Morphine Versus Methadone for Opiate Exposed Infants With Neonatal Abstinence Syndrome

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02851303

Enrollment

Registered

2016-08-01

Start date

2016-10-31

Completion date

2018-09-30

Last updated

2023-05-24

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Neonatal Abstinence Syndrome

Brief summary

This study investigates the use of methadone versus morphine wean for the treatment of neonatal abstinence syndrome for infants exposed to opioids in utero. Half of infants who require pharmacotherapy for NAS will receive a methadone wean, and half will receive a morphine wean. Length of hospital stay, length of treatment and parent satisfaction will be studied.

Detailed description

Neonates exposed to opiates in utero can develop a constellation of withdrawal symptoms known as neonatal abstinence syndrome (NAS). Infants with NAS are at risk for multiple medical complications including failure to thrive and seizures, they often require prolonged hospital stays and account for significant health care costs. At University of New Mexico, infants exposed to methadone or heroin in utero who develop NAS requiring pharmacologic treatment undergo a treatment wean with methadone, whereas infants exposed to buprenorphine undergo a wean with morphine. However, morphine is used frequently to treat neonatal abstinence syndrome among methadone-exposed infants throughout the US, and optimal pharmacologic treatment for NAS remains unknown. Anecdotal evidence at the investigators institution suggests that infants treated with morphine have shorter hospital stays compared to infants treated with methadone. Investigators propose a pilot randomized controlled trial to evaluate morphine vs methadone treatment of infants with in-utero methadone or heroin exposure. Specifically, length of treatment, need for additional medication to treat withdrawal, and length of hospital stay will be compared. When women are admitted to Labor and Delivery and/or up to 12 hours postpartum, research staff will approach patients about study enrollment. Participants will be approached for study enrollment if medication list on admission includes methadone, if participants self-report methadone use prenatally, and/ or if urine drug screen is positive for methadone or opiates on admission. If women choose to enroll in the study, and their infants require treatment for NAS, their infants will be randomized and assigned a study number for treatment using the methadone or morphine protocols at the time treatment is required. All infants will be monitored for signs of withdrawal using the standard UNM NAS scoring protocol. Standard of care at UNM is to treat infants exposed to opioids in-utero with methadone if they require pharmacologic therapy for NAS, therefore treatment will not be withheld if they choose not to enroll in the study. Standard of care is also to obtain a urine drug screen on all infants with reported exposure to opiates in pregnancy. Enrolled patients will thus undergo routine urine drug screening. The only difference from standard care with regards to the study protocol is the treatment of half of the methadone or heroin exposed infants with morphine. The morphine protocol is proven for safety and efficacy currently in buprenorphine exposed infants. Once randomized, infants will continue on the protocol until discharge. At discharge, parents will complete a patient satisfaction survey.

Interventions

DRUGMorphine

Morphine wean protocol as described in arm description

DRUGMethadone

Methadone wean protocol as described in arm description

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

0 Hours to 12 Hours

Healthy volunteers

Inclusion criteria

* Born at University of New Mexico Hospital * Greater than 34 weeks gestation * Primary in-utero drug exposure was opioids other than buprenorphine * Maternal or infant urine drug screen positive for methadone and/or opioids on admission

Exclusion criteria

* Born prior to 34 weeks * Neonatal intensive care unit admission * Serious medical comorbidities * Primary substance exposure in-utero was buprenorphine, or was not opioids

Design outcomes

Primary

Measure	Time frame	Description
Length of Hospital Stay	assessed at hospital discharge, approximately 7-30 days	Number of days in hospital after birth

Secondary

Measure	Time frame	Description
Need for Additional Agent to Treat Withdrawal, Determined by Chart Review of Medication Administration Record of Administered Medications for Withdrawal Treatment (Example: Clonidine or Phenobarbital)	assessed at hospital discharge, approximately 7-30 days	clonidine
Need for Feeding Assistance, Determined by Chart Review of Discharge Summary, Specifically Evaluating for Need for Nasogastric Tube Placement or Peripheral Parenteral Nutrition.	assessed at hospital discharge, approximately 7-30 days	—
Length of Treatment	assessed at hospital discharge, approximately 7-30 days	—
Breastfeeding Initiation and Continuation at Hospital Discharge	assessed at hospital discharge, approximately 7-30 days	Assessed through chart review of discharge summary documentation of method of infant feeding at time of discharge
Total Morphine Equivalent Dose Received	assessed at hospital discharge, approximately 7-30 days	—
Need for NICU Transfer, as Determined by Chart Review of Discharge Summary.	assessed at hospital discharge, approximately 7-30 days	—

Countries

United States

Participant flow

Pre-assignment details

Participants were enrolled as dyads during the initial birth hospitalization. Randomization occured at the time of consent to allow for pharmacologic treatment to begin whenever it was deemed medically necessary without the time constraint of needing randomization by the research team. As not all infants required pharmacologic treatment for withdrawal, they dropped out of the study arm.

Participants by arm

Arm	Count
Morphine Dose given q 3 - 4 hrs with feeds; do not exceed 4 hrs between doses Morphine (0.04mg/0.1ml) Score Dose For Initiation 0-8 0 None 9-12 0.04 mg/dose 13-16 0.08 mg/dose 17-20 0.12 mg/dose 21-24 0.16 mg/dose 25 or above 0.20mg/dose Morphine Maintenance/Escalation * Maintain dose if score 0-8 * Increase dose by 0.02 if score is 9-12 (rescore before dosing) • Increase dose by 0.04 if score 13-16 * Increase score by 0.06 if score 17-20 Weaning Instructions: * Maintain on dose 48 hrs before starting weaning * Wean 0.02 mg morphine every day for a score is 0-8 • Defer wean for score 9-12 Re-escalation * If neonate scores 9-12 re-score as described for initiation, * If second score is in 9-12 increase morphine 0.01 mg q3-4 hrs • If 2 consecutive scores 13-16, increase 0.02 mg q3-4 hrs * If 2 consecutive scores in 17-20, increase 0.04 mg q3-4 hrs etc Morphine: Morphine wean protocol as described in arm description	15
Methadone Step 1: 0.7 mgs/Kg/24 hrs. divided by into six doses (q 4 hrs) is starting dose Step 2: Decrease dose by half, which is 50% of starting dose, EVERY 4 hours. Step 3: Same dose which is 50% of starting dose EVERY 6 hours. Step 4: Same dose which is 50% of starting dose EVERY 8 hours. Step 5: Same dose which is 50% of starting dose EVERY 12 hours. Step 6: Decrease dose by half, which is 25% of starting dose EVERY 12 hours. Step 7: Same dose which is 25% of starting dose q 24 hours Methadone: Methadone wean protocol as described in arm description	13
Total	28

Baseline characteristics

Characteristic	Morphine	Methadone	Total
Age, Continuous	37.7 weeks STANDARD_DEVIATION 1.7	37.5 weeks STANDARD_DEVIATION 1.2	37.6 weeks STANDARD_DEVIATION 1.5
Age, Customized Mean age	27.8 years STANDARD_DEVIATION 4.3	25.4 years STANDARD_DEVIATION 3.1	26.68 years STANDARD_DEVIATION 3.9
Concurrent alcohol use	0 Participants	0 Participants	0 Participants
Concurrent benzodiazepine use	4 Participants	0 Participants	4 Participants
Concurrent illicit opioid use	12 Participants	10 Participants	22 Participants
Concurrent methamphetamine use	10 Participants	2 Participants	12 Participants
Concurrent SSRI	2 Participants	0 Participants	2 Participants
Concurrent tobacco use	9 Participants	6 Participants	15 Participants
Initiation of prenatal care in first trimester	5 Participants	9 Participants	14 Participants
Maternal gestational diabetes	1 Participants	0 Participants	1 Participants
Maternal preeclampsia	1 Participants	2 Participants	3 Participants
Preterm delivery	4 Participants	2 Participants	6 Participants
Race/Ethnicity, Customized hispanic	11 Participants	7 Participants	18 Participants
Race/Ethnicity, Customized native american	2 Participants	0 Participants	2 Participants
Race/Ethnicity, Customized White non-hispanic	2 Participants	6 Participants	8 Participants
Sex: Female, Male Female	15 Participants	13 Participants	28 Participants
Sex: Female, Male Male	0 Participants	0 Participants	0 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 15	0 / 13
other Total, other adverse events	0 / 15	3 / 13
serious Total, serious adverse events	0 / 15	0 / 13