9/23/2019

1

Assessment of Neonatal Opioid

Withdrawal Syndrome and Current Practices

Sarah Newman, DNP, APRN, NNP-BC

Disclosures• I have nothing to disclose.

Objectives1. Identify the incidence of NOWS and the

impact NOWS has on healthcare

2. Define NOWS and discuss the presentation, signs, and symptoms, and common tools used to measure severity

3. Discuss common treatments of neonatal opioid withdrawal syndrome with emphasis on Buprenorphine

The Problem

• Substance abuse is a public

health epidemic nationwide and

abuse occurs across all cultural,

ethnic, religious, and

socioeconomic groups

Perinatal Substance Abuse• Rate of substance dependence or

abuse highest among adults aged 18

to 25 (17.3%) when compared to

youths aged 12 to 17 (5.2%) and

among adults aged 26+ (7%)

• Women represent 30% of the total

addicted population

• Estimated that >4.4% of pregnant

women abuse 1 or more substances

during pregnancy

• For pregnant teenagers, the rate of

recent illicit drug use was

approximately 15 percent• http://www.samhsa.gov/data/population-data-

nsduh/reports• Wendell A. D. (2013). Overview and epidemiology of substance abuse in

pregnancy. Clinical Obstetrics and Gynecology, 56:91-96.

Types of Perinatal Exposure to Opioids

(1) prescriptions for pain management, such as fentanyl and oxycodone

(2) medication-assisted treatment for opioid addiction, such as use of methadone and buprenorphine;

(3) prescription misuse or abuse (such as using without a prescription, using a different dosage than prescribed, or continuing to use a drug when no longer needed for pain)

(4) illicit opioid use, such as heroin. **These types of prenatal opioid use are not mutually exclusive.

9/23/2019

2

• The incidence of NOWS in the United States has increased

five-fold over the past decade.

• A recent study showed that cases of NOWS in the US has

increased from a rate of 1.2 per 1,000 hospital births per year

in the year 2000, to 8 per 1,000 hospital births in 2014.

• Hospital costs for NOWS births have increased from $91

million to $563 million after adjusting for inflation

*National institute on Drug Abuse

National Trends

Figure 1: Incidence of NAS by primary payer

Nebraska Trends

� The rate of NAS/NOWS doubled from 1.0 cases per 1,000 hospital births in 2010 to 2.3 cases per 1,000 hospital births in 2014

Economics • 35% increase in NICU financial expenditures

related to NOWS in the United States between 2000 and 2009

• Newborns with NOWS stayed in the hospital an average of 16 days and incurred hospital charges averaging about $66,000, compared with an average of 3 days and $3,500 for all other hospital births, according to data from 2009

• 2012 birth hospital charges• $93k per pharmacologically treated infant

Patrick S, Schumacher R, Benneyworth B, Krans E, McAllister J, Davis M. Neonatal abstinence syndrome and associated health care expenditures, United States, 2000-2009. JAMA . 2012;307(18):1934-1940.

Maternal Screening• No Federal guidelines- determined by each

State

• Many mothers are not identified

• Pregnancy and motherhood aretimes of increased motivation for treatment

9/23/2019

3

Treatment: PrenatalWHO 2014 Guidelines: “Pregnant women

dependent on opioids should be encouraged to use opioid maintenance treatment whenever available rather than to attempt opioid detoxification. Opioid maintenance treatment in this context refers to either methadone maintenance treatment or buprenorphine maintenance treatment.”

Substance Abuse During Pregnancy May Result in…• Miscarriage• Preterm birth• Behavioral and cognitive problems in

prenatally exposed children• Continuous maternal abuse, especially

during the first half of gestation, is likely to disrupt the complicated neural wiring and associative connections that allow the developing brain to learn and mature.

Studies show that 55% to 94% of infants exposed prenatally to opiates

experience some degree of life-threatening withdrawal symptoms

shortly after birth• “A generalized disorder

characterized by central nervous system hyper-

irritablility, gastrointestinal dysfunction, respiratory

distress, and vague autonomic symptoms.”

-Finnegan & Weiner (1993)

Neonatal Opiod Withdrawal Syndrome

• Constellation of

behavioral

and physiologic signs caused by cessation of

exposure to licit

and illicit drugs

-Handman (2010)

What is NOWS?

There are 2 types:1. Passive Exposure- The fetus is exposed to opioids or opioid derivatives during pregnancy and the infant develops a physical dependence on the substance. (Maternal use during pregnancy)2. Iatrogenic Exposure-Postnatal use i.e. fentanyl or morphine

Detection and ScreeningDiagnostic testing associated with detecting opioids in the infant is typically that of blood and urine drug screens from mother and baby.

• However, if the drug exposure was not recent, these tests are not the most sensitive

Urine-• Obtain as soon as possible after birth-earliest

collection will contain highest concentration of substances

• High false negative rate (up to 60%) due to it reporting only recent drug exposure

• Usually needs confirmatory testingMeconium-

• Testing is quite sensitive• Meconium accumulate drugs in-utero for approx the last 5

months of pregnancyUmbilical Cord-

• Comprehensive high-resolution drug screen• Confirmation testing usually not required

9/23/2019

4

Pathophysiology of NASActivation of opiate receptors in locus ceruleus

Decreases Norepinephrine and Dopaminerelease

With prolonged exposureUpregulates norepinephrine output to

maintain homeostasisAt Birth

Remove inhibition = Noradernergic Overcharge with associated symptoms

***Neuro-chemical reaction due to depletion of drug from receptors in the brain

***Neonate is not addicted but psychologically dependent

Differential Diagnosis

• hypoglycemia• infection• hypocalcemia• hypomagnesemia• hyperthyroidism• CNS injury

Hamdan et al (2012)

Principles of NAS Management (Protocol)

1. Accurate Observation + Assessment2. Supportive Care

*Environment of Care*Therapeutic Handling*Symptomatic Care

3. Pharmacological Intervention

Standardized Protocol�VERMONT OXFORD NETWORK NAS

COLLABORATIVE, 2013-2015

� Participating hospitals, care standardized by protocol or policy development

� Shortened length of treatment from 16 days to 15 days

� Shortened length of stay from 21 days to 19 days

� Hospitals with protocols or policies focused on infant symptom scoring had lowest length of stay

� 3.1 days

Standardized Protocol

• Asti et al• 92 infants total

• 23 infants without standardized protocol • 69 infants with standardized protocol

• LOS in NICU decreased from 36 days to 18 days within 3 years of implementation

Asti et al. Pediatrics. 2015. 135(6). 1494-1500.

Standardized Protocol• Hall et al.• Retrospective

• 981 infants from 6 hospitals in Ohio• Jan 2012-Aug 2014

• Newly implemented protocol group had decreased LOT and LOS

• Treatment days decreased 23 days vs 34 days• LOS 23.7 vs 31.6 days

Hall et al. Pediatrics. 2015. 136(4). E803-e810

9/23/2019

5

Standardized Protocol

• Burnette et al.• Jan 2014-June 2016• 395 infants total• Standard vs strict morphine wean• Decrease in LOS from 23 days to 18 days

Burnette. Journal of Maternal-Fetal Neonatal Med. 2018.

Monitoring/Assessing• Current monitoring and treatment of NAS vary depending on

the institution and the philosophy of the physicians.

• The AAP Committee on Drugs recommends scoring NAS symptoms using an appropriate tool.

• purpose of using tool is to enable a systematic, objective, periodic and thorough eval of the infant to support their care needs and identify the need for pharmacologic therapy

• Finnegan most commonly used

• Contains 21 signs and symptoms of withdrawal

-Finnegan LP (1990)

Finnegan Scoring Tool• Majority of research on neonatal withdrawal has used the Finnegan Scale

• developed/validated in 1975 by Dr. Loretta Finnegan• designed to quantify the severity of NAS and guide treatment

• score infant behaviors associated with withdrawal• used on term or near-term infants• only as reliable as the person scoring

• 3 System Groups1.Central Nervous System Disturbances2.Metabolic/Vasomotor/Respiratory Disturbances3.Gastrointestinal Disturbances

-Hudack & Tan (2012)

Use of the Finnegan Scoring Tool• Scoring should be started within 4 hours after birth on infants with known in-utero drug exposure and started upon suspicion of withdrawal in infants with unknown maternal drug history.

• Scoring should be done every 3-4 hours and that schedule should be kept.

• Score before feeding (or feed some first, then score, then finish feeding)

• Record the time of scoring (this is the end of the current observation interval)

Use of the Finnegan Scoring Tool, continued

• Give points for all behaviors or symptoms observed during the scoring interval

• The infant should be AWAKE to test reflexes. Then calm the infant (may have to give portion of the feed) before observing respirations (make sure to count for the full minute) and muscle tone.

• Remember hunger can have the same S&S of withdrawal

• Start pharmacological therapy if score 3 in a row of 8 or greater or 2 in a row of 12.

9/23/2019

6

Assessment withdrawal symptoms

Autonomic• temperature

instability• low grade

fever• diaphoresis• mottling• tachypnea• nasal

stuffiness

Neurologic Signs

•Irritability

•poor sleep

• increased muscle tone

•tremor

•high pitched cry

•seizure

•sneezing

•yawning

GI Signs•poor feeding

•poor weight gain

•diarrhea

•vomiting

Common Symptoms• The characteristics and symptoms that drug exposed babies have in common-nature of these and their frequency/timing will depend on factors such as:

• Drug baby exposed to/amount of drug used

• Time between last maternal drug use and infant delivery• How each individual baby metabolizes the drug• The babies own tolerance

***No two babies will react exactly alike. It

is the responsibility of the caregiver to

carefully monitor and “read” the infant and

the signs!

Central Nervous System Disturbances scoring

Crying(high-pitched for less than or more than 5 minutes despite

caregiver intervention)

2-3

Sleeping less than 1-3 hours 1-3

Moro Reflex (hyperactive-rhythmic/involuntary or markedly

hyperactive-jitteriness but with hand clonus >8-10 beats)

2-3

Tremors(both disturbed and undisturbed) 1-4

Increased muscle tone 1

Excoriation (chin, knees, elbows, toes, nose-NOT diaper area) 1

myoclonic jerks (involuntary twitching face/jerking of limbs-

more pronounced than jitteriness of tremors)

3

Generalized convulsions 5

Metabolic/vasomotor/respiratory disturbances scoring

sweating (forhead, upper lip, back of head) 1

hyperthermia 1-2

frequent yawning (greater than 3/interval) 1

mottling (marbling discoloration) 1

nasal stuffiness 1

sneezing (greater than 3/interval) 1

nasal flaring 2

tachypnea (RR greater than 60/min) 1

Tachypnea with retractions 2

GI Disturbances Scoringexcessive sucking(vigorous rooting with attempts

to suck fist, hand, or pacifier before/after

feeding)

poor feeding (excessive sucking as above but

infrequent/uncoordinated suck or gulping with

frequent rest periods to breath)

2

regurgitation or projectile vomiting(not

associated with burping)

2-3

loose stools(curdy, seedy or liquid without water

ring)

2

water stools(liquid with water ring) 3

1 Problems with scoring tool• Recently the validity of this tool has been

questioned due to its psychometric properties.• Inconsistency regarding scoring intervals and

feeding schedule.• Inconsistence between staff with scoring.• Inconsistency with defining the signs and

symptoms of withdrawal.• Example: How do you differentiate between

mild/moderate/severe tremors?

• Example: Errors in scoring for excoriation

9/23/2019

7

Eat, Sleep Console (ESC)• Recently, a new approach was reported

• According to the AAP, new research has suggested a “common sense” approach to treating infants with NOWS to reduce length of stay (LOS)

• Yale-New Haven Children’s Hospital researched whether increasing non-pharmacologic interventions could decrease length of stay.

• ESC care method’s sole principles are to:

1. Optimize the newborn’s functioning as a neonate through intensive non-pharmacologic treatment provided by the parent or caregiver

2. Reserving medication treatment only for those newborns who are unable to eat, sleep, or console despite maximal non-pharmacologic care (or if other significant concerns are present such as seizures or apnea).

A Novel Approach-Yale Study• Retrospective study comparing treatment decisions of 50

consecutive opioid-exposed infants (March 2014-August 2015)

• All infants had Finnegan scores recorded but were managed utilizing ESC assessment approach

• Actual treatment decisions made by using the ESC approach were compared to the predicted treatment decisions based on Finnegan scores given.

• ESC approach=6 infants (12%) treated

• Finnegan Scoring results= predicted to treat 31 infants (62%)

• Utilizing ESC model decreased LOS from 22days to 6 days without an increase in readmission rates

Eat, Sleep, Console Approach• Goal of therapy-Infant should be allowed to

function as a normal neonate• ESC approach evaluation:

• Able to eat at least 1 ounce per feed or breastfeed well

• Able to sleep for at least 1 hour undisturbed• Able to be consoled within 10 minutes

ESC Timing of Assessments• Staff should perform ESC care assessments every 3-

4 hours after feedings

• Assessments should be initiated within 4-6 hours of birth and should continue for 4-7 days for infants

• Assessments should include all ESC behaviors that occurred since the infant’s last assessment as well as all non-pharm care interventions implemented.

• Assessments should incorporate input from all infant caregivers

• Infants should be assessed in their own room and do not need to be removed from their mother (or other caregiver) if being held.

Can the infant eat at least 1 ounce per feed or

breastfeed well?

Can the infant sleep at least one hour?

Can the infant be consoled within 10

minutes?

Infant is considered to be well managed and

no further interventions are necessary.

Non-pharmacologic interventions increased if possible:• Feeding on

demand• Swaddling and

holding• Low-stimulation

environment• Parental

presence

Start pharmacologic therapy (per protocol)

Not

Improved

No

No

No

No

Yes

Yes

Yes

Finnegan Scoring VS ESC

Finnegan Scoring• Goal: Suppress withdrawal signs

• NICU: Mom visits

• Finnegan Scoring: treat the number

• “supportive care”

• Feed on demand

• Methadone/Buprenorphine/Morphine

• SURPRISE

• Staff cares for infant

ESC• Goal: Infant to function as normal neonate

• Mother and Child remain together

• Eat/Sleep/Console:treat the infant

• SUPPORTIVE CARE

• No scheduled feeds

• Medication=non-pharm interventions

• Prenatal preparation/planning

• Staff coaches/supports parents

9/23/2019

8

Non-pharmacologic/Therapeutic Handling

� SHOULD ALWAYS BE IMPLEMENTED FIRST AND CONTINUED AS AN ADJUNCT TO DRUG TREATMENT

•Caregivers need appropriate training•Comforting techniques are critical to management of withdrawing infants

•Each type of drug exposure presents its own unique challenges

•Basic principles of handling apply to all

7 Principles Basic Handling

1.Swaddling2.C-position3.Head to toe movement4.Vertical rock5.Clapping6.Feeding 7.Controlling the environment

Pharmalogical TherapyGoal of treatment is to give adequate amounts of medication to control S&S

Wean infant slowly to decrease adverse effects of withdrawal during the weaning process

The AAP guidelines illustrate oral morphine and methadone as first line therapies based on current evidence and practice in the US.BUT buprenorphine is being found to be safe and effective as well.This is a change from the 1998 AAP recommendations, which included tincture of opium as the preferred choice of treatment for opiate withdrawal.

(Hudack &Tan, 2012)

Medications used to treat NOWS

Tolia VN. N Engl J Med. 2015; 372; 2118-2126.

Methadone• Opioid dependence• Preparation- 1 & 2 mg/ml concentration• Contains 8% Alcohol• Dose: 0.05-0.1mg/kg PO every 6-24 hours• Adjust dose 10-20% increments (by 0.05mg/kg until

scores stabilize• No established max dose• Wean based on abstinence score• t1/2 26 hours in neonates

• Long half life allows q day dosing but makes titration difficult

• Peak plasma levels reached in 2-4 hours• Adverse effects: bradycardia and tachycardia and an

ECG may be obtained to evaluate for QT-prolongation.

Neofax, 2014

Morphine• Mu receptor agonist• Opioid dependence• Preparation: 2 or 4 mg/ml• Contains no additives• 10% alcohol• It is the active ingredient in Tincture of Opium and

Paregoric (But much less alcohol)• Diluted to yield a concentration of 0.2 or 0.4 mg/ml

neonatal concentration

(AAP 1998)

9/23/2019

9

Morphine

• 0.03-0.1 mg/kg every 3-4 hours• Maximum dose - 0.2mg/kg/dose• Increase by 20% of initial dose every 8 hours until

symptoms controlled• Wean by 10-20% every 2-3 days based on abstinence

score (0.15mg/kg/d)• t1/2 9 hours• Steady state reached by 24-48 hours

(Kraft, et al., 2011 and Neofax 2014)

Methadone Vs. Morphine• Davis et al. (2018)• Randomized double blind

• Feb 2014-March 2017

• Utilized Finnegan Scoring Tool q 4 hours

• Treatment Arms

• Methadone or placebo q 4hours

• Morphine q 4 hours

• Adjunct Therapy-Phenobarbital

• Wean-Every 12-48 hours

• Discontinue therapy at 20% of initial dose

• Outcome-Primarily looking at LOS also secondarily looking at LOT

Davis et al. 2018. JAMA Pediatrics;177(8): 741-748.

Davis et al. Results• Treatment with methadone vs morphine had better

short term outcomes• Decreased LOT 15 days to 11.5 days• Decrease LOS from 20 days to 16 days

Buprenorphine• Long-acting partial mu-opiod receptor agonist

• Commonly used in treatment of adult abstinence therapy

• Decreased abuse potential, less respiratory depression than other opioid agonists

• Sublingual absorption

• T1/2 12 hours

• Alcohol concentration 30%

• Limited Data

• Side effects: respiratory depression

constipation, and sedation

BuprenorphineKraft et al. 3 phase clinical trial comparing sublingual buprenorphine vs. Oral morphine

� Buprenorphine dosing in study

� 15.9mCg/kg/day in 3 divided doses

� Increased dose by 25% until symptoms controlled

� Phenobarbital added when 60mCg/kg/day reached

� Weaned by 10% per day as tolerated

� Cessation of Therapy when at 10% of initial dose

� Buprenorphine treatment

� Decreased LOS (21days vs 33 days in morphine group)

� Decreased length of treatment (15days vs 28days in morphine group)

� Adjunctive phenobarbital used 5/33 infants in buprenorphine group (15%) and 7/30 infants (23%) in morphine group

Kraft, et al., (2017). Buprenorphine for the treatment of neonatal abstinence syndrome. The New England

Journal of Medicine, 376, 2341-2348.

BuprenorphineHall et al. (2018)

• Retrospective single center study

• July 2013-June 2017

• 360 infants

• Methadone/Morphine group-186 infants

• Buprenorphine group-174 infants

• Decrease LOT-10.4 days to 7.4 days

• Decrease LOS-15.2 days to 12.4 days

Hall et al. 2018. American Journal of Perinatology. 35; 405-412.

9/23/2019

10

BuprenorphineHall et al. (2016)

• Retrospective cohort Southwest Ohio

• January 2012-August 2014

• Buprenorphine group-38 infants

• Methadone group-163 infants

• Decrease LOT-14 days to 9.4 days

• Decrease LOS-20.7 days to 16.3 days

Hall et al. 2016. Journal of Pediatrics.170; 39-44.

Buprenorphine Treatment Protocol-NMC

• Change in first line treatment from methadone to buprenorphine

• Change in adjunct therapy from clonidine to phenobarbital

• Monitor all neonates with known prenatal exposure to opioids for 4 days.

– Baseline score within 2 hours after birth then scheduled every 3-4 hours thereafter

• Start pharmacologic treatment after non-pharmacologic treatments have been unsuccessful

– 3 consecutive scores of 8 or greater or 2 consecutive scores of 12 or greater

• Standardized dosing and weaning protocol

– Vital to reduce LOS/LOT

Evaluation (Analysis)

Compared LOS/LOT 2017 methadone patients to 2018

buprenorphine patients

Results-Demographics

0

5

10

15

20

25

30

35

40

Number of Patients Average Gestational Age Average Birth Weight (kg)

2017

2018

LOS AND LOT COMPARISON

0

10

20

30

40

50

60

LOS (treated in days) LOS (untreated in days) LOT (days)

2017

2018

DISCUSSION• Demographics virtually the same between the 2

comparison groups. • Data from 2018 has shown significant decrease

in LOS and LOT between the pharmacologic treatments

– Need more studies comparing buprenorphine to morphine and methadone

�Definitely need more studies on buprenorphine

9/23/2019

11

Clonidine• Adjunct Therapy-given in addition to Morphine to infants

with moderate to severe NAS uncontrolled by first line agent alone

• Decreases amount of norepinephrine released into the synapse lowering firing rate of adrnergic neurons

• Initial dose 0.5-1mcg/kg every 4 hours• t1/2 in neonate - 44-72 hours • NO alcohol• Adverse effects: hypotension, rebound hypertension if

clonidine not tapered off over more than a week, AV block, and bradycardia.

• Must taper off over 10-14 days

(Neofax Essentials Online 2014 and Bio,et al, 2011)

Phenobarbital• GABA receptor agonist

• Adjunct Therapy-given in addition to Morphine/Buprenorphine/Methadone to infants with moderate to severe NAS uncontrolled by initial drug alone

• Initial dose 20mg/kg loading dose

• Maintenance dosing 5mg/kg/day to begin 24 hours later

• t1/2 40-100 hours

• Obtain levels with goal of 20-30mg/ml

Take Away

Use of a stringent protocol/standardization and utilization of intensive non-

pharmacologic interventions to treat NOWS, regardless of the

initial opioid chosen, reduces the duration of opioid exposure and

length of hospital stay.

Conclusion•NOWS is becoming more prevalent in the US•The AAP Committee on Drugs recommends scoring NAS symptoms using an appropriate tool.

•Finnegan Scoring Tool most widely used but ESC approach is being researched

•VERY important to use non-pharmacologic therapies as first line treatment

•Pharmacologic therapy used will depend on institution

•AAP recommends use of Methadone or Morphine as first line drug of choice

•Research is being done on Buprenorphine-it is being found to be safe and effective