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Low-dose versus high-dose methadone for the management of neonatal abstinence syndrome

Jamie L. Miller, PharmD, BCPS, BCPPS, FPPAG, Kimberly Ernst, MD, MSMI, FAAP, Stephen B. Neely, MPH, Katy Stephens, BS, Philip Barker, Grant H. Skrepnek, PhD, RPh, Peter N. Johnson, PharmD, BCPS, BCPPS, FPPAG, FCCM


Objectives: The primary objective was to compare median time to symptom relief (time from methadone initiation until two consecutive modified Finnegan [neonatal abstinence syndrome, NAS] scores < 8) between neonates receiving low-dose (0.275 mg/kg/day) versus high-dose (>0.275 mg/kg/day) methadone. Secondary objectives included assessment of factors associated with symptom relief.

Design: Retrospective cross-sectional study.

Setting: Ninety-nine bed neonatal intensive care unit within a tertiary-care academic hospital.

Participants: Seventy-two neonates who received methadone for NAS over a 7.5-year period.

Main outcome measures(s): Kaplan-Meier curves with a log-rank test and a stepwise Cox proportional-hazard model were used to analyze outcomes.

Results: The median dose for the low-dose (n = 40) and high-dose (n = 32) groups were 0.19 mg/kg/day (interquartile range [IQR], 0.12-0.24) divided every 6-12 hours and 0.4 mg/kg/day (0.3-0.44) divided every 6-8 hours, respectively. The median time to symptom relief was higher in the low-dose versus high-dose groups, 9.3 (5.8-24.6) versus 6.0 (5.4-12.5) hours, respectively (p = 0.014). Low-dose males had a longer time to symptom resolution than other groups (p = 0.008). Female premature neonates (<37 weeks gestation) had a shorter time to symptom relief than term neonates [adjusted hazard ratio = 2.96 (1.02-8.62)]. The median total duration of methadone was shorter but not statistically significant between high- versus low-dose groups, 17.5 (IQR: 11.0-25.0) versus 21.0 days (IQR: 10.0-28.0), respectively (p = 0.483).

Conclusions: Neonates receiving high-dose methadone had a significantly shorter time to symptom relief. Differences in sex were noted in response to therapy with low-dose males having a longer time to symptom relief and premature neonates a shorter time to symptom relief.


methadone, neonatal abstinence syndrome, withdrawal, pediatrics

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Tolia VN, Patrick SW, Bennett MM, et al.: Increasing incidence of the neonatal abstinence syndrome in U.S. neonatal ICUs. N Engl J Med. 2015; 372: 2118-2126.

Hudak ML, Tan RC, Committee on Drugs and Committee on Fetus and Newborn: Neonatal drug withdrawal. Pediatrics. 2012; 129: e540-e560.

Finnegan LP: Neonatal abstinence. In Nelson NM (ed.): Current Therapy in Neonatal–Perinatal Medicine. 2nd ed. Toronto, ON: BC Decker Inc., 1990.

Lainwala S, Brown ER, Weinschenk NP, et al.: A retrospective study of LOS in infants treated for neonatal abstinence syndrome with methadone versus oral morphine preparations. Adv Neonatal Care. 2005; 5: 265-272.

Backes CH, Backes CR, Gardner D, et al.: Neonatal abstinence syndrome: Transitioning methadone-treated infants from an inpatient to an outpatient setting. J Perinatol. 2012; 32: 425-430.

Brown MS, Hayes MJ, Thornton LM: Methadone versus morphine for treatment of neonatal abstinence syndrome: A prospective randomized clinical trial. J Perinatol. 2015; 35: 278-283.

Young ME, Hager SJ, Spurlock D: Retrospective chart review comparing morphine and methadone in neonates treated for neonatal abstinence syndrome. Am J Health Syst Pharm. 2015; 72: S162-S167.

Ibach BW, Johnson PN, Ernst KD, et al.: Initial dosing and taper complexity of methadone and morphine for treatment of neonatal abstinence syndrome. J Pharm Tech. 2016; 32: 216-222.

Lexi-Comp Online™, Pediatric and Neonatal Lexi-Drugs™ [package insert]. Methadone monograph. Hudson, OH: Lexi Comp, Inc., January 24, 2018.

Micromedex® NeoFax® Mobile [package insert]. Methadone monograph. Ann Arbor, MI: Truven Health Analytics, Inc., January 24, 2018.

Hurley RW, Adams MCB: Sex, gender, and pain: An overview of a complex field. Anesth Analg. 2008; 107: 309-317.

Pud D, Yarnitsky D, Sprecher E, et al.: Can personality traits and gender predict the response to morphine? An experimental cold pain study. Eur J Pain. 2006; 10: 103-112.

Sarton E, Olofsen E, Romberg R, et al.: Sex differences in morphine analgesia: An experimental study in healthy volunteers. Anesthesiology. 2000; 93: 1245-1254.

Fillingim RB, Ness TJ, Glover TL, et al.: Morphine responses and experimental pain: Sex differences in side effects and cardiovascular responses but not analgesia. J Pain. 2005; 6: 116-124.

Romberg R, Olofsen E, Sarton E, et al.: Pharmacokinetic pharmacodynamic modeling of morphine-6-glucuronideinduced analgesia in healthy volunteers: Absence of sex differences. Anesthesiology. 2004; 100: 120-133.

Wiles JR, Isemann B, Mizuno T, et al.: Pharmacokinetics of oral methadone in the treatment of neonatal abstinence syndrome: A pilot study. J Pediatr. 2015; 167: 1214-1220.

Kearns GL, Abdel-Rahman SM, Alander SW, et al.: Developmental pharmacology—Drug disposition, action, and therapy in infants and children. N Engl J Med. 2003; 349: 1157-1167.

Lammers EM, Johnson PN, Ernst KD, et al.: Association of fentanyl with neurodevelopmental outcomes in very-low-birthweight infants. Ann Pharmacother. 2014; 48: 335-342.

McPherson C, Haslam M, Pineda R, et al.: Brain injury and development in preterm infants exposed to fentanyl. Ann Pharmacother. 2015; 49: 1291-1297.

de Graaf J, van Lingen RA, Simons SHP, et al.: Long-term effects of routine morphine infusion in mechanically ventilated neonates on children's functioning: Five-year follow-up of a randomized controlled trial. Pain. 2011; 152: 1391-1397.

Kaltenbach K, Jones HE: Neonatal abstinence syndrome: Presentation and treatment considerations. J Addict Med. 2016; 10: 217-223.

Sarkar S, Donn SM: Management of neonatal abstinence syndrome in neonatal intensive care units: A national survey. J Perinatol. 2006; 26: 15-17.



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