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9/22/2015 Neonatal Abstinence Syndrome Jennifer Manning, DO Neonatologist, Akron Children’s Hospital Mahoning Valley Clinical Associate Professor of Pediatrics, NEOMED September 27, 2015 Adapted from a lecture by Linda Cooper, M.D. Neonatologist, Akron Children’s Hospital Mahoning Valley Clinical Assistant Professor of Pediatrics, NEOMED Objectives • • • • Define Neonatal Abstinence Syndrome (NAS) Discuss the symptoms of NAS List the drugs used by mothers Review the Ohio Dept of Alcohol and Drug Addiction Services (ODADAS ) data on drug patterns • Discuss testing of newborns- urine, meconium, and cord tissue • Describe Finnegan Scoring Objectives, continued • Discuss non-pharmacologic and pharmacologic treatment of NAS • Review our data 2012-2015 • Describe new approaches to treatment for mothers and babies 1 9/22/2015 Why This Matters To You • As family health care providers, you provide care for parents and their children • You have the ability to influence and educate your patients resulting in healthier women and children • You have an established relationship with your patients. They trust you and they will listen to you Neonatal Abstinence Syndrome • A constellation of signs and symptoms of withdrawal in infants who have been exposed to maternal opiates during pregnancy • These symptoms are manifested by CNS irritability, gastrointestinal disturbances, and autonomic instabilities NAS Facts • 55-94 % of term infants exposed to narcotics develop NAS • Severity of withdrawal may not correlate with the dose or duration of exposure • Infants < 34 weeks rarely develop typical symptoms of withdrawal seen in term infants • The early symptoms are mostly autonomic and central nervous system irritability, followed by gastrointestinal dysfunction - American Academy of Pediatrics Committee on Drugs Pediatrics. Jan 30, 2012 2 9/22/2015 More NAS Facts • Seizures occur in 2-10% of infants withdrawing from opioids • Over 30% of infants will have abnormal EEGs without overt seizure activity • Multi-drug exposure may manifest clinically with a biphasic pattern of withdrawal which include an exacerbation of symptoms 1-2 weeks after successful treatment of initial symptom Onset of Withdrawal Symptoms Substance Used Timing of Withdrawal Heroin 24-72 hours Methadone/buprenorphine At birth up to 7 days Benzodiazepines 1-2 weeks CNS Signs/Symptoms • • • • • • • Hypertonia Tremors at rest or when disturbed High-pitched or prolonged crying Extreme irritability and/or restlessness Exaggerated Moro reflex Sleep disturbances Seizures 3 9/22/2015 GI Symptoms • Frequent loose, watery stools • Poor or ineffective feeding (chew or bite the nipple) • Emesis • Poor weight gain • Dehydration • Failure to pass stool in first day or two Autonomic Symptoms • • • • Elevated temperature Nasal stuffiness Sneezing Skin mottling Miscellaneous Symptoms • Tachypnea • Skin excoriation, especially on the buttocks due to loose and frequent stools • Apnea- not commonly seen 4 9/22/2015 Differential Diagnosis Sepsis Hypocalcemia Hypoglycemia CNS hemorrhage Meningitis Perinatal asphyxia Polycythemia Drugs of Abuse Opium Poppy 5 9/22/2015 Opium History • 3400 B.C. in lower Mesopotamia, Sumerians cultivated and used opium for its euphoric effects (the joy plant). They passed it on to the Assyrians, then to the Egyptians • Over the centuries its reputation spread, and the trade stretched to India and China via the Silk Road • The British Empire secretly smuggled it to Chinaresulting in the first Opium War of 1839. Britain won; Hong Kong was ceded to Britain • Chinese immigrants brought opium to the US in the mid 1800’s with the railroad and the Gold Rush Opium Den San Francisco Heroin History • London, 1874: C.R. Alder Wright synthesized first heroin from opium by adding 2 acetyl groups to the molecule (diacetyl morphine) • Germany, 1897: Felix Hoffman was working for the pharmaceutical lab now known as Bayer Labs in Elberfeld, Germany • Hoffman re-synthesized heroin (diacetyl morphine) in an attempt to make codeine, a less potent form of morphine • Bayer named this new compound Heroin, from the Greek heros, or hero 6 9/22/2015 Bayer Heroin Bottle Bayer Heroin • Heroin was marketed from 1898 to 1910 as a non-addicting morphine substitute and cough suppressant • It later became an embarrassment for Bayer when it was discovered that heroin was quickly metabolized to morphine • A federal law banned OTC sale in 1914 • Heroin was banned completely in 1924 by the US Congress Drugs of Abuse Opiates: Heroin Methadone Oxycodone(OxyContin), Morphine Codeine Meperidine Opium Vicodin(hydrocodone/acetaminophen) Buprenorphine(Subutex or Suboxone) Benzodiazepines: diazepam(Valium), alprazolam(Xanax), lorazepam(Ativan) Barbiturates-rare in our infants Alcohol 7 9/22/2015 Opana® • Street names: “pandas”, “bears”, “panas” • Oxymorphone: a semi-synthetic opioid with high abuse potential • Introduced in 1959 as an analgesic • FDA approved immediate release(Opana®) and extended-release (Opana® ER) in 2006 • More potent than oxycodone, hydrocodone, or morphine Substances not associated with NAS • • • • • • • • Tobacco Marijuana Cocaine Antidepressants Amphetamines SSRIs- may have toxicity symptoms Caffeine Bath Salts-designer stimulants e.g. Mephedrone and MDPV Opium Poppy with Latex 8 9/22/2015 9 9/22/2015 Ohio Substance Monitoring June 2013-January 2014 10 9/22/2015 Initial Screening and Subsequent Action • Mother: Ideally, urine toxicology during pregnancy. This should include urine for opiates • Mothers with positive screens should be counseled, and appropriate referrals should be made, e.g. to a drug rehab facility and also to neonatologists to discuss baby’s chances of withdrawal and treatment options • Subutex is preferable to methadone, but not always possible Indications to Screen for Substance Abuse Maternal Factors • Known maternal substance use-either prescribed medication or “street drugs” • Late or no prenatal care • History of depression, chronic pain • Incarceration • Severe mood swings or bizarre behavior Indications to Screen, continued Maternal Factors • Previous infant with NAS • History of physical and/or sexual abuse • History of STIs • Previous unexplained fetal demise • Preterm labor 11 9/22/2015 Indications to Screen for Substance Abuse Neonates with high risk factors • Prematurity • Unexplained IUGR or low birthweight • Abnormal CNS exam: tremors, irritability, poor state control • Emesis, diarrhea, or failure to pass stool in first few days of life Infant Screening • Urine for toxicology • Urine for opiates (above screen does not test for oxycodone, buprenorphine, etc) • Meconium toxicology- must collect all the meconium, not just one sample; reflects any exposure after 20 weeks gestation • Infants with known exposure should remain in hospital for 5 days to assess for neonatal abstinence CordStat • A relatively new drug test that utilizes umbilical cord tissue as the sample matrix • Universal • Noninvasive, simple to collect • Allows for a higher level of sensitivity for specific drugs • Faster turnaround time than meconium screen – USDTL.com 12 9/22/2015 Cord Tissue Testing • A study in Utah of 100 umbilical cord samples demonstrated the ability to assay cord tissue for drugs of abuse • Enzyme-linked immunosorbent assay (ELISA) was compared to gas or liquid chromatography mass spectrometry • Categories: opiates, cocaine, amphetamines, cannabinoids and PCP • Results: > 90% agreement between paired specimens – Montgomery, et.al. Journal Perinatology 2006 Cord Tissue Testing • Follow-up study in Utah and New Jersey • 498 umbilical cord samples • Results: > 90% agreement between paired specimens – Montgomery, et al. Journal of Perinatology, July 2008 CordStat® • • • • • • • • • • • • • Amphetamines Barbiturates Buprenorphine Benzodiazepines Cannabinoids Cocaine Methadone Meperidine Opiates Oxycodone PCP(Phencyclidine), “angel dust” Propoxyphene (Darvon, discontinued) Tramadol 13 9/22/2015 Cordstat® Add-ons • Ethyl glucuride • Designer stimulants (bath salts) • Cotinine CordStat® The opiate screen includes: • Codeine • Morphine • Hydrocodone • Hydromorphone • 6-MAM (heroin metabolite) 14 9/22/2015 The Finnegan Score for Neonatal Abstinence • A tool developed by Loretta Finnegan, M.D. in 1975 • It provides a quantitative measure of the severity of withdrawal symptoms • The most widely used form consists of 21 signs and symptoms grouped by system • The scoring method allows for standardization of assessment, and consistency of management of infants with NAS Finnegan Scoring • Nurses begin the scoring at birth, or whenever symptoms develop • Scores are obtained every 2-4 hours, and reflect the entire time period since the previous score • A score above 8 denotes neonatal abstinence syndrome requiring nonpharmacologic treatment and possibly treatment with phenobarbital, opiates, or both 15 9/22/2015 Finnegan Scoring • Once an infant is stable on treatment protocol, the scores are used for weaning • When scores are consistently <9 for 48 hours, the dose may be decreased by 1015 % every 1-2 days Non-Pharmacologic Treatment • • • • • • Quiet environment in private rooms Swaddling Frequent feeds on demand Low lactose formula Holding, rocking, swinging Massage and calming techniques Encourage parents to stay as much as possible Consults • Infant Therapy • Occupational Therapy • Speech Therapy • Infant Massage • All patients are interviewed by the Staff Social Worker • CSB Referrals when indicated • Lactation and Nutrition 16 9/22/2015 Breastfeeding and NAS • Acceptable: – When the mother is Hepatitis C positive – Low dose Methadone treatment • Morphine best analgesic for breastfeeding mothers – Morphine concentrations in human milk is low and the oral bioavailability is poor • Codeine and hydrocodone are regarded as safe when used in low-to-moderate doses • Methadone concentrations in human milk are very low, generally not exceeding more than 5% of the maternal dose • Not acceptable, if mother has HIV, has active HSV lesions on the breast, untreated active TB, or is an active drug abuser. Pharmacologic Treatment • Any infant who has serious symptoms of withdrawal, or two Finnegan scores >8 is given a loading dose of phenobarbital 16 mg/kg (We use the tablet form) • This is followed by phenobarbital 2.5 mg/kg/dose BID Pharmacologic Treatment, continued. • Infants who have serious NAS at the outset or who are not controlled on Pb alone are given morphine • Starting dose for morphine is 0.03 - 0.05 mg/kg/dose every 3 hours. This may be increased as needed to a maximum of 1.6 mg/kg/day (0.2 mg/kg/dose) 17 9/22/2015 Adjunct Therapy • Clonidine: added to regimen if phenobarbital and morphine do not control symptoms • Dose: 0.1 mcg/kg q 4-6 hours • Clonidine is well studied and used in adult addicts, and has been shown to be effective in newborns as well - A. Agthe, Pediatrics. May 2009 Infants with NAS ACH Mahoning Valley 2008-2015 • • • • • • • 2008: 5 2009: 28 2010: 28 2011: 60 2012: 48 2013: 76 2014: 66 Infants with NAS ACH Mahoning Valley 80 70 60 50 40 NAS Infants 30 20 10 0 2008 2009 2010 2011 2012 2013 2014 18 9/22/2015 Maternal Race N= 207 6% Caucasian African American 94% Marital Status N= 207 2% 11% Single Married Separated 87% Maternal Employment N= 207 9% Unemployed Employed 91% 19 9/22/2015 Prenatal Care N= 207 8% 13% NPC Late Adequate 79% Maternal Smoking N= 207 22% Tobacco No Tobacco 78% Size for Dates N= 207 15% AGA SGA/IUGR 85% 20 9/22/2015 Treatment of Infants with NAS N= 207 11% 14% Pb Only No Rx Opiates 75% Length of Treatment for NAS Akron Children’s Mahoning Valley 2008-2013 • Shortest treatment time: 1 day • Longest treatment time: 81 days • Average length of treatment: 22.6 days Treatment for NAS First 10 months 2014 All GA 37 weeks + < 37 weeks Total exposed 64 51 13 NAS 54 45 9 Phenobarbital only 22 16 6 Length of Rx days 12 12.6 8.8 LOS days 13 13.5 11.6 21 9/22/2015 Promising New Therapies Methadone vs. Buprenorphine • Study in NEJM published in December 2010 • Compared NAS after maternal methadone or buprenorphine • 175 pregnant women were treated with either methadone or buprenorphine in a blinded, randomized trial • Treatment was discontinued by 16 of 89 in methadone group (18 %) • Treatment was stopped by 28 of 86 women in buprenorphine group (33%) Jones,H. et al. NEJM December 9, 2010 Methadone vs. Buprenorphine, cont. • 131 newborns were studied (58 exposed to buprenorphine and 73 to methadone) • Results: Buprenorphine babies had – Significantly less total morphine – Significantly shorter treatment time – Significantly shorter LOS Jones,H. et al. NEJM December 9, 2010 22 9/22/2015 Methadone vs. Buprenorphine Jones et al, NEJM Dec. 9, 2010 Methadone vs. Buprenorphine Jones, et. al, NEJM Dec. 9, 2010 Sublingual Buprenorphine • Study in 2008: compared morphine to sublingual buprenorphine for NAS • Buprenorphine group had shorter length of treatment • 22 days versus 32 days for morphine • Starting dose of buprenorphine was 13.2 mcg/kg/day; increased to max of 39 mcg/kg/day – Kraft WK et al. Pediatrics 2008 23 9/22/2015 Sublingual Buprenorphine, continued. • Follow-up study on treatment of NAS 3 years later • A revised dose schema • Buprenorphine: 15.9 mcg/kg/day in 3 doses – Maximum dose of 60 mcg/kg/day • Morphine: 0.4 mg/kg/day up to 1 mg/kg/day • Phenobarbital was used only if symptoms were not controlled with opiates – Kraft WK et al. Addiction, March 2011 Buprenorphine Study, cont. Buprenorphine and Breast Milk • Recent study looked at 7 women on buprenorphine treatment during lactation • Maternal dose: 2.4 to 24 mg/day (Mean of 7) • Levels of buprenorphine and norbuprenorphine were < 1 % of maternal weight-adjusted dose • Levels were not enough to cause any adverse effects • Levels were also not sufficient to prevent withdrawal – Ilett, et al. Breastfeeding Medicine, August 2012 24 9/22/2015 NAS In Summary • Neonatal Abstinence Syndrome has become a significant problem around the world • Our own population has seen a huge increase in the numbers of affected newborns • Maternal substance patterns change with the availability of drugs on the market or on the street • New and promising treatments for both mother and infant are within reach • Our goal: minimize maternal addiction when possible NAS in Summary, continued The goal for our infants: • Shorten their length of stay • Maintain them in a comfortable, relatively symptom- free environment while under treatment • Encourage maternal-infant bonding when possible and appropriate • Continue our search for novel ways to treat infants with NAS (minimize their time on opiates) How You Can Help • Routinely work to identify mothers with risk factors for substance use • Refer substance abusing mothers for counseling and or treatment programs • Screen all mothers with a urine drug screen during pregnancy • Recognize infants at high risk for Neonatal Abstinence Syndrome and refer when needed for treatment 25 9/22/2015 Questions? 26