Morphine Versus Clonidine forNeonatal Abstinence SyndromeHenrietta S. Bada, MDa, Thitinart Sithisarn, MDa, Julia Gibson, PharmDb, Karen Garlitz, PharmDb,Rhonda Caldwell, BHSa, Gilson Capilouto, PhDc, Yinglei Li, MSd, Markos Leggas, PhDe, Patrick Breheny, PhDf

abstractOBJECTIVE: The study goal was to determine whether clonidine treatment of neonatal abstinencesyndrome (NAS) would result in a better neurobehavioral performance compared with morphine.

METHODS: This pilot study prospectively enrolled infants $35 weeks’ gestational age admitted fortreatment of NAS. After informed consent was obtained, infants were randomized to receivemorphine (0.4 mg/kg per day) or clonidine (5 mg/kg per day) divided into 8 doses. A 25% doseescalation every 24 hours was possible per protocol (maximum of 1 mg/kg per day for morphineand 12 mg/kg per day for clonidine). After control of symptoms, the dose was tapered by 10%every other day. Clinical staff monitored infants by using Finnegan scoring. Masked research staffadministered the NICU Network Neurobehavioral Scale (NNNS) at 1 week and at 2 to 4 weeksafter initiation of treatment and the Bayley Scales III, and Preschool Language Scale IV, at 1-yearadjusted age. Analyses included descriptive statistics, repeated measures analysis of variance, andWilcoxon tests.

RESULTS: Infants treated with morphine (n = 15) versus clonidine (n = 16) did not differ in birthweight or age at treatment. Treatment duration was significantly longer for morphine (median39 days) than for clonidine (median 28 days; P = .02). NNNS summary scores improvedsignificantly with clonidine but not with morphine. On subsequent assessment, those receivingclonidine had lower height of arousal and excitability (P , .05). One-year motor, cognitive, andlanguage scores did not differ between groups.

CONCLUSIONS: Clonidine may be a favorable alternative to morphine as a single-drug therapy forNAS. A multicenter randomized trial is warranted.

WHAT’S KNOWN ON THIS SUBJECT: Increasedcentral adrenergic activity occurs with opiatewithdrawal. Clonidine is an effective drug as anadjunct to morphine in the treatment of neonatalabstinence syndrome. It is unclear whetherclonidine is effective as single-drug therapy.

WHAT THIS STUDY ADDS: Clonidine, aa2-adrenergic agonist, seems to be as effectiveas morphine when used as a single-drug therapyfor neonatal abstinence syndrome. Itsadministration results in improvement inneurobehavioral performance.

Departments of aPediatrics, College of Medicine, cRehabilitation Sciences, College of Health Sciences, dStatistics,College of Arts and Sciences and ePharmaceutical Sciences, College of Pharmacy, University of Kentucky,Lexington, Kentucky; bDepartment of Pharmacy, Kentucky Children’s Hospital, Lexington, Kentucky; andfDepartment of Biostatistics, College of Public Health, University of Iowa, Iowa City, Iowa

Dr Bada conceptualized and designed the study, provided oversight for the research procedures anddata acquisition, contributed to the interpretation of the data, wrote the first draft of the article, andrevised the manuscript for its final form for journal submission; Drs Sithisarn, Caldwell, Capilouto,and Leggas made substantial contributions to the conceptualization and design of the study, performeddata acquisition and interpretation of data, reviewed the manuscript draft, and made revisions;Drs Gibson and Garlitz made substantial contributions to the design and randomization procedures,maintained and ensured the masking of personnel, and reviewed and made revisions to the draft; Ms Liperformed data management and data analysis, contributed to the interpretation of the results,reviewed the manuscript draft, and made revisions; and Dr Breheny made substantial contributions tothe design, performed statistical analysis and interpretation of data, reviewed the manuscript draft, andmade revisions. All authors approved the final version of the manuscript for submission, and all authorsagreed to be accountable for all aspects of the work in ensuring that questions related to the accuracyor integrity of any part of the work are appropriately investigated and resolved.

This trial has been registered at www.clinicaltrials.gov (identifier NCT01734551).

www.pediatrics.org/cgi/doi/10.1542/peds.2014-2377

DOI: 10.1542/peds.2014-2377

Accepted for publication Nov 20, 2014

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The prevalence of nonmedical useof opioid pain relievers is increasing.1

In the United States, nearly 1% ofpregnant women use opiates duringpregnancy.2 Consequently, as thenumber of infants requiringtreatment of neonatal abstinencesyndrome (NAS) rises, the health careexpenditures associated withhospitalization for clinical monitoringand medical therapy are increasing aswell.3,4 There is, however, noconsensus as to the best single-drugtherapy for NAS after failedbehavioral intervention.5 Despiterecommendations from the AmericanAcademy of Pediatrics6 that opioidsare the first-line therapy for NAS,variation exists among centers inthe treatment of NAS.5,7,8 It alsoremains unclear how opiatetreatment of NAS affects children’slong-term outcomes.

Experimental studies revealconcerning data regarding prenatalopiate exposure. Antenatal opiateexposure affects braindevelopment9,10 with resultingdecreases in corticogenesis,neurogenesis, andsynaptogenesis11,12 and alterations inthe ontogeny of the stress axis13–15

and immune response.16 Humanstudies also allude to the associationof prenatal opiate exposure and smallhead circumference17–20 anddecreased brain volumes found onimaging.21 An additional concern isthat infants with NAS receive theirpharmacologic treatment during thefirst few months of life, a period ofrapid postnatal brain development.22

The potential harm of continuingopiate exposure on braindevelopment provides a compellingreason to evaluate the use ofa nonopiate drug, such as clonidine,as an alternative to opiate therapyfor NAS.

With cessation of the antenatalchronic opiate supply at birth, theopiate inhibitory effect on the fetalnoradrenergic neurons is lost,resulting in increased noradrenergic

activity. Clonidine, a a2-adrenergicreceptor agonist, has inhibitoryeffects on the release ofnoradrenaline in the locus coeruleus;its administration decreasesnoradrenergic neuronal activity,thereby lessening withdrawalmanifestations. There have been fewreports on clonidine as single-drugtherapy for NAS in small numbers ofinfants.23,24 Recent studies found thatclonidine was an effective adjunctivetreatment when given with morphineor chloral hydrate.25,26

Because of potential deleteriouseffects of continued postnatal opiateadministration on the developingbrain,27 we evaluated the use ofclonidine in the treatment of infantswith NAS. We tested the hypothesisthat clonidine would be better thanmorphine as a single-drug therapy forNAS as evidenced by improvement inneurobehavior and duration oftreatment.

METHODS

The study was a pilot randomized,double-blind trial with institutionalreview board approval. The datasafety monitoring board membersmet every 10 subjects enrolled andsubmitted the meeting reports to theinstitutional review board. Researchpersonnel obtained informed consentfrom parents when the clinicaldecision was made to startpharmacologic treatment, based onassessments made by using theFinnegan scoring system.28,29

Enrollment criteria included:postnatal age ,7 days, gestationalage $35 weeks, known prenatalopiate exposure (maternal historyof opiate use and/or positive urineopiate screen during pregnancy ordelivery, or infant urine or meconiumtesting positive for opiatemetabolites), no known prenatalcocaine exposure, symptomatic with3 consecutive Finnegan scores (FS)$8 assessed 3 hours apart or 2consecutive FS $12, no seizures, nomajor congenital malformations,

likely to survive, no blood pressureinstability, and no major medicalcondition in addition to NAS. Infantswho did not meet enrollment criteria,including those who developed NASdue to prolonged NICU analgesia andsedation therapy, were excluded.

Nursing personnel had training inassessment of FS, and they performedscoring every 3 hours after nipplefeeding (20 kcal/oz) with no volumerestriction. All infants receivedbehavioral intervention, includingswaddling, rocking, pacifier, dimlighting, and quiet NICUenvironment.30 When the FS metcriteria for pharmacologic treatmentand after consent, the infant receivedthe study drug based on therandomization schedule (4 per block),available only through theinvestigational drug unit of theDepartment of Pharmacy. The drugshad identical physical properties(color, volume, clarity, and odor). Allclinical and research staff other thanthe clinical pharmacists were maskedto the infant’s study medication. Theclinical pharmacists made roundswith the teams, dispensed the studydrugs (single dosing), and monitoredthe physician orders. Doses wereprescribed by the medical provider byindicating the infant was to receivestudy drug at the initial dose perprotocol. Any subsequent order waswritten to maintain dose, increasestudy drug dose by 25%, decreasedose by 10% from the highest dose,or (in some instances) resume theprevious dose.

Infants who were randomized toreceive morphine received a startingdose of 0.4 mg/kg per day,31 dividedevery 3 hours based on the feedingschedule. The dosage was increasedby 25% of the initial dose every 24hours until FS scores wereconsistently ,8 and symptomscontrolled, up to a maximum dose of1 mg/kg per day. After 48 hours ofsymptom control (all FS ,8),weaning was begun by decreasing thedose by 10% of the maximum dose

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every other day. If the lowest dosereached ,0.1 mg/kg per day,morphine was discontinued, and theinfant was monitored for 48 hoursand then discharged. If re-escalationwas needed at any time, the previousdose was administered, and weaningwas resumed after 48 hours. If noimprovement was noted at themaximum dose of 1 mg/kg per day,a second drug was added at theattending physician’s discretion.Those who were randomized to theclonidine group received 5 mg/kg perday divided into 8 doses (0.625 mg/kgper dose every 3 hours). The sameprocedures as used in the morphinetreatment group were followed fordose increases (maximum dose:12 mg/kg per day), decreases, andre-escalation. In addition, if aninfant’s FS was .8 after themaximum dose, a second drug wasinitiated at the attending physician’sdiscretion. Clonidine wasdiscontinued when the dose givenwas ,1 mg/kg per day.

All infants were treated in the NICU.They underwent continuouscardiorespiratory monitoring, andblood pressure measurements wereperformed every 8 hours. Whenclinical blood sampling was ordered,extra blood was collected from theenrolled infant; blood samples wereprocessed and stored for lateranalysis of morphine and clonidineconcentrations. Assays for bloodconcentrations of morphine andclonidine provided a method ofconfirming that infants received therandomized treatment. Theinvestigator responsible fordetermination of drug levels was alsomasked to the treatment assignment.

A trained masked examiner assessedthe infant’s neurobehavioralperformance by using the NICUNetwork Neurobehavioral Scale(NNNS). The first NNNS administrationwas at 5 to 7 days after the startof treatment and again at 40 to44 weeks’ postmenstrual age atdischarge or during clinic follow-up.

At the attending physician’sdiscretion and with the institutionalemphasis on shortened length of stay,infants completed the drug treatmentat home but only after 3 consecutivesuccessful weanings of drug dose.Continuation of therapypostdischarge was possible when theChild Protective Servicesinvestigation indicated that infantcould be discharged to a safeenvironment. The clinical pharmacistcounseled the child’s caregiver onhow to accurately measure andadminister the prescribed dose byusing a 1-mL oral syringe and how towean the medication based on theprovided calendar. Caregivers werefurther instructed to bring the labeledmedication bottle to any visit with thechild’s primary care provider or ifseeking care in the emergencydepartment. The caregiver had tosatisfactorily demonstrate how tocorrectly draw up the liquidmedication, understand the weaningschedule from the calendar, andidentify signs and symptoms ofwithdrawal and when to seek medicalattention. The pharmacist alsocontacted the primary care physicianregarding the child’s treatment andfollow-up and faxed a treatmentcalendar along with the dischargesummary. The infants had a clinicvisit at 40 to 44 weeks’postmenstrual age anda developmental follow-up visit at1-year adjusted age. Assessmentsincluded physical and neurologicexaminations: the Bayley Scales ofInfant and Toddler Development,Edition III, and the PreschoolLanguage Scale, Edition IV.

We planned enrollment of 12 subjectsper group, as proposed by Julious32

and Billingham et al.33 An additional20% (total of 15) was included foreach treatment arm, anticipatingsubject withdrawal or otherunforeseen postenrollmentexclusions from the study.32,33

Descriptive statistics and theWilcoxon rank-sum test or Fisher’sexact test were used to compare

baseline differences betweentreatment groups. To compare theNNNS summary scores during thefirst and second assessments withineach group and between treatmentgroups, a repeated measures analysisof variance was performed. Theproportion of infants that completedtreatment over time were determinedby using the Kaplan-Meier survivalanalysis,34 and the survival curveswere compared by using a log-ranktest. To determine the optimal dosegiven that resulted in control ofsymptoms until continued weaning ofthe dose was possible, the receiver-operating characteristic (ROC) curvewas determined and the Youdenindex criteria were used.35–37

Statistical analysis was conducted byusing SAS version 9.1 (SAS Institute,Inc, Cary, NC).

RESULTS

Figure 1 displays the flow diagram ofthe number of subjects screened,excluded, and enrolled. FromSeptember 2011 to June 2012, a totalof 596 admissions were made to theNICU; of these, 354 were born at$35 weeks and of those, 88 wereopiate exposed. Seventy-four infantsneeded treatment; 11 had treatmentstarted at a referring hospital, 8 hadother medical conditions, and 6 hadparents who could not be reached.The parents of 15 infants refusedstudy participation. Thirty-fourinfants had consent provided andwere enrolled in the study. Afterenrollment, it was determined that 2infants did not meet the study criteria(cocaine exposure according tomeconium drug screen results andchronic hypoxia in utero), and 1 waswithdrawn from the study by theattending physician. Fifteen infantswere assigned to receive morphineand 16 received clonidine. Table 1shows the characteristics of theinfants according to drug assignment.Those who received morphine werenot significantly different from thosewho received clonidine in terms ofbirth weight, gestational age, 1- and

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5-minute Apgar scores, postnatal age,and FS before and after initiation oftreatment. Also listed in Table 1 arethe different drugs of exposure,including methadone, buprenorphine,other opiates (hydrocodone,oxycodone), benzodiazepines, ortobacco. Most mothers used multipledrugs.

In our assessment of neurobehavioralperformance, no statisticallysignificant differences were notedbetween the mean 6 SD intervalsfrom the initiation of pharmacologictreatment and the first NNNSadministration (6.6 6 1.5 days for themorphine group and 5.5 6 2.1 days

for the clonidine group). There werealso no mean between-groupsignificant differences regarding theintervals between the initiation oftreatment and the second NNNS(28.5 6 16.4 days and 24.4 6 18.9days, respectively, for the morphineand clonidine groups). Table 2compares the NNNS summary scoresfrom the first and the second NNNSadministration within and betweentreatment groups. Twelve of 13summary scores are presented.Habituation procedures were notpossible because many infants werenot in a sleep state. The neurobehavioralperformance did not differ between

treatment groups at the firstassessment, except for the meanlethargy score, which was higher inthe clonidine group (5.13 6 2.12)compared with the morphine group(3.6 6 1.6). The morphine-treatedinfants exhibited no differences intheir neurobehavioral performancefrom the first to the secondassessment. However, the clonidine-treated infants showed significantimprovements in areas of attention,handling, arousal, excitability, andlethargy. On the second assessmentand compared with the morphine-treated infants, the clonidine grouphad significantly better scores inarousal and excitability.

The duration of treatmentsignificantly differed between themorphine group and the clonidinegroup (median [range]: 39 [26–89]days vs 27.5 [18–107] days; P = .02).Figure 2 displays the Kaplan-Meiersurvival curve. One clonidine-treatedinfant (an outlier) was excluded fromthis analysis; the infant’s prolongedtreatment was due to the clinicalteam’s decision to wean the doseevery 5 days, which was a deviationfrom the protocol. Two morphine-treated infants completed therapybefore discharge (41 and 31treatment days); the remaininginfants continued their treatment athome. The median (range) durationof home treatment was 13.5 (6–71)days for the clonidine group, whichwas significantly shorter than for themorphine group (26 [16–57] days)(Table 1). No infant received asecond drug.

Because some infants requireda dosage increase of either morphineor clonidine to achieve control ofsymptoms, the ROC curve wasdetermined for each drug (Fig 3). Formorphine, the optimal dose was0.5 mg/kg per day (equivalent to0.0625 mg/kg per dose given every3 hours). For clonidine, the optimaldose was 7.5 mg/kg per day (∼1 mg/kgper dose every 3 hours). This dose ofclonidine is also consistent with

FIGURE 1Diagram showing screening for subjects for participation in the study, inclusion and exclusion, andthe number of subjects included in each treatment arm.

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published population pharmacokineticsin newborn infants.38 Because bloodsampling was not performed inprescribed intervals, kinetic studieswere not possible. However, assaysrevealed that infants received theassigned drug.

Twelve children in each treatmentarm were evaluated at the 1-yearfollow-up visit completed inSeptember 2013. The morphine-treated infants were comparable to

those who received clonidine interms of their cognitive, motor, andlanguage scores (Table 3). For3 subjects, the language score of theBayley Scales of Infant and ToddlerDevelopment, Edition III, wasincluded in the analyses becausethe Preschool Language Scale,Edition IV, score was not available.Table 3 also presents the growthmeasures; these also did not differbetween groups.

DISCUSSION

To our knowledge, this study is thefirst randomized trial comparingmorphine versus clonidine asa single-drug therapy for NAS. Resultsof this pilot study are promising andsuggest that clonidine is comparableto morphine in the treatment of NAS,specifically in terms of infants’neurobehavioral performance. Thosetreated with clonidine exhibitedsignificant improvement in somemeasures of neurobehavior, whereasthose treated with morphinedemonstrated no significant changein their neurobehavior, even aftera few weeks of pharmacologictreatment.

Clonidine, a a2-adrenergic agent, actson the central sympathetic activity,which has been shown to beincreased with opiate withdrawal.Prolonged opiate exposure results inactivation of opiate receptors in thelocus coeruleus, which containsclusters of noradrenergic cells. Opiateexposure decreases adenylate cyclaseactivity, reducing cyclic adenosinemonophosphate levels.39–41 Thiseffect on cyclic adenosinemonophosphate results in increasesin potassium efflux with associateddecreases in calcium influx; theseprocesses are inhibitory to brainnoradrenergic activity.42,43 Cessation

TABLE 1 Characteristics and Response to Treatment of Morphine- and Clonidine-Treated Infants

Characteristic Morphine (n = 15) Clonidine (n = 16)

Birth weight, g 3024.6 6 463 2763.9 6 427Gestational age, wk 37.8 6 1.8 37.8 6 1.4Apgar score, median (range)1 min 8 (7–9) 8 (3–9)5 min 9 (8–10) 9 (5–10)

Male/female 7/8 6/10Prenatal exposuresMethadone 0 5Buprenorphine 6 5Oxycodone, hydrocodone 11 11Benzodiazepines 4 3Tobacco 8 4

Age at treatment, d 2 6 1 3 6 1FSBefore treatment 13.5 6 1.1 12.4 6 1.4At 48 h 7.4 6 0.35 8.5 6 0.30At 7 d 6.6 6 0.65 5.7 6 0.44At 14 d 7.1 6 1.1 6.7 6 0.98

Total length of treatment, d 42.7 6 17.8 32 6 20.4Length of hospital stay, d 21 6 12.3 14.9 6 6.0Length of treatment postdischarge, d 26 6 11.06 18 6 15.06

P . .05 for all comparisons according to the Wilcoxon rank-sum test except total length of treatment (P = .02) andduration of postdischarge treatment (P = .005). Unless otherwise noted, data are presented as mean 6 SD.

TABLE 2 NNNS Summary Scores of Morphine-Treated Versus Clonidine-Treated Newborns During the First and Second Assessments

Behavior Scales(Summary Items)

NNNS Time 1 NNNS Time 2 Time 1 VersusTime 2

Time 1 VersusTime 2

Morphine(n = 15)

Clonidine(n = 16)

P: Morphine VersusClonidine

Morphine(n = 13)

Clonidine(n = 14)

P: Morphine VersusClonidine

P: Morphine P: Clonidine

Attention 5.06 6 0.27 4.51 6 0.263 .15 5.20 6 0.27 5.39 6 0.26 .61 .63 .004Handling 0.36 6 0.06 0.42 6 0.06 .44 0.34 6 0.06 0.18 6 0.06 .07 .79 .004Quality of movement 4.77 6 0.15 4.92 6 0.14 .45 4.58 6 0.16 4.94 6 0.15 .10 .30 .90Regulation 5.2 6 0.18 5.26 6 0.17 .66 5.05 6 0.19 5.56 6 0.18 .06 .63 .14Nonoptimal

reflexes3.73 6 0.42 4.13 6 0.40 .50 4.15 6 0.44 3.55 6 0.43 .33 .56 .41

Asymmetric reflexes 0.20 6 0.14 0.00 6 0.14 .31 0.46 6 0.15 0.076 0.15 .07 .23 .73Stress/abstinence 0.07 6 0.01 0.08 6 0.01 .79 0.08 6 0.01 0.05 6 0.01 .13 .78 .09Arousal 3.91 6 0.13 3.95 6 0.13 .82 4.02 6 0.15 3.54 6 0.14 .02 .57 .04Hypertonicity 0.40 6 0.25 0.25 6 0.24 .67 0.77 6 0.27 0.07 6 0.26 .06 .31 .63Hypotonicity 0.13 6 0.13 0.19 6 0.13 .77 0.23 6 0.14 0.37 6 0.13 .46 .58 .26Excitability 2.6 6 0.53 2.38 6 0.51 .76 2.94 6 0.56 0.84 6 0.54 .009 .59 .02Lethargy 3.6 6 0.50 5.13 6 0.49 .03 2.65 6 0.54 3.70 6 0.52 .17 .17 .04

Data are presented as mean 6 SE.

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of chronic opiate supply results inincreases in noradrenergic activity.44

With the inhibitory effects ofclonidine on noradrenaline release inthe locus coeruleus, thenoradrenergic neuronal activitydecreases, resulting in a decrease inwithdrawal manifestations.

Most studies evaluated clonidine as anadjunct to morphine or chloral hydratefor the treatment of NAS.25,26,45

Clonidine as adjunctive therapy for

NAS was associated with a decrease inthe number of morphine doses,duration of treatment, or length ofhospital stay.25,45 From a recentrandomized trial, clonidine given withmorphine resulted in a shorterduration of therapy compared withthe morphine and phenobarbitalcombination.45 However, these studiescombined clonidine with morphine,and the concern for potentialdetrimental effects of continuingpostnatal opiate exposure remains.27

We observed a longer duration oftreatment than those reported incombination therapy25,45; this outcomemay be related to the single-drugtherapy. In addition, the dose for thisstudy is at the lower end reported inthe literature, especially forclonidine.25 A higher initial dose formorphine and clonidine is suggestedfrom the ROC curves in our study.We also used a slow weaning schedule,being careful to monitor and avoidpotential adverse effects from clonidineadministration. In the NICU, infantshad routine cardiovascular andrespiratory monitoring. We found nosignificant fluctuation in bloodpressure (ie, decreases with initiationof dose or with dose increases,increases in blood pressure whendoses were decreased). Otherinvestigators found no significant bloodpressure changes with clonidine doseshigher than used in our study.25,46

Our research protocol did not dictatethat treatment be completed beforedischarge; thus, infants weredischarged to continue treatment athome. The length of stay is oftenemphasized as a benchmark ofefficient care. However, multiple,complex issues, such as familyinvolvement with child protectiveservices, ensuring infant’s dischargeto a safe home, and assisting themother to access treatment programsare considerations in the evaluationof length of hospital stay.

Coyle et al47 evaluated theneurobehavior of infants born tomothers on methadone orbuprenorphine; 69% were treatedwith morphine. Overall, their infants’scores for attention, quality ofmovement, and self-regulationincreased over days while scores forhandling, arousal, excitability,depression, and hypertonia decreasedwith time. We found similar changesbetween the first and secondassessments in our study but more soamong the infants treated withclonidine. With our randomizationschedule, an unbalanced distribution

FIGURE 2Kaplan-Meier survival plot comparing duration of treatment in days between morphine and cloni-dine. There was a significantly shorter duration of treatment with clonidine (log-rank test, P = .0007).

FIGURE 3Comparison between morphine (top panel) and clonidine (bottom panel) as to ROC curves. Thesensitivity against 1-specificity is plotted for each treatment (left panel, A and B). The Youden index,a function of sensitivity and specificity, was used as a measure of overall treatment effectiveness(right panel, C and D).

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of prenatal exposure to methadonewas noted. It is interesting that theinfants with methadone exposure hadbetter scores with clonidinetreatment compared with those withno methadone exposure treated withmorphine. The significantimprovement of infants in some areasof neurobehavioral performanceespecially with clonidine isa pertinent consideration for long-term outcomes. Investigators havereported that the behavior profilefrom the NNNS of drug-exposedchildren predicted later childhoodcognitive and behavior outcomes.48

The masking of clinical and researchpersonnel, except for the clinicalpharmacists for the duration of hospitalstay was feasible. Masking of examinerswas also feasible during the NNNSadministration and long-term follow-up.

There are limitations to the presentstudy. It was a pilot study witha small sample. The small numberprecluded a meaningful analysis as towhich of the drugs predicted thehighest FS to initiate pharmacologictreatment. We did not systematicallydetermine prenatal drug exposure byusing meconium assays. The nursingpersonnel had training in assessingFS, but we did not assessinterobserver reliability. In addition,we did not include a protocol foradjunctive treatment. We continuedtreatment postdischarge, but thisresulted in unmasking of thecaretaker and the primary carephysician. Although the caretaker hadinstructions to administer themedication with the dosing schedulenoted on a calendar, concern stillremains regarding caretaker’scompetence to recognize changes in

the child’s withdrawal manifestationsand thus close outpatient follow-up isneeded. Lastly, our preliminaryfindings are not generalizable.

CONCLUSIONS

Our findings suggest that clonidinemay be as effective as morphine asa single-drug therapy for NAS. Arandomized multicenter trial withlong-term follow-up is warrantedwhile considering other prenatalexposures, including nonopiate drugs.Longitudinal studies suggest thatchanges in behavioral outcomes occurafter prenatal opiate exposure.49,50

The effects of NAS or its treatment onlater development remain unclear.

ACKNOWLEDGMENTS

The authors acknowledge theassistance of Stephen C. Sitzlar ofthe Investigational Drug Unit for therandomization, study drugpreparation, and dispensing; they alsoacknowledge the research nurses(Vicki Whitehead, Debra Grider, TracyRobinson) and Meredith Edens whotracked these families to return fortheir follow-up visits. The authorsappreciate the efforts of the membersof the data safety monitoring committee(Mark Vranicar, MD [chair], MartaMendiondo, PhD, Timothy N. Crawford,PhD, and Karen Garlitz, PharmD) fortheir committee participation andtimely submission of reports to theinstitutional review board.

Address correspondence to Henrietta S. Bada, MD, MPH, Department of Pediatrics, University of Kentucky, 800 Rose St, Room MN 140-A, Lexington, KY 40536. E-mail:

hbada2@uky.edu

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2015 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

FUNDING: Funded in part by a Children’s Miracle Network grant awarded to the Kentucky Children’s Hospital.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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TABLE 3 Bayley Scores, Preschool Language Scale Scores, and Growth Measurements at 1-YearAdjusted Age in Children Treated With Morphine or Clonidine

Variable Morphine (n = 12) Clonidine (n = 12) P a

Bayley III scoresMotor 97.6 6 10.4 95.8 6 7.2 .93Cognitive 92.9 6 8.4 93.3 6 7.2 .93

PLS-IVLanguage, total 98.0 6 13.8 95.8 6 10.4 .64Language, receptive 101.1 6 14.3 95.0 6 12.2 .25Language, expressive 100.0 6 13.1 99.2 6 13.6 .72

Physical growthWeight, kg 10.0 6 1.3 9.6 6 1.0 .66Length, cm 75.6 6 2.6 76.1 6 3.5 .81Head circumference, cm 46.3 6 1.2 46.4 6 1.3 .76

Data are presented as mean6 SD. Bayley III, Bayley Scales of Infant and Toddler Development, Edition III; PLS-IV, PreschoolLanguage Scale, Edition IV.a P values (all nonsignificant) were derived from Wilcoxon tests.

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Gilson Capilouto, Yinglei Li, Markos Leggas and Patrick BrehenyHenrietta S. Bada, Thitinart Sithisarn, Julia Gibson, Karen Garlitz, Rhonda Caldwell,

Morphine Versus Clonidine for Neonatal Abstinence Syndrome

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