<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03024736</url>
  </required_header>
  <id_info>
    <org_study_id>26451</org_study_id>
    <nct_id>NCT03024736</nct_id>
  </id_info>
  <brief_title>Neonatal and Maternal Effects of Buprenorphine and Methadone</brief_title>
  <official_title>Neonatal and Maternal Effects of Buprenorphine and Methadone in the Treatment of Opioid-Maintained Pregnant Women: A Retrospective Cohort Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>St. Louis University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>St. Louis University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      In this retrospective chart review, the investigators plan to analyze the effects of&#xD;
      buprenorphine compared to methadone in opioid-maintained pregnant women. The investigators&#xD;
      will evaluate both maternal and neonatal outcomes, with a primary outcome of infant hospital&#xD;
      length of stay. The investigators will evaluate patients receiving care in a single setting.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In 2012, 5.4% of pregnant women ages 15 to 44 reported using illicit drugs; however this is&#xD;
      lower compared to 11.4% in the non-pregnant population. Illicit drug use is highest in the&#xD;
      first trimester (9.0%) and continues to decline as the pregnancy progresses (4.8% 2nd&#xD;
      trimester and 2.4% 3rd trimester).&#xD;
&#xD;
      The opioid agents include heroin, codeine, fentanyl, hydrocodone, hydromorphone, meperidine,&#xD;
      morphine, methadone, and oxycodone. Patients will experience euphoria during intoxication&#xD;
      followed by withdrawal, both of which pose a threat to mother and fetus. During euphoria,&#xD;
      there is an increased risk of maternal respiratory depression and fetal growth restriction.&#xD;
      During withdrawal, tachycardia, hypertension, nausea, vomiting, and increased metabolic&#xD;
      demand can occur, which can cause negative outcomes for the fetus such as spontaneous&#xD;
      abortion, preterm labor, premature preterm rupture of membranes, intrauterine growth&#xD;
      restriction (IUGR) and intrauterine fetal demise (IUFD). Withdrawing is not ideal in&#xD;
      pregnancy due to risks to the baby and high risk of relapse in the mother. Heroin withdrawal&#xD;
      can occur within the first 24 hours of birth and usually peaks within 48 to 72 hours, but may&#xD;
      take up to 7 days for withdrawal to occur.&#xD;
&#xD;
      At birth, infants born to women using illicit drugs can also go through withdrawal,otherwise&#xD;
      known as neonatal abstinence syndrome (NAS). NAS is defined as the hyperactivity of the&#xD;
      central and autonomic nervous systems. Clinical presentation depends on duration of opioid&#xD;
      use, duration of use prior to delivery, maternal metabolism, and placental metabolism.&#xD;
      Symptoms of NAS manifest in the CNS and gastrointestinal (GI) tract. If the mother uses&#xD;
      nicotine, stimulants, sedatives, SSRIs, etc, this can also affect withdrawal, as all of these&#xD;
      agents cause fetal withdrawal as well. Clinicians in the United States primarily use the&#xD;
      modified Finnegan's Neonatal Abstinence scoring tool to assess for signs and symptoms and&#xD;
      severity of NAS. This tool evaluates 21 items in the areas of CNS disturbances, GI&#xD;
      disturbances, and metabolic/vasomotor/respiratory disturbances. Scores can range from 0 to 44&#xD;
      with a score &gt; 8 indicating need of pharmacologic treatment.5 Medication treatment is used to&#xD;
      relieve moderate to severe signs of NAS and to prevent complications and may include an&#xD;
      opioid, barbiturate, benzodiazepine, clonidine, or chlorpromazine. Methadone has been the&#xD;
      standard of treatment for opioid addiction during pregnancy since the 1970s. Methadone is a&#xD;
      full mu-agonist that can be used for analgesia or maintenance of opioid addiction. Methadone&#xD;
      is dispensed on a daily basis by a registered substance abuse treatment program and is&#xD;
      usually started at 10 to 30 mg/day. Methadone can cause serious adverse events such as&#xD;
      respiratory depression, QTc prolongation, hypotension, and sedation, with other adverse&#xD;
      events including lightheadedness, dizziness, nausea, vomiting, and diaphoresis. Infants&#xD;
      exposed to methadone usually experience withdrawal within the first 72 hours, but can occur&#xD;
      within the first two weeks and can last for several days to weeks. Recently there has been&#xD;
      increasing evidence for the use of buprenorphine in pregnancy due to the potential of less&#xD;
      neonatal abstinence syndrome (NAS). Buprenorphine is a partial mu agonist that is indicated&#xD;
      for the treatment of opioid dependence with typical doses of 2 to 24 mg. Infants exposed to&#xD;
      buprenorphine usually experience withdrawal within 12 to 48 hours, peaks between 72 and 96&#xD;
      hours, and resolves by 7 days.2 Like methadone, there are still risks of respiratory&#xD;
      depression, central nervous system (CNS) depression, and hypotension. There is a lower risk&#xD;
      of overdose, fewer drug interactions, and does not need to be dispensed daily at clinic,&#xD;
      making it a more favorable option over methadone. Buprenorphine does require additional&#xD;
      registration for providers to prescribe it, but can be filled at any pharmacy.&#xD;
&#xD;
      The PROMISE trial is a randomized, double-blind, double-dummy, parallel-group controlled&#xD;
      trial that was designed to compare methadone and buprenorphine for the treatment of&#xD;
      opioid-dependent pregnant patients. A total of 30 patients were enrolled who received&#xD;
      methadone or buprenorphine with dosing based on compliance, urine samples, and patient report&#xD;
      of withdrawal symptoms and cravings.&#xD;
&#xD;
      The primary outcomes analyzed were number of neonates requiring morphine for NAS, peak NAS&#xD;
      score, total amount of morphine given, and total days of neonatal hospital stay. There were&#xD;
      several secondary neonatal and maternal outcomes as well. Neonatal length of stay was the&#xD;
      only statistically significant outcome, with a difference of 1.3 days in favor of&#xD;
      buprenorphine (p= 0.021). There was no difference in adverse events amongst the two groups.&#xD;
      This trial was limited due to its small size, but supported the need for a larger trial.8&#xD;
&#xD;
      The MOTHER trial is a multi-center, randomized, double-blind, double-dummy trial that was&#xD;
      designed to compare methadone and buprenorphine for the treatment of opioid-dependent&#xD;
      pregnant patients. A total of 175 patients were enrolled and received methadone or&#xD;
      buprenorphine with dosing based on compliance, urine samples, and patient report of&#xD;
      withdrawal symptoms and cravings.&#xD;
&#xD;
      The primary outcomes analyzed were number of neonates requiring treatment for NAS, peak NAS&#xD;
      score, total amount of morphine needed for treatment of NAS, length of neonatal hospital&#xD;
      stay, and head circumference. There were several secondary neonatal and maternal outcomes&#xD;
      measured as well. The total amount of morphine needed and neonatal length of stay were&#xD;
      statistically significant. Neonates taking buprenorphine required 1.1 ± 0.7 mg morphine,&#xD;
      whereas the methadone group required 10.4 ±2.6 mg morphine (p = 0.0091). The buprenorphine&#xD;
      group had a shorter length of stay of 10.0 ± 1.2 days compared to 17.5 ± 1.5 days in the&#xD;
      methadone group (p = 0.0091). In regards to secondary outcomes, duration of treatment was&#xD;
      significant favoring buprenorphine (4.1 vs. 9.9 days, p = 0.003125). None of the secondary&#xD;
      maternal outcomes were statistically significant. The methadone group had a higher incidence&#xD;
      of non-serious maternal events and non-serious cardiovascular events. This trial supports&#xD;
      that buprenorphine is a safe and effective treatment for opioid dependence in pregnant women.&#xD;
&#xD;
      Based on the aforementioned studies, the investigators established a clinic which has been&#xD;
      prescribing buprenorphine for the treatment of opioid dependence for a small group of&#xD;
      patients. Patients who are opioid-dependent were evaluated to see if buprenorphine is the&#xD;
      best option for them. There is also a prescribing regulation in the first year that limits&#xD;
      the provider to prescribing buprenorphine to 30 patients. The remainder of patients has been&#xD;
      treated with methadone.&#xD;
&#xD;
      The clinic is multi-disciplinary, and the patients are seen by the maternal fetal medicine&#xD;
      specialist, a nurse practitioner, a pharmacist, the social services department, a nurse&#xD;
      coordinator, a neonatologist, a lactation nurse, the anesthesia department, and a dietician&#xD;
      throughout the pregnancy. Patients enrolled in the clinic must receive all of their obstetric&#xD;
      care through the clinic and should deliver within the same health system. Patients starting&#xD;
      buprenorphine are initiated in clinic if they are in the first or second trimesters, but&#xD;
      admitted for monitoring during buprenorphine induction if 24 weeks or further. After&#xD;
      buprenorphine induction, patients are seen weekly for 4 weeks, then every other week over 6&#xD;
      weeks, then every 4 weeks thereafter and as needed for traditional prenatal care needs.&#xD;
      Patients must also attend counseling and narcotics anonymous meetings. Once the patient&#xD;
      delivers, they are seen twice in the 6 weeks post-partum.&#xD;
&#xD;
      In this retrospective chart review, the investigators plan to analyze the effects of&#xD;
      buprenorphine compared to methadone in opioid-maintained pregnant women. The investigators&#xD;
      will evaluate both maternal and neonatal outcomes, with a primary outcome of infant hospital&#xD;
      length of stay.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 2015</start_date>
  <completion_date type="Actual">September 30, 2016</completion_date>
  <primary_completion_date type="Actual">September 30, 2016</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Retrospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>infant hospital length of stay</measure>
    <time_frame>1 year</time_frame>
    <description>The investigators will evaluate both maternal and neonatal outcomes, with a primary outcome of infant hospital length of stay.</description>
  </primary_outcome>
  <enrollment type="Actual">40</enrollment>
  <condition>Opioid-maintained Pregnant Women</condition>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>buprenorphin</intervention_name>
    <description>if buprenorphine has better neonatal outcomes compared to methadone in&#xD;
the treatment of opioid-maintained pregnant women</description>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Gender: Female ethnic background: all age 13-55yrs of age&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  patients on buprenorphine or methadone.&#xD;
&#xD;
          -  pregnant&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Not meeting inclusion criteria&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>13 Years</minimum_age>
    <maximum_age>55 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jaye Shyken, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>St. Louis University</affiliation>
  </overall_official>
  <verification_date>November 2017</verification_date>
  <study_first_submitted>January 16, 2017</study_first_submitted>
  <study_first_submitted_qc>January 18, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 19, 2017</study_first_posted>
  <last_update_submitted>November 17, 2017</last_update_submitted>
  <last_update_submitted_qc>November 17, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">November 21, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>St. Louis University</investigator_affiliation>
    <investigator_full_name>Jaye Shyken, MD</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03024736
org study id: 26451
nct id: NCT03024736
lead sponsor: 
has dmc: No
In this retrospective chart review, the investigators plan to analyze the effects of
      buprenorphine compared to methadone in opioid-maintained pregnant women. The investigators
      will evaluate both maternal and neonatal outcomes, with a primary outcome of infant hospital
      length of stay. The investigators will evaluate patients receiving care in a single setting.
In 2012, 5.4% of pregnant women ages 15 to 44 reported using illicit drugs; however this is
      lower compared to 11.4% in the non-pregnant population. Illicit drug use is highest in the
      first trimester (9.0%) and continues to decline as the pregnancy progresses (4.8% 2nd
      trimester and 2.4% 3rd trimester).

      The opioid agents include heroin, codeine, fentanyl, hydrocodone, hydromorphone, meperidine,
      morphine, methadone, and oxycodone. Patients will experience euphoria during intoxication
      followed by withdrawal, both of which pose a threat to mother and fetus. During euphoria,
      there is an increased risk of maternal respiratory depression and fetal growth restriction.
      During withdrawal, tachycardia, hypertension, nausea, vomiting, and increased metabolic
      demand can occur, which can cause negative outcomes for the fetus such as spontaneous
      abortion, preterm labor, premature preterm rupture of membranes, intrauterine growth
      restriction (IUGR) and intrauterine fetal demise (IUFD). Withdrawing is not ideal in
      pregnancy due to risks to the baby and high risk of relapse in the mother. Heroin withdrawal
      can occur within the first 24 hours of birth and usually peaks within 48 to 72 hours, but may
      take up to 7 days for withdrawal to occur.

      At birth, infants born to women using illicit drugs can also go through withdrawal,otherwise
      known as neonatal abstinence syndrome (NAS). NAS is defined as the hyperactivity of the
      central and autonomic nervous systems. Clinical presentation depends on duration of opioid
      use, duration of use prior to delivery, maternal metabolism, and placental metabolism.
      Symptoms of NAS manifest in the CNS and gastrointestinal (GI) tract. If the mother uses
      nicotine, stimulants, sedatives, SSRIs, etc, this can also affect withdrawal, as all of these
      agents cause fetal withdrawal as well. Clinicians in the United States primarily use the
      modified Finnegan's Neonatal Abstinence scoring tool to assess for signs and symptoms and
      severity of NAS. This tool evaluates 21 items in the areas of CNS disturbances, GI
      disturbances, and metabolic/vasomotor/respiratory disturbances. Scores can range from 0 to 44
      with a score > 8 indicating need of pharmacologic treatment.5 Medication treatment is used to
      relieve moderate to severe signs of NAS and to prevent complications and may include an
      opioid, barbiturate, benzodiazepine, clonidine, or chlorpromazine. Methadone has been the
      standard of treatment for opioid addiction during pregnancy since the 1970s. Methadone is a
      full mu-agonist that can be used for analgesia or maintenance of opioid addiction. Methadone
      is dispensed on a daily basis by a registered substance abuse treatment program and is
      usually started at 10 to 30 mg/day. Methadone can cause serious adverse events such as
      respiratory depression, QTc prolongation, hypotension, and sedation, with other adverse
      events including lightheadedness, dizziness, nausea, vomiting, and diaphoresis. Infants
      exposed to methadone usually experience withdrawal within the first 72 hours, but can occur
      within the first two weeks and can last for several days to weeks. Recently there has been
      increasing evidence for the use of buprenorphine in pregnancy due to the potential of less
      neonatal abstinence syndrome (NAS). Buprenorphine is a partial mu agonist that is indicated
      for the treatment of opioid dependence with typical doses of 2 to 24 mg. Infants exposed to
      buprenorphine usually experience withdrawal within 12 to 48 hours, peaks between 72 and 96
      hours, and resolves by 7 days.2 Like methadone, there are still risks of respiratory
      depression, central nervous system (CNS) depression, and hypotension. There is a lower risk
      of overdose, fewer drug interactions, and does not need to be dispensed daily at clinic,
      making it a more favorable option over methadone. Buprenorphine does require additional
      registration for providers to prescribe it, but can be filled at any pharmacy.

      The PROMISE trial is a randomized, double-blind, double-dummy, parallel-group controlled
      trial that was designed to compare methadone and buprenorphine for the treatment of
      opioid-dependent pregnant patients. A total of 30 patients were enrolled who received
      methadone or buprenorphine with dosing based on compliance, urine samples, and patient report
      of withdrawal symptoms and cravings.

      The primary outcomes analyzed were number of neonates requiring morphine for NAS, peak NAS
      score, total amount of morphine given, and total days of neonatal hospital stay. There were
      several secondary neonatal and maternal outcomes as well. Neonatal length of stay was the
      only statistically significant outcome, with a difference of 1.3 days in favor of
      buprenorphine (p= 0.021). There was no difference in adverse events amongst the two groups.
      This trial was limited due to its small size, but supported the need for a larger trial.8

      The MOTHER trial is a multi-center, randomized, double-blind, double-dummy trial that was
      designed to compare methadone and buprenorphine for the treatment of opioid-dependent
      pregnant patients. A total of 175 patients were enrolled and received methadone or
      buprenorphine with dosing based on compliance, urine samples, and patient report of
      withdrawal symptoms and cravings.

      The primary outcomes analyzed were number of neonates requiring treatment for NAS, peak NAS
      score, total amount of morphine needed for treatment of NAS, length of neonatal hospital
      stay, and head circumference. There were several secondary neonatal and maternal outcomes
      measured as well. The total amount of morphine needed and neonatal length of stay were
      statistically significant. Neonates taking buprenorphine required 1.1 ± 0.7 mg morphine,
      whereas the methadone group required 10.4 ±2.6 mg morphine (p = 0.0091). The buprenorphine
      group had a shorter length of stay of 10.0 ± 1.2 days compared to 17.5 ± 1.5 days in the
      methadone group (p = 0.0091). In regards to secondary outcomes, duration of treatment was
      significant favoring buprenorphine (4.1 vs. 9.9 days, p = 0.003125). None of the secondary
      maternal outcomes were statistically significant. The methadone group had a higher incidence
      of non-serious maternal events and non-serious cardiovascular events. This trial supports
      that buprenorphine is a safe and effective treatment for opioid dependence in pregnant women.

      Based on the aforementioned studies, the investigators established a clinic which has been
      prescribing buprenorphine for the treatment of opioid dependence for a small group of
      patients. Patients who are opioid-dependent were evaluated to see if buprenorphine is the
      best option for them. There is also a prescribing regulation in the first year that limits
      the provider to prescribing buprenorphine to 30 patients. The remainder of patients has been
      treated with methadone.

      The clinic is multi-disciplinary, and the patients are seen by the maternal fetal medicine
      specialist, a nurse practitioner, a pharmacist, the social services department, a nurse
      coordinator, a neonatologist, a lactation nurse, the anesthesia department, and a dietician
      throughout the pregnancy. Patients enrolled in the clinic must receive all of their obstetric
      care through the clinic and should deliver within the same health system. Patients starting
      buprenorphine are initiated in clinic if they are in the first or second trimesters, but
      admitted for monitoring during buprenorphine induction if 24 weeks or further. After
      buprenorphine induction, patients are seen weekly for 4 weeks, then every other week over 6
      weeks, then every 4 weeks thereafter and as needed for traditional prenatal care needs.
      Patients must also attend counseling and narcotics anonymous meetings. Once the patient
      delivers, they are seen twice in the 6 weeks post-partum.

      In this retrospective chart review, the investigators plan to analyze the effects of
      buprenorphine compared to methadone in opioid-maintained pregnant women. The investigators
      will evaluate both maternal and neonatal outcomes, with a primary outcome of infant hospital
      length of stay.
observational model: Cohort
time perspective: Retrospective
measure: infant hospital length of stay
time frame: 1 year
description: The investigators will evaluate both maternal and neonatal outcomes, with a primary outcome of infant hospital length of stay.
intervention type: Other
intervention name: buprenorphin
description: if buprenorphine has better neonatal outcomes compared to methadone in
the treatment of opioid-maintained pregnant women
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: Female
minimum age: 13 Years
maximum age: 55 Years
healthy volunteers: No
last name: Jaye Shyken, MD
role: Principal Investigator
affiliation: St. Louis University
responsible party type: Principal Investigator
investigator affiliation: St. Louis University
investigator full name: Jaye Shyken, MD
investigator title: Principal Investigator
sharing ipd: No