OBJECTIVE: The abstraction ambition was to actuate whether clonidine assay of neonatal abnegation affection (NAS) would aftereffect in a bigger neurobehavioral achievement compared with morphine.
METHODS: This pilot abstraction prospectively enrolled breed ≥35 weeks’ gestational age accepted for assay of NAS. Afterwards a accord was obtained, breed were randomized to accept morphine (0.4 mg/kg per day) or clonidine (5 μg/kg per day) disconnected into 8 doses. A 25% dosage accretion every 24 hours was accessible per agreement (maximum of 1 mg/kg per day for morphine and 12 μg/kg per day for clonidine). Afterwards ascendancy of symptoms, the dosage was cone-shaped by 10% every added day. Analytic agents monitored breed by application Finnegan scoring. Masked assay agents administered the NICU Network Neurobehavioral Scale (NNNS) at 1 anniversary and at 2 to 4 weeks afterwards admission of assay and the Bayley Scales III, and Preschool Accent Scale IV, at 1-year adapted age. Analyses included anecdotic statistics, afresh measures assay of variance, and Wilcoxon tests.
RESULTS: Breed advised with morphine (n = 15) adjoin clonidine (n = 16) did not alter in bearing weight or age at treatment. Assay continuance was decidedly best for morphine (median 39 days) than for clonidine (median 28 days; P = .02). NNNS arbitrary array bigger decidedly with clonidine but not with morphine. On afterwards assessment, those accepting clonidine had lower acme of activation and affect (P < .05). One-year motor, cognitive, and accent array did not alter amid groups.
CONCLUSIONS: Clonidine may be a favorable another to morphine as a single-drug assay for NAS. A multicenter randomized balloon is warranted.
Increased axial adrenergic action occurs with gesic withdrawal. Clonidine is an able biologic as an accessory to morphine in the assay of neonatal abnegation syndrome. It is cryptic whether clonidine is able as single-drug therapy.
Clonidine, a α2-adrenergic agonist, seems to be as able as morphine back acclimated as a single-drug assay for neonatal abnegation syndrome. Its administering after-effects in advance in neurobehavioral performance.
The prevalence of nonmedical use of opioid affliction relievers is increasing.1 In the United States, about 1% of abundant women use opiates during pregnancy.2 Consequently, as the cardinal of breed acute assay of neonatal abnegation affection (NAS) rises, the bloom affliction expenditures associated with assay for ytic ecology and medical assay are accretion as well.3,4 There is, however, no accord as to the best single-drug assay for NAS afterwards bootless behavioral intervention.5 Despite recommendations from the American Academy of Pediatrics6 that opioids are the first-line assay for NAS, aberration exists amid centers in the assay of NAS.5,7,8 It additionally charcoal cryptic how gesic assay of NAS affects children’s abiding outcomes.
Experimental studies accede apropos abstracts apropos prenatal gesic exposure. Antenatal gesic acknowledgment affects academician development9,10 with constant decreases in corticogenesis, neurogenesis, and synaptogenesis11,12 and alterations in the ontogeny of the accent axis13–15 and allowed response.16 Human studies additionally allude to the affiliation of prenatal gesic acknowledgment and baby arch circumference17–20 and decreased academician volumes begin on imaging.21 An added affair is that breed with NAS accept their pharmacologic assay during the aboriginal few months of life, a aeon of accelerated postnatal academician development.22 The abeyant abuse of continuing gesic acknowledgment on academician development provides a acute acumen to appraise the use of a nonopiate drug, such as clonidine, as an another to gesic assay for NAS.
With abeyance of the antenatal abiding gesic accumulation at birth, the gesic inhibitory aftereffect on the fetal noradrenergic neurons is lost, constant in added noradrenergic activity. Clonidine, a α2-adrenergic receptor agonist, has inhibitory furnishings on the absolution of noradrenaline in the locus coeruleus; its administering decreases noradrenergic neuronal activity, thereby abbreviation abandonment manifestations. There accept been few letters on clonidine as single-drug assay for NAS in baby numbers of infants.23,24 Contempo studies begin that clonidine was an able accessory assay back accustomed with morphine or chloral hydrate.25,26
Because of abeyant deleterious furnishings of connected postnatal gesic administering on the developing brain,27 we evaluated the use of clonidine in the assay of breed with NAS. We activated the antecedent that clonidine would be bigger than morphine as a single-drug assay for NAS as apparent by advance in neurobehavior and continuance of treatment.
The abstraction was a pilot randomized, double-blind balloon with institutional assay lath approval. The abstracts assurance ecology lath associates met every 10 capacity enrolled and submitted the affair letters to the institutional assay board. Assay cadre acquired a accord from parents back the ytic accommodation was fabricated to alpha pharmacologic treatment, based on assessments fabricated by application the Finnegan scoring system.28,29 Acceptance belief included: postnatal age <7 days, gestational age ≥35 weeks, accepted prenatal gesic acknowledgment (maternal history of gesic use and/or absolute urine gesic awning during abundance or delivery, or baby urine or meconium testing absolute for gesic metaites), no accepted prenatal cocaine exposure, appropriate with 3 afterwards Finnegan array (FS) ≥8 adjourned 3 hours afar or 2 afterwards FS ≥12, no seizures, no above complete malformations, acceptable to survive, no claret burden instability, and no above medical action in accession to NAS. Breed who did not accommodated acceptance criteria, including those who developed NAS due to abiding NICU gesia and balance therapy, were excluded.
Nursing cadre had training in appraisal of FS, and they performed scoring every 3 hours afterwards nipple agriculture (20 kcal/oz) with no aggregate restriction. All breed accustomed behavioral intervention, including swaddling, rocking, pacifier, dim lighting, and quiet NICU environment.30 Back the FS met belief for pharmacologic assay and afterwards consent, the baby accustomed the abstraction biologic based on the randomization agenda (4 per block), accessible alone through the investigational biologic assemblage of the Administering of Pharmacy. The drugs had identical concrete backdrop (color, volume, clarity, and odor). All ytic and assay agents added than the ytic pharmacists were masked to the infant’s abstraction medication. The ytic pharmacists fabricated circuit with the teams, dispensed the abstraction drugs (single dosing), and monitored the physician orders. Doses were assigned by the medical provider by advertence the baby was to accept abstraction biologic at the antecedent dosage per protocol. Any afterwards adjustment was accounting to advance dose, admission abstraction biologic dosage by 25%, abatement dosage by 10% from the accomplished dose, or (in some instances) resume the antecedent dose.
Infants who were randomized to accept morphine accustomed a starting dosage of 0.4 mg/kg per day,31 disconnected every 3 hours based on the agriculture schedule. The dosage was added by 25% of the antecedent dosage every 24 hours until FS array were consistently <8 and affection controlled, up to a best dosage of 1 mg/kg per day. Afterwards 48 hours of evidence ascendancy (all FS <8), weaning was amorphous by abbreviating the dosage by 10% of the best dosage every added day. If the everyman dosage accomplished <0.1 mg/kg per day, morphine was discontinued, and the baby was monitored for 48 hours and afresh discharged. If re-escalation was bare at any time, the antecedent dosage was administered, and weaning was resumed afterwards 48 hours. If no advance was acclaimed at the best dosage of 1 mg/kg per day, a added biologic was added at the accessory physician’s discretion. Those who were randomized to the clonidine accumulation accustomed 5 μg/kg per day disconnected into 8 doses (0.625 μg/kg per dosage every 3 hours). The aforementioned procedures as acclimated in the morphine assay accumulation were followed for dosage increases (maximum dose: 12 μg/kg per day), decreases, and re-escalation. In addition, if an infant’s FS was >8 afterwards the best dose, a added biologic was accomplished at the accessory physician’s discretion. Clonidine was discontinued back the dosage accustomed was <1 μg/kg per day.
All breed were advised in the NICU. They underwent connected cardiorespiratory monitoring, and claret burden abstracts were performed every 8 hours. Back ytic claret sampling was ordered, added claret was calm from the enrolled infant; claret samples were candy and stored for afterwards assay of morphine and clonidine concentrations. Assays for claret concentrations of morphine and clonidine provided a adjustment of acknowledging that breed accustomed the randomized treatment. The investigator amenable for assurance of biologic levels was additionally masked to the assay assignment.
A accomplished masked examiner adjourned the infant’s neurobehavioral achievement by application the NICU Network Neurobehavioral Scale (NNNS). The aboriginal NNNS administering was at 5 to 7 canicule afterwards the alpha of assay and afresh at 40 to 44 weeks’ postmenstrual age at acquittal or during dispensary follow-up.
At the accessory physician’s acumen and with the institutional accent on beneath breadth of stay, breed completed the biologic assay at home but alone afterwards 3 afterwards acknowledged weanings of biologic dose. Continuation of assay postdischarge was accessible back the Adolescent Careful Casework assay adumbrated that baby could be absolved to a safe environment. The ytic pharmacist counseled the child’s caregiver on how to accurately admeasurement and administrate the assigned dosage by application a 1-mL articulate syringe and how to wean the medication based on the provided calendar. Caregivers were added instructed to accompany the labeled medication canteen to any appointment with the child’s primary affliction provider or if gluttonous affliction in the emergency department. The caregiver had to abundantly authenticate how to accurately draw up the aqueous medication, accept the weaning agenda from the calendar, and yze signs and affection of abandonment and back to seek medical attention. The pharmacist additionally contacted the primary affliction physician apropos the child’s assay and aftereffect and faxed a assay agenda forth with the acquittal summary. The breed had a dispensary appointment at 40 to 44 weeks’ postmenstrual age and a adorning aftereffect appointment at 1-year adapted age. Assessments included concrete and neurologic examinations: the Bayley Scales of Baby and Toddler Development, Edition III, and the Preschool Accent Scale, Edition IV.
We planned acceptance of 12 capacity per group, as proposed by Julious32 and Billingham et al.33 An added 20% (total of 15) was included for anniversary assay arm, anticipating answerable abandonment or added abrupt postenrollment exclusions from the study.32,33 Anecdotic statistics and the Wilcoxon rank-sum assay or Fisher’s exact assay were acclimated to yze baseline differences amid assay groups. To yze the NNNS arbitrary array during the aboriginal and added assessments aural anniversary accumulation and amid assay groups, a afresh measures assay of about-face was performed. The admeasurement of breed that completed assay over time were bent by application the Kaplan-Meier adaptation ysis,34 and the adaptation curves were compared by application a log-rank test. To actuate the optimal dosage accustomed that resulted in ascendancy of affection until connected weaning of the dosage was possible, the receiver-operating appropriate (ROC) ambit was bent and the Youden basis belief were used.35–37 Statistical assay was conducted by application SAS adaptation 9.1 (SAS Institute, Inc, Cary, NC).
Figure 1 displays the breeze diagram of the cardinal of capacity screened, excluded, and enrolled. From September 2011 to June 2012, a absolute of 596 admissions were fabricated to the NICU; of these, 354 were built-in at ≥35 weeks and of those, 88 were gesic exposed. Seventy-four breed bare treatment; 11 had assay started at a apropos hospital, 8 had added medical conditions, and 6 had parents who could not be reached. The parents of 15 breed banned abstraction participation. Thirty-four breed had accord provided and were enrolled in the study. Afterwards enrollment, it was bent that 2 breed did not accommodated the abstraction belief (cocaine acknowledgment according to meconium biologic awning after-effects and abiding hypoxia in utero), and 1 was aloof from the abstraction by the accessory physician. Fifteen breed were assigned to accept morphine and 16 accustomed clonidine. Table 1 shows the characteristics of the breed according to biologic assignment. Those who accustomed morphine were not decidedly altered from those who accustomed clonidine in agreement of bearing weight, gestational age, 1- and 5-minute Apgar scores, postnatal age, and FS afore and afterwards admission of treatment. Additionally listed in Table 1 are the altered drugs of exposure, including methadone, buprenorphine, added opiates (hydrocodone, oxycodone), benzodiazepines, or tobacco. Most mothers acclimated assorted drugs.
Diagram assuming screening for capacity for accord in the study, admittance and exclusion, and the cardinal of capacity included in anniversary assay arm.
Characteristics and Acknowledgment to Assay of Morphine- and Clonidine-Treated Infants
In our appraisal of neurobehavioral performance, no statistically cogent differences were acclaimed amid the beggarly ± SD intervals from the admission of pharmacologic assay and the aboriginal NNNS administering (6.6 ± 1.5 canicule for the morphine accumulation and 5.5 ± 2.1 canicule for the clonidine group). There were additionally no beggarly between-group cogent differences apropos the intervals amid the admission of assay and the added NNNS (28.5 ± 16.4 canicule and 24.4 ± 18.9 days, respectively, for the morphine and clonidine groups). Table 2 compares the NNNS arbitrary array from the aboriginal and the added NNNS administering aural and amid assay groups. Twelve of 13 arbitrary array are presented. Habituation procedures were not accessible because abounding breed were not in a beddy-bye state. The neurobehavioral achievement did not alter amid assay groups at the aboriginal assessment, except for the beggarly apathy score, which was college in the clonidine accumulation (5.13 ± 2.12) compared with the morphine accumulation (3.6 ± 1.6). The morphine-treated breed apparent no differences in their neurobehavioral achievement from the aboriginal to the added assessment. However, the clonidine-treated breed showed cogent improvements in areas of attention, handling, arousal, excitability, and lethargy. On the added appraisal and compared with the morphine-treated infants, the clonidine accumulation had decidedly bigger array in activation and excitability.
NNNS Arbitrary Array of Morphine-Treated Adjoin Clonidine-Treated Newborns During the Aboriginal and Added Assessments
The continuance of assay decidedly differed amid the morphine accumulation and the clonidine accumulation (median [range]: 39 [26–89] canicule vs 27.5 [18–107] days; P = .02). Figure 2 displays the Kaplan-Meier adaptation curve. One clonidine-treated baby (an outlier) was afar from this ysis; the infant’s abiding assay was due to the ytic team’s accommodation to wean the dosage every 5 days, which was a aberration from the protocol. Two morphine-treated breed completed assay afore acquittal (41 and 31 assay days); the actual breed connected their assay at home. The average (range) continuance of home assay was 13.5 (6–71) canicule for the clonidine group, which was decidedly beneath than for the morphine accumulation (26 [16–57] days) (Table 1). No baby accustomed a added drug.
Kaplan-Meier adaptation artifice comparing continuance of assay in canicule amid morphine and clonidine. There was a decidedly beneath continuance of assay with clonidine (log-rank test, P = .0007).
Because some breed appropriate a dosage admission of either morphine or clonidine to accomplish ascendancy of symptoms, the ROC ambit was bent for anniversary biologic (Fig 3). For morphine, the optimal dosage was 0.5 mg/kg per day (equivalent to 0.0625 mg/kg per dosage accustomed every 3 hours). For clonidine, the optimal dosage was 7.5 μg/kg per day (∼1 μg/kg per dosage every 3 hours). This dosage of clonidine is additionally constant with appear citizenry pharmacokinetics in bairn infants.38 Because claret sampling was not performed in assigned intervals, active studies were not possible. However, assays appear that breed accustomed the assigned drug.
Comparison amid morphine (top panel) and clonidine (bottom panel) as to ROC curves. The acuteness adjoin 1-specificity is advised for anniversary assay (left panel, A and B). The Youden index, a action of acuteness and specificity, was acclimated as a admeasurement of all-embracing assay capability (right panel, C and D).
Twelve accouchement in anniversary assay arm were evaluated at the 1-year aftereffect appointment completed in September 2013. The morphine-treated breed were commensurable to those who accustomed clonidine in agreement of their cognitive, motor, and accent array (Table 3). For 3 subjects, the accent account of the Bayley Scales of Baby and Toddler Development, Edition III, was included in the yses because the Preschool Accent Scale, Edition IV, account was not available. Table 3 additionally presents the advance measures; these additionally did not alter amid groups.
Bayley Scores, Preschool Accent Scale Scores, and Advance Abstracts at 1-Year Adapted Age in Accouchement Advised With Morphine or Clonidine
To our knowledge, this abstraction is the aboriginal randomized balloon comparing morphine adjoin clonidine as a single-drug assay for NAS. After-effects of this pilot abstraction are able and advance that clonidine is commensurable to morphine in the assay of NAS, accurately in agreement of infants’ neurobehavioral performance. Those advised with clonidine apparent cogent advance in some measures of neurobehavior, admitting those advised with morphine accustomed no cogent change in their neurobehavior, alike afterwards a few weeks of pharmacologic treatment.
Clonidine, a α2-adrenergic agent, acts on the axial affectionate activity, which has been apparent to be added with gesic withdrawal. Abiding gesic acknowledgment after-effects in activation of gesic receptors in the locus coeruleus, which contains clusters of noradrenergic cells. Analgesic acknowledgment decreases adenylate cyclase activity, abbreviation circadian adenosine monophosphate levels.39–41 This aftereffect on circadian adenosine monophosphate after-effects in increases in potassium address with associated decreases in calcium influx; these processes are inhibitory to academician noradrenergic activity.42,43 Abeyance of abiding gesic accumulation after-effects in increases in noradrenergic activity.44 With the inhibitory furnishings of clonidine on noradrenaline absolution in the locus coeruleus, the noradrenergic neuronal action decreases, constant in a abatement in abandonment manifestations.
Most studies evaluated clonidine as an accessory to morphine or chloral hydrate for the assay of NAS.25,26,45 Clonidine as accessory assay for NAS was associated with a abatement in the cardinal of morphine doses, continuance of treatment, or breadth of hospital stay.25,45 From a contempo randomized trial, clonidine accustomed with morphine resulted in a beneath continuance of assay compared with the morphine and phenobarbital combination.45 However, these studies accumulated clonidine with morphine, and the affair for abeyant adverse furnishings of continuing postnatal gesic acknowledgment remains.27
We empiric a best continuance of assay than those appear in aggregate therapy25,45; this aftereffect may be accompanying to the single-drug therapy. In addition, the dosage for this abstraction is at the lower end appear in the literature, abnormally for clonidine.25 A college antecedent dosage for morphine and clonidine is appropriate from the ROC curves in our study. We additionally acclimated a apathetic weaning schedule, actuality accurate to adviser and abstain abeyant adverse furnishings from clonidine administration. In the NICU, breed had accepted cardiovascular and respiratory monitoring. We begin no cogent aberration in claret burden (ie, decreases with admission of dosage or with dosage increases, increases in claret burden back doses were decreased). Added lath begin no cogent claret burden changes with clonidine doses college than acclimated in our study.25,46
Our assay agreement did not behest that assay be completed afore discharge; thus, breed were absolved to abide assay at home. The breadth of break is generally emphasized as a criterion of able care. However, multiple, circuitous issues, such as ancestors captivation with adolescent careful services, ensuring infant’s acquittal to a safe home, and acceptable the mother to admission assay programs are considerations in the appraisal of breadth of hospital stay.
Coyle et al47 evaluated the neurobehavior of breed built-in to mothers on methadone or buprenorphine; 69% were advised with morphine. Overall, their infants’ array for attention, affection of movement, and self-regulation added over canicule while array for handling, arousal, excitability, depression, and hypertonia decreased with time. We begin agnate changes amid the aboriginal and added assessments in our abstraction but added so amid the breed advised with clonidine. With our randomization schedule, an asymmetric administering of prenatal acknowledgment to methadone was noted. It is absorbing that the breed with methadone acknowledgment had bigger array with clonidine assay compared with those with no methadone acknowledgment advised with morphine. The cogent advance of breed in some areas of neurobehavioral achievement abnormally with clonidine is a pertinent application for abiding outcomes. Lath accept appear that the behavior contour from the NNNS of drug-exposed accouchement predicted afterwards adolescence cerebral and behavior outcomes.48
The appearance of ytic and assay personnel, except for the ytic pharmacists for the continuance of hospital break was feasible. Appearance of examiners was additionally achievable during the NNNS administering and abiding follow-up.
There are limitations to the present study. It was a pilot abstraction with a baby sample. The baby cardinal precluded a allusive assay as to which of the drugs predicted the accomplished FS to admit pharmacologic treatment. We did not systematically actuate prenatal biologic acknowledgment by application meconium assays. The nursing cadre had training in assessing FS, but we did not appraise interobserver reliability. In addition, we did not accommodate a agreement for accessory treatment. We connected assay postdischarge, but this resulted in apprehension of the babysitter and the primary affliction physician. Although the babysitter had instructions to administrate the medication with the dosing agenda acclaimed on a calendar, affair still charcoal apropos caretaker’s adequacy to admit changes in the child’s abandonment manifestations and appropriately aing outpatient aftereffect is needed. Lastly, our basic allegation are not generalizable.
Our allegation advance that clonidine may be as able as morphine as a single-drug assay for NAS. A randomized multicenter balloon with abiding aftereffect is acceptable while because added prenatal exposures, including nonopiate drugs. Longitudinal studies advance that changes in behavioral outcomes action afterwards prenatal gesic exposure.49,50 The furnishings of NAS or its assay on afterwards development abide unclear.
The authors accede the abetment of Stephen C. Sitzlar of the Investigational Biologic Assemblage for the randomization, abstraction biologic preparation, and dispensing; they additionally accede the assay nurses (Vicki Whitehead, Debra Grider, Tracy Robinson) and Meredith Edens who tracked these families to acknowledgment for their aftereffect visits. The authors acknowledge the efforts of the associates of the abstracts assurance ecology lath (Mark Vranicar, MD [chair], Marta Mendiondo, PhD, Timothy N. Crawford, PhD, and Karen Garlitz, PharmD) for their lath accord and appropriate acquiescence of letters to the institutional assay board.
Dr Bada conceptualized and advised the study, provided blank for the assay procedures and abstracts acquisition, contributed to the estimation of the data, wrote the aboriginal abstract of the article, and revised the arrangement for its final anatomy for account submission; Drs Sithisarn, Caldwell, Capilouto, and Leggas fabricated abundant contributions to the abstraction and architecture of the study, performed abstracts accretion and estimation of data, advised the arrangement draft, and fabricated revisions; Drs Gibson and Garlitz fabricated abundant contributions to the architecture and randomization procedures, maintained and ensured the appearance of personnel, and advised and fabricated revisions to the draft; Ms Li performed abstracts administration and abstracts ysis, contributed to the estimation of the results, advised the arrangement draft, and fabricated revisions; and Dr Breheny fabricated abundant contributions to the design, performed statistical assay and estimation of data, advised the arrangement draft, and fabricated revisions. All authors accustomed the final adaptation of the arrangement for submission, and all authors agreed to be answerable for all aspects of the assignment in ensuring that questions accompanying to the accurateness or candor of any allotment of the assignment are appropriately advised and resolved.
This balloon has been registered at www.clinicaltrials.gov (identifier NCT01734551).
FINANCIAL DISCLOSURE: The authors accept adumbrated they accept no banking relationships accordant to this commodity to disclose.
FUNDING: Funded in allotment by a Children’s Miracle Network admission awarded to the Kentucky Children’s Hospital.
POTENTIAL CONFLICT OF INTEREST: The authors accept adumbrated they accept no abeyant conflicts of absorption to disclose.
Liu A, Bjorkman T, Stewart C, Nanan R. Pharmacological assay of neonatal gesic withdrawal: amid the devil and the abysmal dejected sea. Int J Pediatr. 2011;2011:935631
Finnegan LP. Neonatal abnegation syndrome: appraisal and pharmacotherapy. In: Rubatelli F, Granati B, eds. Neonatal Therapy: An Update. New York, NY: Elsevier Science Publishers BV (Biomedical Division); 1986:122–146
Kandall SR. Assay Options for Drug-Exposed Infants. In: Chiang CN, Finnegan LP, eds. Medications Development for the Assay of Abundant Addicts and Their Infants. Vol 149. 1995/01/01 ed. Rockville, MD: National Institute on Biologic Abuse NIH Publication No. 95-3891; 1995:78–99
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