Pharmacologically-based Strategies for Buprenorphine Treatment During Pregnancy

Opioid use has reached a staggering level and the associated deaths, neonatal consequences
and economic impact are devastating. Pregnancy provides a window of opportunity for women
with an opioid use disorder (OUD) to seek assistance by participating in a program that
offers medication-assisted treatment (MAT), most commonly with buprenorphine (BUP) or
methadone. BUP offers advantages over methadone including ease of administration and less
severe neonatal abstinence syndrome (NAS) but has a higher discontinuation rate, especially
during induction. The high discontinuation rate may be due to an inadequate dosing as the
current dosing strategies are not informed by pharmacokinetic (PK) or pharmacodynamic (PD)
data in pregnancy. The lack of BUP PD data hampers development of an effective dosing
strategy and challenges the validity of the primary tools used to gauge maternal and infant
withdrawal. Neither the Clinical Opioid Withdrawal Scale (COWS) nor the Finnegan score for
the diagnosis of NAS considers the pharmacology of BUP and therefore may not provide a valid
representation of opioid withdrawal. BUP PD data are critically necessary to address these
issues and are also necessary to develop detoxification regimens. Creation of safe and
effective detoxification regimens requires a pharmacological basis and must be developed in
the context that the brain requires time to adjust to opioid induced changes. In this
proposal, investigators hypothesize that determination of BUP pharmacodynamics will improve
care for the pregnant opioid dependent mother and her baby and will fill the critical
knowledge gaps needed for safe and effective management of women with an OUD.

As part of the dose reduction clinical trial, investigators will compare dose reduction
strategies for BUP in pregnancy that are based on the pharmacodynamic and pharmacokinetic
characteristics of BUP. The dose reduction strategies that will be evaluated in this clinical
trial are part of a larger project including an observational study.

Specific Aim 1a:

Inclusion Criteria:

1. Singleton gestation between 14-35 weeks (pharmacokinetics of BUP are unchanged from
20-34 weeks)

2. On a stable BUP dose (for at least 2 weeks) through a MAT program.

3. Willingness to consent to the study and to experience mild, temporary withdrawal
symptoms

4. No poppy seed consumption in for the week prior to study

Exclusion Criteria:

1. Multifetal gestation, major fetal malformation

2. Neonates of uncertain viability

3. Current use of benzodiazepines, cocaine, heroin, or opioids other than BUP

4. Currently taking more than one mental health medication

5. Active moderately severe depression (PHQ-9 score ≥15 or suicidal ideation)

6. Clinical signs of intoxication or mental disorientation at time of study

7. Maternal disorders such as azotemia, elevated liver function tests (>2x normal limit),
cholestasis, uncontrolled hypertension, preeclampsia

Specific Aim 1b:

Inclusion Criteria:

1. Mother on BUP for at least 8 weeks prior to delivery.

2. Mother in a MAT program.

3. Infant with 5 minute Apgar scores >6.

4. No maternal cocaine, heroin, benzodiazepines, or opioids other than BUP in last 8
weeks of pregnancy, based on the urine drug screen results from the PRC

Exclusion Criteria:

1. Major fetal/neonatal malformation.

2. Delivery at non-study hospital.

3. Fetal growth restriction - BW < 10th percentile

4. Known fetal renal or hepatic disease that affects drug metabolism or elimination

5. Infant on ventilator support

6. Neonates of uncertain viability

Specific Aim 2:

Inclusion Criteria:

1. Singleton gestation

2. Mother on BUP through a MAT program for at least 8 weeks prior to delivery

3. Mother not currently on cocaine, heroin, benzodiazepines, or opioids other than BUP.

4. Willingness to consent to study requirements

5. Availability of prenatal records from Ob care provider and BUP dosing records

Exclusion Criteria:

1. Multifetal gestation

2. Major fetal malformation

3. Neonates of uncertain viability

4. No maternal cocaine, heroin, benzodiazepines, or opioids other than BUP in last 8
weeks of pregnancy, based urine drug screen results from the PRC

Specific Aim 3:

Inclusion Criteria:

1. On a stable BID, TID or QID dosing regimen of BUP for at least 2 weeks as part of an
established medication- assisted treatment (MAT) program.

2. Willingness to undergo supervised dose reduction

3. Subjects on TID or QID dosing, willingness to undergo randomization to either the
Magnitude or Interval group

4. Gestational age at initiation of dose reduction between 14-30 weeks

5. On a BUP dose between 6- 24 mg daily (lower doses will not provide sufficient data
points)

6. Willingness to have weekly urine samples tested for drugs of abuse and blood samples
tested for BUP+M concentrations

7. Willingness to attend weekly PRC clinic appointments and to have daily contact (phone
call, email, or text) and complete daily log of sleep quality, withdrawal symptoms and
symptoms of craving

8. Willingness to attend weekly psychosocial support meetings at Western Psychiatric
Institute and Clinic (WPIC) at the University of Pittsburgh.

Exclusion Criteria:

1. Current use of cocaine, heroin, benzodiazepines, or opioids other than BUP.

2. Depression requiring more than one mental health drug or active moderately severe
depression (PHQ-9 score ≥15 or suicidal ideation)

3. Current incarceration

4. Lack of a phone or transportation to and from clinic

5. Neonates of uncertain viability