Abstract
Objective:
To compare the efficacy of clonidine versus phenobarbital in reducing morphine sulfate treatment days for neonatal abstinence syndrome (NAS).
Study Design:
Prospective, non-blinded, block randomized trial at a single level III NICU (Neonatal Intensive Care Unit). Eligible infants were treated with a combination of medications as per protocol. Primary outcome was treatment days with morphine sulfate. Secondary outcomes were the mean total morphine sulfate dose, outpatient phenobarbital days, adverse events and treatment failures.
Results:
A total of 82 infants were eligible, of which 68 were randomized with 34 infants in each study group. Adjusting for covariates phenobarbital as compared with clonidine had shorter morphine sulfate treatment days (−4.6, 95% confidence interval (CI): −0.3, −8.9; P=0.037) with no difference in average morphine sulfate total dose (1.1 mg kg−1, 95% CI: −0.1, 2.4; P=0.069). Post-discharge phenobarbital was continued for an average of 3.8 months (range 1 to 8 months). No other significant differences were noted.
Conclusion:
Phenobarbital as adjunct had clinically nonsignificant shorter inpatient but significant overall longer therapy time as compared with clonidine.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Khalsa J, Gfroerer J . Epidemiology and health consequences of drug abuse among pregnant women. Semin Perinatol 1991; 15: 265–270.
Dicker M, Leighton E . Trends in diagnosed drug problems among newborns: United States, 1979–1987. Drug Alcohol Depend 1991; 28: 151–165.
Finnegan L, Connaughton J, Kron R . A scoring system for evaluation and treatment of the neonatal abstinence syndrome: a new clinical and research tool In: Marselli P, Garanttini S, Sereni F (eds). Basic and Therapeutic Aspects of Perinatal Pharmacology. Raven: New York, NY, USA, 1995 pp 139–152.
Patrick S, Schumacher R, Benneyworth B, Krans E, McAllister J, Davis M . Neonatal abstinence syndrome and associated health care expenditures United States, 2000-2009. JAMA 2012; 307: 1934–1940.
Doberczak T, Kandall S, Friedmann P . Relationships between maternal methadone dosage, maternal-neonatal methadone levels, and neonatal withdrawal. Obstet Gynecol 1993; 81: 936–940.
Mattick R, Breen C, Kimber J, Davoli M . Methadone maintenence therapy versus no opioid replacement therapy for opioid dependence. Cochrane Database Syst Rev 2009; 3: CD002209.
Mack G, Thomas D, Giles W, Buchanan N . Methadone levels and neonatal withdrawal. J Paediatr Child Health 1991; 27: 96–100.
Jernite M, Vivelle B, Escande B, Brettes J, Messer J . Buprenorphine and pregnancy. Analysis of 24 cases. Arch Pediatr 1999; 6: 1179–1185.
Johnson R, Jones H, Jasinski D, Svikis DS, Haug NA, Jansson LM et al. Buprenorphine treatment of pregnant opioid-dependent women: maternal and neonatal outcomes. Drug Alcohol Depend 2001; 63: 97–103.
Coyle M, Ferguson A, Lagasse L, Oh W, Lester B . Diluted tincture of opium (DTO) and Phenobarbital versus DTO alone for neonatal opiate withdrawal in term infants. J Pediatr 2002; 140: 561–564.
Agthe A, Kim G, Mathias K, Hendrix C, Chavez-Valdez R, Jansson L et al. Clonidine as an adjunct therapy to opioids for neonatal abstinence syndrome: a randomized, controlled trial. Pediatrics 2009; 123: e849–e856.
Wachman E, Hayes M, Brown M, Paul J, Harvey-Wilkes K, Terrin N et al. Association of OPRM1 and COMT single-nucleotide polymorphisms with hospital length of stay and treatment of neonatal abstinence syndrome. JAMA 2013; 309: 1821–1827.
CDC Grand Rounds: Prescription Drug Overdoses—a U.S. Epidemic. CDC MMWR. January 2012; 61:10-13. Available at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6101a3.htm . Accessed February 27 2013.
American Academy of Pediatrics Committee on Drugs and the Committee on Fetus and Newborn. Neonatal drug withdrawal. Pediatrics 2012; 129: e540–e560.
Sarkar S, Donn S . Management of neonatal abstinence syndrome in neonatal intensive care units: a national survey. J Perinatol 2006; 26: 15–17.
Chen J, Cai F, Cho J, Zhang X, Li S . Long-term antiepileptic drug administration during early life inhibits hippocampal neurogenesis in the developing brain. J Neurosci Res 2009; 87: 2898–2907.
Meador K, Baker G, Cohen M, Gaily E, Westerveld M . Cognitive/behavioral teratogenetic effects of antiepileptic drugs. Epilepsy Behav 2007; 11: 292–302.
Washton A, Resnick R . Clonidine in opiate withdrawal: review and appraisal of clinical findings. Pharmacology 1981; 1: 140–146.
Kleber H, Gold M, Riordan C . The use of clonidine in detoxification from opiates. Bull Narc 1980; 32: 1–10.
Hoder E, Leckman J, Ehrenkranz R, Kleber H, Cohen D, Poulsen J . Clonidine in neonatal narcotic abstinence syndrome. N Engl J Med 1981; 305: 1284.
Leikin J, Mackendrick W, Maloney G, Rhee J, Farrell E, Wahl M et al. Use of clonidine in the prevention and management of neonatal abstinence syndrome. Clin Toxicol 2009; 47: 551–555.
Vittinghoff E, Glidden D, Shiboski S, McCulloch C . Regression Methods in Biostatistics: Linear, Logistic, Survival, and Repeated Measures Models 2nd edn. Springer: New York, NY, USA, 2012.
Proschan M, Lan K, Wittes J . Statistical Monitoring of Clinical Trials: A Unified Approach. Springer: New York, NY, USA, 2010.
Chen Y, DeMets D, Lan K . Increasing the sample size when the unblinded interim result is promising. Stat Med 2004; 23: 1023–1038.
Liu A, Bjorkman T, Stewart C, Nanan R . Pharmacological treatment of neonatal opiate withdrawal: between the devil and the deep blue sea. Int J Pediatr 2011; 2011: 935631.
Ebner N, Rohrmeister K, Winklbaur B . Management of neonatal abstinence syndrome in neonates born to opioid maintained women. Drug Alcohol Depend 2007; 87: 131.
Coyle M, Ferguson A, LaGasse L, Liu J, Lester B . Neurobehavioral effects of treatment for opiate withdrawal. Arch Dis Child Fetal Neonatal Ed 2005; 90: F73–F74.
Forcelli P, Janssen M, Stamps L, Sweeney C, Vicini S, Gale K . Therapeutic strategies to avoid long-term adverse outcomes of neonatal antiepileptic drug exposure. Epilepsia 2010; 51: 18–23.
Chen J, Cai F, Cao J, Zhang X, Li S . Long-term antiepileptic drug administration during early life inhibits hippocampal neurogenesis in the developing brain. J Neurosci Res 2009; 87: 2898–2907.
Stefovska V, Uckermann O, Czuczwar M, Smitka M, Czuczwar P, Kis J et al. Sedative and anticonvulsant drugs suppress postnatal neurogenesis. Ann Neurol 2008; 64: 434–445.
Reinisch J, Sanders S, Mortensen E, Rubin D . In utero exposure to phenobarbital and intelligence deficits in adult men. JAMA 1995; 274: 1518–1525.
Bhardwaj S, Forcelli P, Palchik G, Gale K, Srivastava L, Kondratyev A . Neonatal exposure to phenobarbital potentiates schizophrenia-like behavioral outcomes in the rat. Neuropharmacology 2012; 62: 2336–2344.
American Academy of Pediatrics Committee on Drugs. Ethanol in liquid preparations intended for children. Pediatrics 1984; 73: 405.
Levinson M, Johnson C . “Stability of an extemporaneously compounded clonidine hydrochloride oral liquid.”. Am J Hosp Pharm 1992; 49: 122–125.
Xie H, Cao Y, Gauda E, Agthe A, Hendrix C, Lee H . Clonidine clearance matures rapidly during the early postnatal period: a population pharmacokinetic analysis in newborns with neonatal abstinence syndrome. J Clin Pharmacol 2011; 51: 502–511.
Acknowledgements
We acknowledge the support provided by the Department of Pediatrics in funding our trial, Ms Tammy Sears for her role as a research assistant on the project, Mr Gerald Korona and the investigational pharmacy team at Baystate Medical Center and the invaluable support of the Davis Neonatal Intensive Care Unit nursing staff, without whose exceptional support the project could not have been completed. This work was funded by the Department of Pediatrics, Baystate Children’s Hospital.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on the Journal of Perinatology website
Supplementary information
Rights and permissions
About this article
Cite this article
Surran, B., Visintainer, P., Chamberlain, S. et al. Efficacy of clonidine versus phenobarbital in reducing neonatal morphine sulfate therapy days for neonatal abstinence syndrome. A prospective randomized clinical trial. J Perinatol 33, 954–959 (2013). https://doi.org/10.1038/jp.2013.95
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/jp.2013.95
Keywords
This article is cited by
-
Comparison of the effect of phenobarbital & levetiracetam in the treatment of neonatal abstinence syndrome (NAS) as adjuvant treatment in neonates admitted to the neonatal intensive care unit: a randomized clinical trial
BMC Pregnancy and Childbirth (2024)
-
Lactose-free infant formula does not change outcomes of neonatal abstinence syndrome (NAS): a randomized clinical trial
Journal of Perinatology (2021)
-
Clonidine versus phenobarbital as adjunctive therapy for neonatal abstinence syndrome
Journal of Perinatology (2020)
-
Comparative effectiveness of opioid replacement agents for neonatal opioid withdrawal syndrome: a systematic review and meta-analysis
Journal of Perinatology (2019)
-
Therapeutic approaches for neonatal abstinence syndrome: a systematic review of randomized clinical trials
DARU Journal of Pharmaceutical Sciences (2019)