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.
WHATS 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 Childrens 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).
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 childrenslong-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 axis1315
and immune response.16 Humanstudies also allude to the associationof prenatal opiate exposure and smallhead circumference1720 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.
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 infants 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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