<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/NCT01723722</url>
  </required_header>
  <id_info>
    <org_study_id>07-2-M-107</org_study_id>
    <nct_id>NCT01723722</nct_id>
  </id_info>
  <brief_title>Treatment of Neonatal Abstinence Syndrome</brief_title>
  <acronym>HOMENOW</acronym>
  <official_title>Treatment of Neonatal Abstinence Syndrome: Evaluation of Efficacy of Phenobarbital in Combination With Either Methadone or Diluted Deodorized Tincture of Opium as Stabilizing and Tapering Regiments</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Eastern Maine Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Eastern Maine Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study compares treatment of Neonatal Abstinence Syndrome (NAS) with two different drugs&#xD;
      for the difference in the length of treatment. This is a randomized, open-label comparison of&#xD;
      phenobarbital and methadone versus phenobarbital and diluted deodorized tincture of opium&#xD;
      (dDTO) where phenobarbital is the initial drug used to stabilize neonatal withdrawal.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      a.Procedures: NAS scoring is currently done on infants meeting the inclusion criteria [IDD&#xD;
      29:070]. NAS scores are initially done every 2 hours for 24 hours and then every 4 hours when&#xD;
      awake or before feeding for the duration of observation or treatment.&#xD;
&#xD;
      i. NAS scores may indicate more than withdrawal. Conditions such as colic, reflux, or&#xD;
      baseline irritability may influence the baseline scores. Decisions made based on the NAS&#xD;
      scores should take into account these factors and the baseline for the infant.&#xD;
&#xD;
      b.Emergence of symptom, dosing, and initiation of treatment: Withdrawal is defined as at&#xD;
      least 2 NAS scores &gt;8 or 1 NAS score &gt;12. Once withdrawal has emerged, the infant will be&#xD;
      given: i. Phenobarbital 20 to 30 mg/kg to load divided in up to 3 doses over 24 hours and&#xD;
      maintenance phenobarbital should be started at 2.5 mg/kg/dose administered Q 12h, 12 hours&#xD;
      after the loading dose is ended. NAS scoring is continued and if scores remain &lt;8 for a&#xD;
      minimum of 5 days after starting phenobarbital, the infant is eligible for discharge.&#xD;
&#xD;
      ii. If after phenobarbital treatment has been started, at least 2 NAS scores &gt;8 or 1 NAS&#xD;
      score &gt;12, then a phenobarbital level will be drawn and a mini-load calculated to reach a&#xD;
      level of 30 mg/dl. If withdrawal is not controlled or re-emerges after the mini-load dose,&#xD;
      the infant will be randomized to one of the two arms of the study - methadone or dDTO.&#xD;
&#xD;
      iii. Twins will be randomized together to the same arm. iv. Randomization will be stratified&#xD;
      into mothers on narcotic treatment &gt;3 months and those not in treatment or &lt;3 months.&#xD;
      Randomization will be done in blocks of 10 for each stratum.&#xD;
&#xD;
      v. For both drugs, the neonatal preparation will be used. vi. The following is a dosing guide&#xD;
      for methadone:&#xD;
&#xD;
        1. The neonatal concentration is 1 mg/ml of methadone. It is administered orally every 12&#xD;
           hours - standardized eventually to 0900 and 2100.&#xD;
&#xD;
        2. For the first 24 hours, doses will be prescribed every 6 hours for 4 doses, using a&#xD;
           sliding scale in response to the last NAS score:&#xD;
&#xD;
           NAS Score Methadone dose 8-11 0.05 mg/kg/dose 12-15 0.1 mg/kg/dose &gt;16 0.15 mg/kg/dose&#xD;
&#xD;
        3. Maximum loading dose of methadone will be 0.15 mg/kg/dose Q 6 hour&#xD;
&#xD;
        4. After the first 24 hours of treatment, the total methadone dose will be summed and that&#xD;
           dose divided into two doses, given 12 hours apart. Subsequently, PRN doses of 0.05&#xD;
           mg/kg/dose may be given every 6 hours for scores &gt;8 X 2 and added to the next 24 hour's&#xD;
           doses, divided every 12 hours, until NAS scores are consistently &lt;8 for 48 hours.&#xD;
&#xD;
        5. If at any point the maximum dose of methadone is reached and withdrawal is not&#xD;
           controlled, then in the opinion of two neonatologists the patient can be crossed-over to&#xD;
           the dDTO arm.&#xD;
&#xD;
      vii. The following is a dosing guide for dDTO:&#xD;
&#xD;
        1. The neonatal concentration is 1:24 dilution for a concentration of 0.4%, equivalent to&#xD;
           0.4 mg/ml of morphine. It is administered orally every 4 hours - standardized eventually&#xD;
           to 0400, 0800, 1200, 1600, 2000, 0000.&#xD;
&#xD;
        2. The starting dose is determined by using a sliding scale in response to the last NAS&#xD;
           score before starting:&#xD;
&#xD;
           NAS Score dDTO dose 8-11 0.1 mg/kg/day 12-15 0.15 mg/kg/day &gt;16 0.2 mg/kg/day&#xD;
&#xD;
           For next day, the maintenance dose will return to the previous dose and given in 6&#xD;
           divided doses given Q 4 hours.&#xD;
&#xD;
           iv. For either methadone or dDTO, dosing will be held at this level and weaning will be&#xD;
           resumed when the infant has NAS scores &lt;8 for 48 hours.&#xD;
&#xD;
           e. Holding of doses: Methadone or dDTO will be held for poor feeding, respiratory&#xD;
           depression, or somnolence at any time in the protocol.&#xD;
&#xD;
           f. Behavioral assessment: Behavioral assessment will be done by two methods. The first&#xD;
           by actigraphy and the second by NINS, both during the second week of weaning. The latter&#xD;
           will be done prior to a scheduled phenobarbital dose.&#xD;
&#xD;
           g. Formula: A 24 kcal/ounce formula should be fed initially using either standard&#xD;
           formula or by adding breast milk fortifier. During the weaning period, when weight gain&#xD;
           is &gt;30 grams/day for at least 2 days, formula will be changed to 20 kcal/ounce and&#xD;
           weight gain monitored. If not sustained, then formula should be changed back to 24&#xD;
           kcal/ounce.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>January 2007</start_date>
  <completion_date type="Actual">September 2009</completion_date>
  <primary_completion_date type="Actual">September 2009</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Length of Treatment With Opioid Medication</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>Up to 12 months</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">40</enrollment>
  <condition>Neonatal Abstinence Syndrome</condition>
  <arm_group>
    <arm_group_label>1 (Phenobarbital and Methadone)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>The following is a dosing guide for methadone:&#xD;
The neonatal concentration is 1 mg/ml of methadone. It is administered orally every 12 hours.&#xD;
For the first 24 hours, doses will be prescribed every 6 hours using a sliding scale in response to the last NAS score:&#xD;
NAS Score Methadone dose 8-11 0.05 mg/kg/dose 12-15 0.1 mg/kg/dose&#xD;
≥16 0.15 mg/kg/dose&#xD;
Maximum dose of methadone will be 0.15 mg/kg/dose.&#xD;
After the first 24 hours of treatment, the total methadone dose will be summed and that dose divided into two doses, given 12 hours apart. For the following 24 hours, additional doses may be given every 6 hours as needed and added to the next 24 hour's doses divided every 12 hours, until NAS scores are consistently &lt;8 for 48 hours.&#xD;
If at any pointthe maximum dose of methadone is reached and withdrawal is not controlled, then in the opinion of two neonatologists the patient can be crossed-over to the dDTO arm.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>2 (Phenobarbital and Diluted Deodorized Tincture of Opium)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>The following is a dosing guide for dDTO:&#xD;
The neonatal concentration is 1:24 dilution for a concentration of 0.4%, equivalent to 0.4 mg/ml of morphine. It is administered orally every 4 hours.&#xD;
The starting dose will be determined using a sliding scale in response to the last NAS score before starting.&#xD;
NAS Score Starting dDTO dose 8-11 0.4 mg/kg/day 12-15 0.6 mg/kg/day&#xD;
≥16 0.8 mg/kg/day&#xD;
The maximum dose of DTO will be 0.8 mg/kg/day.&#xD;
After the first 24 hours of treatment, if the NAS scores are still ≥8, the dose will be increased to the next level.&#xD;
If at any point the maximum dose of methadone is reached and withdrawal is not controlled, then in the opinion of two neonatologists the patient can be crossed-over to the methadone arm.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Methadone</intervention_name>
    <description>Concentration is 1mg/mL administered every 12 hours given on sliding scale in response to last NAS score.</description>
    <arm_group_label>1 (Phenobarbital and Methadone)</arm_group_label>
    <other_name>Dolophine</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Diluted Deodorized Tincture of Opium</intervention_name>
    <description>Concentration is 1:24 dilution for a concentration of 0.4%</description>
    <arm_group_label>2 (Phenobarbital and Diluted Deodorized Tincture of Opium)</arm_group_label>
    <other_name>Laudanum</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Evidence of opioid withdrawal clinically as defined by 2 NAS scores &gt;8 or 1 NAS score&#xD;
             &gt;12 over a 4 to 8 hour time period, AND&#xD;
&#xD;
          -  Gestation &gt;=35 weeks at entry defined by best obstetrical and physical exam criteria,&#xD;
             AND&#xD;
&#xD;
          -  Medically stable condition, other than in opioid withdrawal, in the opinion of the&#xD;
             attending neonatologist, AND EITHER,&#xD;
&#xD;
          -  Meconium or urine drug screen positive for opioids on mother or newborn, OR&#xD;
&#xD;
          -  Known maternal prescription of opioids for chronic pain management during at least the&#xD;
             last trimester of pregnancy, OR&#xD;
&#xD;
          -  Known maternal prescription of opioids for treatment of addiction, OR&#xD;
&#xD;
          -  Suspected or admitted abuse with opioid drugs&#xD;
&#xD;
          -  Infants of mothers with a medical or psychiatric diagnosis will not be excluded,&#xD;
             unless the maternal diagnosis precludes informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Gestation &lt;35 weeks at entry defined by best obstetrical and physical exam criteria.&#xD;
&#xD;
          -  Hypoglycemia, hypomagnesaemia, or hypocalcaemia until corrected.&#xD;
&#xD;
          -  Serious medical illness such as sepsis, pneumonia, hyperthyroidism, meningitis,&#xD;
             intracranial hemorrhage, perinatal depression, or respiratory failure requiring&#xD;
             admission to the NICU.&#xD;
&#xD;
          -  Evidence of major congenital anomalies or genetic syndromes that impact the neonatal&#xD;
             course.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Day</minimum_age>
    <maximum_age>6 Days</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mark S. Brown, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Eastern Maine Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Eastern Maine Medical Center</name>
      <address>
        <city>Bangor</city>
        <state>Maine</state>
        <zip>04401</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>November 2013</verification_date>
  <study_first_submitted>January 27, 2011</study_first_submitted>
  <study_first_submitted_qc>November 6, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 8, 2012</study_first_posted>
  <results_first_submitted>March 1, 2013</results_first_submitted>
  <results_first_submitted_qc>November 5, 2013</results_first_submitted_qc>
  <results_first_posted type="Estimate">November 27, 2013</results_first_posted>
  <last_update_submitted>November 5, 2013</last_update_submitted>
  <last_update_submitted_qc>November 5, 2013</last_update_submitted_qc>
  <last_update_posted type="Estimate">November 27, 2013</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Eastern Maine Medical Center</investigator_affiliation>
    <investigator_full_name>Mark S Brown, MD</investigator_full_name>
    <investigator_title>Chief of Pediatric Service, Neonatalogy</investigator_title>
  </responsible_party>
  <keyword>Neonatal Abstinence Syndrome</keyword>
  <keyword>Methadone</keyword>
  <keyword>Diluted Deodorized Tincture of Opium</keyword>
  <keyword>dDTO</keyword>
  <keyword>Phenobarbital</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neonatal Abstinence Syndrome</mesh_term>
    <mesh_term>Syndrome</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Methadone</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Recruitment period 11/15/2007 through 9/1/2009; location Eastern Maine Medical Center NICU</recruitment_details>
      <pre_assignment_details>Exclusion for other medical conditions causing withdrawal symptoms, gestation less than 35 weeks</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Methadone After Phenobarbital for Withdrawal</title>
          <description>for withdrawal reaching treatment threshold phenobarbital was first started and if a second drug was needed randomization was done after consent; this arm started methadone</description>
        </group>
        <group group_id="P2">
          <title>Deodorized Tincture Opium After Phenobarbital for Withdrawal</title>
          <description>for withdrawal reaching treatment threshold phenobarbital was first started and if a second drug was needed randomization was done after consent; this arm started dilute deordorized tincture of opium</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="20"/>
                <participants group_id="P2" count="20"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="20"/>
                <participants group_id="P2" count="20"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Methadone After Phenobarbital for Withdrawal</title>
          <description>for withdrawal reaching treatment threshold phenobarbital was first started and if a second drug was needed randomization was done after consent; this arm started methadone</description>
        </group>
        <group group_id="B2">
          <title>DTO After Phenobarbital for Withdrawal</title>
          <description>for withdrawal reaching treatment threshold phenobarbital was first started and if a second drug was needed randomization was done after consent; this arm started dilute deordorized tincture of opium</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="20"/>
            <count group_id="B2" value="20"/>
            <count group_id="B3" value="40"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                    <measurement group_id="B2" value="20"/>
                    <measurement group_id="B3" value="40"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0.005" spread="0"/>
                    <measurement group_id="B2" value="0.005" spread="0"/>
                    <measurement group_id="B3" value="0.005" spread="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="17"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="23"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                    <measurement group_id="B2" value="20"/>
                    <measurement group_id="B3" value="40"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Length of Treatment With Opioid Medication</title>
        <description>Up to 12 months</description>
        <time_frame>Up to 12 months</time_frame>
        <population>Completion of treatment</population>
        <group_list>
          <group group_id="O1">
            <title>Deodorized Tincture Opium After Phenobarbital for Withdrawal</title>
            <description>for withdrawal reaching treatment threshold phenobarbital was first started and if a second drug was needed randomization was done after consent; this arm started dilute deordorized tincture of opium</description>
          </group>
          <group group_id="O2">
            <title>Methadone After Phenobarbital for Withdrawal</title>
            <description>for withdrawal reaching treatment threshold phenobarbital was first started and if a second drug was needed randomization was done after consent; this arm started methadone</description>
          </group>
        </group_list>
        <measure>
          <title>Length of Treatment With Opioid Medication</title>
          <description>Up to 12 months</description>
          <population>Completion of treatment</population>
          <units>days</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="19.1" spread="8.8"/>
                    <measurement group_id="O2" value="17.7" spread="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <group_list>
        <group group_id="E1">
          <title>Methadone After Phenobarbital for Withdrawal</title>
          <description>for withdrawal reaching treatment threshold phenobarbital was first started and if a second drug was needed randomization was done after consent; this arm started methadone</description>
        </group>
        <group group_id="E2">
          <title>DTO After Phenobarbital for Withdrawal</title>
          <description>for withdrawal reaching treatment threshold phenobarbital was first started and if a second drug was needed randomization was done after consent; this arm started dilute deordorized tincture of opium</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr Mark S Brown</name_or_title>
      <organization>Eastern Maine Medical Center</organization>
      <phone>207-973-8670</phone>
      <email>mbrown@emh.org</email>
    </point_of_contact>
  </clinical_results>
</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/NCT01723722
org study id: 07-2-M-107
nct id: NCT01723722
lead sponsor: 
has dmc: Yes
This study compares treatment of Neonatal Abstinence Syndrome (NAS) with two different drugs
      for the difference in the length of treatment. This is a randomized, open-label comparison of
      phenobarbital and methadone versus phenobarbital and diluted deodorized tincture of opium
      (dDTO) where phenobarbital is the initial drug used to stabilize neonatal withdrawal.
a.Procedures: NAS scoring is currently done on infants meeting the inclusion criteria [IDD
      29:070]. NAS scores are initially done every 2 hours for 24 hours and then every 4 hours when
      awake or before feeding for the duration of observation or treatment.

      i. NAS scores may indicate more than withdrawal. Conditions such as colic, reflux, or
      baseline irritability may influence the baseline scores. Decisions made based on the NAS
      scores should take into account these factors and the baseline for the infant.

      b.Emergence of symptom, dosing, and initiation of treatment: Withdrawal is defined as at
      least 2 NAS scores >8 or 1 NAS score >12. Once withdrawal has emerged, the infant will be
      given: i. Phenobarbital 20 to 30 mg/kg to load divided in up to 3 doses over 24 hours and
      maintenance phenobarbital should be started at 2.5 mg/kg/dose administered Q 12h, 12 hours
      after the loading dose is ended. NAS scoring is continued and if scores remain <8 for a
      minimum of 5 days after starting phenobarbital, the infant is eligible for discharge.

      ii. If after phenobarbital treatment has been started, at least 2 NAS scores >8 or 1 NAS
      score >12, then a phenobarbital level will be drawn and a mini-load calculated to reach a
      level of 30 mg/dl. If withdrawal is not controlled or re-emerges after the mini-load dose,
      the infant will be randomized to one of the two arms of the study - methadone or dDTO.

      iii. Twins will be randomized together to the same arm. iv. Randomization will be stratified
      into mothers on narcotic treatment >3 months and those not in treatment or <3 months.
      Randomization will be done in blocks of 10 for each stratum.

      v. For both drugs, the neonatal preparation will be used. vi. The following is a dosing guide
      for methadone:

        1. The neonatal concentration is 1 mg/ml of methadone. It is administered orally every 12
           hours - standardized eventually to 0900 and 2100.

        2. For the first 24 hours, doses will be prescribed every 6 hours for 4 doses, using a
           sliding scale in response to the last NAS score:

           NAS Score Methadone dose 8-11 0.05 mg/kg/dose 12-15 0.1 mg/kg/dose >16 0.15 mg/kg/dose

        3. Maximum loading dose of methadone will be 0.15 mg/kg/dose Q 6 hour

        4. After the first 24 hours of treatment, the total methadone dose will be summed and that
           dose divided into two doses, given 12 hours apart. Subsequently, PRN doses of 0.05
           mg/kg/dose may be given every 6 hours for scores >8 X 2 and added to the next 24 hour's
           doses, divided every 12 hours, until NAS scores are consistently <8 for 48 hours.

        5. If at any point the maximum dose of methadone is reached and withdrawal is not
           controlled, then in the opinion of two neonatologists the patient can be crossed-over to
           the dDTO arm.

      vii. The following is a dosing guide for dDTO:

        1. The neonatal concentration is 1:24 dilution for a concentration of 0.4%, equivalent to
           0.4 mg/ml of morphine. It is administered orally every 4 hours - standardized eventually
           to 0400, 0800, 1200, 1600, 2000, 0000.

        2. The starting dose is determined by using a sliding scale in response to the last NAS
           score before starting:

           NAS Score dDTO dose 8-11 0.1 mg/kg/day 12-15 0.15 mg/kg/day >16 0.2 mg/kg/day

           For next day, the maintenance dose will return to the previous dose and given in 6
           divided doses given Q 4 hours.

           iv. For either methadone or dDTO, dosing will be held at this level and weaning will be
           resumed when the infant has NAS scores <8 for 48 hours.

           e. Holding of doses: Methadone or dDTO will be held for poor feeding, respiratory
           depression, or somnolence at any time in the protocol.

           f. Behavioral assessment: Behavioral assessment will be done by two methods. The first
           by actigraphy and the second by NINS, both during the second week of weaning. The latter
           will be done prior to a scheduled phenobarbital dose.

           g. Formula: A 24 kcal/ounce formula should be fed initially using either standard
           formula or by adding breast milk fortifier. During the weaning period, when weight gain
           is >30 grams/day for at least 2 days, formula will be changed to 20 kcal/ounce and
           weight gain monitored. If not sustained, then formula should be changed back to 24
           kcal/ounce.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Length of Treatment With Opioid Medication
time frame: Up to 12 months
description: Up to 12 months
arm group label: 1 (Phenobarbital and Methadone)
arm group type: Active Comparator
description: The following is a dosing guide for methadone:
The neonatal concentration is 1 mg/ml of methadone. It is administered orally every 12 hours.
For the first 24 hours, doses will be prescribed every 6 hours using a sliding scale in response to the last NAS score:
NAS Score Methadone dose 8-11 0.05 mg/kg/dose 12-15 0.1 mg/kg/dose
≥16 0.15 mg/kg/dose
Maximum dose of methadone will be 0.15 mg/kg/dose.
After the first 24 hours of treatment, the total methadone dose will be summed and that dose divided into two doses, given 12 hours apart. For the following 24 hours, additional doses may be given every 6 hours as needed and added to the next 24 hour's doses divided every 12 hours, until NAS scores are consistently <8 for 48 hours.
If at any pointthe maximum dose of methadone is reached and withdrawal is not controlled, then in the opinion of two neonatologists the patient can be crossed-over to the dDTO arm.
arm group label: 2 (Phenobarbital and Diluted Deodorized Tincture of Opium)
arm group type: Active Comparator
description: The following is a dosing guide for dDTO:
The neonatal concentration is 1:24 dilution for a concentration of 0.4%, equivalent to 0.4 mg/ml of morphine. It is administered orally every 4 hours.
The starting dose will be determined using a sliding scale in response to the last NAS score before starting.
NAS Score Starting dDTO dose 8-11 0.4 mg/kg/day 12-15 0.6 mg/kg/day
≥16 0.8 mg/kg/day
The maximum dose of DTO will be 0.8 mg/kg/day.
After the first 24 hours of treatment, if the NAS scores are still ≥8, the dose will be increased to the next level.
If at any point the maximum dose of methadone is reached and withdrawal is not controlled, then in the opinion of two neonatologists the patient can be crossed-over to the methadone arm.
intervention type: Drug
intervention name: Methadone
description: Concentration is 1mg/mL administered every 12 hours given on sliding scale in response to last NAS score.
arm group label: 1 (Phenobarbital and Methadone)
other name: Dolophine
intervention type: Drug
intervention name: Diluted Deodorized Tincture of Opium
description: Concentration is 1:24 dilution for a concentration of 0.4%
arm group label: 2 (Phenobarbital and Diluted Deodorized Tincture of Opium)
other name: Laudanum
criteria: 
gender: All
minimum age: 1 Day
maximum age: 6 Days
healthy volunteers: No
last name: Mark S. Brown, MD
role: Principal Investigator
affiliation: Eastern Maine Medical Center
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Eastern Maine Medical Center
investigator full name: Mark S Brown, MD
investigator title: Chief of Pediatric Service, Neonatalogy
mesh term: Neonatal Abstinence Syndrome
mesh term: Syndrome
mesh term: Methadone
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 