Neonatal Opioid Withdrawal Syndrome

Full update March 2021

Neonatal opioid withdrawal syndrome (NOWS), a specific type of neonatal abstinence syndrome (NAS), occurs when a baby withdraws from opiates the mother took or used chronically during pregnancy.2,13 The chart below answers common questions about NOWS.

Question

Answer/Pertinent Information

What are the signs and symptoms of neonatal opioid withdrawal syndrome?

Symptoms typically occur within 24 to 72 hours of delivery.1

  • Symptoms may be delayed until up to seven days or longer after delivery with exposure to longer-acting meds
    (e.g., buprenorphine, methadone).1,2,13
  • Common symptoms include:2,13
    • central nervous system (e.g., high-pitched crying, sleep disturbances, tremors)
    • gastrointestinal (e.g., diarrhea, poor feeding, regurgitation)
    • autonomic (e.g., nasal flaring or stuffiness, sneezing, yawning, tachypnea [rapid breathing], sweating)
  • Symptoms can progress to dehydration, weight loss, seizures, or death.1,2

How should newborns be screened for neonatal opioid withdrawal syndrome?

Take a thorough history about maternal drug use, including prescription and non-prescription products.1

  • Use non-judgmental, open-ended questions to encourage honest responses regarding substance use.7

Urine and/or meconium (newborn’s first stool) can be tested for opiates.2,12,13

  • Natural opiates show up on opiate screening (e.g., codeine, heroin, morphine).2
  • Synthetic opiates may not be detected on opiate screenings and need to be tested for separately (e.g., methadone, oxycodone).2

Several screening tools are available to assess the baby’s symptoms. Use a screening tool to assist with facility NOWS treatment, titration, and weaning protocol parameters. Examples include:2

How is the Modified Finnegan Scoring System used?

Scoring typically begins within two hours of birth, and is re-evaluated every few hours (e.g., every two to four hours).12

  • Follow-up scores may be measured sooner based on scores (e.g., within 30 minutes of a score >8).

Most institutions and studies define neonatal withdrawal as a score of ≥8.1,2

The Modified Finnegan Scoring System evaluates signs and symptoms in the following areas:

  • central nervous system (e.g., high-pitched crying, sleep after feeding, reflexes, tremors)
  • autonomic (e.g., sweating, nasal stuffiness, respiratory rate >60 breaths/minute)
  • gastrointestinal (e.g., excessive sucking, regurgitation, loose or watery stools)

Facility protocols then determine interventions based on individual, average, or consecutive scores.1,2

Examples of existing protocols can be found at:

What supportive measures are recommended?

The “eat, sleep, console” or ESC method is a strategy used in the management of NOWS. The ESC method involves assessing if babies can eat well, sleep undisturbed, or be consoled within ten minutes before using medications.24 In addition, facilities may encourage the use of prn medications instead of using scheduled doses.25 Some data suggest that using ESC, instead of traditional scoring methods, may reduce length of stay [Evidence Level B-3].24,27

The nonpharmacologic suggestions below are included as part of ESC, but also encouraged even if other scoring methods are used instead of the ESC method at your facility.

  • Encourage breastfeeding for optimal nutrition unless contraindicated (e.g., mom actively abusing drugs and not in treatment program), due to potential benefits.1,3,7,10,13
    • may delay NOWS onset, decrease severity, and decrease need for medication treatment of NOWS.
    • promotes mother-infant bonding.
    • consider even for mothers in treatment programs on stable doses (e.g., buprenorphine, methadone).
      • Only about 3% of maternal methadone dose reaches milk.2
  • Utilize supportive measures, such as:3,10
    • comforting techniques (e.g., holding skin to skin, swaying, rocking, swaddling, offering a pacifier)
    • frequent, small volume, high-calorie feedings
    • minimizing environmental stimuli (e.g., limit exposure to light or noise)
  • Encourage infants “rooming-in” with mothers.3,7,10
    • May reduce prevalence and severity of NOWS, as well as the likelihood for medication treatment of NOWS.3

When are medications appropriate?

Follow facility protocols for pharmacologic interventions. Using a protocol may be more impactful than the choice of medication used for weaning.7

  • Protocol-based therapy reduces opioid treatment duration and length of stay.6,7

Many protocols initiate medications using the following or similar cutoffs:4,5

  • 24 Rule: either three consecutive Modified Finnegan scores ≥8 or two scores >12.
  • withdrawal-associated seizures
  • if using ESC, when non-pharmacologic methods (e.g., rooming in, swaddling, holding, minimizing light and noise) are maximized and newborns are still unable to eat at least one ounce or breastfeed well, sleep for one hour undisturbed, or be consoled within ten minutes.26

Which medications should be used to treat neonatal opioid withdrawal syndrome?

Start with opioid replacement.7

  • Oral morphine is the most commonly used, likely because of short half-life and easy dosage adjustments.7,13
  • Oral methadone or buprenorphine (sublingual) is less commonly used compared to morphine, but may be associated shorter lengths of stay.2,7,11,14,15 (Note that morphine and methadone are generally preferred over buprenorphine until more data are available with buprenorphine.)17
  • May provide more consistent levels with less frequent adjustments.7
  • Use may be limited by ethanol content (~8% to 15% [methadone solution]; ~30% [compounded buprenorphine solution]).7,15

Adjunctive medications most often include clonidine or phenobarbital.7,13

  • Oral clonidine
    • Not typically used as monotherapy. Usually added to opiate therapy (e.g., morphine).17 Often added when total daily morphine doses are >1 to 1.6 mg/kg or in patients with significant diarrhea or insomnia.5,17
    • Clonidine may reduce the number of NOWS treatment days and the total dose of opioids used to treat NOWS over that period [Evidence Level B-2].19
    • Preferred over phenobarbital due to phenobarbital-associated neurotoxicity in animal studies and use being associated with adverse developmental outcomes.13
    • Monitor blood pressure and heart rate with use.2
  • Oral phenobarbital
    • Not typically used as monotherapy however, may be preferred for non-opioid withdrawal.5 Usually added to opiate therapy (e.g., morphine) especially when total daily morphine doses are >1 to 1.6 mg/kg or in patients when polysubstance use is suspected or known for the mother.5,16,17
    • Not effective for gastrointestinal symptoms of NOWS.23
    • Causes central nervous system depression and impairs sucking reflex.23
    • Clonidine generally preferred over phenobarbital (see above).

How should morphinea be dosed for neonatal opioid withdrawal syndrome?

Initial oral dose: 0.05 to 0.1 mg/kg every three to four hours.5,17

  • Increase doses by 10% to 20% about every 12 hours for three consistent Modified Finnegan scores >8 or two consistent scores >12.5 Use caution with total daily doses above 1.6 mg/kg, as these doses may lead to significant sedation or hypotension.17

Max dose: 2.3 mg/kg in 24 hours.17

Add additional therapy (e.g., clonidine) when total daily morphine doses are >1 to 1.6 mg/kg or in patients with significant diarrhea or insomnia.5,17

Consider weaning morphine once symptoms are stable and controlled (e.g., Modified Finnegan scores consistently <8) for about 24 to 48 hours. Reduce doses by about 10% to 20% every 24 to 48 hours.5,17

  • May discontinue once stable on 0.02 mg/kg/dose every four hours or 0.12 to 0.16 mg/kg/day for 24 to 48 hours.5

May discharge home 48 hours after discontinuation, as long as all Modified Finnegan scores remain <8 off therapy.7

How should methadonea be dosed for neonatal opioid withdrawal syndrome?

Initial oral dose: 0.05 mg/kg every 12 hours.18

  • Increase doses by ≤0.05 mg/kg/dose every 12 to 24 hours until Modified Finnegan scores stabilize.17,18 Use caution with doses above 0.1 mg/kg/dose every six hours, as these doses may lead to significant sedation or hypotension.17

Max dose: 0.2 mg/kg/dose every six hours.17

Consider weaning methadone once symptoms are stable and controlled (e.g., Modified Finnegan scores consistently <8) for about 24 to 48 hours.17 Tapering schedules vary and may be slower (e.g., lower methadone by 0.02 to 0.05 mg per dose, either once or twice weekly) compared to tapering off morphine.9

May discharge home 72 hours after discontinuation7 or some protocols may allow for tapers to be completed at home due to the slow nature of the taper in situations where caregivers can demonstrate the ability to measure appropriate doses.9

How should buprenorphinea be dosed for neonatal opioid withdrawal syndrome?

Initial sublingual dose: 4 to 6 mcg/kg/dose given every eight hours.11,15

  • Buprenorphine dose can be increased by about 25% if the sum of the previous three Modified Finnegan scores is higher than 24 or after one score ≥12.11,22

Max dose: 60 mcg/kg/day.11

Consider weaning newborns off of buprenorphine by reducing the dose by about 10% per day if the total of the previous three Modified Finnegan scores is less than 18. Buprenorphine can be discontinued once the dose has been reduced to 10% of the initial dose.11,22

Monitor newborns for at least 48 hours after discontinuation prior to discharge.11

How should clonidinea be dosed for neonatal opioid withdrawal syndrome?

Initial oral dose: 0.5 to 1 mcg/kg every three to six hours1,17 Higher doses (e.g., 1.5 mcg/kg/dose every four to six hours) can be used after the second week of life in newborns with severe NOWS.17

  • Clonidine may be increased by 0.05 mcg/kg/dose every 12 to 24 hours for two consecutive Modified Finnegan scores ≥8 or any single Modified Finnegan score ≥12. Typical clonidine doses range from 2 to 6 mcg/kg/day.17,21

Max dose: 24 mcg/kg/day.20

May be added to morphine when total daily morphine doses are >1 to 1.6 mg/kg or in patients with significant diarrhea or insomnia.5,17

Wean clonidine slowly (e.g., reduce doses by 0.25 mcg/kg every six hours, reduce dose by 25% per day by increasing dosing interval [for example, change every six-hour dosing to every eight-hour dosing]) over about three days starting the taper AFTER morphine is discontinued.17

Monitor blood pressure for at least 48 hours after discontinuation of clonidine before discharging home.21

How should phenobarbitala be dosed for neonatal opioid withdrawal syndrome?

Initial oral dose: 10 to 20 mg/kg loading dose. Then starting 12 hours later, give 1.5 to 2.5 mg/kg every 12 hours or 3 to 5 mg/kg every 24 hours.5,17 Note: loading dose is NOT necessary in the absence of seizures.17

  • Phenobarbital bolus doses (e.g., 5 to 10 mg/kg) can be given for seizures occurring while on phenobarbital.
  • Adjust dose based on monitoring and clinical parameters.8

Max dose: Specific maximum dosage not available.8

May discontinue (not necessary to taper phenobarbital, though some protocols may reduce dose by 20% each day5,13) after weaning has been completed for other medications (e.g., morphine).17

May discharge after discontinuation or some protocols may allow newborns to go home during phenobarbital taper.13

  1. Facility protocol may vary from these doses. These are example doses summarized from available NOWS protocols and clinical trial data.

Levels of Evidence

In accordance with our goal of providing Evidence-Based information, we are citing the LEVEL OF EVIDENCE for the clinical recommendations we publish.

Level

Definition

Study Quality

A

Good-quality patient-oriented evidence.*

  1. High-quality RCT
  2. SR/Meta-analysis of RCTs with consistent findings
  3. All-or-none study

B

Inconsistent or limited-quality patient-oriented evidence.*

  1. Lower-quality RCT
  2. SR/Meta-analysis with low-quality clinical trials or of studies with inconsistent findings
  3. Cohort study
  4. Case control study

C

Consensus; usual practice; expert opinion; disease-oriented evidence (e.g., physiologic or surrogate endpoints); case series for studies of diagnosis, treatment, prevention, or screening.

*Outcomes that matter to patients (e.g., morbidity, mortality, symptom improvement, quality of life).

RCT = randomized controlled trial; SR = systematic review [Adapted from Ebell MH, Siwek J, Weiss BD, et al. Strength of Recommendation Taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician 2004;69:548-56. http://www.aafp.org/afp/2004/0201/p548.pdf.]

References

  1. Hudak ML, Tan RC, Committee on Drugs, Committee on Fetus and Newborn. Neonatal drug withdrawal. Pediatrics 2012;129:e540-60.
  2. Holmes AP. NICU primer for pharmacists. Chapter 5: neonatal abstinence syndrome. 2016. https://www.ashp.org/-/media/store-files/p4757-sample-chapter-5.ashx. (Accessed February 18, 2021).
  3. MacMullen NJ, Dulski LA, Blobaum P. Evidence-based interventions for neonatal abstinence syndrome. Pediatr Nurs 2014;40:165-72, 203.
  4. University of Texas kids. University Health System: modified Finnegan’s neonatal abstinence scoring tool. June 2015. https://www.universityhealthsystem.com/~/media/files/clinical-pathways/modified-finnegans-nas-scoring-tool-pt-approved-0615.pdf?la=en. (Accessed February 18, 2021).
  5. Children’s Hospital of Philadelphia. Inpatient pathway for the evaluation/treatment of infants with neonatal abstinence syndrome. Revised January 2019. http://www.chop.edu/clinical-pathway/neonatal-abstinence-syndrome-clinical-pathway. (Accessed February 18, 2021).
  6. Joint Commission. Quick safety. Managing neonatal abstinence syndrome. September 2016. https://www.jointcommission.org/assets/1/23/Quick_Safety_Issue_27_Sep_2016.pdf. (Accessed February 18, 2021).
  7. McQueen K, Murphy-Oikonen J. Neonatal abstinence syndrome. N Engl J Med 2016;375:2468-79.
  8. Clinical Pharmacology powered by ClinicalKey. Tampa (FL): Elsevier. 2021. http://www.clinicalkey.com. (Accessed February 22, 2021).
  9. Johnston A, Metayer J, Robinson E. Management of neonatal opioid withdrawal. https://pqcnc-documents.s3.amazonaws.com/nas/nasresources/VCHIP_5NEONATAL_GUIDELINES.pdf. (Accessed February 18, 2021).
  10. Dow K, Ordean A, Murphy-Oikonen J, et al. Neonatal abstinence syndrome clinical practice guidelines for Ontario. J Popul Ther Clin Pharmacol 2012;19:e488-506.
  11. Kraft WK, Adeniyi-Jones SC, Chervoneva I, et al. Buprenorphine for the treatment of neonatal abstinence syndrome. N Engl J Med 2017;376:2341-8.
  12. HSHS St. Vincent, St. Mary’s, St. Nicholas. Neonatal abstinence syndrome. https://wispqc.org/wp-content/uploads/HSHSSt.Vincent.pdf. (Accessed February 18, 2021).
  13. Patrick SW, Barfield WD, Poindexter BB, et al. Neonatal opioid withdrawal syndrome. Pediatrics 2020;146:e2020029074.
  14. Davis JM, Shenberger J, Terrin N, et al. Comparison of safety and efficacy of methadone vs morphine for treatment of neonatal abstinence syndrome: a randomized clinical trial. JAMA Pediatr 2018;172:741-8.
  15. Lee JJ, Chen J, Eisler L, et al. Comparative effectiveness of opioid replacement agents for neonatal opioid withdrawal syndrome: a systematic review and meta-analysis. J Perinatol 2019;39:1535-45.
  16. Alabama Perinatal Quality Collaborative. Neonatal opioid withdrawal syndrome initiative: hospital team toolkit. https://cpb-us-w2.wpmucdn.com/sites.uab.edu/dist/1/156/files/2020/11/NOWS-Toolkit-Checklist.pdf. (Accessed February 22, 2021).
  17. Government of Indiana. Perinatal substance use taskforce. NAS pharmacologic therapy protocol. https://www.in.gov/laboroflove/files/NAS%20Pharmacologic%20Therapy%20Protocol.pdf. (Accessed February 22, 2021).
  18. University of Iowa Children’s Hospital. Identifying neonatal abstinence syndrome (NAS) and treatment guidelines. November 2014. https://uichildrens.org/sites/default/files/neonatal_abstinence_syndrome_treatment_guidelines_feb2013_revision-1.pdf. (Accessed February 22, 2021).
  19. D’Abaco E. Does the addition of clonidine to opioid therapy improve outcomes in infants with neonatal abstinence syndrome? J Paediatr Child Health 2021;57:155-9.
  20. NationwideChildrens.org. Neonatal abstinence syndrome management: initiation, escalation and stabilization. https://www.nationwidechildrens.org/Document/Get/168003. (Accessed February 22, 2021).
  21. Golisano Children’s Hospital of Southwest Florida- NICU. Management of the infant with neonatal abstinence syndrome. https://health.usf.edu/-/media/Files/Public-Health/Chiles-Center/FPQC/Golisano-NAS-guideline.ashx?la=en&hash=731C989F9BFDBFFE3C9D78F0C292D18055DB3221. (Accessed February 22, 2021).
  22. Kraft WK, van den Anker JN. Pharmacologic management of the opioid neonatal abstinence syndrome. Pediatr Clin North Am 2012;59:1147-65.
  23. Siu A, Robinson CA. Neonatal abstinence syndrome: essentials for the practitioner. J Pediatr Pharmacol Ther 2014;19:147–55.
  24. American Academy of Pediatrics News. Alternative treatment approach for neonatal abstinence syndrome may shorten hospital stay. May 4, 2017. https://www.aappublications.org/news/2017/05/04/PASNAS050417. (Accessed February 23, 2021).
  25. Allen A. Multi-site statewide collaboration for standardization of care for opioid exposed newborns. August 11, 2020. https://www.aappublications.org/news/2020/08/11/standardization-care-opioid-exposed-newborns-hospitalpediatrics. (Accessed February 23, 2021).
  26. Illinois prenatal quality collaborative. Sample decision tree flowchart eat, sleep, console method. https://ilpqc.org/wp-content/docs/toolkits/MNO-Neo/Sample-Decision-Tree-Flowchart-ESC.pdf. (Accessed February 26, 2021).
  27. Grossman MR, Lipshaw M, Osborn RR, Berkwitt AK. A novel approach to assessing infants with neonatal abstinence syndrome. Hosp Pediatr 2018;8:1-6. [abstract].

Cite this document as follows: Clinical Resource, Neonatal Opioid Withdrawal Syndrome. Hospital Pharmacist’s Letter/Pharmacy Technician’s Letter. March 2021. [370322]