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Guidance for the Clinician in Rendering Pediatric Care

CLINICAL REPORT Neonatal

Mark L. Hudak, MD, Rosemarie C. Tan, MD,, PhD, THE abstract COMMITTEE ON DRUGS, and THE COMMITTEE ON FETUS AND Maternal use of certain drugs during can result in transient NEWBORN neonatal signs consistent with withdrawal or acute toxicity or cause KEY WORDS , , , fentanyl, , , sustained signs consistent with a lasting drug effect. In addition, hos- , SSRI, drug withdrawal, neonate, abstinence pitalized who are treated with or to syndrome provide analgesia or sedation may be at risk for manifesting signs ABBREVIATIONS of withdrawal. This statement updates information about the clinical CNS—central nervous system — presentation of infants exposed to intrauterine drugs and the thera- DTO diluted tincture of opium ECMO—extracorporeal membrane oxygenation peutic options for treatment of withdrawal and is expanded to include FDA—Food and Drug Administration evidence-based approaches to the management of the hospitalized in- 5-HIAA—5-hydroxyindoleacetic acid fant who requires weaning from analgesics or . ICD-9—International Classification of Diseases, Ninth Revision — – NAS neonatal abstinence syndrome 2012;129:e540 e560 SSRI—selective serotonin reuptake inhibitor INTRODUCTION This document is copyrighted and is property of the American fi Academy of Pediatrics and its Board of Directors. All authors Use and abuse of drugs, , and contribute signi cantly have filed conflict of interest statements with the American to the health burden of society. The 2009 National Survey on Drug Use Academy of Pediatrics. Any conflicts have been resolved through and Health reported that recent (within the past month) use of illicit a process approved by the Board of Directors. The American Academy of Pediatrics has neither solicited nor accepted any drugs, binge or heavy alcohol ingestion, and use of tobacco products commercial involvement in the development of the content of occurred in 8.7%, 23.7%, and 27.7%, respectively, of the population this publication. 1 12 years or older. Numerous case reports have documented the use The guidance in this report does not indicate an exclusive of a variety of drugs by women of childbearing age (Table 1). In- course of treatment or serve as a standard of medical care. trauterine exposure to certain drugs may cause congenital anomalies Variations, taking into account individual circumstances, may be appropriate. and/or fetal growth restriction, increase the risk of , produce signs of withdrawal or toxicity in the neonate, or impair normal neurodevelopment.2 Fetal exposure to marijuana, the illicit drug most commonly used by pregnant women, does not cause clinically important signs but may have subtle effects on long-term neurobehavioral outcomes.3 With the use of computer-assisted interviewing techniques that preserved confiden- tiality, the 2009 National Survey on Drug Use and Health noted that 4.5% of pregnant women 15 to 44 years of age reported recent use of illicit drugs (eg, marijuana, cocaine, , heroin, meth- www.pediatrics.org/cgi/doi/10.1542/peds.2011-3212 , and nonmedical use of prescription drugs). Binge or heavy drinking in the first trimester was reported by 11.9%, and doi:10.1542/peds.2011-3212 recent tobacco use was reported by 15.3%. Rates of recent illicit drug All clinical reports from the American Academy of Pediatrics automatically expire 5 years after publication unless reaffirmed, use and smoking were lower among pregnant compared with non- revised, or retired at or before that time. pregnant women across all age groups, except for those 15 to 17 PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). years of age. In the latter age group, the rates of illicit drug use and Copyright © 2012 by the American Academy of Pediatrics smoking were higher among those who were pregnant compared with those who were not pregnant (15.8% vs 13.0% and 20.6% vs 13.9%, respectively). The reported rates of illicit drug use most likely underestimate true rates, because the percentage of pregnant women who report the recent use of illicit drugs on screening interviews can

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TABLE 1 Major Drugs of Abusea Opioids CNS CNS Hallucinogens Agonists Amphetamines Alcohol Indolealkylamines (LSD, psilocin, psilocybin, DMT, DET) Morphine (Dexedrine) Phenylethylamines (mescaline, peyote) Methamphetamine Benzodiazepines Phenylisopropylamines (MDA, MMDA, MDMA, MDEA) Methadone sulfate Other - Meperidine (Demerol) Amphetamine congeners Methaqualone (Quaalude) Solvents and aerosols (glues, gasoline, paint thinner, cleaning solutions, nail polish remover, Freon) (Percodan, OxyIR, Benzphetamine (Didrex) (Doriden) Nitrites Percolone, Roxicodone, Percocet, OxyContin) Propoxyphene (Darvon) Diethylpropion (Tenuate) Nitrous oxide Hydromorphone (Dilaudid) Fenfluramine Cannabinoids Hydrocodone (Lortab, Vicodin) Phendimetrazine (Adipost, Bontril, Marijuana Prelu-2) Fentanyl (Sublimaze) Phentermine (Adipex-P, Zantryl) Hashish Tramadol (Ultram, Ultracet) Cocaine Heroin (Ritalin, Concerta) Antagonists Pemoline (Cylert) Naloxone (Narcan) Phenylpropanolamine Naltrexone (ReVia) Phencyclidines Mixed Agonist-Antagonists Pentazocine (Talwin) (Buprenex) DET, diethyltryptamine; DMT, dimethyltryptamine; LSD, lysergic acid diethylamide; MDA, methylenedioxyamphetamine; MDEA, 3,4-methylenedioxyethamphetamine; MDMA, 3,4-methylene- dioxymethamphetamine (ecstasy); and MMDA, 3-methoxy-4,5-methylenedioxyamphetamine. a Adapted from Milhorn.160 be substantially lower than that de- or . In a recent report, syndrome (NAS). Among neonates ex- termined by drug screening using bi- chronic use of narcotic prescriptions posed to opioids in utero, withdrawal – ological samples. For infants, the use (use for ≥1 intrapartum month) among signs will develop in 55% to 94%.6 9 of International Classification of Dis- pregnant women cared for at a single Neonatal withdrawal signs have also eases, Ninth Revision (ICD-9)-based hos- clinic increased fivefold from 1998 to been described in infants exposed an- 10,11 pital discharge databases to determine 2008, and 5.6% of infants delivered tenatally to benzodiazepines, bar- 12,13 14,15 the incidence of neonatal drug with- to these women manifested signs of biturates, and alcohol. drawal secondary to intrauterine expo- neonatal withdrawal.5 sure has in the past underestimated Signs characteristic of neonatal with- the incidence of this condition.4 Data COCAINE AND OTHER STIMULANTS drawal have been attributed to intra- compiled by the Agency for Health- An abstinence syndrome after intra- uterine exposure to a variety of drugs care Research and Quality and by the uterine exposure to central nervous (Table 2). Other drugs cause signs in Florida Department of Health attest to system (CNS) stimulants such as co- neonates because of acute toxicity. an increased incidence and/or recog- caine and amphetamine has not been Chronic in utero exposure to a drug (eg, nition of neonatal withdrawal syn- clearly defined. Many studies that have drome (ICD-9 code 779.5). Nationally, the alcohol) can lead to permanent phe- assessed behavior and neurologic signs number of infants coded at discharge notypical and/or neurodevelopmental- in cocaine-exposed infants have used with neonatal withdrawal increased behavioral abnormalities consistent scoring systems that were designed from 7653 in 1995 to 11 937 in 2008. In with drug effect. to evaluate . Neuro- Florida, the number of newborns dis- of withdrawal worsen as drug levels behavioral abnormalities16,17 frequently charged with ICD-9 code 779.5 climbed decrease, whereas signs and symp- occur in neonates with intrauterine by more than 10-fold, from 0.4 to 4.4 toms of acute toxicity abate with drug cocaine exposure, most frequently on discharges per 1000 live births, from elimination. Clinically important neo- the second or third postnatal days.18 1995 to 2009. An indeterminate part of natal withdrawal most commonly re- These abnormalities may include ir- these observed increases has resulted sults from intrauterine opioid exposure. ritability, hyperactivity, tremors, high- from more liberal use of prescription The constellation of clinical findings pitched cry, and excessive sucking. opiates in pregnant women to palliate associated with opioid withdrawal has Because cocaine or its metabolites a wide variety of etiologies of acute been termed the neonatal abstinence may be detected in neonatal urine

PEDIATRICS Volume 129, Number 2, February 2012 e541 Downloaded from www.aappublications.org/news by guest on September 30, 2021 TABLE 2 Maternal Nonnarcotic Drugs That Cause Neonatal Psychomotor Behavior Consistent With Withdrawal Drug Signs Onset of Signs Duration of Signsa Ref. No. Alcohol Hyperactivity, crying, irritability, poor suck, tremors, ; 3–12 h 18 mo 14,15 onset of signs at birth, poor sleeping pattern, hyperphagia, diaphoresis Barbiturates Irritability, severe tremors, hyperacusis, excessive crying, 1–14 d 4-6 mo with prescription 12,13 vasomotor instability, diarrhea, restlessness, increased tone, hyperphagia, vomiting, disturbed sleep; onset first 24 h of life or as late as 10–14 d of age Jitteriness, vomiting, bradycardia, tachypnea At birth 1-7 d 161 Irritability, tremors; signs may start at 21 d Days–weeks 9 mo; 11/2 mo with prescription 11 Clomipramine Hypothermia, cyanosis, tremors; onset 12 h of age 4 d with prescription 162 , poor suck, hypothermia, apnea, , Hours–weeks 8 mo; 10–66 d with prescription 10 hyperreflexia, tremors, vomiting, hyperactivity, tachypnea ( receiving multiple drug therapy) Ethchlorvynol Lethargy, jitteriness, hyperphagia, irritability, poor suck, Possibly 10 d with prescription 163 hypotonia (mother receiving multiple drug therapy) Glutethimide Increased tone, tremors, opisthotonos, high-pitched cry, 6 mo 164 hyperactivity, irritability, colic Hydroxyzine Tremors, irritability, hyperactivity, jitteriness, shrill cry, 5 wk with prescription 58 myoclonic jerks, hypotonia, increased respiratory and heart rates, feeding problems, clonic movements (mother receiving multiple drug therapy) Meprobamate Irritability, tremors, poor sleep patterns, 9 mo; 3 mo with prescription 165 SSRIs Crying, irritability, tremors, poor suck, feeding difficulty, Hours–days 1–4wk 31–33,35 hypertonia, tachypnea, sleep disturbance, hypoglycemia, seizures a Prescription indicates the was treated with pharmacologic agents, and the natural course of the signs may have been shortened. for as long as 7 days after delivery,18 from metabolite-negative infants with a sympathomimetic agent that induces observed abnormalities in exposed in- history of exposure nor from cocaine- euphoria and increases alertness and fants may reflect drug effect rather naïve infants. These findings supported self-confidence, because it produces a than withdrawal. In an unmasked study, neither a withdrawal nor a drug tox- massive efflux of in the CNS. 6%, 14%, and 35% of infants exposed icity syndrome. Cocaine-exposed infants Pregnant women who abuse metham- to cocaine only, heroin only, or cocaine have been described as having a higher phetamine are at increased risk of pre- plus heroin, respectively, qualified for incidence of abnormal auditory brain- term birth, placental abruption, fetal treatment on the basis of scoring.19 stem responses and EEGs, compared distress, and intrauterine growth re- Several studies that used masked eval- with nonexposed infants.24,25 In another striction at rates similar to those for uators found that cocaine-exposed in- study, infants with heavy exposure to pregnant women who use cocaine. In fants had either no20,21 or minimal22 cocaine had similar Brazelton findings 1 study, only 4% of infants exposed to withdrawal signs compared with cocaine- at 2 to 3 days of age as did infants methamphetamine were treated for naïve infants (ie, those never exposed). with light or no exposure; however, by drug withdrawal, but it was not pos- Eyler et al16 conducted a prospective 17 days of age, heavily exposed infants sible to exclude concomitant abuse of controlled study of 3 groups of infants: were more excitable and demonstrated other drugs as contributory in all 1 group had no documented exposure poorer state regulation.26 No published cases.27 There are reports of long-term to cocaine by history or by maternal studies have carefully evaluated phar- adverse neurotoxic effects of in utero and infant urine testing; a second group macologic treatment of infants with methamphetamine exposure on behav- was cocaine exposed but had negative signs attributable to prenatal cocaine ior, cognitive skills, and physical dex- 28,29 urine screening at birth; and a third exposure. terity. group had cocaine metabolites de- Methamphetamine abuse has been tected in neonatal urine. Observers reported among pregnant women,27 SELECTIVE SEROTONIN REUPTAKE masked to infant status performed as- although overall rates are low com- INHIBITORS sessments using the Brazelton Neo- pared with cocaine and appear to Selective serotonin reuptake inhibitors natal Behavioral Assessment Scale.23 have decreased in the general popu- (SSRIs) are a class of Infants who were positive for cocaine lation between 2006 and 2008.1 Meth- that became available for metabolites did not differ significantly amphetamine is an extremely potent widespread clinical use in 1988. SSRIs

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(eg, fluoxetine [Prozac], paroxetine nausea, fatigue, low mood, and, rarely, in infants with prenatal exposure to [Paxil], sertraline [Zoloft], citalopram extrapyramidal signs such as dysto- SSRIs,42 several recent reviews have [Celexa], [Lexapro], and nia. Hence, in most cases, the clinical not identified adverse neurodevelop- fluvoxamine [Luvox]) are now the most syndrome reported among neonates mental outcomes among infants born frequently used drugs to treat depres- born to on SSRI treatment is to women treated with SSRIs dur- sion both in the general population and consistent with a gradual resolution of ing pregnancy.30,34,43,44 SSRI treatment in pregnant women.30 Case reports,31 a hyperserotonergic condition rather should be continued during preg- adverse drug reaction reports,32 and than with the evolution of a hyposer- nancy at the lowest effective dose, prospective studies33,34 linked third- otonergic state. Still, in a few cases, because withdrawal of trimester use of SSRIs in pregnant drug withdrawal may be a better ex- may have harmful effects on the women to a constellation of neonatal planation.35 mother-infant dyad. Clinicians should signs that include continuous crying, ir- Biochemical studies that correlate be aware that infants are at risk for ritability, jitteriness, and/or restlessness; serial serum SSRI (or active metabo- manifesting clinical signs of drug fi shivering; fever; tremors; hypertonia or lite) concentrations and markers of toxicity or withdrawal over the rst rigidity; tachypnea or respiratory dis- CNS serotonin activity (eg, 5-hydrox- week of life and arrange for early tress; feeding difficulty; sleep distur- yindoleacetic acid [5-HIAA], a metabo- follow-up after the initial hospital dis- 35 bance; hypoglycemia; and seizures. lite of serotonin) with changes in charge. Ideally, recommendations about lactation and should The onset of these signs ranged from clinical signs could be helpful in dif- be made in consideration of what is several hours to several days after ferentiating toxicity from withdrawal. known about the differences among birth and usually resolved within 1 to 2 In adults, cerebrospinal fluid concen- drugs in a therapeutic class vis-à-vis weeks. In 1 infant exposed to parox- trations of 5-HIAA (but not serum the ratio of human milk to maternal etine, signs persisted through 4 weeks concentrations of serotonin) correlate 36 plasma drug concentration, the likely of age. In severely affected infants, a inversely with increased CNS serotonin total daily infant drug dose (as a short-term course of chlorpromazine activity that results from SSRI treat- fraction of the daily maternal drug provided measurable relief of symp- ment. One prospective study compared dose normalized for weight), and the toms.36 concentrations of SSRI and active ratio of infant to maternal plasma metabolites at birth, 2 days of life, and Several authors have discussed whether drug concentration. However, in the 2 weeks of life; cord blood monoamine these signs are better explained by se- absence of known adverse effects (eg, and metabolite; and serial serotoner- rotonin syndrome (attributable to in- diminished suck, sleep disturbances, gic scores in infants born to mothers creased serotonin concentration in the decreased growth), what constitutes on treatment with SSRIs and those intersynaptic cleft) or by SSRI with- an acceptable fractional drug dose of SSRI-naïve control infants.39 The in- drawal (attributable to a relative hypo- or ratio of plasma concentrations is 30,32,35,37–40 fants born to mothers on SSRIs had serotonergic state). In adults, arbitrary—is 0.10 acceptable but 0.20 treatment with a single SSRI may an average serotonergic score four- not? Paroxetine is the only SSRI for cause mild to moderate serotonin syn- fold greater than SSRI-naïve infants. which the ratio of infant to maternal drome, but severe signs are more Cord blood 5-HIAA concentrations plasma concentrations is low and likely to occur when 2 or more drugs were inversely related to the initial uniformly <0.10.45 Fortinguerra et al46 that increase serotonin concentration serotonergic score, and the resolution documented that paroxetine, sertra- by different mechanisms are pre- of neonatal signs correlated with line, and fluvoxamine are minimally 35 scribed. In adults, serotonin syn- rapid declines in serially measured excreted in human milk and provide drome is characterized by the following serum SSRI and metabolite concen- the infant <10% of the maternal daily 39 triad of clinical signs: changes in men- trations. These results do support dose (normalized for weight). Yet, tal status (agitation, confusion); auto- drug toxicity rather than drug with- Weissman et al45 cite studies in which nomic hyperactivity (fever, , drawal as the cause of clinical signs. 6% and 33% of the reported paired tachypnea, diaphoresis, mydriasis); and Recent authors have suggested the infant to maternal plasma concentra- neuromuscular abnormalities (tremor, terms “serotonin discontinuation syn- tion ratios for sertraline and fluvox- 34 clonus, hyperreflexia, hypertonia). On drome” or “prenatal antidepressant amine, respectively, are >0.10. A 41 the other hand, serotonin withdrawal exposure syndrome.” mother on treatment with an SSRI in adults manifests with subjective symp- Although 1 study reported decreased who desires to nurse her infant toms that include anxiety, headache, pain reactivity at 2 months of age should be counseled about the

PEDIATRICS Volume 129, Number 2, February 2012 e543 Downloaded from www.aappublications.org/news by guest on September 30, 2021 benefits of breastfeeding as well as Opioid abuse in pregnant women methadone. Recent results from the the potential risk that her infant may presents additional risks for the fetus Maternal Opioid Treatment: Human continue to be exposed to a measure- and newborn. Opioids are small lipo- Experimental Research study suggest able level of the SSRI with unknown philic molecular weight compounds that buprenorphine has some advan- long-term effects. that cross placental and blood-brain tages to methadone as a treatment of barriers. Active or passive maternal opioid in pregnant women. detoxification is associated with in- Infants born to mothers treated with OPIOIDS creased risk of fetal distress and fe- buprenorphine had shorter hospital Opioids are a class of natural, en- tal loss. Maintenance programs with stays (10 vs 17.5 days), had shorter dogenous, and synthetic compounds methadone (a full µ-opioid agonist treatment durations for NAS (4.1 vs that activate primarily µ-opioid (but and a Food and Drug Administration 9.9 days), and required a lower cumu- also κ- and δ-opioid) receptors in the [FDA] schedule II controlled substance) lative dose of morphine (1.1 vs 10.4 mg) CNS to produce supraspinal analgesia. for pregnant women can sustain opi- compared with infants born to moth- 48 Other acute effects include sedation, oid concentrations in the mother and ers on . euphoria, miosis, respiratory depres- fetus in ranges that minimize opioid sion, and decreased gastrointestinal craving, suppress abstinence symp- CLINICAL PRESENTATION OF motility. Prolonged use results in phys- tomatology, block heroin-induced eu- OPIOID WITHDRAWAL ical and . As phoria, and prevent fetal stress. Other a class, opioids demonstrate a nar- The clinical presentation of NAS varies benefits from this once controversial row therapeutic index. On the other with the opioid, the maternal drug treatment are optimization of prenatal hand, the interpatient range of dose history (including timing of the most care and general maternal physical necessary to achieve a similar thera- recent use of drug before delivery), and , as well as antici- peutic effect is fairly wide because maternal metabolism, net transfer of pation of potential withdrawal signs in of genetic differences in pharmacoki- drug across the placenta, placental the newborn infant. Disadvantages of netics and pharmacodynamics.47 Mor- metabolism (W. Snodgrass, MD, PhD, phine is 1 of many natural opioids methadone include the extremely un- personal communication, 2008), infant that can be extracted from the opium likely achievement of successful de- metabolism and excretion, and other fi poppy. Codeine, heroin (diacetylmor- toxi cation after delivery and a more factors. In addition, maternal use of phine), hydromorphone (Dilaudid), fen- severe and prolonged course of NAS other drugs and substances such tanyl (Sublimaze), and methadone are compared with heroin exposure. These as cocaine, barbiturates, hypnotics- examples of synthetic opioids. Endog- issues have encouraged the develop- sedatives, and cigarettes may influ- enous opioids include enkephalins, ment of other synthetic opioids as al- ence the severity and duration of endorphins, and endomorphins. The ternative treatments to methadone. NAS. Because opioid receptors are term opiate refers to a subclass of Subsequent to the Drug Addiction concentrated in the CNS and the alkaloid opioids. Methadone exerts Treatment Act of 2000 that allowed gastrointestinal tract, the predom- secondary effects by acting as an office-based treatment of addiction by inant signs and symptoms of pure fl N-methyl-D-aspartate receptor antago- using FDA schedule III to V drugs, opioid withdrawal re ect CNS irrita- nist, blocking the actions of glutamate, the synthetic opioid buprenorphine bility, autonomic overreactivity, and gas- the primary excitatory neurotrans- (a partial µ-opioid agonist) was ap- trointestinal tract dysfunction (Table 3). mitter in the CNS. Opioids acutely in- proved by the FDA in 2002 as a sched- Excess environmental stimuli and hun- hibit the release of noradrenaline at ule III controlled substance for the ger will exacerbate the perceived se- synaptic terminals. With chronic opi- treatment of opioid dependence. Nei- verity of NAS. oid exposure, tolerance develops as ther methadone nor buprenorphine is Onset of signs attributable to neonatal the rate of noradrenaline release approved for use in pregnant women, withdrawal from heroin often begins over time increases toward normal. and both are categorized by the FDA within 24 hours of birth, whereas Abrupt discontinuation of exogenous as class C pregnancy drugs. None- withdrawal from methadone usually opioids results in supranormal re- theless, buprenorphine, either alone commences around 24 to 72 hours of lease of noradrenaline and produces (Subutex) or in combination with nal- age.49 For both opioids, evidence of the autonomic and behavioral signs oxone (Suboxone), has been used both withdrawal may be delayed until 5 to and symptoms characteristic of with- as a first-line treatment of heroin ad- 7 days of age or later, which is typi- drawal. diction and as a replacement drug for cally after hospital discharge.50 For

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TABLE 3 Clinical Features of the Neonatal Narcotic Abstinence Syndrome be expected to vary among infants Neurologic Excitability Gastrointestinal Dysfunction born to mothers on equivalent metha- Tremors Poor feeding done regimens. Irritability Uncoordinated and constant sucking Methadone concentrations in cord Increased wakefulness Vomiting 72 High-pitched crying Diarrhea blood and at 48 hours of age, as well Increased muscle tone Dehydration as the rate of decline in neonatal se- Hyperactive deep tendon reflexes Poor wt gain rum concentration,65 appear to corre- Exaggerated Moro reflex Autonomic signs 72 Seizures Increased sweating late with NAS signs. Kuschel et al Frequent yawning and sneezing Nasal stuffiness found that infants who required rescue Fever treatment had lower cord blood meth- Mottling adone concentrations and that, in all Temperature instability but 1 infant, methadone concentrations were undetectable in the serum at 48 hours. Doberczak65 noted that faster infants exposed to buprenorphine, 1 life. withdrawal has a me- declines in postnatal blood methadone study found that onset of withdrawal dian onset of 4 to 7 days, but a wide concentrations were associated with peaked at 40 hours and that signs range from days 1 through 14.12,13 more severe CNS withdrawal. were most severe at 70 hours of Other sedative-hypnotics have exhibi- age.51 The different time courses re- ted even later onset, including as late Preterm Infants 10 flect variations in the half-lives of as day 12 for diazepam and day 21 Preterm infants have been described 11 drug elimination. However, if 1 week for chlordiazepoxide. as being at lower risk of drug with- or longer has elapsed between the Studies of the relationship between drawal with less severe and/or pro- last maternal opioid use and delivery maternal methadone dose and the longed courses. Infants born at <35 of the infant, the incidence of neona- incidence and severity of NAS have weeks’ gestation whose mothers re- 52 tal withdrawal is relatively low. The provided contradictory findings. Some ceived methadone maintenance had incidence and severity of NAS are studies demonstrated that larger significantly lower total and CNS ab- greater in infants exposed to metha- maternal methadone dosages in late stinence scores than did term infants done compared with those exposed to pregnancy were associated with greater of mothers receiving similar metha- 48 buprenorphine or heroin. Still, se- neonatal concentrations and increased done dosages.64 In a more recent vere withdrawal has been described risk of withdrawal,8,9,62–68 but others study, lower corre- in 0 to 50% of buprenorphine-exposed refuted a correlation.69–74 This lack of lated with a lower risk of neonatal 53–55 infants. In the acute phase, seiz- consensus is explained in part by dif- withdrawal.68 The apparent decreased ures have occurred in 2% to 11% of ferent approaches to the management severity of signs in preterm infants 49,50,56 infants withdrawing from opioids ; of antenatal methadone maintenance may relate to developmental immatu- however, abnormal EEG results with- therapy. There were substantial var- rity of the CNS, differences in total out overt activity have been iations in the mean and range of daily drug exposure, or lower fat depots 57,58 reported in >30% of neonates. methadone dose in the populations of drug. Alternatively, the clinical Subacute signs of opioid withdrawal studied. Studies that found no corre- evaluation of the severity of absti- 59 may last up to 6 months. lation tended to enroll infants born to nence may be more difficult in pre- Seizures also may be associated with mothers who had been prescribed term infants, because scoring tools withdrawal from a variety of non- higher doses of methadone (50–200 to describe withdrawal were largely narcotic drugs (eg, barbiturates,12,14 mg/day), whereas those that did note developed in term or late preterm alcohol,14 and sedative-hypnotics60,61). a relationship between maternal dose infants.76,77 In a retrospective study, The mechanism and significance of and NAS sequelae reported lower Dysart et al78 compared the length of seizures associated with withdrawal maternal doses (eg, <50 mg/day) or hospital stay, duration of medication, are unclear. Withdrawal from included women undergoing partial and cumulative medication exposure begins early, in general, during the detoxification.67 Another potential ex- for preterm and term infants born first 3 to 12 hours after delivery.12,15 planatory factor is the significant in- to mothers enrolled in a methadone Diagnosis of sedative withdrawal is terindividual variability in maternal maintenance program. Infants were more difficult, because classically it methadone metabolism.75 As a re- evaluated by using an abstinence appears after the first few days of sult, cumulative fetal exposure can scoring system77 and treated uniformly

PEDIATRICS Volume 129, Number 2, February 2012 e545 Downloaded from www.aappublications.org/news by guest on September 30, 2021 with a neonatal opiate solution. All inadequate prenatal care; a previously ternal ingestion. Amphetamines, ben- adverse outcomes were reduced in the documented or admitted history of zodiazepines, cocaine metabolites, and preterm cohort. drug abuse; a previous unexplained late opioids are usually cleared within 1 to fetal demise; precipitous labor; abruptio 3 days after birth. Marijuana and co- Abuse of Multiple Drugs placentae; hypertensive episodes; se- caine metabolites may be detectable for 94 The abuse of multiple drugs during vere mood swings; cerebrovascular weeks, depending on maternal usage. pregnancy is not uncommon,79 but its accidents; myocardial infarction; and Drugs that are excreted in the hep- 80,83–88 effect on the occurrence and severity repeated spontaneous abortions. atobiliary system as well as drugs of neonatal abstinence is controver- The legal implications of testing and the excreted by the fetal kidneys into the sial. In 1 study, abstinence scores of need for consent from the mother may amniotic fluid are concentrated in infants whose mothers abused co- vary among the states.89 Each hospital meconium. Hence, meconium analysis caine and methadone were similar to should consider adopting a policy for is most useful when the history and the scores of infants whose mothers maternal and newborn screening to clinical presentation strongly suggest received high-dose maintenance meth- avoid discriminatory practices and to neonatal withdrawal, but the maternal adone.64 In another study, the neuro- comply with local laws. and neonatal urine screening results behavioral scores of infants exposed Withdrawal signs in the newborn may are negative. Drawbacks of testing for to intrauterine cocaine were similar mimic other conditions, such as in- drugs in meconium are that it is not to those of infants exposed to both fection, hypoglycemia, hypocalcemia, typically performed by hospitals and 80 cocaine and methadone. Conversely, hyperthyroidism, intracranial hemor- that results are often not available for an unmasked study reported higher rhage, hypoxic-ischemic encephalopa- days to weeks. Meconium must be abstinence scores in infants exposed thy, and hyperviscosity.90 If none of collected before it is contaminated by to both cocaine and heroin in compar- these diagnoses is readily apparent, transitional, human milk, or formula ison with those exposed to heroin or a detailed maternal drug history stools—otherwise, the assay may not 19 cocaine alone. Infants born to moth- should be obtained that includes be valid or the reference laboratory ers maintained on methadone who interviewing the mother about drug may reject the sample. Assay of me- > were also heavy smokers ( 20 ciga- use and abuse by her partner, friends, conium, although not conclusive if the rettes per day) demonstrated higher and , in addition to queries results are negative, is more likely withdrawal scores that peaked later about the mother’s prescription and to identify infants of drug-abusing 81 than infants born to light smokers. nonprescription drug use.90,91 Because mothers than is the testing of infant 95,96 A 1989 case report linked the adminis- maternal self-reporting underestimates or maternal urine. Other speci- tration of naloxone for the treatment of drug exposure and maternal urine mens that have been tested in re- apnea in a baby born to a mother with search laboratories are maternal and screening during pregnancy fails to 97,98 recent methadone ingestion to the onset identify many cases of drug use,83 neonatal hair. Recently, testing of of seizures. The seizures resolved after appropriate neonatal drug screening tissue by using drug fi morphine treatment but did not respond should be performed. Conversely, no class-speci cimmunoassayswasshown to administration of or clinical signs should be attributed to be in concordance with testing of 82 paired meconium specimens at rates diazepam. For this reason, maternal solely to drug withdrawal on the basis of 97%, 95%, 99%, and 91% for the use of opiates during pregnancy has of a positive maternal history without a detection of amphetamines, opiates, co- remained a relative contraindication to careful assessment to exclude other caine, and cannabinoids, respectively.99 the use of naloxone for the treatment of causes. apnea or hypoventilation during the The availability of this tissue from the Screening is most commonly accom- transition period after birth. moment of birth (in contrast to the plished by using neonatal urine speci- inherent delay in collecting urine or mens. A urine sample must be collected DIFFERENTIAL DIAGNOSIS meconium) may foster the adoption of as soon as possible after birth, be- this method of testing. The presence of maternal character- cause many drugs are rapidly me- istics known to be associated with tabolized and eliminated.90,92,93 Even drug abuse during pregnancy can be so, a positive urine screening result ASSESSMENT AND considered an indication to screen may only reflect recent drug use. Al- NONPHARMACOLOGIC TREATMENT for intrauterine drug exposure. These cohol is detectable in neonatal urine Several semiobjective tools are avail- characteristics include absent, late, or for 6 to 16 hours after the last ma- able for quantifying the severity of

e546 FROM THE AMERICAN ACADEMY OF PEDIATRICS Downloaded from www.aappublications.org/news by guest on September 30, 2021 FROM THE AMERICAN ACADEMY OF PEDIATRICS neonatal withdrawal signs. Clinicians 21 items relating to signs of neonatal history. An infant born to a mother on have used discrete or serial scores to withdrawal.103 In 1 study, administra- a low-dose prescription opiate with assist with therapeutic decisions. The tion of this scoring system with in- a short half-life (eg, hydrocodone; av- Lipsitz tool, also known as the Neonatal fants verifiednottohavebeenexposed erage half-life, 4 hours) may be safely 76 Drug Withdrawal Scoring System, to prenatal opiates by meconium anal- discharged if there are no signs of was recommended in the 1998 Amer- withdrawal by 3 days of age, whereas ysis resulted in a stable median score ican Academy of Pediatrics statement an infant born to a mother on an opiate of 2 during each of the first 3 days of “Neonatal Drug Withdrawal,”100 prob- with a prolonged half-life (eg, metha- ably because it is a relatively simple life, with 95th percentile scores of 5.5 done) should be observed for a mini- 104 metric with good sensitivity for iden- and 7 on days 1 and 2, respectively. mum of 5 to 7 days. Initial treatment tifying clinically important withdrawal. Infants at risk for NAS should be of infants who develop early signs The modified Neonatal Abstinence carefully monitored in the hospital of withdrawal is directed at minimiz- Scoring System (Fig 1),101 is the pre- for the development of signs consis- ing environmental stimuli (both light dominant tool used in the United tent with withdrawal. The appropriate and sound) by placing the infant in a States.102 This more comprehensive duration of hospital observation is dark, quiet environment; avoiding auto- instrument assigns a cumulative score variable and depends on a careful stimulation by careful ; re- based on the interval observation of assessment of the maternal drug sponding early to an infant’s signals;

FIGURE 1 Modified Finnegan’s Neonatal Abstinence Scoring Tool. Adapted from ref 101.

PEDIATRICS Volume 129, Number 2, February 2012 e547 Downloaded from www.aappublications.org/news by guest on September 30, 2021 adopting appropriate infant position- buprenorphine, there is no clear rea- Studies have not addressed whether ing and comforting techniques (sway- son to discourage breastfeeding in long-term morbidity related to neona- ing, rocking); and providing frequent mothers who adhere to methadone tal drug withdrawal is decreased by small volumes of hypercaloric formula or buprenorphine maintenance treat- pharmacologic management of affected or human milk to minimize hunger and ment.111 infants, or whether continued postnatal allow for adequate growth. Caloric Each nursery should adopt a protocol drug exposure augments the risk of needs may be as high as 150 to 250 for the evaluation and management of neurobehavioral and other morbidities. cal/kg per day because of increased neonatal withdrawal, and staff should It is possible that pharmacologic ther- energy expenditure and loss of calories be trained in the correct use of an apy of the infant may introduce or re- from regurgitation, vomiting, and/or abstinence assessment tool. In a re- inforce a maternal disposition to rely 105,106 loose stools. The infant needs cent survey of accredited US neo- on drugs for the treatment of infant to be carefully observed to recognize natology fellowship programs, only discomfort or annoying behavior.112 fever, dehydration, or weight loss 55% had implemented a written NAS Clinicians have treated NAS with a va- promptly. The goals of therapy are to protocol, and only 69% used a pub- riety of drug preparations, including 102 ensure that the infant achieves ade- lished abstinence scoring system. opioids (tincture of opium, neonatal quate sleep and nutrition to establish morphine solution, methadone, and a consistent pattern of weight gain paregoric), barbiturates (phenobar- and begins to integrate into a social RATIONALE AND COMPARATIVE bital), benzodiazepines (diazepam, environment. Maternal screening for EVIDENCE FOR PHARMACOLOGIC lorazepam), , and phenothia- comorbidities, such as HIV or hepatitis TREATMENT zines (chlorpromazine). Information C virus infections and polydrug abuse, Drug therapy is indicated to relieve pertinent to the use of these drug needs to be performed. Additional moderate to severe signs of NAS and to preparations in infants is well sum- supportive care in the form of intra- prevent complications such as fever, marized in the previous American venous fluids, replacement electro- weight loss, and seizures if an infant Academy of Pediatrics statement.100 lytes, and gavage feedings may be does not respond to a committed Recent surveys have documented that, necessary to stabilize the infant’s con- program of nonpharmacologic sup- in accord with the recommendations dition in the acute phase and obviate port. Since the introduction of the of that statement, 94% of UK and 83% the need for pharmacologic interven- abstinence scales in 1975, published of US clinicians use an opioid (mor- tion. When possible, and if not other- reports have documented that the phine or methadone) as the drug of wise contraindicated, mothers who decision to initiate pharmacologic first choice. The majority of practi- adhere to a supervised drug treat- treatment has been based on single or tioners use phenobarbital as a second ment program should be encouraged serial withdrawal scores. However, no drug if the opiate does not adequately to breastfeed so long as the infant con- studies to date have compared the use 102,113 tinues to gain weight. Breastfeeding or of different withdrawal score thresh- control withdrawal signs. Daily doses of morphine ranged from 0.24 the feeding of human milk has been olds for initiating pharmacologic in- 113 associated with less severe NAS that tervention on short-term outcomes mg/kg per day to 1.3 mg/kg per day. presents later and less frequently re- (eg, severity and duration of with- Paregoric is no longer used, because quires pharmacologic intervention.107,108 drawal signs, weight gain, duration of it contains variable concentrations of Methadone is present in very low con- hospitalization, need for pharmaco- other opioids, as well as toxic ingre- centrations in human milk. Cumula- logic treatment, or cumulative drug dients such as camphor, anise oil, al- 100 tive daily intake of methadone in fully exposure). Withdrawal from opioids cohol, and benzoic acid. The use of breastfed infants has been estimated or sedative- drugs may be diazepam has also fallen into disfavor fi to range from 0.01 to 0.15 mg/day in life-threatening, but ultimately, drug because of a documented lack of ef - the first 30 days of life109 and 0.15 to withdrawal is a self-limited process. cacy compared with other agents and 0.30 mg/day between 30 and 180 days Unnecessary pharmacologic treatment becauseofitsadverseeffectsoninfant 114–116 of age.110 Similarly, the amount of will prolong drug exposure and the suck and swallow reflexes. buprenorphine excreted in human duration of hospitalization to the pos- Meta-analyses of published trials re- milk is small. Although more informa- sible detriment of maternal-infant bond- garding the pharmacologic treatment of tion is needed to evaluate long-term ing. The only clearly defined benefitof neonatal withdrawal are available.117,118 neurodevelopmental outcome of in- pharmacologic treatment is the short- In 2 Cochrane meta-analyses, either an fants exposed to small quantities of term amelioration of clinical signs. opioid117 or a sedative118 drug treatment

e548 FROM THE AMERICAN ACADEMY OF PEDIATRICS Downloaded from www.aappublications.org/news by guest on September 30, 2021 FROM THE AMERICAN ACADEMY OF PEDIATRICS was compared with a control treatment seizures in the opioid (paregoric) no differences in primary or second- that could include a nonpharmacologic treatment group.122 No consistent ary outcomes. intervention, a placebo treatment, or trends in secondary outcomes were Since 2004, a number of small studies another opioid and/or sedative drug. observed, although 1 study reported of varying methodologic quality have The authors prospectively designated a shorter duration of therapy in the compared pharmacologic treatments. 4 primary outcomes (failure of treatment phenobarbitone compared with the In a prospective randomized double- 123 to control withdrawal signs; incidence paregoric treatment group, and masked study, Langenfeld et al126 of seizures; survival; and neurodevel- another made the opposite observa- could not identify differences in du- opmental outcome) for meta-analysis. tion when the opioid used was oral ration of treatment, duration of hos- 121 Treatment failure was defined vari- morphine. Three studies individually pitalization, or in weight gain (g/day) ously as the inability of the treatment and in combination reported signifi- in infants treated with either DTO or to maintain abstinence scores within cantly lower rates of treatment failure oral morphine drops. A retrospective a preset “safe” level and/or the need in infants assigned to opioid (pare- study found no difference in length of to add another drug therapy. Some goric or methadone) compared with hospitalization in infants with NAS 8,114,120 studies did not report primary out- diazepam therapy but did not who were treated with methadone or comes and instead quantified second- define differences in secondary out- oral morphine solution, but did cor- ary outcomes (eg, duration of treatment, comes. No studies reported mortality relate higher maternal methadone duration of hospitalization, rate of or neurodevelopmental outcomes. doses with longer lengths of stay.127 weight gain, etc). A second Cochrane review analyzed 6 Ebner et al128 examined the incidence Seven studies of opioid treatment that trials involving 305 infants published of NAS in infants born to mothers enrolled a total of 585 infants were between 1969 and 2002 in which sed- maintained with methadone, morphine, identified between 1983 and 2004. ative treatment of NAS was compared or buprenorphine and compared phe- Methodologic flaws were common and with a nonopioid therapy. Methodologic nobarbital and oral morphine treat- included quasirandom patient alloca- concerns were similar to the opioid ments in affected infants. Sixty-eight tion; substantial and often unexplained treatment trials. In the sole study of percent of infants born to mothers differences in allocation of patients phenobarbitone versus supportive care, maintained on methadone required to treatment groups; imbalances in no difference in treatment failure was pharmacologic treatment at a mean group characteristics after randomi- found, but treatment significantly in- age of 58 hours, compared with 82% zation; failure to mask study treat- creased the duration of therapy and of infants at a mean age of 33 hours ments; and failure to mask outcome hospital stay.119 A small study that in the morphine group and 21% of measurements. In the single study that allocated infants already treated with infants at a mean age of 34 hours in assessed oral morphine treatment diluted tincture of opium (DTO) to phe- the buprenorphine group. The dura- versus supportive therapy only, 3 con- nobarbitone as a second drug versus tion of treatment was significantly secutive Finnegan scores ≥8 promp- no additional treatment identified no shorter for infants who received mor- ted institution of the intervention.119 infants in either group with treatment phine compared with infants who were No significant effect of morphine was failure but observed significant reduc- treated with phenobarbital. A random- found on the rate of treatment failure. tions in the duration of hospitalization ized comparison trial of sublingual Oral morphine significantly increased (38 vs 79 days) and the maximal daily buprenorphine versus neonatal opium the duration of treatment and the dose of opioid in the phenobarbitone- solution for the treatment of NAS length of hospital stay, but it did re- treated infants.124 Infants were dis- showed a nonsignificant reduction in duce the number of days required to charged from the hospital once they length of treatment and duration of regain and duration of were no longer taking opioids. How- hospitalization in the buprenorphine 129 supportive care. Four studies com- ever, the mean duration of phenobar- group. Buprenorphine therapy was pared treatment failures of opioids bitone treatment was 3.5 months. Of well tolerated.

(paregoric, oral morphine, or metha- 3 studies that compared phenobarbi- Clonidine is an α2-adrenergic receptor done) with phenobarbitone.8,119–121 tone and diazepam treatment, 1 found agonist that has been used in combi- Neither the meta-analysis nor any in- asignificantly lower rate of treat- nation with an opioid or other drug in dividual study identified a significant ment failure in the phenobarbitone older children and adults to reduce difference in treatment failure. One group.8,114,120 One study of phenobar- withdrawal symptoms.130,131 Via a neg- study reported a lower incidence of bitone versus chlorpromazine125 found ative feedback mechanism, clonidine

PEDIATRICS Volume 129, Number 2, February 2012 e549 Downloaded from www.aappublications.org/news by guest on September 30, 2021 reduces CNS sympathetic outflow and A recently published case series from for evaluation at 1 year of age; results palliates symptoms of autonomic over- France that used a historical cohort of neurologic examinations were nor- activity such as tachycardia, hyper- for a comparison has suggested that mal in 9 of the 12 infants evaluated. tension, diaphoresis, restlessness, and the treatment of NAS with the pheno- EEG results were abnormal in 9 neo- diarrhea. Cessation of clonidine treat- thiazine, chlorpromazine, as a single nates; however, subsequent EEGs for ment can result in a rebound of auto- drug may be more effective than treat- 7 of 8 of these infants normalized nomic activity. Reported experience ment with morphine.136 Infants treated during follow-up. Mean scores on the with clonidine as a primary or ad- with oral morphine had significantly Bayley Scales of Infant Development junctive treatment of NAS is limited longer median durations of treatment were also normal by 1 year of age, but promising. In a small case series, and hospitalization in comparison with similar to matched controls that were 6 of 7 infants with NAS showed signif- infants treated with chlorpromazine. drug exposed, but in whom withdrawal- icant resolution of signs when treated No adverse affects were reported. associated seizures did not develop.24 with oral clonidine.132 In a randomized Withdrawal-associated seizures seem double-masked controlled trial, Agthe OUTCOME to be primarily myoclonic, to respond et al133 compared the efficacy and to opiates, and to carry no increased safety of treating NAS with DTO plus Assessment of potential long-term risk of poor outcome. Withdrawal- oral clonidine (1 µg/kg every 3 hours) morbidity specifically attributable to associated seizures in neonates are versus DTO plus placebo in 80 infants neonatal drug withdrawal and its different from those associated with with prenatal exposure to methadone treatment is difficult to evaluate. Few other causes. Based on the and/or heroin. The combination ther- studies have followed drug-exposed of norepinephrine and dopamine ob- apy significantly reduced the median children beyond the first few years served with methadone exposure in an- length of treatment of all infants and of life. Confounding variables, such as imal models, withdrawal seizures are for infants exposed to methadone, environment and dysfunctional care- speculated to be attributable to low- but more infants in the DTO/clonidine givers, complicates the interpretation ered levels of neurotransmitters.137,138 group required resumption of DTO of outcomes. In a small study, devel- The normalization of the EEG and nor- after initial discontinuation. The mean opmental scores on the mental index mal neurologic development are be- total dose of morphine over the treat- on the Bayley Scales of Infant Devel- lieved to reflect recovery of normal ment course was ∼60% lower in the opment were not affected by the se- neurotransmitter concentrations dur- combination therapy group. No clini- verity of withdrawal or the treatment ing early infancy. Bandstra et al139 114 cally significant differences in feeding, chosen. Mean scores on the Bayley have comprehensively reviewed out- weight gain or loss, heart rate, or blood Scales of Infant Development were comes of infants and toddlers who pressure were observed. In another similar for all infants treated for were exposed prenatally to opioids case series, oral clonidine was ad- withdrawal, including those receiving and cocaine. ministered either as a primary or phenobarbital, paregoric, or a combina- adjunctive therapy for the prevention tion therapy. Scores of infants whose or treatment of narcotic withdrawal withdrawal was too mild to qualify for MANAGEMENT OF ACQUIRED in infants on intravenous fentanyl or pharmacologic intervention were also OPIOID AND BENZODIAZEPINE infants with antenatal exposure to similar. DEPENDENCY opiates.134 In all cases, treatment was Fourteen drug-exposed infants with One of the cornerstones in caring for successful and clonidine was discon- withdrawal-associated seizures were critically ill children is to provide ad- tinued without sequelae after a mean reported by Doberczak et al.25 The equate and safe analgesia, sedation, duration of 7 days. In a retrospective abstinence scores for 5 of these , and anxiolysis by using both case series, infants who had evidence infants were <7 (the cutoff for treat- pharmacologic and nonpharmacologic of NAS attributable to antenatal meth- ment); hence, they received no phar- measures. Pharmacologic treatment adone exposure had lower severity macologic therapy before the onset of typically includes medications in the scores and required fewer days of drug seizures. Thirteen of the 14 infants opioid and benzodiazepine drug clas- therapy and hospitalization if they had were offspring of mothers enrolled in ses. However, if these drugs cannot been treated with a combination of a methadone treatment program; how- safely be discontinued within a few clonidine and chloral hydrate rather ever, the success of maternal treat- days, on 1 or than a combination of morphine and ment was not described. Of the 14 both of these classes of medication phenobarbital.135 infants with seizures, 12 were available can develop and manifest with signs

e550 FROM THE AMERICAN ACADEMY OF PEDIATRICS Downloaded from www.aappublications.org/news by guest on September 30, 2021 FROM THE AMERICAN ACADEMY OF PEDIATRICS and symptoms of withdrawal on acute 70% sensitivity and 78% specificity were among the first investigators to dosage reduction or cessation of and that an infusion duration ≥8 days describe treatment of opioid with- therapy. Infants who undergo complex was 90% sensitive and 67% specific drawal by conversion to enteral surgery, who require prolonged med- for withdrawal. In adults, concomitant methadone. Methadone was chosen ical intensive care for conditions such treatment with neuromuscular para- as the opioid of choice because of its as respiratory failure or persistent lytic agents or propofol for >24 hours excellent oral bioavailability (70%– pulmonary , or who are also increased the likelihood of with- 100%) and long half-life (19–41 supported with extracorporeal mem- drawal.144 Signs and symptoms of with- hours), which allowed for long inter- brane oxygenation (ECMO) therapy are drawal from fentanyl commence within vals between doses.148 In this initial among those at greatest risk of ac- 24 hours of cessation of therapy. report, 3 symptomatic patients who quired drug dependency. The refinement of pain management in had been exposed to continuous or Extended treatment with opioids via children over the past 2 decades has bolus opioids for up to 7 weeks were continuous intravenous infusion re- witnessed an expansion of the use of transitioned to a methadone regimen sults in . Even short- opioids in the intensive care setting. of 0.1 mg/kg, orally, every 12 hours. term opioid exposure alters the As a result, more children have been Dose reduction by 10% to 20% of the number and affinity of receptors in key treated for actual or potential with- initial dose per week resulted in suc- neuronal centers so that an escala- drawal symptoms as a comorbidity of cessful weaning in 4 to 6 weeks. tion of the opioid infusion rate (which hospitalization. Fentanyl, a pure µ-opioid In 2000, Robertson and et al149 re- produces an increase in opioid plasma receptor antagonist, has become the ported the outcomes of 10 children concentrations) becomes necessary to opioid of choice because of its rapid 6 months to 18 years of age who had achieve the same physiologic effect.140 onset of action, short duration of ef- received >7 days of opioids (range, 7– By itself, the development of tolerance fect (half-life of 0.5–1 hour), excellent 53 days). An amount of methadone, does not predict physical dependency potency, and minimal acute adverse equipotent to the existing daily fen- or withdrawal.141 Cumulative expo- effects. However, fentanyl has not been tanyl or morphine dose, was deter- sure to fentanyl, quantified by the to- demonstrated to be safer or more ef- mined. This amount was reduced by tal dose in milligrams per kilogram or fective than morphine for the provision a factor of 6 because of the longer the number of consecutive days of of long-term analgesia. Indeed, 1 study half-life of methadone to calculate the treatment, correlated with the likeli- has reported that patients who were initial total daily methadone dose. hood of withdrawal.140,142,143 By using treated prospectively with a continu- Protocols specified 2 different wean- a multiple logistic regression analysis, ous morphine infusion during ECMO ing schedules, depending on whether Arnold et al140 found that the duration experienced a significantly lower need the patient had been treated with of ECMO therapy was an even more for supplemental analgesia, a lower opioids (fentanyl or morphine) for ei- powerful predictor of withdrawal than rate of dependency, and a shorter hos- ther 7 to 14 days or for >14 days. was cumulative fentanyl exposure. pital stay compared with a previous Treatment intervals were gradually Katz et al142 reported that among 23 group of patients treated with fentanyl lengthened from every 6 hours to ev- 145 mechanically ventilated children aged during ECMO. ery 24 hours when methadone was 1 week to 22 months (mean, 6 months) Practitioners have employed a variety discontinued. Outcomes of these pa- who were treated for >24 hours with of strategies to treat or, in high-risk tients were compared with recent a continuous fentanyl infusion, 13 of patients, to prevent signs and symp- control patients who had also been 23 children (57%) developed withdrawal toms of opioid withdrawal in infants treated with enteral methadone but as defined by a Finnegan score ≥8. In and children. Carr and Todres146 not under a standard protocol. Among this prospective study, a cumulative fen- reported success with a gradual taper the protocol patients, there were no tanyl exposure in excess of 2.5 mg/kg of the opioid infusion rate. Children treatment failures. Weaning was ac- or 9 days of therapy was 100% pre- who had received continuous opioid complished in a median of 9 days dictive of withdrawal. More recently, infusions for more than a week re- (range, 5–10 days), which was signif- in a prospective study of 19 neonates quired 2 to 3 weeks for complete icantly less than the median of 20 treated with fentanyl for a minimum weaning. One disadvantage of this days (range, 9–31 days) observed in of 24 hours, Dominquez et al143 docu- approach was that intravenous access the nonprotocol children. Concurrent mented that a cumulative fentanyl dose had to be maintained for the entire use of benzodiazepines occurred in 6 ≥415 µg/kg predicted withdrawal with course of treatment. Tobias et al147 of the protocol children, compared

PEDIATRICS Volume 129, Number 2, February 2012 e551 Downloaded from www.aappublications.org/news by guest on September 30, 2021 with 3 of the nonprotocol group, so found that in a group of 37 fentanyl- benzodiazepine dependency can be that the decreased taper time on treated patients, a 5-day methadone recommended, because the necessary protocol was unlikely to have been taper was as successful as the longer comparative studies of safety and ef- confounded by other drug therapy. 10-day course (13 of 16 vs 17 of 21 ficacy are not available.156 Hence, it is Weaning and discontinuation from [not significant]) in discontinuing opi- even more incumbent on the practi- benzodiazepines were successful dur- oid infusions without causing with- tioner to prescribe pharmacologic ing the methadone taper in all pro- drawal. In contrast to their previous interventions with the goal of achiev- tocol patients. study, a standardized taper of lor- ing the desired therapeutic effect by Meyer et al150 described a protocol for azepam was allowed in 17 of the 37 using the fewest drugs at the lowest rescue therapy in 29 patients 1 day to patients while on the methadone doses and for the shortest durations 20 years of age on admission who protocol. Only 1 of these 17 patients possible. developed withdrawal during the who underwent dual tapers required Nonetheless, because many critically course of nonstandardized tapers of rescue treatment with an increased ill infants and children do receive treat- prolonged continuous fentanyl in- dose of opioids. ment with prolonged courses of opioids fusion. Withdrawal was defined as the Several factors potentially complicate and benzodiazepines, the following observation of 3 consecutive Finnegan the adoption of the protocols reported practices are reasonable based on the scores ≥8 obtained at 2-hour inter- by Robertson, Meyer, and Berens (see available evidence: vals. The daily fentanyl dose for the Table 4) into routine neonatal clinical 1. Each clinical unit can establish period 24 to 48 hours before with- practices. Most obvious is that these a threshold level of cumulative drawal symptoms was used to calcu- studies were conducted in a PICU exposure to opioids and benzodia- late an equipotent dose of morphine setting; few neonates were included, zepines above which drug depen- sulfate. Morphine was administered and their outcomes were not sepa- dency can be expected to occur as a bolus dose every 4 hours and rately analyzed. Other investigators with a likelihood that justifies an- titrated to effect (Finnegan score have emphasized that the Finnegan ticipatory initiation of a weaning consistently <8) over 12 to 24 hours. instrument common to all 3 studies protocol. For example, setting a An equipotent amount of methadone has been validated only in term in- threshold at a cumulative fentanyl was then determined by using the fants undergoing withdrawal secondary exposure of >2 mg/kg or >7 days’ effective morphine dose. Three load- to in utero opioid exposure.152,153 duration would predict a likeli- ing doses of methadone at 12-hour Therefore, the use of this tool may hood of dependency >50% but 141,142 intervals were administered. After- have underestimated withdrawal symp- <100%. ward, doses were given every 24 tomatology in an older pediatric pop- 2. Infants with a cumulative exposure hours and weaned by 10% per day. ulation. A third concern is that opioids to opioids or benzodiazepines be- Ten patients were receiving concomi- and benzodiazepines are often used low the thresholds for initiation of tant treatment with a benzodiazepine concurrently in the same patient, yet weaning protocols can undergo or chloral hydrate, but these medi- symptoms of opioid and benzodiaze- a rapid taper of these medications cations were not weaned during the pine withdrawal overlap to a great ex- over a 24- to 48-hour period. Many methadone taper. Twenty-five of 29 tent. Hence, current instruments will such children will not subsequently patients successfully completed this not reliably differentiate whether with- exhibit drug dependency. taper over 10 days. Three patients drawal symptoms stem from relative 3. Signs and symptoms of withdrawal 153 required 21 days, and 1 patient died of opioid or benzodiazepine abstinence. will develop within 24 hours of dis- sepsis. Sixteen of the patients were Other scales have been proposed for continuation or during the course discharged from the hospital and children and are in various stages of of a rapid taper of an opioid. If this completed methadone tapers on an evaluation, including the Opioid and occurs, 1 of the rescue approaches 151 outpatient basis. Nine of the patients Benzodiazepine Withdrawal Scale, in Table 4 can be chosen as a guide 154 had been started on clonidine during the Sedation Withdrawal Score, and to facilitate conversion to enteral the phase of nonstandardized opioid the Sophia Benzodiazepine and Opioid methadone management and to 155 weaning in unsuccessful attempts to Withdrawal Checklist. initiate a weaning strategy, with 2 prevent withdrawal. A subsequent ran- At this time, no optimal pharmacologic caveats. Infants on very high daily domized double-blind follow-up study regimen for the prevention or treat- doses of continuous intravenous by the same group of investigators151 ment of acquired opioid and/or opioid may require less than the

e552 FROM THE AMERICAN ACADEMY OF PEDIATRICS Downloaded from www.aappublications.org/news by guest on September 30, 2021 FROM THE AMERICAN ACADEMY OF PEDIATRICS

TABLE 4 Weaning Protocols by Using Conversion of Continuous Opioid Infusions to Enteral Methadone and for Conversion of (Versed) Infusion to Enteral Lorazepam (Ativan) Robertson et al149 Conversion of continuous intravenous fentanyl of 7–14 d duration to enteral methadone: 1. By using the current hourly infusion rate, calculate the 24-h fentanyl dose. 2. Multiply the daily fentanyl dose by a factor of 100 to calculate the equipotent amount of methadone (ratio of potencies assumed to be fentanyl: methadone = 100:1). 3. Divide this amount of methadone by 6 (a correction for the longer half-life of methadone) to calculate an initial total daily dose of methadone, and on day 1 provide this amount orally in 4 divided doses every 6 h for 24 h. 4. Day 2: Provide 80% of original daily dose in 3 divided oral doses every 8 h for 24 h. 5. Day 3: Provide 60% of original daily dose in 3 divided oral doses every 8 h for 24 h. 6. Day 4: Provide 40% of original daily dose in 2 divided oral doses every 12 h for 24 h. 7. Day 5: Provide 20% of original daily dose × 1. 8. Day 6: Discontinue methadone. Conversion of continuous intravenous fentanyl greater than 14 d duration to enteral methadone: 1. Repeat steps 1–2 above. 2. Days 1–2: Divide the dose of methadone by 6 (a correction for the longer half-life of methadone) and on day 1 provide this amount orally in 4 divided doses every 6 h for 48 h. 3. Days 3–4: Provide 80% of original daily dose in 3 divided oral doses every 8 h for 48 h. 4. Days 5–6: Provide 60% of original daily dose in 3 divided oral doses every 8 h for 48 h. 5. Days 7–8: Provide 40% of original daily dose in 2 divided oral doses every 12 h for 48 h. 6. Days 9–10: Provide 20% of original daily dose once per day for 48 h. 7. Day 11: Discontinue methadone. For patients on continuous intravenous morphine, proceed as above but do not multiply the daily fentanyl dose by 100, because morphine and methadone are nearly equipotent.

Meyer and Berens150 Conversion of continuous intravenous fentanyl to intermittent intravenous morphine: 1. By using the target hourly infusion rate of fentanyl, calculate the 24-h fentanyl dose. 2. Multiply the daily fentanyl dose by a factor of 60 to calculate the equipotent dose of morphine (ratio of potencies assumed to be fentanyl: morphine = 60:1). 3. Divide the dose of morphine by 4 (correcting for the longer half-life of morphine) and on day 1 administer this amount intravenously in 6 divided doses every 4h. 4. Titrate the morphine dose for adequate effect over 12 to 24 h. Conversion of intermittent intravenous morphine to enteral methadone: 1. Multiply the dose of morphine given every 4 h by 2 (ratio of potencies assumed to be morphine: methadone = 2:1) to determine an equipotent amount of methadone. 2. Provide this amount of methadone as an oral dose every 12 h for 3 doses. 3. Double this amount of methadone and provide as a single oral dose per day at bedtime. 4. Provide 90% of the initial dose on day 2, 80% on day 3, etc, so that the last dose of methadone (10% of the original dose) is given on day 10.

Protocols at Wolfson Children’s Hospital, Jacksonville, Florida Conversion of continuous intravenous fentanyl >7 d duration to enteral methadone: 1. By using the current hourly infusion rate, calculate the 24-h fentanyl dose. 2. Multiply the daily fentanyl dose by a factor of 100 to calculate the equipotent amount of methadone (ratio of potencies assumed to be fentanyl: methadone = 100:1). 3. Divide this amount of methadone by 8–12 (a correction for the longer half-life of methadone) to calculate an initial total daily dose of methadone (not to exceed 40 mg/day). 4. Days 1–2: Provide the total daily dose of methadone orally in 4 divided doses every 6 h for 48 h. At the time of the second methadone dose, reduce the fentanyl infusion rate to 50%; at the time of the third dose, reduce the fentanyl infusion rate to 25%; and after the fourth methadone dose, discontinue the fentanyl infusion. 5. Days 3–4: Provide 80% of original daily dose in 3 divided oral doses every 8 h for 48 h. 6. Days 5–6: Provide 60% of original daily dose in 3 divided oral doses every 8 h for 48 h. 7. Days 7–8: Provide 40% of original daily dose in 2 divided oral doses every 12 h for 48 h. 8. Days 9–10: Provide 20% of original daily dose once per day for 48 h. 9. Day 11: Discontinue methadone. Conversion of continuous intravenous midazolam >7 d duration to enteral lorazepam: 1. By using the current hourly infusion rate, calculate the 24-h midazolam dose. 2. Because lorazepam is twice as potent as midazolam and has a sixfold longer half-life, divide the 24 h midazolam dose by 12 to determine the daily lorazepam dose. 3. Divide the calculated lorazepam dose by 4 and initiate every 6 h oral treatments with the intravenous product or an aliquot of a crushed tablet. 4. Wean lorazepam by 10% to 20% per day. The dosage interval can also be increased gradually to every 8 h, then every 12 h, then every 24 h, and then every other day before lorazepam is discontinued.

PEDIATRICS Volume 129, Number 2, February 2012 e553 Downloaded from www.aappublications.org/news by guest on September 30, 2021 TABLE 4 Continued

Robertson et al149 Summary of Conversion Of Intravenous Opioids to Enteral Methadone

1. Tobias et al147: Converted 2 patients on morphine (0.1–0.15 mg/kg q3h) and 1 patient on fentanyl (1–2 µg/kg every 1–2 h) to methadone at a starting dose of 0.2 mg/kg per day. 2. Robertson et al149:1µg/kg per h fentanyl = 0.4 mg/kg per day methadone. 3. Meyer and Berens150:1µg/kg per h fentanyl = 0.24 mg/kg per day methadone. 4. Wolfson Children’s Hospital: 1 µg/kg per h fentanyl = 0.2–0.3 mg/kg per day methadone.

calculated methadone equivalent intravenous low-dose naloxone157,158 drug exposure. Although new- to achieve a successful conversion. during the course of continuous born meconium screening also Also, the rate of weaning should be opioid infusions will reduce the may yield false-negative results, adjusted on the basis of careful con- likelihood or severity of opioid the likelihood is lower than with tinuing clinical assessment. Eighty dependency. urinary screening. The more recent percent of children can be success- availability of testing of umbilical fully weaned from methadone com- cord samples may be considered pletely within 5 to 10 days. CLINICAL HIGHLIGHTS a viable screening tool, because it 4. Signs and symptoms of withdrawal appears to reflect in utero expo- 1) Each nursery that cares for from benzodiazepine therapy can sures comparable to meconium infants with neonatal withdrawal be delayed. Intravenous benzodia- screening. should develop a protocol that zepines can be converted to oral defines indications and proce- 3) Drug withdrawal should be consid- lorazepam (Table 4). The required dures for screening for maternal ered in the differential diagnosis time for weaning can be expected . In addition, each for infants in whom compatible to be proportional to the dura- nursery should develop and ad- signs develop. Physicians should tion of intravenous benzodiazepine here to a standardized plan for be aware of other potential diag- treatment. the evaluation and comprehensive noses that need to be evaluated fi 5. Infants and children at risk for treatment of infants at risk for or and, if con rmed, treated appro- withdrawal are prudently observed showing signs of withdrawal. priately. in the hospital for signs and symp- 2) Screening for maternal substance 4) Nonpharmacologic supportive toms. Each clinical unit can choose abuse is best accomplished by us- measures that include minimiz- 1 assessment tool and train staff to ing multiple methods, including ing environmental stimuli, pro- minimize individual variability in maternal history, maternal urine moting adequate rest and sleep, scoring. fi testing, and testing of newborn and providing suf cient caloric 6. Discharge from the hospital for urine and/or meconium speci- intake to establish weight gain infants and very young children is mens that are in compliance with should constitute the initial ap- prudently delayed until they are local laws. The screening of bio- proach to therapy. free of withdrawal signs and symp- logical samples is an adjunct to 5) Signs of drug withdrawal can be toms for a period of 24 to 48 hours provide additional information scored by using a published ab- after complete cessation of opioids. helpful in the ongoing medical stinence assessment tool. Infants Earlier discharge of an older of the infant. The duration with confirmed drug exposure who can be individualized in consider- of urinary excretion of most drugs are unaffected or demonstrating ation of the child’s overall clinical is relatively short, and maternal minimal signs of withdrawal do status, the home environment, and or neonatal urinary screening only not require pharmacologic ther- the availability of adequate and addresses drug exposure in the apy. Caution should be exercised prompt follow-up. hours immediately before urine before instituting pharmacologic 7. No clinical studies to date support collection. Thus, false-negative urine therapy that could lengthen the the premise that initiation of cloni- results may occur in the pres- duration of hospitalization and inter- dine, chloral hydrate, or continuous ence of significant intrauterine fere with maternal-infant bonding.

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Together with individualized clini- and clinical situations, a number 12) Given the natural history of with- cal assessment, the serial and of important caveats apply. Treat- drawal, it is reasonable for neo- accurate use of a withdrawal as- ment with paregoric is contrain- nates with known antenatal sessment tool may facilitate a de- dicated, because this preparation exposure to opioids and benzo- cision about the institution of contains multiple opiates in addi- diazepines to be observed in the pharmacologic therapy and there- tion to morphine, as well as other hospital for 4 to 7 days. After after can provide a quantitative potentially harmful compounds discharge, outpatient follow-up measurement that can be used (alcohol, anise). Morphine pre- should occur early and include to adjust drug dosing. scriptions should be written as of the education of 6) The optimal threshold score for milligrams of morphine per kilo- the caregiver about the risk of the institution of pharmacologic gram and not as milliliters of DTO late withdrawal signs. therapy by using any of the pub- per kilogram. Tincture of opium 13) Neonates cared for in ICUs who lished abstinence assessment in- contains a 25-fold higher concen- have developed tolerance to opioids struments is unknown. tration of morphine than do avail- and benzodiazepines as a result 7) Breastfeeding and the provision able oral morphine solutions; of an extended duration of treat- of expressed human milk should hence, it increases the likelihood ment can be converted to an be encouraged if not contraindi- of drug error and morphine over- equivalent regimen of oral meth- 111,159 cated for other reasons. dose. The relative efficacy and adone and lorazepam. Doses may 8) Pharmacologic therapy for safety of buprenorphine for the be increased as necessary to withdrawal-associated seizures treatment of NAS require addi- achieve patient comfort. These med- is indicated. Other causes of neo- tional comparative study. The op- ications can then be reduced by natal seizures must also be eval- timal pharmacologic treatment of 10% to 20% of the initial dose every uated. infants who are withdrawing 1 to 2 days on the basis of clinical 9) Vomiting, diarrhea, or both asso- from sedatives or hypnotics is un- response and serial assessments ciated with dehydration and poor known. Finally, there is also insuf- by using a standardized neonatal fi weight gain in the absence of cient evidence to state whether abstinence instrument. an infant born to a mother with other diagnoses are relative indi- 14) Significant gaps in knowledge cations for treatment, even in the multiple drug abuse who meets concerning the optimal treatment criteria for pharmacologic ther- absence of high total withdrawal strategy (including the criteria apy of withdrawal signs is best scores. for instituting pharmacologic ther- treated with an opioid, a barbitu- 10) The limited available evidence apy, the drug of first choice, and rate, a medication from another from controlled trials of neonatal the strategy for weaning) of infants drug class, or a combination of opioid withdrawal supports the with neonatal withdrawal should drugs from different classes. use of oral morphine solution be addressed in well-designed and methadone when pharmaco- 11) Physicians need to be aware that randomized controlled studies logic treatment is indicated. the severity of withdrawal signs, that are adequately powered to Growing evidence suggests that including seizures, has not been assess short-term outcomes and oral clonidine is also effective ei- proven to be associated with dif- to provide for long-term follow-up. ther as a primary or adjunctive ferences in long-term outcome af- therapy, but further prospective ter intrauterine drug exposure. Furthermore, treatment of drug trials are warranted. Dosing regi- LEAD AUTHORS mens are listed in Table 5. With withdrawal may not alter the Mark L. Hudak, MD respect to other drug treatments long-term outcome. Rosemarie C. Tan, MD, PhD

TABLE 5 Drugs Used in the Treatment of Neonatal Narcotic Withdrawal Drug Initial Dose Increment Maximum Dose Ref. No. Oral morphine 0.04 mg/kg every 3–4 h 0.04 mg/kg per dose 0.2 mg/kg per dose 119,121,126,133 Oral methadone 0.05–0.1 mg/kg every 6 h 0.05 mg/kg per dose To effect 127 Oral clonidine 0.5–1 µg/kg every 3–6 h Not studied 1 µg/kg every 3 h 132–135

PEDIATRICS Volume 129, Number 2, February 2012 e555 Downloaded from www.aappublications.org/news by guest on September 30, 2021 COMMITTEE ON DRUGS, 2011–2012 Adelaide Robb, MD – American Academy of Kasper S. Wang, MD Daniel A. C. Frattarelli, MD, Chairperson Child and Adolescent Kristi L. Watterberg, MD Jeffrey L. Galinkin, MD Hari C. Sachs, MD – Food and Drug Adminis- Thomas P. Green, MD tration FORMER COMMITTEE ON FETUS AND Mark L. Hudak, MD Anne Zajicek, MD, PharmD – National Institutes NEWBORN MEMBERS Kathleen A. Neville, MD of Health David H. Adamkin, MD Ian M. Paul, MD John N. Van Den Anker, MD, PhD FORMER COMMITTEE ON DRUGS LIAISONS LIAISONS CAPT Wanda D. Barfield, MD, MPH – Centers for FORMER COMMITTEE ON DRUGS George P. Giacoia, MD Disease Control and Prevention MEMBERS George Macones, MD – American College of Mary Hegenbarth, MD STAFF Obstetricians and Gynecologists Mark L. Hudak, MD Mark Del Monte, JD Ann L. Jefferies, MD – Canadian Paediatric Matthew Knight, MD Raymond J. Koteras, MHA Society Robert E. Shaddy, MD Rosalie O. Mainous, PhD, RNC, NNP – National Wayne R. Snodgrass, MD, PhD COMMITTEE ON FETUS AND Association of Neonatal Nurses NEWBORN, 2011–2012 Tonse N. K. Raju, MD, DCH – National Institutes of LIAISONS Lu-Ann Papile, MD, Chairperson Health John J. Alexander, MD – Food and Drug Ad- Jill E. Baley, MD ministration Vinod K. Bhutani, MD FORMER COMMITTEE ON FETUS AND Nancy C. Chescheir, MD – American College of Waldemar A. Carlo, MD NEWBORN LIAISONS Obstetricians and Gynecologists James J. Cummings, MD William H. Barth, Jr, MD Janet D. Cragan, MD – Centers for Disease Praveen Kumar, MD Control and Prevention Richard A. Polin, MD STAFF – Michael J. Rieder, MD Canadian Paediatric Rosemarie C. Tan, MD, PhD Jim Couto, MA Society

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