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ARTICLES: Alexander G. Agthe, George R. Kim, Kay B. Mathias, Craig W. Hendrix, Raul Chavez-Valdez, Lauren Jansson, Tamorah R. Lewis, Myron Yaster, and Estelle B. Gauda Clonidine as an Adjunct Therapy to Opioids for Neonatal Abstinence Syndrome: A Randomized, Controlled Trial Pediatrics 2009; 123: e849-e856 [Abstract] [Full text] [PDF]

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Clonidine as adjunct therapy for Neonatal Narcotic Abstinence, why not first-line therapy?

Peter Gal, John Wimmer, J. Laurence Ransom   (7 June 2009)

Clonidine as adjunct therapy for Neonatal Narcotic Abstinence, why not first-line therapy? 7 June 2009
Peter Gal, Pharmacist Faculty Graduate Pharmacy Education, Greensboro Area Health Education Center, and Women's Hospital, Greensbo, John Wimmer, J. Laurence Ransom Send letter to journal: Re: Clonidine as adjunct therapy for Neonatal Narcotic Abstinence, why not first-line therapy? peter.gal{at}mosescone.com Peter Gal, et al.	The study by Agthe et al1 reporting the benefits of clonidine as an adjunct to opioid therapy for neonatal narcotic abstinence syndrome (NNAS) is an excellent endorsement for the benefits of using clonidine in NNAS. The fact that a primary goal of therapy was to minimize the length of narcotic therapy, raises the question of how early clonidine should be used in NNAS management. It is our contention, that the need for scheduled narcotics may be totally avoided in many patients if an alpha-2 agonist such as clonidine (or demedetomidine if the patient cannot take oral medication) is used as a first-line agent. The most significant argument for alpha-2 agonists to replace opioids as primary management of NNAS is based on the neuroprotective properties of this class of drugs.2-5 On the basis of animal models, these neuroprotective mechanisms include: (1) modulation of central catcholamine release; (2) modulation of central glutamate release; reduction in glutamate receptor (N-methyl-D-aspartate receptor, NMDA-receptor) activity; and (3) reduced calcium entry into neuronal cells.2-5 These actions are in marked contrast to the neuroapoptotic actions of drugs now commonly used for management of NNAS, such as narcotics, benzodiazepines, and phenobarbital.6-8 NNAS is occurring at a time when synaptogenesis is very active and thus most vulnerable to adverse actions on neuronal survival. Despite the known adverse effects of NMDA inhibitors on neuronal survival and behavior in newborn animals, and the lack of comparative long-term studies in humans, a recent survey showed most practitioners consider opioids first-line therapy.9 Alpha-2 adrenergic receptor agonists have preserved neuronal function in animal models3,4,5 and are proven comparable to opioids in management of narcotic abstinence in animal models and adults.10-12 Consequently we feel this class of drugs actually makes the most sense as first-line treatment of NNAS in neonates. The potential toxicities of clonidine, opioids, benzodiazepines, and phenobarbital are substantial. With proper monitoring, however, these drugs can be used safely, singly or in combination, even with escalating doses. In the case of clonidine the main concerns are bradycardia, hypotension, and excess sedation. These can be easily monitored, allowing dosing escalation when abstinence symptoms persist and adverse effects are absent. The risks of toxicity with clonidine are no greater than with narcotics when used in clinical trials. Because of the risks of drug diversion when discharging NNAS infants home on maintenance therapy to drug abusing parents, there are obvious advantages to use of non-narcotic medication. Each of the drugs used for NNAS have potentially serious toxicity if overdosed, including clonidine. As with prior published cases13,14, our experience with clonidine as a first-line agent to treat narcotic withdrawal has been very favorable. The dosing strategy has been to start at 1 mcg/kg oral solution every 4 to 6 hours if the Lipsitz score15 for neonatal abstinence is > 6 on two consecutive evaluations at least 2 hours apart. Our target Lipsitz score for response is < 4 (ideally 1-3). Lipsitz scores are obtained at the middle and end of each dosing interval. If both scores are >4, then clonidine dose is increased, if only the pre-dose score is >4, the clonidine dosing interval is shortened. Feeding times are taken into account for dosing intervals to simplify nursing care and minimize more frequent stimulation. The severity of symptoms and anticipated clinical course based on the maternal narcotic use history dictated the rate of increase. Our other use of clonidine is to facilitate weaning fentanyl in newborns who have developed narcotic dependence following its prolonged use. The same clonidine dosing strategy is used here, while fentanyl doses are cut in half for 3 consecutive days and discontinued on day 4 of clonidine. We have treated 8 neonates, 34 to 41 weeks gestation, whose mothers used methadone 25 to 250 mg/day, 1 case with maternal dilaudid plus morphine (totaling 554 mg morphine equivalent), and one case of multiple opioid use with unknown quantities. In all cases the mothers were using concurrent benzodiazepines and/or antidepressants. In addition we treated 8 neonates, 23 to 40 weeks gestation, who had become dependent on fentanyl (used to treat pain and sedation) and were difficult to wean because of narcotic withdrawal symptoms. No patient had clonidine discontinued for toxicity, although one patient had systolic blood pressure below 60 mmHg on 2 occasions and had clonidine held for a dose in each case. In this patient, higher doses were subsequently well tolerated with no problems. Nine patients required additional drugs to control abstinence (phenobarbital for 6 patients, morphine for 2 patients and lorazepam for 1 patient). This is similar to other case series using opioids or phenobarbital. Others13,14 have reported success with clonidine but used limited doses. During short term use toxicity can be avoided by holding doses at lower limits for blood pressure and heart rate. This strategy allowed us to use clonidine daily doses ranging from 1 mcg/kg every 6 hours (mcg/kg/day) to 4 mcg/kg every 3 hours (32 mcg/kg/day). Treatment duration ranged from 3 to 28 days, and 2 patients were discharged on clonidine maintenance therapy. The longest treatments were when maternal methadone use was the cause of abstinence. We hope that other investigators will consider this a challenge to examine both short- and long-term outcomes comparing a first-line agent that is neuroprotective, such as clonidine (or dexmedetomidine), with the currently recommended therapies known to be neuroapoptotic in animals, such as narcotics. We look forward to follow up neurodevelopmental outcomes from the study by Agthe and coworkers1 since there may be neuroprotective benefits from adjunctive alpha-2-agonists also.4,5 Meanwhile, in the absence of compelling short- and long-term results from controlled trials, it is difficult to see how any treatment can be considered standard for NNAS, and each practitioner must weigh available human and animal data to decide what is best. References: 1. Agthe AG, Kim GR, Mathias KB, et al. Clonidine as an adjunct therapy to opioids for neonatal abstinence syndrome: a randomized controlled trial. Pediatrics 2009;123:e849-e856. 2. Ma D, Rajakumaraswamy N, Maze M. α2-Adrenoreceptor agonists: shedding light on neuroprotection. British Medical Bulletin 2005;71:77-92. 3. Soto-Moyano R, Hernandez A, Perez H, et al. Clonidine treatment during gestation prevents functional deficits induced by prenatal malnutrition in the rat visual cortex. Intern J Neuroscience 1994;76:237-248. 4. Jevtovic-Todorovic V, Wozniak DF, Powell S, Nardi A, Olney JW. Clonidine potentiates the neuropathic pain-relieving action of MK-801 while preventing its neurotoxic and hyperactivity side effects. Brain Res 1998;781:202-211. 5. Dexmedetomidine attenuates isoflurane-induced neurocognitive impairment in neonatal rats. Anesthesiology 2009;110:1077-1085. 6. Mellon RD, Simone AF, Rappaport BA. Use of anesthetic agents in neonates and young children. Pediatric Anesthesia 2007;104:509-520. 7. Mao J, Sung B, Ji RR, Lim G. Neuronal apoptosis associated with morphine tolerance: evidence for an opioid-induced neurotoxic mechanism. J Neurosci 2002;22:7650-7661. 8. Antiepileptic drugs and apoptotic neurodegeneration in the developing brain. PNAS 2002;23:15089-15094. 9. Sarkar S, Donn SM. Management of neonatal abstinence syndrome in neonatal intensive care units: a national survey. J Perinatol 2006;26:15- 17. 10. Chen S, Zhai H, Cui Y, Shi J, Foll BLE, Lu L. Clonidine attenuates morphine withdrawal and subsequent drug sensitization in rhesus monkeys. Acta Pharmacol Sin 2007;28:473-483. 11. Tobias JD. Dexmedetomidine effectively controls opioid withdrawal in the pediatric ICU patient. Pediatr Crit Care Med 2005;6:625 12. Gowing L, Farrell M, Ali R, White J. Alpha2 adrenergic agonists for the management of opioid withdrawal (review). Cochrane Library 2005;4:1- 35. 13. McClain BC, Probst LA, Pinter E, Hartmannsgruber M. Intravenous clonidine use in a neonate experiencing opioid-induced myoclonus. Anesthesiol 2001;95:549-550. 14. Hoder EL, Leckman JF, Poulsen J, et al. Clonidine treatment of neonatal narcotic abstinence syndrome. Psychiatry Res 1984;13:243-251. Conflict of Interest: none