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Management of Neonatal Abstinence Syndrome and Iatrogenic Drug Withdrawal Kirsten H. Ohler, Pharm.D., BCPS Clinical Assistant Professor Neonatal / Pediatric Clinical Pharmacist University of Illinois at Chicago Objectives Define tolerance, dependence, addiction, and withdrawal. Describe the available scoring systems for assessing drug withdrawal. Discuss the pharmacologic management of narcotic / opioid withdrawal. Discuss the management of other possible causes of neonatal & pediatric drug withdrawal. Describe the pharmacist’s role in the care of a neonate or child experiencing withdrawal. Definitions Tolerance increasing dosage requirement to achieve the same pharmacologic effect that was previously achieved with a lower dose tolerance potential of various opioid agents fentanyl > morphine > methadone Definitions Physical dependence physiological state produced by repeated exposure to a drug which necessitates the continued administration of the drug to prevent withdrawal symptoms related to cumulative dose and duration occurs in up to 2/3 of patients Definitions Addiction complex behavior pattern of drug use involving both physical and psychological dependence including drug-seeking behavior Definitions Withdrawal a syndrome manifested by the occurrence of symptoms characteristic of the drug self-limited process may be life-threatening Opioid Withdrawal Neonatal Abstinence Syndrome (NAS) occurs in ~ 60 - 90% of neonates born to narcotic-addicted mothers Iatrogenic tolerance / withdrawal more likely with fentanyl vs. morphine more likely with infusions vs. bolus doses incidence with use > 5 - 7 days Opioid Withdrawal Signs and symptoms Neurologic - tremors, irritability, high-pitched cry, tone, wakefulness, yawning, sneezing, seizures Gastrointestinal - vomiting, diarrhea Autonomic - sweating, nasal stuffiness, tachycardia, fever / temperature instability, hypertension, mottling “Diagnosis” of Withdrawal Toxicology screening meconium – fetal drug exposure after 12th week urine – drug exposure w/in hours to a few days “False” positive test “False” negative test May withdrawal without toxicology screen “Diagnosis” of Withdrawal No validated assessment tool for iatrogenic drug withdrawal Several scales for neonatal abstinence syndrome Finnegan Scale A score of < 7 = absent, 8-12 = mild, 13-16 = moderate, > 17 = severe Sign / Symptom Score High-pitched cry excessive 2 continuous 3 Sleep after feeding < 1 hour 3 < 2 hours 2 < 3 hours 1 Moro reflex hyperactive 2 markedly hyperactive 3 Tremors mild when disturbed 1 marked when disturbed 2 mild when undisturbed 3 marked when undisturbed 4 Increased muscle tone 2 Sign / Symptom Seizure Excessive sucking Poor feeding Regurgitation Projectile vomiting Stools loose watery Sweating Fever < 101 F (38.2C) > 101 F (38.4C) Yawning / Sneezing (> 4x) Respiratory rate Score 5 1 2 2 3 2 3 1 1 2 1 each >60 breaths / min 1 >60 / min w/ retractions 2 Finnegan Scale Advantages reliable and valid for assessment of NAS most comprehensive assessment of symptoms bed-side nurse driven Disadvantages not validated in the ICU setting not validated for agents other than opioids not validated in pre-term infants cumbersome Lipsitz Tool Score > 4 = significant withdrawal Score Signs 0 1 2 3 Tremors Normal Min ↑, disturbed Mod-Marked ↑, undisturbed Marked ↑, undisturbed Irritability None Slight ↑ Mod-Marked, disturbed Marked, undisturbed Reflexes Normal ↑ Markedly ↑ Stools Normal Explosive, normal freq Explosive, > 8/day Muscle tone Normal ↑ Rigidity Skin abrasions No Redness Skin breakdown Respiratory rate < 55 55 – 75 76 – 95 Repetitive sneezing No Yes Repetitive yawning No Yes Vomiting No Yes Fever No Yes Lipsitz Tool Advantages simple numeric scale bed-side nurse driven Disadvantages more subjective evaluation of symptoms not validated in the ICU setting not validated for agents other than opioids not validated for pre-term infants Other Withdrawal Scales Kahn system & Ostrea system subjective / descriptive assessments Neonatal Narcotic Withdrawal Index (Green) objective scoring of 7 elements physician-based Moro Scale Score primarily assesses muscle tone / tremor physician-based scale for chronic withdrawal Withdrawal Management Goals severity of symptoms to a tolerable level allow adequate sleep between feeds agitation & distress caused by procedures Withdrawal Management Prevention strategies NAS use lowest possible maternal methadone dose Iatrogenic withdrawal use lowest effective analgesic / sedative dose wean continuous infusions after long-term use low dose naloxone infusion Withdrawal Management Prevention strategies Low dose naloxone infusion AC-cAMP superactivation: chronic opioid administration activates G1 and Gs proteins → upregulation of AC-cAMP → ↑ neuron action potential duration and neurotransmitter release decreased analgesia & possibly tolerance naloxone blocks Gs binding → theoretical decrease in tolerance • randomized, placebo-controlled trial showed no difference in total fentanyl dose received Withdrawal Management Weaning Strategies identify patients at risk for withdrawal duration of exposure long half-life agent utilize withdrawal scoring tool rate / length of wean less frequent weaning Withdrawal Management Non-pharmacologic vs. pharmacologic Indications for drug therapy: seizures, excessive weight loss / dehydration, inability to sleep, fever Use an agent in the same drug class from which the infant is withdrawing Opioid Withdrawal Management Paregoric 46% alcohol, camphor, benzoic acid, & others no longer recommended Tincture of opium 17-21% alcohol requires a 25-fold dilution for dosing Opioid Withdrawal Management Morphine oral solution alcohol free short half-life conversion from fentanyl or IV morphine usual initial dose for NAS 0.1 – 0.2 mg/kg/dose PO q 6 hours Methadone 8% alcohol long half-life Opioid Withdrawal Management Benzodiazepines increased sedation and poor sucking poor control of GI and autonomic symptoms adjunct for controlling irritability Phenobarbital greater sedation and poor sucking does not control vomiting and diarrhea hyperalgesia, drug interactions, long half-life Opioid Withdrawal Management Clonidine may suppress autonomic symptoms may not effect GI symptoms or poor sleeping may produce hypotension extemporaneous liquid preparation Naloxone opioid antagonist may precipitate withdrawal symptoms Other Withdrawal Syndromes Benzodiazepines no validated assessment tool treatment principles similar to opioid withdrawal Barbiturates Other Withdrawal Syndromes Nicotine conflicting data supportive management Caffeine scant reports supportive management Other Withdrawal Syndromes Alcohol tremors, sleep, crying, tone, supportive management sucking Inhalants solvents, paint thinner, glue high-pitched cry, sleeplessness, tremors, hypertonia, poor feeding case report using phenobarbital for management Other Withdrawal Syndromes Selective Serotonin Reuptake Inhibitors (SSRI) ~30% of infants with in utero exposure have withdrawal symptoms withdrawal vs. serotonin toxicity (?) GI symptoms, tremors, sleep, high-pitched cry supportive management Role of the Pharmacist Recognize signs / symptoms of withdrawal Educate the healthcare team on the use of withdrawal scores Assist in the selection of the most appropriate pharmacological agent for the management of withdrawal Develop a weaning plan to minimize the occurrence of withdrawal Questions Case Discussion #1 A male infant is born at 35 5/7 weeks gestation, birth weight 2430 grams Maternal history: IV drug abuse (heroin & cocaine), methadone treatment program (80 mg/day), bipolar disease (alprazolam, quetiapine, sertraline) Maternal urine toxicology screen positive for benzodiazepine and methadone one week prior to delivery. Physical exam at birth: hypertonic, nasal flaring / grunting, microcephalic, bilateral club feet Admitted to NICU for respiratory support & monitoring for withdrawal symptoms Case Discussion #1 DOL 3: reported to be hypertonic, jittery, intolerant of oral feeds, meconium toxicology screen reported negative Finnegan score: 6 – 7 DOL 6: questionable seizure activity overnight Neurology consult recommends EEG (no focal findings) DOL 7: generalized seizure Phenobarbital initiated per neurology recommendation DOL 11: remains jittery, multiple loose stools Finnegan score: 11 - 12 Case Discussion #1 Thoughts…. regarding patient presentation? regarding management thus far? Case Discussion #1 DOL 11: oral morphine ordered DOL 12-13: requiring escalating doses of morphine to control symptoms (1 mg/kg/dose q6 hours) DOL 15 – 17: Finnegan scores improving (7 – 8), feeding tolerance improving Case Discussion #1 DOL 43: weaned morphine to 0.1 mg/kg/dose q 8 hours Finnegan scores 8 – 13 irritable cry, hypertonic, jittery Thoughts… regarding patient status at this point? regarding management / weaning strategies? Case Discussion #2 Six days ago, a 2 year old, 12 kg girl underwent the Fontan procedure for HLHS. She was placed on a fentanyl drip postoperatively and the dose was escalated (initial 1 mcg/kg/hr, max 5 mcg/kg/hr). Her current fentanyl dose is 3 mcg/kg/hr. Her vasopressor support was weaned off and she is ready for extubation. What recommendation would you make regarding her fentanyl drip? Case Discussion #2 Discontinue fentanyl drip? Wean fentanyl drip? Convert to another agent? Opioid Comparison Drug Fentanyl Methadone Morphine Equianalgesic IM Dose (mg) Equianalgesic PO Dose (mg) Parenteral : Oral ratio 0.1 -- -- Acute: 10 Chronic: 2 – 4 Acute: 20 Chronic: 2 – 4 -- 10 30 1:6 1:1.5 – 2.5 chronic Case Discussion #2 Current fentanyl dose: 12 kg x 3 mcg/kg/hr x 24 hr/day = 864 mcg/day = 0.864 mg/day Conversion to morphine: 0.1 mg fentanyl 10 mg morphine = X = 86 mg morphine ** CAUTION** 0.864 mg fentanyl X