Babies Breaking Bad: Neonatal and Iatrogenic Withdrawal Syndromes

REVIEW

CURRENT OPINION Babies breaking bad: neonatal and iatrogenic withdrawal syndromes

Rachel E.M. Cramtona,b and Nancy E. Gruchalaa,b

Purpose of review This review will summarize the symptoms, evaluation, and treatment of neonatal and iatrogenic withdrawal syndromes. Recent findings Buprenorphine is emerging as the drug of choice for maintaining opioid-dependent women during pregnancy, because of its association with less severe withdrawal symptoms. Recent findings suggest it may be the drug of choice for treating the opioid-exposed neonate as well. Summary Healthcare workers should be cognizant of the risk factors for neonatal abstinence syndrome (NAS), as well as its symptoms, so that nonpharmalogic and pharmacologic therapies can be initiated. With increased emphasis on pain control in children, it is likely that iatrogenic withdrawal will continue to be a concern, and healthcare workers should understand the similarities and differences between this and NAS. Keywords buprenorphine, methadone, neonatal abstinence syndrome, opiate withdrawal

INTRODUCTION recognition, and management of withdrawal syn- Recent studies have shown an increase in neonatal dromes in pediatrics. abstinence syndrome (NAS) over the last decade [1&]. During the same time period, increased awareness RISK FACTORS of the need for adequate pain control and sedation in critically ill children resulted in more liberal use Both human and drug characteristics impact the of opioids and benzodiazepines, leading to an severity of withdrawal as measured by the length increased incidence of iatrogenic chemical depend- of hospital stay and the need for pharmacologic ence. These two trends prompt the need to review therapy. the identification, management, and prevention of withdrawal syndromes in pediatrics. Neonatal withdrawal The best-described withdrawal syndrome is NAS that occurs after birth, when intrauterine exposure to In the neonate, gestational age affects the severity of certain substances is abruptly discontinued. This has NAS, with milder symptoms developing in prema- been documented for opioids, benzodiazepines, ture infants. This is thought to be related to imma- selective serotonin reuptake inhibitors, mood stabil- turity of the central nervous system, lower fat izers, and nicotine [2&&,3&&]. A similar syndrome occurs when critically ill infants and children develop aDepartment of Pediatrics, University of Arizona College of Medicine and physical dependence on medications, most com- b monly opioids and benzodiazepines, used to achieve University of Arizona Health Network, Tucson, Arizona, USA analgesia and sedation. Withdrawal commonly Correspondence to Rachel Cramton, MD, Assistant Professor of Clinical Pediatrics, Section of Hospital Medicine and Outreach, Department of becomes an issue in critically ill, mechanically venti- Pediatrics, The University of Arizona Health Sciences Center, Post Office lated patients who often require prolonged sedation Box 245073, 1501N. Campbell Avenue, Tucson, AZ 85724, USA. [4]. Inadequate attention to withdrawal can lead to Tel: +1 520 626 6614; fax: +1 520 626 2883; e-mail: rcramton@peds. life-threatening complications, patient discomfort, arizona.edu and prolonged hospital stays. The following article Curr Opin Pediatr 2013, 25:532–542 serves to review the current literature on prevention, DOI:10.1097/MOP.0b013e328362cd0d

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Keeping these criteria in mind can aid in identifying KEY POINTS children at greatest risk of withdrawal, developing NAS and iatrogenic withdrawal syndrome have assessment tools, and initiating weaning protocols similar symptoms. appropriately.

Recognition and treatment of opioid withdrawal are confounded by concurrent benzodiazepine withdrawal. SYMPTOMS Assessment of iatrogenic withdrawal remains In order to assess, treat, or ideally prevent with- challenging given the paucity of research beyond the drawal syndromes, it is essential not only to identify neonatal period. risk factors, but also to recognize the symptoms. Evidence-based clinical guidelines are needed for optimal management of pediatric withdrawal syndromes. Neonatal withdrawal The timing and features of withdrawal symptoms in NAS depend on the substance. They begin within 24 h of birth for heroin and 2 to 6 days after deposits of drug, and decreased total drug exposure birth for methadone or BPH. Symptoms of benzo- [3&&,5,6,7&]. Although Jansson et al. [8] found diazepine withdrawal can be delayed a week or more increased symptoms and need for greater pharma- [2&&,3&&]. The abrupt discontinuation of exogenous cologic therapy in males, multiple other studies opioids results in supra-normal noradrenaline found each sex to be equally affected [9,10]. release, which in turn causes autonomic, neuro- Wachman et al. [11] believe that they may have logic, and gastrointestinal symptoms (Table 1) identified a single nucleotide polymorphism that [2&&,3&&,14,15,17,19,22&&,23,24]. The localization is associated with more severe NAS. Maternal factors of symptoms to these areas is because of the con- predictive of worse neonatal withdrawal symptoms centration of opioid receptors in the CNS and include polysubstance use (opioids and benzo- gastrointestinal tracts. Although the symptoms of diazepines in particular) [6,12,13&] and perinatal opioid withdrawal are largely the same, regardless methadone use, whereas maternal use of buprenor- of the opioid to which the infant was exposed, there phine (BPH) predicts less severe symptoms [8,14]. have been minor differences noted. Neonates with Some controversy surrounds whether or not exposuretomethadonehavemoreundisturbed increased maternal methadone dosage is associated tremors and hyperactive moro reflex compared with an increased rate or severity of symptoms with neonates with BPH exposure, who have nasal [13&,15,16]. It does appear that maternal dose has stuffiness, sneezing, and loose stools [25&]. a positive correlation with length of hospital stay [7&], but if the mother has not used opioids within 1 week of delivery there is a lower risk of NAS [3&&]. Iatrogenic withdrawal Iatrogenic withdrawal develops with abrupt discontinuation of medication after as little as 72 h of Iatrogenic withdrawal exposure [4,21&] and onset of symptoms occurs most There are multiple risk factors that contribute to the quickly with short-acting opioids like fentanyl. development of iatrogenic withdrawal. Regardless Benzodiazepine withdrawal symptoms can be of the medication dose, genetic variations influence delayed for a week or more [2&&,3&&]. Most of the individual response to opioid analgesia and devel- understanding of pediatric withdrawal has been opment of tolerance [4]. There are also drug-related derived from research on intrauterine drug-exposed risk factors that have been identified in children, newborns and opioid-addicted adults [14]. Symp- including rapid tapering or abrupt discontinuation toms of opioid withdrawal are similar in newborns of opioids and benzodiazepines, length of exposure/ and children [14]; however, unlike in neonates, duration of treatment, and high total cumulative most critically ill ventilated children receive both dose [3&&,4,14,17–19]. Although data on defining opioids and benzodiazepines. The concurrent use of high dose vary, exceeding 5–7 days of therapy these medications makes it difficult to differentiate has consistently been identified as a risk factor. A the symptoms of one from the other. Research recent clinical report published by the American suggests that they have a similar withdrawal profile, Academy of Pediatrics (AAP) suggests that setting perhaps with the exception of gastrointestinal a threshold at 2 mg/kg of fentanyl exposure or symptoms observed in opioid withdrawal. Major 7 days’ duration of therapy would predict likelihood symptoms of benzodiazepine withdrawal in chil- of withdrawal to fall between 50–100% [3&&,20,21&]. dren are included in Table 1. Until recently these

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Table 1. Withdrawal symptoms

Autonomic Neurologic signs Gastrointestinal signs

Opioids Temperature instability Irritabilitya Poor feeding Low-grade fever Poor sleepa Poor weight gain Diaphoresis Increased muscle tone Diarrhea Mottling Tremora Vomiting Piloerection High-pitched cry Tachypnea Seizure Nasal stuffiness Sneezing/yawning Benzodiazepines Muscle twitching Inconsolable cryinga Grimacing Jitteriness Visual/auditory hallucination Disorientation Seizures Movement disordera

aIndicates presence in combined benzodiazepine and opioid withdrawal.

symptoms have been described on the basis of single accredited neonatology fellowships showed that case reports and small case series that correspond to only slightly more than half had a written NAS studies in adult patients [14]. A recent larger pro- policy, and fewer than three-quarters used a pub- spective study by Ista et al. [19] expanded to include lished NAS scoring system [30]. Despite these all 24 symptoms of opioid and benzodiazepine with- statistics from accredited training programs, any drawal described in the literature for ICU patients. healthcare organization that serves neonates should Unlike previous studies, this study suggested that adopt a single abstinence scoring form to avoid gastrointestinal symptoms such as vomiting and individual variation in assessment [3&&]. Direct diarrhea may also be part of benzodiazepine instruction and education regarding the scoring withdrawal [19], making differentiation even more sheet improves interrater reliability and decreases challenging. subjectivity [29&,31&&]. Infants with known intrauterine exposure should be monitored for at least 72 h. ASSESSMENT In order to optimally treat withdrawal, one must both recognize the symptoms and have an objec- Iatrogenic withdrawal tive-validated reliable tool to measure severity. Adequate pain control and sedation have caused an increased incidence of tolerance, physical dependence, and subsequent withdrawal mainly from Neonatal withdrawal morphine, fentanyl, and midazolam (the most com- The majority of research on neonatal withdrawal monly used agents). This is largely observed in has used the Finnegan Scale [26], or the modified critically ill children in the Pediatric Intensive Care Finnegan Scale, as these scales were developed in Unit (PICU). Studies have suggested that opioid 1975 [27,28] (Table 2). These scales, developed on withdrawal occurs in as many as 57% of PICU term and near-term infants, score infant behaviors patients [4,14,18–20,32] and the incidence of associated with withdrawal [15]. The infant is eval- benzodiazepine withdrawal ranges from 17–35% uated every 4 h and their Finnegan Score is based on depending on the study [14,17,19,33]. Although behaviors during that period. If the score is greater adequate pain control and sedation are considered than or equal to 8 on any three consecutive ratings, essential, the consequences of oversedation include the average of two scores is greater than or equal to increased time on ventilator support, prolonged 12, or the scores for two consecutive ratings are PICU stay and overall lengthened hospital course, greater than or equal to 12, the infant should be highlighting the need for balance. Despite this, started on pharmacologic therapy [29&]. A survey of evidence-based practice guidelines for appropriate

534 www.co-pediatrics.com Volume 25 Number 4 August 2013 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Neonatal and iatrogenic withdrawal syndromes Cramton and Gruchala C) 2 C) 1 8 3–4 times/interval) 1 8 > 60/min 1 60/min with retractions 2 > > F (39.3 F (39.3 8 3–4 times/interval) 1 8 > 1 h after feeding2 h after feeding 3 2 101 101 < < < > SweatingFever Fever Frequent yawning ( MottlingNasal stuffinessSneezing ( Nasal flaringRespiratory rate Respiration rate 1 1 1 2 Continuous high-pitched crySleeps Sleeps Hyperactive moro reflexMarkedly hyperactive moro reflexMild tremors disturbed 3 Moderate severe tremors disturbedMild tremors undisturbedModerate 3 severe tremors undisturbedIncreased muscletone 2 3 Excoriation (specify area): ______Myoclonic 2 jerks 2 Generalized convulsions 1 1 2 3 3 Poor feedingRegurgitationProjectile vomitingLoose stoolsWatery stoolsScorer’s initials Status of therapy 2 3 2 2 3 disturbances Table 2. Finnegan neonatal abstinence scoring SystemsCentral nervous system disturbances High-pitched cry Signs and symptoms 2 Metabolic vasomotor/respiratory Score AM 2 4 6 8 10 12 PMDisturbances 4 6 8 10 12Summary Daily Wt. Excessive sucking Total score 1 Adapted from [28].

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management of analgesia/sedation and withdrawal [19,34,36&]. This prospective, repeated measures are lacking and assessment remains challenging. study included children who received greater than Most research in iatrogenic withdrawal syn- or equal to 5 days of continuous IV opioid and/or drome relies on tools validated only in the neonate, benzodiazepine infusion [19,34] and used the scoring some clinical findings only observed during SBOWC as the basis for constructing the SOS to the neonatal period, such as the moro reflex, which monitor iatrogenic withdrawal symptoms in PICU disappears by 3 months of age, or high-pitched cry patients [23]. The prevalence of withdrawal syn- [14,34,35]. These scales have limited clinical appli- dromes in this study correlated with previous cation given issues with validity, frequency of assess- scales; however, almost 75% of the patients were ments, and absence of guidelines for pain and infants, suggesting that the symptoms may not sedation management in most PICUs [34]. In necessarily apply to older children [19,34]. As the addition, during evaluation it is often difficult to SOS included more benzodiazepine withdrawal differentiate the signs and symptoms of withdrawal symptoms than the WAT-1, the authors concluded from those of illness, inadequate pain control/seda- that this tool was a more sensitive scale for detecting tion, or agitation from medical interventions such benzodiazepine withdrawal [23]. Because most PICUs as mechanical ventilation [19], potentially leading utilize both opioids and benzodiazepines simul- to overdiagnosis of withdrawal. taneously in their intubated patients, the SOS may Multiple assessment tools have been used to offer an advantage over the WAT-1 once cut-off score symptom severity in iatrogenic withdrawal scores, sensitivity, and specificity are delineated, an syndrome, the newest and most promising being important factor given the different treatment. the Withdrawal Assessment Tool (WAT-1) and the Sophia Observation Withdrawal Symptoms-scale (SOS). Franck et al. [24,35,36&] developed and MANAGEMENT studied the WAT-1 during a prospective study in The management techniques used to resolve with- two University-affiliated PICUs enrolling children drawal symptoms depend in part on the substance weaning from more than 5 days of continuous use that led to the withdrawal and in part on the age opioid and benzodiazepine infusions. It examined and circumstance of the patient. 19 withdrawal symptoms derived from the Opioid Benzodiazepine Withdrawal Scale (OBWS), pre- viously the only tool with prospective validation Neonatal withdrawal in PICU patients, in combination with literature The goal of the therapy is to relieve signs of with- review and expert opinion. This study suggested drawal and to prevent complications such as fever, that the WAT-1 was superior to the OBWS, demon- weight loss, and seizures [3&&]. Although between strating improved sensitivity in detecting with- 50 and 95% of all opioid-exposed infants require drawal symptoms (87% as compared with 50%) pharmacologic therapy [15], nonpharmacologic and a specificity of 88%, when using a score of strategies exist that have been found to decrease greater than or equal to 3 to define significant with- signs and symptoms of NAS. Swaddling, gentle drawal [24,35] (Table 3). Later Franck et al. [24] handling, decreasing noise, and minimizing over- performed a similar study expanded to include 22 head lights have all been shown to be beneficial in PICUs to support validity, reliability, and general- symptom reduction by limiting external stimu- izability of the WAT-1 in measuring iatrogenic lation [3&&,15,29&,36&]. The utilization of frequent, withdrawal. The authors confirmed their previous small, hypercaloric feeds (24 kcal/oz) has been findings. Although WAT-1 has advantages over shown to minimize weight loss [3&&,15]. Interest- previous tools in that it is simpler and less time ingly, although absorption of methadone through consuming to use, it is limited in that the scale lacks breast milk is minimal, breastfeeding by mothers on symptoms specific to benzodiazepine withdrawal, methadone has been found to minimize NAS symp- making it better in identifying withdrawal from toms [3&&,7&,13&,34,37,38]. It should be noted that opioids. Additionally, both studies were con- breastfeeding is only to be encouraged among founded by polypharmacy, with 39% of patients mothers whose drug use is limited to methadone in the initial study receiving one to three non- or BPH. Use of illicit drugs is a contraindication for opioid/nonbenzodiazepine medications [24,35]. breastfeeding. Although no current research docu- Investigations by Ista et al. used the self-devel- ments the efficacy of acupuncture in the treatment oped Sophia Benzodiazepine Opioid Withdrawal of NAS, one study did find active points in infants Checklist (SBOWC) to expand from previous studies with withdrawal symptoms [39]. These active points and include all withdrawal symptoms from benzo- may be sites for intervention in future studies. diazepines and opioids described in the literature Wherever possible, it is important that the parents

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Table 3. Withdrawal Assessment Tool-1 (WAT-1)

Reprinted with permission from [24].

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and family be encouraged to actively participate in showed benefit over methadone for length of treat- management of NAS, to promote bonding between ment and length of hospital stay [43]. Other benefits parent and child and to provide opportunity to include a ceiling effect for respiratory depression, observe interactions assessing for social risks and and less cardiovascular lability than methadone safety [29&]. [43]. Interestingly, the serum concentration of There have been many studies evaluating single BPH required for amelioration of symptoms in neo- and multidrug therapies for NAS [40,41]. Multiple nates is significantly less than that required for sources identify opioid replacement as the ideal adults [43]. treatment for opioid withdrawal [3&&,15,40–42], With all of the above opioid replacement thera- finding that it improves weight gain. However, it pies, it is sometimes necessary to add an additional increases length of stay when compared with non- agent (Table 4) [2&&,15,29&,36&,43–45]. Usually this pharmacologic interventions [41]. The most com- occurs when the infant continues to show signs of mon single agent in use is oral morphine, which is withdrawal despite escalation of the primary initiated when infants score greater than or equal to therapy to maximal well tolerated dosing [2&&]. 8 on three consecutive Finnegan ratings [29&,36&]. The most common adjunctive therapy is phenobar- Although some research institutions used a fixed bital. It has been found to be useful in controlling dosing for each range of scores, most utilize weight- the hyperactive symptoms of withdrawal, but inef- based dosing [2&&,29&]. Tincture of opium and pare- fective in managing the gastrointestinal symptoms goric are no longer recommended in neonates, as [15]. A recent Cochrane Review concluded that they have high alcohol content and other additives phenobarbital was better than diazepam as an including camphor, which are not well tolerated in adjunct, particularly if there has been multidrug infants [15,29&]. exposure [40]. There is some concern about the Methadone and BPH are also options for the neurodevelopmental effects of phenobarbital on first-line treatment of NAS. In most studies, BPH the neonate, which may be addressed in the

Table 4. Pharmacologic therapy for neonatal abstinence syndrome

Add adjuvant Weaning Drug Initial dosing Dosing increases Rescue dosing therapy schedule

Morphine 0.1 mg kgÀ1 doseÀ1 Increase by 20–30% Repeat previous At morphine dose Decrease by orally every 4 h every 12 h until dose between of 1.25 mg kgÀ1 10% every scores <8 Â 24 h scheduled dose doseÀ1, add 24 h, while intervals phenobarbital or scores <8. clonidine Discontinue when 0.15 mg kgÀ1 doseÀ1 Methadone 0.1 mg kgÀ1 doseÀ1 Calculate entire Additional dosing When max dosing Decrease by orally every 12 h methadone dose for of 0.025 mg kgÀ1 has been reached 10% every previous 24 h and doseÀ1every 4 h 1–2 weeks. divide by two for while scoring Discontinue BID dosing >8. Max dose when 0.05 mg 0.5 mg kgÀ1 kgÀ1 doseÀ1 doseÀ1 Buprenorphine 15.9 mcg kgÀ1 doseÀ1 Increase by 25% Max dose After 3 days of divided in three doses, 60 mcg kgÀ1 stabilization, orally doseÀ1 decrease by 10% while scores <8. Discontinue when dose is 10% of initial dose Phenobarbital 20 mg/kg loading Maintenance dose Adjuvant 5 mg/kg Clonidine 0.5 to 1.5 mcg/kg Increase by over 1 to Adjuvant No taper required orally 2 days to target dose, 3 to 5 mcg kgÀ1 dayÀ1, divided every 4–6 h

max, maximum.

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Prophylactic Phenobarbital After Neonatal Seizures randomized trial of patients who received fentanyl trial, due to end in 2014 [2&&]. Both phenobarbital with or without benzodiazepine infusion for greater and diazepam have been trialed as first-line therapy; than or equal to 5 days, Bowens et al. [32] found no neither was as effective as an opioid [41]. advantage of high-dose over low-dose methadone in Clonidine has also shown utility as an adjunc- successfully completing a 10-day taper regardless of tive therapy. When combined with an opioid, it total dose or length of fentanyl therapy. Unfortu- decreases the length of treatment [29&,46] and nately, the results were confounded by concurrent reduces morphine dosages required for neonates benzodiazepine withdrawal and by use of a non- exposed to heroin or methadone. Studies showed validated assessment tool. In addition, 42% of an increased rate of rebound, but a shorter course patients enrolled in the study failed to complete of treatment overall. At this time, there are no the taper because of deviations from protocol. published studies regarding the use of clonidine Another small study looking at a similar population and BPH. found no difference in withdrawal symptoms Two medications not recommended in the man- between five and 10-day weaning protocols [36&]. agement of NAS are chlorpromazine and naloxone The optimal rate of methadone tapering is not clear, [15]. Although helpful in controlling the gastroin- with one study reducing doses 10–20% daily testinal and CNS effects of withdrawal, chlorproma- depending on length of wean resulting in an 87% zine has many side effects, including decreased incidence of withdrawal symptoms [14,36&]. Five to seizure threshold and cerebellar dysfunction [15]. 10% incremental reductions are typical in adult Naloxone in the drug-exposed neonate can be life- patients [14]. Perhaps the key is not the details of threatening by precipitating acute withdrawal and the protocol, but adherence to a single protocol. seizure activity. Given the prevalence of withdrawal in the PICU, Although much of the current research in phar- a structured strategy for therapy is needed. Reason- macotherapy for NAS uses the compounds described able practices based on available evidence outlined above, there are novel strategies being considered in the AAP clinical report [3&&] include: establish- such as targeting serotonergic pathways, developing ment of weaning protocols, based on likelihood of immunotherapies, using vaccines and antibodies, drug dependence, which are initiated when certain and further investigating pharmacogenomics dosage thresholds are exceeded. Medications can [47&]. These novel approaches may prove safer and be tapered rapidly over 24 to 48 h if the defined have better outcomes than the traditional therapies threshold has not been surpassed, as there is for NAS. decreased likelihood of withdrawal in these patients; selection of a standardized rescue protocol for withdrawal symptoms that guides conversion Iatrogenic withdrawal to methadone and lorazepam [36&], one example Recognizing the dearth of guidelines for the man- outlined in Table 5 [3&&,20]. Use of such protocols agement of iatrogenic withdrawal, The United has been shown to decrease total duration of meth- Kingdom Paediatric Intensive Care Society, Analge- adone therapy [20] and incidence of withdrawal sia and Neuromuscular Blockade Working Group symptoms [36&]. Interestingly, recent literature published multidisciplinary consensus guidelines suggests that even when guidelines are in place to help establish consistency in analgesia and seda- practitioners may not consistently follow them tion practices for critically ill children [33]. This was [21&]; adoption of the idea that 80% of children followed in 2012 by a clinical report published by can successfully be weaned from methadone in the AAP recommending reasonable practices based 5–10 days and that the duration of benzodiazepine on available evidence to help predict and manage wean should be proportional to the days of therapy; acquired opioid and benzodiazepine dependency selection of one assessment tool to be used consist- [3&&]. Both reports cite a lack of high-quality evi- ently in monitoring patients for signs and symp- dence to support recommendations, and thus there toms of withdrawal; adoption of a policy to observe is still no optimal regimen for treatment of pediatric young children for signs and symptoms of with- iatrogenic withdrawal. drawal for 24–48 h after discontinuation of opioid Methadone is the most common agent used to therapy; recognition that use of clonidine, chloral treat opioid withdrawal in children given its good hydrate, or low-dose naloxone infusion [48] has not bioavailability and long half-life allowing for been proven to reduce withdrawal. One small case extended dosing intervals. There are a number of series suggests that transdermal clonidine may be weaning protocols available, each with variations in useful in prevention of opioid withdrawal [49] with dosages, weaning increments, and length of the additional limited evidence to suggest dexmedeto- weaning period. In a prospective, double-blind, midine may play a similar role [50]. However, both

1040-8703 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-pediatrics.com 539 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Office pediatrics methadone. Discontinue 10–20% daily, then extend dosing interval to Q8h, then Q12then h, Q24h then Q48h. Continue to decrease by Discontinue lorazepam. in one dose. Give 20% of original dose, in four divided doses, Q6h. Decrease by 10–20%, in two divided doses, Q12h. Give 40% of original dose, in three divided doses, Q8h. Give 60% of original dose, four divided doses, Q6h. Decrease by 10–20%, in in three divided doses, Q8h. Give 80% of original daily dose, 12 Â 100. Â 7 days of continuous IV midazolam to oral lorazepam > using current hourly rate. methadone dose by longer half-life, to getmethadone total daily dose. Give in four divided doses, Q6h. current hourly rate. potency and half-life by to get total daily lorazepam dose. Q6h. Table 5. Sample weaning protocols Conversion from 7–14 days ofInitial continuous dose IV fentanyl to oral methadone 1. Calculate 24-h dose by 2. Calculate equipotent 3. Divide by 6 to account for Day 2Conversion from Initial dose1. Calculate 24-h dose by using 2. Account Day for 3 differences in 3. Give in four divided doses, Day 4 Day 2 Day 5 Day 3 Day 6 Subsequent days

540 www.co-pediatrics.com Volume 25 Number 4 August 2013 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Neonatal and iatrogenic withdrawal syndromes Cramton and Gruchala alpha 2 agonists can themselves cause withdrawal, Acknowledgements possibly limiting their utility. We would like to thank Sonia Matthews, MD, for her thoughtful review of this article. Thanks also to Dr PREVENTION Nathaniel Johnson, MD for the inspired title. It is important to remember that fetal exposure to opioids can occur when the mother is addicted to Conflicts of interest either prescription or illicit opioids, or required There are no conflicts of interest. opioids for the management of another disease process, or is maintained on an opioid agent to facilitate well-tolerated withdrawal from addiction && REFERENCES AND RECOMMENDED [31 ]. Although abrupt cessation of drug use during READING pregnancy is not recommended, there are maternal Papers of particular interest, published within the annual period of review, have been highlighted as: behaviors that diminish the likelihood or severity of & of special interest NAS. The risk of complications from illicit opioid use && of outstanding interest Additional references related to this topic can also be found in the Current in pregnancy is significant, and pregnant women World Literature section in this issue (p. 548). should be assisted in the transition to a substitute for heroin. If the mother already receives substitutive 1. Patrick SW, Schumacher RE, Benneyworth BD, et al. Neonatal abstinence & syndrome and associated healthcare expenditures: United States, 2000– maintenance therapy, there is data to support BPH 2009. JAMA 2012; 307:1934–1940. Patrick et al. clearly state the ﬁnancial costs associated with NAS. over methadone, and either is preferable to mor- 2. 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Semin Fetal Neonatal Med 2013; 35–41. 27. Finnegan LP. Neonatal abstinence. In: Nelson NM, editor. Current Therapy in A discussion of three strategies for treatment of NAS that go beyond straight Neonatal-Perinatal Medicine. Toronto, Ontario: BC Decker Inc; 1985 . pp. pharmacotherapy: immunotherapeutics, pharmacogenomics, and the impact of 262–270. the serotonin pathway. 28. Finnegan LP. Neonatal abstinence syndrome: assessment and 48. Darnell CM, Thompson J, Stromberg D, et al. Effect of low-dose naloxone pharmacotherapy. In: Rabaltelli FF, Grandi B, editors. Neonatal Therapy: infusion on fentanyl requirements in critically ill children. Pediatrics 2008; an update. Elsevier Science Publishers B.V. (Biomedical Division); 1986. 121:e1363–e1371. pp. 122–146. 49. Honey BL, Benefield RJ, Miller JL, Johnson PN. Alpha2-receptor agonists for 29. Dow K, Ordean A, Murphy-Oikonen J, et al. Neonatal abstinence syndrome treatment and prevention of iatrogenic opioid abstinence syndrome in criti- & clinical practice guidelines for Ontario. J Popul Ther Clin Pharmacol 2012; cally ill patients. Ann Pharmacother 2009; 43:1506–1511. 19:e488–e506. 50. Oschman A, McCabe T, Kuhn RJ. Dexmedetomidine for opioid and benzo- A concise description of the clinical practice guildelines for NAS in one Canadian diazepine withdrawal in pediatric patients. Am J Health Syst Pharm 2011; province. Important, because it includes the level of evidence for each guideline, 68:1233–1238. and would be useful to anyone trying to develop clinical guidelines for their 51. Ebner N, Rohrmeister K, Winklbaur B, et al. Management of neonatal institution. abstinence syndrome in neonates born to opioid maintained women. Drug 30. Sarkar S, Donn SM. Management of neonatal abstinence syndrome in Alcohol Depend 2007; 87:131–138. neonatal intensive care units: a national survey. J Perinatol 2006; 26:15–17. 52. 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