Journal of Perinatology (2015) 35, 891–892 © 2015 Nature America, Inc. All rights reserved 0743-8346/15 www.nature.com/jp
LETTERS TO THE EDITOR
Neonatal abstinence syndrome: use of clonazepam? Journal of Perinatology (2015) 35, 891. doi:10.1038/jp.2015.49
We read with interest the article entitled ‘Methadone versus morphine for treatment of neonatal abstinence syndrome: a prospective randomized clinical trial’.1 However, we were perplexed when clonazepam was referred to as a first-line adjunct treatment for the treatment of neonatal abstinence syndrome (NAS) when phenobarbital and clonidine are typically used as the standard of practice. The reference given2 cites the use of clonazepam from the adult literature describing the utility of benzodiazepines in the treatment of narcotic withdrawal, yet provides no explanation for its use in neonates. Furthermore, upon investigating pediatric dosing of clonazepam for the treatment of seizure disorders (0.1 to 0.5 mg/kg/day daily in 2 to 3 divided doses)3 and clonidine for the treatment of NAS (0.5 to 1 μg/kg every 4 to 6 h),4–6 the dose of 0.005 mg/kg/ dose given every 8 h does not seem to elucidate which agent was used, although the dosing may fall in line with pediatric dosing of clonazepam for the treatment of seizure disorders. In addition, we were curious as to why clonidine was referred to as a noradrenergic antagonist rather than a noradrenergic agonist in the introduction of the article, as this seems to pose a discrepancy.
Concerning the aforementioned findings, we would appreciate the authors’ clarification, especially with regard to the use of clonazepam in the treatment of NAS. Thank you for your time and effort. C Henderson1 and C Karnack1 Mylan School of Pharmacy, Duquesne University, Pittsburgh, PA, USA E-mail: [email protected]
1
REFERENCES 1 Brown MS, Hayes MJ, Thornton LM. Methadone versus morphine for treatment of neonatal abstinence syndrome: a prospective randomized clinical trial. J Perinatol 2015; 35(4): 278–283. 2 Lintzeris N, Nielsen S. Benzodiazepines, methadone and buprenorphine: interactions and clinical management. Am J Addict 2010; 19: 59–72. 3 Lexicomp Online, Pediatric & Neonatal Lexi-Drugs. Lexi-Comp, Inc.: Hudson, OH, USA, 2015. 4 Hudak ML, Tan RC. Neonatal drug withdrawal. Pediatrics 2012; 129(2): e540–e560. 5 Bio LL, Siu A, Poon CY. Update on the pharmacologic management of neonatal abstinence syndrome. J Perinatol 2011; 31(11): 692–701. 6 Agthe AG, Kim GR, Mathias KB, Hendrix CW, 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(5): e849–e856.
Reply to ‘Methadone versus morphine for treatment of neonatal abstinence syndrome: a prospective randomized clinical trial’ Journal of Perinatology (2015) 35, 891–892. doi:10.1038/jp.2015.47
The comments prompted by our recent manuscript ‘Methadone versus morphine for neonatal abstinence syndrome: a prospective randomized trial’1 raise questions about adjunct rescue medications for treatment of opiate withdrawal in newborns. First, as pointed out, we misidentified clonidine which is an alpha-adrenergic agonist (paragraph 1, line 18). However, this should not be confused with the second issues of using a benzodiazepine, clonazepam, for rescue treatment during neonatal abstinence syndrome. The questions about using clonazepam as a second drug were thoughtful. We are not aware of any specific studies in newborns using clonazepam as adjunct therapy for treating withdrawal. We have used clonazepam in place of phenobarbital as an adjunct agent for treating opiate withdrawal for several years. There are several reasons for this. First, long-term use of phenobarbital in infants has been associated with poorer neurodevelopmental outcome.2 Although
its use to treat neonatal abstinence syndrome gained popularity in shortening the inpatient stay by completing wean at home after discharge,3 others including ourselves have noted that the post-discharge wean can be difficult for parents. Infants may remain on phenobarbital for months longer than intended as was noted in the trial reported by Surran et al.4 In this report, infants were on phenobarbital for up to 8 months. Third, when the report by Agthe et al.,5 using clonidine, was published, we were concerned about several deaths in the clonidine group. Although there were explanations for these, we did not adopt clonidine as rescue treatment at that time pending further study. We began using benzodiazepine for neonatal withdrawal in dually exposed newborns that had poor control of withdrawal with an opiate alone. We were successful with several infants in controlling the withdrawal after starting a benzodiazepine. On the basis of this experience and the potentiation of opiates by benzodiazepine, we began using it as a rescue agent. In the wean process, we stop clonazepam before discharge, which avoids discharge on any medications.
Letters to the Editor
892
CONFLICT OF INTEREST The author declares no conflict of interest.
MS Brown1 Department of Pediatrics, Eastern Maine Medical Center, Bangor, ME, USA E-mail: [email protected]
1
REFERENCES 1 Brown MS, Hayes MJ, Thornton LM. Methadone versus morphine for treatment of neonatal abstinence syndrome: a prospective randomized clinical trial. J Perinatol 2015; 35(4): 278–283.
Journal of Perinatology (2015), 891 – 892
2 Farwell JR, Lee YJ, Hirtz DG, Sulzbacher SI, Ellenberg JH, Nelson KB. Phenobarbital for febrile seizures—effects on intelligence and on seizure recurrence. N Engl J Med 1990; 322(6): 364–369. 3 Coyle MG, 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(5): 561–564. 4 Surran B, Visintainer P, Chamberlain S, Kopcza K, Shah B, Singh R. Efficacy of clonidine versus phenobarbital in reducing neonatal morphine sulfate therapy days for neonatal abstinence syndrome. A prospective randomized clinical trial. J Perinatol 2013; 33(12): 954–959. 5 Agthe AG, Kim GR, Mathias KB, Hendrix CW, 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(5): e849–e856.
© 2015 Nature America, Inc.
LETTERS TO THE EDITOR
Neonatal abstinence syndrome: use of clonazepam? Journal of Perinatology (2015) 35, 891. doi:10.1038/jp.2015.49
We read with interest the article entitled ‘Methadone versus morphine for treatment of neonatal abstinence syndrome: a prospective randomized clinical trial’.1 However, we were perplexed when clonazepam was referred to as a first-line adjunct treatment for the treatment of neonatal abstinence syndrome (NAS) when phenobarbital and clonidine are typically used as the standard of practice. The reference given2 cites the use of clonazepam from the adult literature describing the utility of benzodiazepines in the treatment of narcotic withdrawal, yet provides no explanation for its use in neonates. Furthermore, upon investigating pediatric dosing of clonazepam for the treatment of seizure disorders (0.1 to 0.5 mg/kg/day daily in 2 to 3 divided doses)3 and clonidine for the treatment of NAS (0.5 to 1 μg/kg every 4 to 6 h),4–6 the dose of 0.005 mg/kg/ dose given every 8 h does not seem to elucidate which agent was used, although the dosing may fall in line with pediatric dosing of clonazepam for the treatment of seizure disorders. In addition, we were curious as to why clonidine was referred to as a noradrenergic antagonist rather than a noradrenergic agonist in the introduction of the article, as this seems to pose a discrepancy.
Concerning the aforementioned findings, we would appreciate the authors’ clarification, especially with regard to the use of clonazepam in the treatment of NAS. Thank you for your time and effort. C Henderson1 and C Karnack1 Mylan School of Pharmacy, Duquesne University, Pittsburgh, PA, USA E-mail: [email protected]
1
REFERENCES 1 Brown MS, Hayes MJ, Thornton LM. Methadone versus morphine for treatment of neonatal abstinence syndrome: a prospective randomized clinical trial. J Perinatol 2015; 35(4): 278–283. 2 Lintzeris N, Nielsen S. Benzodiazepines, methadone and buprenorphine: interactions and clinical management. Am J Addict 2010; 19: 59–72. 3 Lexicomp Online, Pediatric & Neonatal Lexi-Drugs. Lexi-Comp, Inc.: Hudson, OH, USA, 2015. 4 Hudak ML, Tan RC. Neonatal drug withdrawal. Pediatrics 2012; 129(2): e540–e560. 5 Bio LL, Siu A, Poon CY. Update on the pharmacologic management of neonatal abstinence syndrome. J Perinatol 2011; 31(11): 692–701. 6 Agthe AG, Kim GR, Mathias KB, Hendrix CW, 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(5): e849–e856.
Reply to ‘Methadone versus morphine for treatment of neonatal abstinence syndrome: a prospective randomized clinical trial’ Journal of Perinatology (2015) 35, 891–892. doi:10.1038/jp.2015.47
The comments prompted by our recent manuscript ‘Methadone versus morphine for neonatal abstinence syndrome: a prospective randomized trial’1 raise questions about adjunct rescue medications for treatment of opiate withdrawal in newborns. First, as pointed out, we misidentified clonidine which is an alpha-adrenergic agonist (paragraph 1, line 18). However, this should not be confused with the second issues of using a benzodiazepine, clonazepam, for rescue treatment during neonatal abstinence syndrome. The questions about using clonazepam as a second drug were thoughtful. We are not aware of any specific studies in newborns using clonazepam as adjunct therapy for treating withdrawal. We have used clonazepam in place of phenobarbital as an adjunct agent for treating opiate withdrawal for several years. There are several reasons for this. First, long-term use of phenobarbital in infants has been associated with poorer neurodevelopmental outcome.2 Although
its use to treat neonatal abstinence syndrome gained popularity in shortening the inpatient stay by completing wean at home after discharge,3 others including ourselves have noted that the post-discharge wean can be difficult for parents. Infants may remain on phenobarbital for months longer than intended as was noted in the trial reported by Surran et al.4 In this report, infants were on phenobarbital for up to 8 months. Third, when the report by Agthe et al.,5 using clonidine, was published, we were concerned about several deaths in the clonidine group. Although there were explanations for these, we did not adopt clonidine as rescue treatment at that time pending further study. We began using benzodiazepine for neonatal withdrawal in dually exposed newborns that had poor control of withdrawal with an opiate alone. We were successful with several infants in controlling the withdrawal after starting a benzodiazepine. On the basis of this experience and the potentiation of opiates by benzodiazepine, we began using it as a rescue agent. In the wean process, we stop clonazepam before discharge, which avoids discharge on any medications.
Letters to the Editor
892
CONFLICT OF INTEREST The author declares no conflict of interest.
MS Brown1 Department of Pediatrics, Eastern Maine Medical Center, Bangor, ME, USA E-mail: [email protected]
1
REFERENCES 1 Brown MS, Hayes MJ, Thornton LM. Methadone versus morphine for treatment of neonatal abstinence syndrome: a prospective randomized clinical trial. J Perinatol 2015; 35(4): 278–283.
Journal of Perinatology (2015), 891 – 892
2 Farwell JR, Lee YJ, Hirtz DG, Sulzbacher SI, Ellenberg JH, Nelson KB. Phenobarbital for febrile seizures—effects on intelligence and on seizure recurrence. N Engl J Med 1990; 322(6): 364–369. 3 Coyle MG, 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(5): 561–564. 4 Surran B, Visintainer P, Chamberlain S, Kopcza K, Shah B, Singh R. Efficacy of clonidine versus phenobarbital in reducing neonatal morphine sulfate therapy days for neonatal abstinence syndrome. A prospective randomized clinical trial. J Perinatol 2013; 33(12): 954–959. 5 Agthe AG, Kim GR, Mathias KB, Hendrix CW, 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(5): e849–e856.
© 2015 Nature America, Inc.
