Symptom-Based Dosing for Neonatal Abstinence Syndrome

(OPTimize NOW Trial)

Not currently recruiting at 22 trial locations

Overseen By HELP for NOWS Consortium

Age: < 18

Sex: Any

Trial Phase: Phase 3

Sponsor: HELP for NOWS Consortium

Disqualifiers: Major birth defects, Neonatal encephalopathy, Respiratory support, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to identify the best method for administering medicine to babies with Neonatal Opioid Withdrawal Syndrome (NOWS). It compares two approaches: the Scheduled Opioid Taper Approach, which involves giving medicine on a regular schedule and reducing it as symptoms improve (potentially using methadone), and the Symptom-based Dosing Approach, which involves administering medicine only when symptoms appear. Babies at least 36 weeks old who have been exposed to opioids before birth may be suitable for this trial. The study seeks to determine which method more effectively treats NOWS symptoms such as tremors, excessive crying, and feeding difficulties. As a Phase 3 trial, it represents the final step before FDA approval, offering participants the opportunity to contribute to a potentially groundbreaking treatment for NOWS.

Will I have to stop taking my current medications?

The trial information does not specify whether participants must stop taking their current medications. However, there is a mention of a 'washout period' (time without taking certain medications) for the study site, but it is unclear if this applies to individual participants.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that gradually reducing medication is a common way to treat babies with Neonatal Opioid Withdrawal Syndrome (NOWS). Babies receive drugs like morphine or methadone at set intervals, with the dosage slowly decreased as they improve. This method is usually well-tolerated, and studies have found it leads to fewer instances of treatment failure.

Another method involves administering medicine only when babies exhibit NOWS symptoms. This approach aims to limit the amount of medicine babies receive. Early research suggests this method is safe and might be as safe or safer than the scheduled method. In these studies, fewer babies needed extra medication.

Both methods have been studied for safety and effectiveness and are considered safe for treating NOWS. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this trial because it explores two different approaches to treating Neonatal Abstinence Syndrome (NAS). Unlike the standard care, which often involves a fixed opioid tapering schedule, this trial compares a symptom-based dosing approach. This method allows treatment to be adjusted based on the baby's specific symptoms, potentially leading to more personalized and effective care. By comparing these two strategies, researchers hope to find out which approach maximizes relief for newborns while minimizing medication use.

What evidence suggests that this trial's treatments could be effective for Neonatal Opioid Withdrawal Syndrome?

Research has shown that the scheduled opioid taper method, one approach studied in this trial, has helped babies with Neonatal Opioid Withdrawal Syndrome (NOWS) for many years. This method involves administering regular doses of medicine like morphine or methadone and gradually reducing the dose as the baby improves. Studies have found that this can help babies leave the hospital sooner. In contrast, the symptom-based dosing method, another approach in this trial, administers medicine only when the baby exhibits symptoms. Early findings suggest this can reduce the amount of medicine needed and also help babies go home sooner compared to scheduled dosing. Both methods offer advantages, and ongoing research aims to find the best way to care for babies with NOWS. ^{1 2 4 5 6}

Who Is on the Research Team?

Lori Devlin, MD

Principal Investigator

University of Louisville

Are You a Good Fit for This Trial?

This trial is for babies at risk of Neonatal Opioid Withdrawal Syndrome (NOWS) who are 36 weeks gestation or older, with prenatal opioid exposure. Babies must not need respiratory support at 48 hours old, have no major birth defects, and cannot have started treatment elsewhere.

Inclusion Criteria

My baby was exposed to opioids before birth.

The infant is greater than or equal to 36 weeks gestation

My infant is being treated for opioid withdrawal at a qualified study location.

Exclusion Criteria

My infant needed breathing support at 48 hours old.

My infant was exposed to opioids before starting treatment for withdrawal.

The infant has major birth defect(s)

Timeline for a Trial Participant

Run-in Period

A three-week run-in period to prepare for the treatment phase

3 weeks

Treatment Period 1

Infants receive either a scheduled opioid taper approach or a symptom-based dosing approach for five months

5 months

Washout Period

A three-week washout period between treatment phases

3 weeks

Treatment Period 2

Infants receive the alternate treatment approach (either scheduled opioid taper or symptom-based dosing) for five months

5 months

Follow-up

Participants are monitored for safety and effectiveness after treatment until hospital discharge or up to 1 year

Up to 1 year

What Are the Treatments Tested in This Trial?

Interventions

• Scheduled Opioid Taper Approach
• Symptom-based Dosing Approach

Trial Overview The study compares two methods to treat NOWS in infants: a scheduled opioid taper approach where medicine is reduced over time, and a symptom-based dosing approach that administers medication only when withdrawal symptoms appear.

How Is the Trial Designed?

Group I: Sequence 2 Experimental Treatment 2 Interventions

This sequence will assign eligible participants to a three-week run-in period followed by a symptom-based dosing approach for five months followed by a three-week washout period followed by scheduled opioid taper approach for five months.

Group II: Sequence 1 Experimental Treatment 2 Interventions

This sequence will assign eligible participants to a three-week run-in period followed by a scheduled opioid taper approach for five months followed by a three-week washout period followed by symptom-based dosing approach for five months.

Scheduled Opioid Taper Approach is already approved in United States, European Union for the following indications:

Approved in United States as Methadose for:

• Detoxification and maintenance treatment of opioid addiction
• Relief of moderate to severe pain

Approved in European Union as Methadone for:

• Treatment of opioid dependence
• Severe chronic pain

Who Is Running the Clinical Trial?

HELP for NOWS Consortium

Lead Sponsor

Trials

1

Recruited

480+

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Collaborator

Trials

2,103

Recruited

2,760,000+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

Published Research Related to This Trial

In a study comparing neonates of opioid-dependent women treated with buprenorphine versus methadone, buprenorphine-exposed neonates required less opioid medication for neonatal abstinence syndrome (NAS) and had shorter hospital stays, indicating a potential safety and efficacy advantage.

The study found that 20% of buprenorphine-exposed neonates were treated for NAS compared to 45.5% of methadone-exposed neonates, suggesting that buprenorphine may be as effective as methadone in managing NAS outcomes when treatment begins in the second trimester.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Buprenorphine versus methadone in the treatment of pregnant opioid-dependent patients: effects on the neonatal abstinence syndrome. Jones, HE., Johnson, RE., Jasinski, DR., et al.[2022]

In a study of 174 pregnant women on methadone maintenance, the incidence of clinically significant neonatal abstinence syndrome (NAS) was similar across different maternal methadone dosing groups, indicating that higher doses do not increase the risk of NAS.

The study found no significant differences in birth weight, preterm birth rates, or neonatal morbidities based on methadone dosage, suggesting that concerns about NAS should not limit methadone dosing during pregnancy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Higher maternal doses of methadone does not increase neonatal abstinence syndrome. Pizarro, D., Habli, M., Grier, M., et al.[2021]

The Medication Taper Complexity Score (MTCS) was validated as a reliable tool for assessing the complexity of methadone tapers in children with opioid abstinence syndrome, achieving a high reliability coefficient of 0.9949.

The MTCS effectively distinguished between 'easy,' 'medium,' and 'difficult' tapers, indicating its potential usefulness in clinical practice and research for managing methadone treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

External validation of the medication taper complexity score for methadone tapers in children with opioid abstinence syndrome. Johnson, PN., Miller, JL., Hagemann, TM., et al.[2019]

Infants with neonatal opioid withdrawal syndrome (NOWS) treated with a novel symptom-triggered methadone approach (STMA) had a significantly shorter median hospital length of stay (10.5 days) compared to those treated with a fixed-schedule methadone taper (FSMT) (17.0 days), indicating improved hospitalization outcomes.

The STMA also resulted in fewer methadone treatment days (2.5 days) compared to FSMT (11.7 days), suggesting that this approach not only reduces hospital time but also minimizes medication exposure for infants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Standard Fixed-Schedule Methadone Taper Versus Symptom-Triggered Methadone Approach for Treatment of Neonatal Opioid Withdrawal Syndrome. Wachman, EM., Minear, S., Hirashima, M., et al.[2020]

In a study of 117 pregnant women on methadone maintenance treatment, 40.4% had their methadone dose decreased during pregnancy, but this change did not affect the incidence of neonatal abstinence syndrome (NAS) in their newborns.

The study also found that a significant number of women were prescribed additional medications, such as antidepressants (25.7%) and benzodiazepines (38.0%), during pregnancy, indicating the complexity of managing opioid dependence in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Methadone dosing and prescribed medication use in a prospective cohort of opioid-dependent pregnant women. Cleary, BJ., Reynolds, K., Eogan, M., et al.[2013]

The study reviewed 49 articles on managing opioid abstinence syndrome in critically ill pediatric patients, highlighting the importance of methadone for preventing withdrawal symptoms during opioid tapering.

It was found that using a standardized tapering protocol for methadone significantly reduced the incidence of abstinence symptoms, and the Withdrawal Assessment Tool - 1 was effective for monitoring withdrawal signs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Opioid tapering and weaning protocols in pediatric critical care units: a systematic review. Bichaff, P., Setani, KT., Motta, EHG., et al.[2019]

In a study of 156 infants with neonatal abstinence syndrome (NAS) due to in utero methadone exposure, those treated with buprenorphine had significantly shorter treatment lengths (8 days) and hospital stays (13 days) compared to those treated with methadone (15 days and 20 days, respectively).

Buprenorphine-treated infants also had lower cumulative opioid exposure (0.6 mg/kg) compared to methadone-treated infants (1.05 mg/kg), and fewer required ongoing therapy after discharge, suggesting that buprenorphine may be a more effective first-line treatment for NAS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Buprenorphine pharmacotherapy for the management of neonatal abstinence syndrome in methadone-exposed neonates. Taleghani, AA., Isemann, BT., Rice, WR., et al.[2022]

In a unique case series involving three women from the MOTHER study, both methadone and buprenorphine were found to be effective and safe for treating opioid dependence during pregnancy, with methadone leading to higher neonatal birth weights.

Buprenorphine exposure was associated with lower neonatal abstinence syndrome (NAS) scores compared to methadone, suggesting it could be a viable alternative treatment for pregnant women with opioid dependence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized controlled trials in pregnancy: scientific and ethical aspects. Exposure to different opioid medications during pregnancy in an intra-individual comparison. Unger, A., Jagsch, R., Jones, H., et al.[2021]

Buprenorphine shows better or similar safety outcomes compared to methadone for treating neonatal abstinence syndrome (NAS), with fewer infants requiring treatment and shorter hospital stays, based on a review of 5 critical studies.

Both medications are effective for pregnant women with opioid dependence, but buprenorphine may be a preferable option due to its improved outcomes, although more extensive studies are needed to confirm its safety and advantages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Buprenorphine Versus Methadone for Opioid Dependence in Pregnancy. Noormohammadi, A., Forinash, A., Yancey, A., et al.[2018]

Citations

1. heal.nih.gov heal.nih.gov/research/infants-and-children/act-now

Advancing Clinical Trials in Neonatal Opioid Withdrawal ... Under a traditional scheduled opioid taper approach, babies with NOWS get morphine or methadone at regular set times. As symptoms get better, ...

2. trialsjournal.biomedcentral.com trialsjournal.biomedcentral.com/articles/10.1186/s13063-025-09035-x

Optimizing pharmacologic treatment for neonatal opioid ... The scheduled opioid taper approach is traditional management for infants with NOWS; it was developed empirically in the 1970 s and is widely ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/31270130/

Standard Fixed-Schedule Methadone Taper Versus ... Infants successfully treated with the STMA (N = 22) had a median LOS of 10.0 days (IQR 4.0) compared with 17.0 (IQR 3.9) in the baseline FSMT group (P < .0001).

4. publications.aap.org publications.aap.org/pediatrics/article/129/2/e540/32573/Neonatal-Drug-Withdrawal

Neonatal Drug Withdrawal | Pediatrics Three studies individually and in combination reported significantly lower rates of treatment failure in infants assigned to opioid (paregoric ...

5. acog.org acog.org/clinical/clinical-guidance/committee-opinion/articles/2017/08/opioid-use-and-opioid-use-disorder-in-pregnancy

Opioid Use and Opioid Use Disorder in Pregnancy Infants born to women who used opioids during pregnancy should be monitored for neonatal abstinence syndrome by a pediatric care provider. Early universal ...

6. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK551498/

Neonatal Abstinence Syndrome - StatPearls - NCBI Bookshelf Neonatal abstinence syndrome (NAS) is a spectrum of clinical manifestations seen in neonates due to withdrawal secondary to intrauterine drug exposure.