally recommended that if a pregnant person is already
receiving therapy with methadone, she should not transition to buprenorphine because
of the significant risk of precipitated withdrawal and destabilization. Staying on
maintenance therapy has been shown to improve outcomes and saves lives.[9] Shared decision making and patient-centered care were instrumental in supporting
this patient's decision to switch from methadone to buprenorphine. This allowed her
to maintain MOUD throughout pregnancy and reduce her risk of relapse and overdose.
Buprenorphine acts on the same µ-opioid receptors as heroin and morphine, but functions
as a partial rather than full agonist, making overdose less likely. Other advantages
of buprenorphine over methadone include fewer drug interactions, the ability to be
treated on an outpatient basis without the need for daily visits to an opioid treatment
program, and evidence of less need for dosage adjustments throughout pregnancy. Lastly,
several trials demonstrate evidence of less-severe NOWS.[10] Decreasing her nicotine use may have also contributed to a more favorable neonatal
outcome.[2]
The patient slowly weaned herself down to a methadone dose of 30 mg in anticipation
of a traditional buprenorphine induction where patients are requested to abstain from
opiates until they are in mild-to-moderate withdrawal. However, higher doses of methadone
such as 100 mg have been successfully transitioned to buprenorphine using a microdosing
protocol.[11]
A growing body of literature supports microdosing of buprenorphine in nonpregnant
persons.[2]
[4]
[5] Pregnancy is a window of opportunity to provide MOUD to persons with an opioid use
disorder.[6] Given the safety profile of buprenorphine, its potential to be a lifesaving intervention,
and the avoidance of withdrawal symptoms, a study of microdosing in pregnancy is indicated.
