Opioid Dependence, Opioid Related Disorders, Pregnancy
Conditions
Keywords
opiate addiction, opiate dependence, substance abuse, addiction, substance addiction, pregnancy, buprenorphine, methadone, fetal, neonatal, post-partum
Brief summary
Children born to women who abuse drugs have a high risk of being born with birth defects and developmental problems. Methadone is a drug that is commonly used for treating opioid dependence. However, its use by a pregnant woman can cause severe withdrawal symptoms in a newborn because of the prenatal exposure. The purpose of this study is to evaluate the effectiveness of buprenorphine, another drug, versus methadone in reducing withdrawal symptoms in children born to opioid-dependent women.
Detailed description
Women who use drugs during pregnancy place their unborn children at high risk for being born addicted to drugs. Such children may also be born with birth defects and may experience learning and behavioral problems. Methadone, a synthetic narcotic, is commonly prescribed to treat opioid addiction. It may not be an optimal solution for opioid-dependent pregnant women, however, because a large percentage of children born to women taking methadone experience severe drug withdrawal symptoms at birth that often require medical treatment. Common opioid withdrawal symptoms, described as neonatal abstinence syndrome (NAS) in babies, include tremors, irritability, sleep problems, seizures, dehydration, and fever. Buprenorphine is a medication that has been approved to treat opioid dependence in individuals who are not pregnant but has not been approved for pregnant individuals. Past research has shown that use of buprenorphine in pregnant women results in improved birth outcomes over methadone. The purpose of this study is to evaluate the effectiveness of buprenorphine versus methadone at reducing opioid withdrawal symptoms in babies born to opioid-dependent women. This study will enroll opioid-dependent pregnant women who are 13 to 30 weeks pregnant and will follow each woman and her child throughout the pregnancy until 6 weeks postpartum. All participants will undergo an initial screening that will last several hours. Participants will then be randomly assigned to receive either methadone or buprenorphine on a daily basis, and will be required to visit the clinic each day to receive their medication. Outcome measurements will be assessed at weekly study visits throughout the pregnancy, and will include drug use, HIV risk behaviors, medication dose adequacy and safety, treatment retention, and psychosocial functioning. Urine samples will be collected 3 times a week, and blood will be drawn throughout the pregnancy for safety monitoring. Outcome measurements related to the baby will include head circumference measurement, length of hospital stay, severity and frequency of withdrawal symptoms, and amount of medication needed to control withdrawal symptoms.
Interventions
DRUGBuprenorphine
sl daily 2-32 mg
DRUGMethadone
daily oral dosing 20-140 mg
Sponsors
National Institute on Drug Abuse (NIDA)
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 41 Years
Healthy volunteers
No
Inclusion criteria
* Current opioid dependence * Current opioid use, as determined by a urine drug test * Pregnant with a single child with a gestational age of 6 to 30 weeks, as determined by a sonogram
Exclusion criteria
* Current medical condition that would make study participation dangerous, as determined by study physician * Diagnosed with an acute, severe psychiatric illness * Current SCID I-E module diagnosis of benzodiazepine or alcohol abuse * Use of alcohol or benzodiazepines in the 30 days prior to study entry, as determined by the Addiction Severity Index * Pending legal action that may prohibit or interfere with study participation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Amount of Morphine Sulfate That a Neonate Receives to Treat NAS | Start of NAS treatment until discontinuation of NAS treatment (min=0 days, max=76 days) | Total amount in mg |
| Child's Head Circumference Measurement (Measured at Birth) | birth | — |
| Child's Length of Hospital Stay | delivery until hospital discharge (min=2 days, max=79 days) | — |
| Number of Children Requiring Treatment for Neonatal Abstinence Signs (NAS) | From birth until hospital discharge (min=4 days, max=10, depending on site) | Neonatal abstinence syndrome (NAS) characterized by hyperirritability of the central nervous system and dysfunction in the autonomic nervous system, gastrointestinal tract, and respiratory system.11 When left untreated, NAS can result in serious illness (e.g., diarrhea, feeding difficulties, weight loss, and seizures) and death. |
| Child's Peak Daily Total NAS Score | minimum twice daily from birth until NAS no longer measured (min=10 days) | NAS was measured with the MOTHER NAS scale, which includes 28 items, 19 of which are used for scoring and medication decisions. Scores can range from 0 to 42, with higher scores indicating more severe withdrawal. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mother's HIV Risk Behaviors (Measured Monthly by Risk Behavior Assessment) | monthly from study entry until discontinuation or delivery (min=29 days, max=239 days) | — |
| Mother's Measures of Dose Adequacy and Acceptance Over Time (Measured Weekly by Dose Adequacy Measure) | from study entry until discontinuation or delivery (min=29 days, max=239 days) | Pregnant women maintained on an opioid agonist medication may require upward adjustment to their medication during the course of pregnant. The Dose Adequacy Measure represented a recordation of dosing adjustments during the course of the study. |
| Mother's Psychosocial Functioning at Delivery as Measured by the Addiction Severity Index Psychosocial Index Score | at delivery | The Addiction Severity Index is a structured clinical interview that assesses problem severity in 7 areas of functioning: alcohol use, drug use, medical, legal, employment, psychosocial, and psychiatric status. Each area of functioning yields a composite scale score between 0 and 1, with higher scores indicating greater problem severity in that area. Only the psychosocial index was examined in this study. |
| Mother's Self-report of Drug Use (Measured Monthly by Time Line Follow Back) | monthly from study entry until discontinuation or delivery (min=29 days, max=239 days) | — |
Countries
Austria, Canada, United States
Participant flow
Recruitment details
1074 Patients were screened for eligibility. 175 underwent randomization. 86 were assigned to receive buprenorphine. 58 of the patients assigned to buprenorphine completed the study. 89 were assigned to receive methadone. 73 of the patients assigned to methadone completed the study.
Pre-assignment details
Of the 1074 screened: 243 did not give consent. 656 were excluded for a variety of reasons ranging from an estimated gestation age outside the range, to impending legal issues, to multiple-fetus pregnancy.
Participants by arm
| Arm | Count |
|---|---|
| Methadone Methadone
Methadone : daily oral dosing 20-140 mg | 73 |
| Buprenorphine Buprenorphine
Buprenorphine : sl daily 2-32 mg | 58 |
| Total | 131 |
Baseline characteristics
| Characteristic | Methadone | Buprenorphine | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 73 Participants | 58 Participants | 131 Participants |
| Age, Continuous | 27.7 years STANDARD_DEVIATION 0.7 | 25.3 years STANDARD_DEVIATION 0.7 | 26.5 years STANDARD_DEVIATION 0.7 |
| Region of Enrollment Austria | 19 participants | 18 participants | 37 participants |
| Region of Enrollment United States | 54 participants | 40 participants | 94 participants |
| Sex: Female, Male Female | 73 Participants | 58 Participants | 131 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 83 / 89 | 66 / 86 | 34 / 73 | 29 / 58 |
| serious Total, serious adverse events | 14 / 89 | 8 / 86 | 6 / 73 | 1 / 58 |
Outcome results
Primary
Child's Head Circumference Measurement (Measured at Birth)
Time frame: birth
| Arm | Measure | Value (MEAN) |
|---|---|---|
| A Methadone | Child's Head Circumference Measurement (Measured at Birth) | 33.0 cm |
| B Buprenorphine | Child's Head Circumference Measurement (Measured at Birth) | 33.8 cm |
Primary
Child's Length of Hospital Stay
Time frame: delivery until hospital discharge (min=2 days, max=79 days)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| A Methadone | Child's Length of Hospital Stay | 17.5 days |
| B Buprenorphine | Child's Length of Hospital Stay | 10.0 days |
Primary
Child's Peak Daily Total NAS Score
NAS was measured with the MOTHER NAS scale, which includes 28 items, 19 of which are used for scoring and medication decisions. Scores can range from 0 to 42, with higher scores indicating more severe withdrawal.
Time frame: minimum twice daily from birth until NAS no longer measured (min=10 days)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| A Methadone | Child's Peak Daily Total NAS Score | 12.8 Score on the scale |
| B Buprenorphine | Child's Peak Daily Total NAS Score | 11.0 Score on the scale |
Primary
Number of Children Requiring Treatment for Neonatal Abstinence Signs (NAS)
Neonatal abstinence syndrome (NAS) characterized by hyperirritability of the central nervous system and dysfunction in the autonomic nervous system, gastrointestinal tract, and respiratory system.11 When left untreated, NAS can result in serious illness (e.g., diarrhea, feeding difficulties, weight loss, and seizures) and death.
Time frame: From birth until hospital discharge (min=4 days, max=10, depending on site)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A Methadone | Number of Children Requiring Treatment for Neonatal Abstinence Signs (NAS) | 41 participants |
| B Buprenorphine | Number of Children Requiring Treatment for Neonatal Abstinence Signs (NAS) | 27 participants |
Primary
Total Amount of Morphine Sulfate That a Neonate Receives to Treat NAS
Total amount in mg
Time frame: Start of NAS treatment until discontinuation of NAS treatment (min=0 days, max=76 days)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| A Methadone | Total Amount of Morphine Sulfate That a Neonate Receives to Treat NAS | 10.4 mg |
| B Buprenorphine | Total Amount of Morphine Sulfate That a Neonate Receives to Treat NAS | 1.1 mg |
Secondary
Mother's HIV Risk Behaviors (Measured Monthly by Risk Behavior Assessment)
Time frame: monthly from study entry until discontinuation or delivery (min=29 days, max=239 days)
Population: frequency of occurrence too low to be estimated with accuracy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A Methadone | Mother's HIV Risk Behaviors (Measured Monthly by Risk Behavior Assessment) | NA percentage of HIV risk behaviors |
| B Buprenorphine | Mother's HIV Risk Behaviors (Measured Monthly by Risk Behavior Assessment) | NA percentage of HIV risk behaviors |
Secondary
Mother's Measures of Dose Adequacy and Acceptance Over Time (Measured Weekly by Dose Adequacy Measure)
Pregnant women maintained on an opioid agonist medication may require upward adjustment to their medication during the course of pregnant. The Dose Adequacy Measure represented a recordation of dosing adjustments during the course of the study.
Time frame: from study entry until discontinuation or delivery (min=29 days, max=239 days)
Population: intra-subject variability in dosing (typically 1 dose) over course of the trial was too small to estimate the parameter of interest with sufficient accuracy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A Methadone | Mother's Measures of Dose Adequacy and Acceptance Over Time (Measured Weekly by Dose Adequacy Measure) | NA dose increase per trimester |
| B Buprenorphine | Mother's Measures of Dose Adequacy and Acceptance Over Time (Measured Weekly by Dose Adequacy Measure) | NA dose increase per trimester |
Secondary
Mother's Psychosocial Functioning at Delivery as Measured by the Addiction Severity Index Psychosocial Index Score
The Addiction Severity Index is a structured clinical interview that assesses problem severity in 7 areas of functioning: alcohol use, drug use, medical, legal, employment, psychosocial, and psychiatric status. Each area of functioning yields a composite scale score between 0 and 1, with higher scores indicating greater problem severity in that area. Only the psychosocial index was examined in this study.
Time frame: at delivery
| Arm | Measure | Value (MEAN) |
|---|---|---|
| A Methadone | Mother's Psychosocial Functioning at Delivery as Measured by the Addiction Severity Index Psychosocial Index Score | .014 Score on the scale |
| B Buprenorphine | Mother's Psychosocial Functioning at Delivery as Measured by the Addiction Severity Index Psychosocial Index Score | .088 Score on the scale |
Secondary
Mother's Self-report of Drug Use (Measured Monthly by Time Line Follow Back)
Time frame: monthly from study entry until discontinuation or delivery (min=29 days, max=239 days)
Population: frequency of use during the course of the study was too low to estimate the parameter with sufficient accuracy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A Methadone | Mother's Self-report of Drug Use (Measured Monthly by Time Line Follow Back) | NA percentage of drug use |
| B Buprenorphine | Mother's Self-report of Drug Use (Measured Monthly by Time Line Follow Back) | NA percentage of drug use |