Neonatal Abstinence: It s No Child s Play!

Transcription

1 Neonatal Abstinence: It s No Child s Play! Claudia Summa BScPhm Pharmacy Resident Wednesday, March 28, 2007 Objectives To present a case of neonatal abstinence syndrome (NAS) To discuss the incidence, complications, pathophysiology of NAS To illustrate which drugs can cause NAS To discuss treatment for opiate associated NAS To provide the evidence for SSRI associated NAS To provide recommendations for treatment of both opiate and SSRI associated NAS Case Baby S Term baby 40 6 born March 15 BW: 3040g Apgar scores No resuscitation required Mother attempted breastfeeding but failed vomiting RR (71), O 2 Sat 88-92% Sweaty, high pitch cry, jittery, mild tremors Case Mother s L&D Labour was initiated because of failure to progress No complications GBS negative Case Mother s PMHx and Social Hx Initial Management March 17 Addiction to codeine, Tylenol, morphine (since 1999) Depression Smoker 10 cigarettes/day Methadone 150mg PO daily (during pregnancy) Methadone 80mg PO daily (prior to pregnancy) Setraline 100mg PO daily Ampicillin 152mg IV q12h 25mg/kg/dose Gentamicin 7.6mg IV q18h 2.5mg/kg/dose Morphine 0.36mg PO per dose 0.48mg/kg/day divided doses (q3-4h based on feeds) NAS Score 10, 13

2 Neonatal Abstinence (NAS): Incidence National Institute on Drug Abuse 1990 survey of 60M pregnant women (15-44 years old) 50.8% used alcohol, 29% smoked cigarettes, 8% used illicit drugs, 6.5% used marijuana, 0.9% used cocaine Maternal complications Spontaneous abortion, PROM, abruptio placentae, IUGR, maternal infection, stillbirth, congenital malformations Postnatal complications Disturbances of growth & behaviour SIDS NAS - Incidence Difficult to determine unreliable histories from mothers & limited skills from HCP diagnosing nonopiate drug exposure Use of > 1 drug Drug exposed infants: 3 50% Levy M, Spino M. Pharmacotherapy. 1993; 13(3): NAS Mortality & Morbidity Drug Causes of NAS Extremely low Risk of SIDS among infants exposed to opiates Methadone exposed 3.7-fold higher risk Heroin exposed 2.3-fold higher risk Opiates & narcotics Codeine Fentanyl Heroin & methadone Meperidine Morphine Pentazocine propoxyphene Other drugs: Barbiturates Caffeine Chlordiazepoxide Cocaine Diazepam & lorazepam Diphenhydramine Ethanol Marijuana * Nicotine Phencyclidine SSRI Pathophysiology of NAS Multi-system disorder CNS and GI Manifestation depends on: Type of drug dose, frequency, half-life Infants metabolism & excretion of active metabolite Infants last intrauterine drug exposure Mother s metabolism & excretion Manifestations CNS High pitched cry Restlessness with duration of sleep < 1-3hours after feeding Hyperactive reflexes Tremors muscle tone Myoclonic jerks Generalized convulsions

3 Manifestations Metabolic, Vasomotor, and Respiratory Sweating Fever Mottling Frequent yawning Sneezing (> 3X per interval) Nasal flaring RR > 60/min without retractions Apnea Manifestations GI dysfunction Excessive suckling or rooting Poor feeding Regurgitation or projectile vomiting Loose or watery stools Differential Diagnosis Must rule out the following before making the diagnosis of NAS: Infection Hypoglycemia Hypomagnesemia Hypocalcemia Hyperthyroidism CNS hemorrhage Anoxia Timing & Onset of NAS Timing depends on the time of last drug exposure Less likely if > 1 week has elapsed between last maternal use & delivery Half-life of elimination Longer the half-life, the later the withdrawal Onset hours for methadone Can be delayed as late as 4 weeks Barbiturates median onset 4-7 days (wide range 1-14 days) Diazepam 12 days Chlordiazepoxide 21 days AAP Committee on Drugs. Pediatrics. 1998; 101(6): Diagnostic Testing Early drug screening during pregnancy Radioimmunoassays & Enzyme immunoassays (?) Blood tests (?) Urine toxicology assays Meconium analysis Hair analysis Non-Pharmacologic Measures Self-limiting condition Quiet, calm environment Gentle handling & swaddling sensory stimulation Frequent feeding Breast feeding Fluid & electrolyte replacement Adequate nutrition TPN

4 Assessment of Withdrawal Each nursery should adopt an abstinence scoring method to measure the severity of withdrawal signs Neonatal Abstinence Scoring Finnegan (1975) & Lipsitz (1975) Measure the degree of withdrawal sx Once on tx resolution of S&Sx Whether a drug dose should be or Scoring Tool Used at MSH Finnegan Scoring System for NAS Score all infants born to mothers with known or suspected substance abuse (initiate the scoring with 2 hrs of admission to the NICU/Level 1 Nursery) Score at 2hr intervals for 1 st 48hrs of life Uses 31 items Assessment of CNS, metabolic/vasomotor, respiratory disturbances, GI disturbances If the score > or = 8 morphine is initiated Continue scoring for 5 days or as long as morphine treatment & weaning is necessary See attached MSH Algorithm CHN Guideline Management of Perinatal Substance Use and Abuse. June Treatment of NAS Opiate withdrawal morphine Sedative-hypnotic phenobarbital Other drugs supportive treatment Breast feeding is encouraged Paregoric Anhydrous morphine 0.4mg/mL Contains: camphor, alcohol (44-46%), benzoic acid, glycerin, opium alkaloids, papaverine, codeine, noscapine, thebaine Advantages Ease of administration Improvement in sucking behaviour, nutrient composition & weight gain, effective for seizure control Disadvantages Associated SE with additives Heinze et al: study showed longer duration of tx may be required when compared with phenobarbital Levy M, Spino M. Pharmacotherapy. 1993; 13(3): Morphine IV contains phenol & sodium bisulfite anaphylaxis & jaundice Oral 1mg/mL & 5mg/mL Contains no additives and less alcohol (10%) compared with Paregoric Evidence for Morphine Use in NAS: Study by Ebner et al Objective Compare birth parameters & assess the incidence & timing of NAS Assess the intensity & duration of NAS with 2 different psychopharmacological agents (morphine vs. phenobarbital) Patients Pregnant women with opioid dependence enrolled in opioid maintenance therapy Ebner N et al. Drug and Alcohol Dependence. 2007; 87:

5 Evidence for Morphine Use in NAS: Study by Ebner et al Methods Symptoms of NAS scored every 4 hrs using a modified Finnegan Score During the 1 st 13 months of the study phenobarbital was used During the last 17 months of the study morphine was used Treatment Phenobarbital 5-10mg/kg/day for scores >10; when scores <10 for 24hrs then tx d/c Morphine mg/kg/dose; during each assessment if score >10 additional dose would be administered up to 6 doses Evidence for Morphine Use in NAS: Study by Ebner et al Results 40% (21/53) had mild to no symptoms of NAS no tx required 60% (32/53) required tx for NAS 15 received phenobarbital 17 received morphine Duration of treatment was lower in the morphine tx group than in the phenobarbital tx group (p=0.021; 9.9 days vs days) After 7 days, 8 neonates in the morphine group required no further tx Ebner N et al. Drug and Alcohol Dependence. 2007; 87: Ebner N et al. Drug and Alcohol Dependence. 2007; 87: Opiate Treatment: Cochrane Database of Systematic Reviews Objective Effectiveness & safety of using an opiate, compared to sedative or nonpharm tx for NAS due to withdrawal from opiates Search & Selection Criteria Medline (1966-December 2004) EMBASE (1980-December 2004) Opiate Treatment: Cochrane Database of Systematic Reviews Findings Morphine and supportive tx compared with supportive care alone does not affect tx failure rate Morphine tx results in significant reduction in time to regain BW & supportive care duration of hospital stay Opiate vs. phenobarbitone no difference in tx failure, but incidence of seizures Osborn DA et al. The Cochrane Library. May 2005; Volume 4. Osborn DA et al. The Cochrane Library. May 2005; Volume 4. Take Home Points: NAS due to Opiates NAS Scoring should be instituted in all neonates who are at risk of developing withdrawal symptoms within 2 hours of admission to NICU or Level 1 Nursery If score is > or = 8 treatment is required Drug of choice: morphine O/L Withdrawal Due to SSRI in Newborns Health Canada Advisory (Aug 9, 2004): Women taking SSRIs and other newer antidepressants during 3 rd trimester of pregnancy Complications at birth requiring prolonged hospitalization, breathing support, and tube feeding Possibly due to a discontinuation syndrome caused by sudden withdrawal from the drug Health Canada Advisory August 9, 2004.

6 Perinatal Outcome Following 3 rd Trimester Exposure to Paroxetine Prospective study Investigate whether a clinically significant discontinuation syndrome exists in neonates exposed to paroxetine in utero Motherisk Program September 1996 September 1999 Followed through telephone calls after delivery Perinatal Outcome Following 3 rd Trimester Exposure to Paroxetine Groups Women counselled by Motherisk gestational use of paroxetine during 1 st and 2 nd trimester Daily dose 10-40mg Women counselled by Motherisk 1 st trimester exposure to non-teratogenic agents (acetaminophen or dental X- rays) Costei AM et al. Arch Pediatr Adolesc Med. 2002; 156: Costei AM et al. Arch Pediatr Adolesc Med. 2002; 156: Perinatal Outcome Following 3 rd Trimester Exposure to Paroxetine Results 55 infants were exposed to paroxetine in 3 rd trimester 12 infants neonatal complications requiring hospitalization (hypoglycemia, RDS, jaundice) 36 women breastfed 8 reported symptoms of alertness, constipation, sleepiness, and irritability Indication for paroxetine: depression, anxiety, anxiety & depression, panic attacks Daily dose: 10mg to 60mg Neonate Characteristics After Maternal Use of Antidepressants in Late Pregnancy Prospective study Investigating neonatal outcomes in 997 infants (987 mothers) after maternal use of antidepressants Swedish Medical Birth Registry December 31, 2001 July 1, 1995 Exposed infants were compared to all infants in registry adjusted for confounders Costei AM et al. Arch Pediatr Adolesc Med. 2002; 156: Kallen B. Arch Pediatr Adolesc Med. 2004; 158: Neonate Characteristics After Maternal Use of Antidepressants in Late Pregnancy Results: 997 infants (987 mothers) 395 TCA (clomipramine, amitriptylline) 558 SSRI (citalopram, paroxetine, fluoxetine, sertraline) 63 other antidepressants (venlafaxine) Pregnancy weeks when drugs had been used not stated in 387 cases In 70 cases drug use stopped before 24 weeks In 561 cases drug use started after or continued past week 23 Neonate Characteristics After Maternal Use of Antidepressants in Late Pregnancy Results cont d Increased risk for preterm birth and low BW Increased risk for a low Apgar score, respiratory distress, neonatal convulsions No significant effect on hypoglycemia SSRI only Effects of SSRI were not drug specific No difference between paroxetine & other SSRIs Kallen B. Arch Pediatr Adolesc Med. 2004; 158: Kallen B. Arch Pediatr Adolesc Med. 2004; 158:

7 Statement By Motherisk Infants be monitored for > hrs after birth Poor neonatal instability 10 30% of infants Weigh the risks vs. benefits Untreated depression miscarriage, perinatal complications, risk of preeclampsia, low neonatal Apgar scores, admissions to NICU Most serious ramification risk of postpartum depression After consultation with MD decision to continue tx, discontinue tx, or taper doses should be made What Should We Tell Mothers Already Taking SSRIs? Risk vs. benefits When tx indicated mother should be treated with an antidepressant Mothers should be informed of the withdrawal symptoms that may occur in the infant that has been exposed Mothers also should be informed that abrupt cessation of medication can lead to withdrawal symptoms for them as well Kaira S et al. The Hospital For Sick Children Motherisk Statement. August (accessed March 19, 2007). Recommendations for NAS due to SSRIs Breast feeding is encouraged as passage of drug through breast milk may alleviate the symptoms of withdrawal Not the same as opiate NAS will not treat the infant with offending agent SELF-LIMITING condition Supportive measures should be instituted and close monitoring for RDS, hypoglycemia, jaundice, and convulsions Infants should be monitored for > hrs after birth Back to Baby S March 18 th NAS Score was 9, 8, 10 (still experiencing sx) Dose maintained (0.36mg PO q4h) March 19 th NAS Score 8-13 Dose maintained (0.36mg PO q4h) No weaning Active, alert, crying, moving limbs with no abnormal movements Baby S was transferred to St. Michael s Hospital f/u NAS and murmur (murmur developed March 19 th ) Antibiotics were d/c blood cultures negative Summary Questions NAS is a self-limiting condition Time of onset and duration of NAS depend on the type of drug that was used Opiate associated NAS should be treated with morphine when tx is indicated SSRI associated NAS should be treated through observation & supportive measures