Neonatal Abstinence Syndrome - PowerPoint Presentation

Neonatal Abstinence Syndrome Lauritz Meyer, MDSeptember 11, 2015SDPA Conference

Disclosure I have no financial relationships to disclose.

Objectives Describe the incidence of Neonatal Abstinence Syndrome in the United StatesIdentify common symptoms of Neonatal Abstinence SyndromeFamiliarize with scoring systems for Neonatal Abstinence SyndromeIdentify treatment strategies for Neonatal Abstinence Syndrome

Neonatal Abstinence Syndrome Defined as a group of clinical signs and symptoms in a neonate resulting from prolonged exposure to illicit or prescribed drugsAlso called Neonatal Drug WithdrawalShort term syndrome but may have long lasting effectsCan be caused by in-utero exposure or iatrogenic exposure in hospitalized neonates

Opiate History Opium derived from the poppyFirst records of opium addiction are from the late 18th centuryIncrease in opioid addiction among women noted in the 19 th century

Opiate History Morphine isolated in 1804Use among women was associated with sterilityHeroin synthesized in 1874Initially thought addiction among women did not affect infants

Opiate History 1875: first reported case of neonatal abstinenceMore over years, most died, no specific treatment1903: First report of neonate surviving abstinence after Tx with morphine Called Congenital Morphinism1947: Seizures in a baby with Congenital Morphinism were successfully treated with morphine Led to increased awareness and name changed to Abstinence Syndrome in Neonates

Opiate History Methadone:Introduced in 1964 as a replacement treatment for opioid addictionMethadone clinics became very common for treating recovering heroin addictsInitially thought to not cause withdrawal in neonates, likely secondary to increased half life but since has become a common cause of NAS

Opiate History Buprenorphine:Approved as an alternative to methadone for opioid addiction in U.S. in 2002Sublingual tabletsAlso leads to NAS May cause less severe NAS symptoms than methadone

Illicit Drug Use in the U.S. 2013 National Survey on Drug Use and Health9.4% of population age 12 and older used illicit drugs within the past month (24.6 million individuals)5.4% of pregnant women aged 15-44 were current illicit drug users14.6% in age 15-17 year olds 9% in the first trimester4.8% in the second trimester2.4% in the third trimester22.9% of population age 12 and older were binge alcohol users in the past month (60.1 million individuals) 6.3% were defined as heavy drinkers 9.4% of pregnant women were current alcohol users, 2.3% were binge drinkers, and 0.4% were heavy drinkers

Illicit Drug Use in the Upper Midwest 2013 National Survey on Drug Use and HealthSouth Dakota6.17% of 12 years and older have used illicit drugs in the past month (42 thousand individuals)Minnesota 7.63% of 12 years and older have used illicit drugs in the past month (343 thousand individuals)Iowa 7.34% of 12 years and older have used illicit drugs in the past month (188 thousand individuals)

Incidence of NAS RisingIncidence has nearly doubled in the past 15 years based on national ICD-9 codingBecoming more widespreadNo longer just inner citiesIncreased use of prescription pain medications in pregnant women Improved recognition of NAS

NAS Causing Drugs OpioidsMorphine, Methadone, Hydromorphone, Fentanyl, HeroinCNS DepressantsBenzodiazepines, Alcohol, Barbiturates CNS StimulantsAmphetamines, Cocaine, Nicotine, CaffeineHallucinogensLSD, inhalants, mescalinePolysubstance use SSRIs

Opioids Among the world’s oldest known drugsUse of opium poppy goes back milenniaThree types: natural, endogenous, and syntheticProduces analgesia by binding to mu-opioid receptors in the CNS, PNS, and GI system Leads to inhibition of noradrenaline releaseEffects include:SedationEuphoria Respiratory depression Decreased GI motility Long term use leads to physical dependence

Opioids WithdrawalThe initial condition that led to the diagnosis of NASAbrupt discontinuation leads to:Massive release of noradrenalineLeads to autonomic, behavioral, and GI symptoms/signs Timing, presentation, and severity of symptoms dependent upon maternal and neonatal factorsDrug, dosage, time since last use, placental transfer, metabolismMu-opioid receptor (OPRM1) and catechol-o- methyltransferase (COMT) gene genetic variations affect the need for and the length of treatment

Opioids Neonates exposed in-utero have signs/symptoms of opioid withdrawal 55-94% of the timeAddition of other maternal or neonatal medications, neonatal diet, and environmental stimuli can affect the severity and incidence of NASSymptoms can present within the first 24 hours of life, or be delayed for 7 days or longer Dependent on type of drug, metabolism, etc.

Clinical Symptoms of NAS due to Opioids GastrointestinalVomiting/diarrheaPoor feedingUncoordinated suck Constant suckingDehydrationPoor weight gain/FTTAutonomicExcessive sweating Temperature instability Nasal stuffiness Mottling Yawning Neurologic Tremors Irritability Increased wakefulness High-pitched cry Hypertonicity Hyperactive reflexes Exaggerated Moro Seizures Frequent sneezing/yawning

Video https://www.youtube.com/watch?v=2eP5EnFSG0c

Clinical Symptoms (cont.) Seizures occur in 2-11 percent of NAS casesEEG abnormalities have been seen in up to 30% of NAS cases attributed to opioidsIncreased incidence of Small for Gestational Age (SGA) birthsIncreased incidence of respiratory difficulties

Timing of Withdrawal Wide variation dependent upon the half-life of the drug and the recent history of drug useSymptoms can present within the first 24 hours for short half life drugs (Heroin), but may not present for 72 hours up to 7 days or longer for long half life drugs (Methadone, Buprenorphine)Neonates born to mothers who have gone >7 days from last use are at much lower risk for NAS, but still require close monitoring

Methadone Common prescription drug used for recovering Heroin addictsLong half life leads to delayed presentation of NAS symptoms for several daysHigher daily doses are more likely to lead to NAS>95% of infants will develop symptoms with doses >20mg/day Difficult to wean mothers during pregnancy due to high risk of fetal complications with abrupt dose changes

Buprenorphine Increasing use for opiate withdrawal including during pregnancyLower transplacental transfer due to higher molecular weightThought to lower the incidence and severity of NAS Decreased length of stay for infants with NASSubutex – buprenorphine onlySuboxone – buprenorphine plus naloxone to guard against misuse

Fentanyl Use of transdermal patch increasing for treatment of chronic painShort half life leads to rapid symptoms of NAS in the first 24 hoursRisk of rapid withdrawal for mother if lose access to supply of patchesBreastfeeding a concern due to risk of rapid withdrawal

Depressants Alcohol withdrawal can present 3-12 hours after birthMay show symptoms of NAS similar to opioid withdrawal although usually more mildBenzodiazepine withdrawal can have a variable onset dependent upon half life and dosage

Stimulants Methamphetamine and cocaine have low rates of NAS requiring therapySymptoms at birth more likely the result of drug effects vs withdrawalSimilar symptoms to opioid NAS – tremors, irritability, poor sleep pattern, excessive sucking, etc High rates of prematurity and IUGR statusIncreased risk of placental abruptionCommon to see polysubstance use

SSRIs Used in 7-13% of pregnancies10-30% risk of Poor Neonatal Adaptation SyndromeTremors, increased tone, high pitched cry, poor sleep patterns are common symptomsIncreased rate of respiratory distressIncreased risk of PPHN Generally presents in the first 48 hours of life and resolve within another 48 hoursParoxetine (Paxil) carries the highest risk

Withdrawal vs Toxicity Withdrawal:Symptoms develop as the amount of drug decreases, indicative of dependence on the drugMost common with opioids, but also with depressants and SSRIsToxicity: Symptoms present early and decrease as the drug is metabolizedMost common with stimulants such as cocaine or methamphetamine

Premature Infants Lower risk of developing NAS <35 weeksCentral Nervous System developmentally immatureMotor dysfunction less able to be expressedLower total drug exposure in-uteroLower fat stores limits build up in the body Lack of accurate assessment tools to identify symptoms in premature infants – all assessment tools created for term infantsRisk decreases with decreasing GA

Iatrogenic NAS Many NICU patients are exposed to opioids and benzodiazepines during their stay (surgical, sedation for PPHN, ect.)May develop after 5-7 days of exposure to fentanyl/morphine or benzodiazepinesImportant to recognize the risk and treat these infants similar to in-utero exposure to avoid adverse outcomes

What To Do? Neonate is at risk for NAS based on known exposure history or has other risk factors that are concerning for possible NASDrug ScreenInitiate abstinence scoring systemClose observation

Drug Screening UrineLow sensitivity due to need for a recent exposure to show positiveRapid turn around time (within 24 hours)MeconiumHigh sensitivity and specificity Slow turn around time (days to a week)May miss meconium if stooled in-utero or at birth and not collectedUmbilical Cord Increasing use Not dependent upon collection of urine or meconium Eliminates possibility of false positive secondary to exposure after birth

Abstinence Scoring Several scoring systems are available with no clear standardNot drug specific – primarily for opiatesMost hospitals choose one and adapt to their needsTwo most common: Finnegan Neonatal Abstinence Scoring System, Neonatal Withdrawal Scoring System ( Lipsitz)Others available: Ostrea criteria, Neonatal Withdrawal Inventory, Riley Infant Pain Scale

Finnegan

Finnegan Most widely used scoring systemComprised of 20 most common signs and grouped into CNS, metabolic/respiratory, and GI categoriesEach symptom assigned a score based on significance and potential for harmCumulative score of 7 or less considered mild NAS without need for pharmacologic treatment Scores >8 suggest careful monitoring and likely need for pharmacotherapy

Lipsitz Assigns a score of 0 to 3 for tremors, irritability, reflexes, stools, muscle tone, skin abrasions, and tachypneaAssigns a score of 0 to 1 for frequent sneezing, frequent yawning, and vomiting or feverA score of 5 or greater suggests opiate exposureA score of 8 or greater indicates need for pharmacotherapy

Treatment Goals of treatment:Allow the infant to withdraw without excessive excitation that can lead to withdrawal symptomsEspecially important to avoid the most severe, i.e. seizuresEstablish a physiologic sleep pattern Establish consistent weight gainAllow the infant to communicate needs with caregiversHelp the infant manage new stimuli in its new environment

Non-pharmacologic Treatment First line therapy is ALWAYS non-pharmacologicRequired for all infants with suspected NASKeep environmental stimulation to a minimumLow lightQuiet environment SwaddlingGentle handling with cares/cluster caresQuick response to symptomsDemand feeding*** Cuddlers ***

Non-pharmacologic treatment Many large centers with a high population of NAS cases have a specific section or completely separate NICU dedicated to the care of NAS babiesNursing care with experience in caring for NAS babies is crucial to help ensure a safe and swift recovery

Pharmacotherapy Decision to initiate pharmacotherapy based on abstinence scoring and the known or suspected drug exposureIndicated when non-pharmacologic treatment is insufficientIndicated for moderate/severe symptomsRequired to prevent severe complications, i.e. seizures

Pharmacotherapy Drawbacks:Increases length of drug exposureIncreases length of stayMay impact maternal-infant bonding as a result Benefits:Decreases the acute signs of NASDecreases the risk of severe complications like seizures or failure to thrive

Pharmacotherapy Ideally treat with the same class of drug as that causing NASChoice can be a challenge when drug of exposure is unknown or in setting of polysubstance use

Pharmacotherapy Mainstay of therapy has been opioidsOpioids are first line treatment based on available evidenceHistoric use of tincture of opium and paregoric have fallen out of favor due to safety concernsMorphine and Methadone are the two most common opioids used to treat NAS Buprenorphine is a potential option but limited safety and efficacy data in neonatesSublingual dosing appeal

Pharmacotherapy - Morphine Variety of dosing regimens available for MorphineHigh dose0.08-0.1 mg/kg every 4 hours POLow dose0.03-0.04 mg/kg every 4 hours PO With either regimen, the dose may be increased by 20% every 8 hours until symptoms are well controlledTypical maximum dose is 0.2 mg/kg/doseOther regimens include escalation by changing to every 3 hour dosing

Pharmacotherapy - Morphine Weaning is individualized to each patientTypical approach is to maintain current dose when adequate symptom control is achievedAfter 48-72 hours of stability may begin weaningWean by decreasing dose by 20% every other day May require delayed taper or escalation if symptoms worsen

Pharmacotherapy - Methadone Typical starting dose of 0.05-0.1 mg/kg every 6 hours POAdjust doses up and down by ~20% as needed similar to MorphineMay require less frequent adjustments since half life is longer and effects of dose changes may be slower to manifest than with Morphine

2nd Line TreatmentUsed for severe NAS that is not controlled with a first line agentPhenobarbital Most commonly used second line drug Diazepam First line if the known cause of NAS is a benzodiazepineClonidine Used to avoid the sedative effects of phenobarbital

Phenobarbital Preferred medication for non-opiate NASGABA agonistDoes not prevent seizures at typical NAS dosesMinimal benefit for GI symptomsUsual dose: 16 mg/kg loading dose, then 2-8 mg/kg/day divided BID for maintenance Route: Oral, IV, or IMContinue treatment until Morphine or Methadone are weaned off before weaning phenobarbitalTaper phenobarbital by 10-20% per day

Diazepam Requires caution due to limited capacity of infants to metabolizeContains sodium benzoateRequires monitoring for jaundice as it may displace bilirubin for conjugation and excretionInitial dose 1-2 mg every 8-12 hours May also consider lorazepam or midazolam dependent on preference and experience

Clonidine Effective adjunctive medication with opioids in shortening the duration of treatmentCentrally acting alpha adrenergic agonistRequires monitoring for hypotension and bradycardiaInitial dose 0.5-1 mcg/kg followed by 3-5 mcg/kg/day divided every 4-6 hours Requires taper due to risk of hypertension and tachycardia with abrupt discontinuation

Naloxone Contraindicated in the treatment of NAS due to the risk for rapid and severe NAS symptomsMay precipitate seizures in some neonates

Iatrogenic NAS Treat with same drug class that was used for pain control/sedationCalculate total daily cumulative dose and divide into a schedule of equivalent medicationDo not forget PRN doses!!

Nutrition and NAS May have increased metabolic demandsMay require significant increase in kcal/kg/day to offset losses from NASFortified feedsAd lib demand schedule Prompt response to hunger cues important May be frequent, small volume feedersRequires close monitoring of weight gain/loss and fluid status Vomiting and loose stools may lead to increased fluid requirements PO intake may be poor N N G supplementation or IV hydration

Breastfeeding Low rates of breastfeeding among NAS affected neonatesAAP supports breastfeeding in appropriate situationsMay help with withdrawal symptomsRequires strict adherence and review of risks and benefits with the mother before initiation

Breastfeeding Allowed Ok to breastfeed when mothers are on a stable dose of methadone or buprenorphineLow doses excreted in breastmilkMothers who are in a treatment program prior to delivery or are enrolled into a program at birthRequires strict adherence to the program with continued close follow up No other contraindications to breastfeeding

Breastfeeding Contraindications Polysubstance abuse or history of non-adherence to treatment programsHIV or other infectious riskMothers taking hydrocodone or oxycodoneRequire closer monitoring as these drugs are highly excreted in breastmilk Any illicit drug use during the 30 day period prior to delivery

Breastfeeding Best to follow strict feeding protocols to ensure a similar amount of breastmilk is provided each dayHave mothers pump and provided pumped breastmilk early on to ensure consistent volumesProvide for 1-2 feeds on day 1, and gradually increase as supply increases over the following days Discontinuation of breastfeedingImportant to stress weaning off of breastmilk as abrupt discontinuation may precipitate NAS symptoms at that time

Discharge and Follow Up Infants at risk for NAS require in-hospital monitoring until past the window for severe withdrawalDependent upon the drug exposureWith known history of short half life drugs such as morphine or hydrocodone, may be discharged after 72 hours With known history of long half life drugs such as methadone, may be discharged after 5-7 daysFollow up visit should be scheduled within 2 days of discharge to ensure continued close monitoring

Discharge after Treatment Infants requiring pharmacotherapy:Discharge frequently delayed until fully weaned off of medications with an adequate observation period off pharmacotherapy to ensure no rebound NASDischarge while still on therapy is an option if parents are reliable, taper is easily followed, and adequate follow up is assured Extensive education about non-pharmacologic measures for treatment of symptoms and strict criteria for seeking evaluation are vital at discharge

Prenatal Counseling Important to be empathetic and nonjudgementalTeratogenicityOpioids and stimulants can cause SGA status, prematurity, abruption, SAB Cocaine and methamphetamine may lead to long term neurodevelopmental issuesExpected Clinical CourseObservation for at least 3-7 days for signs and symptoms of NASNon-pharmacologic therapy is the primary treatment Pharmacotherapy will require treatment that may last weeks to months

Prenatal Counseling BreastfeedingBreastfeeding may be suitable in certain situations dependent upon the drugs usedBreastfeeding may help decrease NAS symptomsHelpful to have a breastfeeding plan prior to delivery Social ConcernsVital to discuss the importance of caregiver involvement in treatment of NASAdherence to follow up schedule and treatment recommendations will be vital to outcomes

Take Home Points NAS is a common condition in newborns and the incidence is risingClose monitoring is vital for infants at risk of NASInfants who demonstrate symptoms without known risk factors require evaluation for NASNon-pharmacologic measures are the first line therapy for NAS Breastfeeding is not contraindicated in NAS in some situations and can be beneficial in NAS treatment

References Avery’s Diseases of the Newborn, 9th Ed. 2012Burgos A, Burke B. Neonatal Abstinence Syndrome. NeoReviews . 2009;10(5)e222-229.Kocheriakota P. Neonatal Abstinence Syndrome. Pediatrics. 2014;134(2):e547-561.Tolia V, Patrick S, Bennett M, et al. Increasing Incidence of the Neonatal Abstinence Sydrome in the U.S. Neonatal ICUs. NEJM. 2015;372(22)2118-2126. Jansson L. Neonatal abstinence syndrome. UpToDate . 2015. Patrick S, Davis M, Lehman C, Cooper W. Increasing incidence and geographic distribution of neonatal abstinence syndrome: United States 2009-2012. J Perinatology. 2015. 1-6. 2013 National Survey on Drug Use and Health. http://www.samhsa.gov/data/population-data-nsduh