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
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
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
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
Differential Diagnosis Sepsis Hypocalcemia Hypoglycemia CNS hemorrhage Meningitis Perinatal asphyxia Polycythemia Drugs of Abuse Opium Poppy 5
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
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
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
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Ohio Substance Monitoring June 2013-January 2014 10
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
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
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
Cordstat Add-ons Ethyl glucuride Designer stimulants (bath salts) Cotinine CordStat The opiate screen includes: Codeine Morphine Hydrocodone Hydromorphone 6-MAM (heroin metabolite) 14
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
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 10-15 % 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
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
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 80 Infants with NAS ACH Mahoning Valley 70 60 50 40 30 NAS Infants 20 10 0 2008 2009 2010 2011 2012 2013 2014 18
Maternal Race 6% N= 207 Caucasian African American 94% Marital Status N= 207 2% 11% Single Married Separated 87% Maternal Employment N= 207 9% Unemployed Employed 91% 19
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
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
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
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
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
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
Questions? 26