Free
Case Reports  |   August 2001
Intravenous Clonidine Use in a Neonate Experiencing Opioid-induced Myoclonus
Author Affiliations & Notes
  • Brenda C. McClain, M.D.
    *
  • Luke A. Probst, B.S.Pharm.
  • Emese Pinter, M.D.
  • Maximilian Hartmannsgruber, M.D.
    §
  • * Associate Professor of Anesthesiology and Pediatrics and Director of Pediatric Pain Management Services, Departments of Anesthesiology and Pediatrics, † Pharmacist, Pharmacy Department, ‡ Assistant Professor, Newborn Special Care Unit, § Assistant Professor of Anesthesiology, Department of Anesthesiology.
  • Received from the Departments of Anesthesiology and Pediatrics, Yale New Haven Children’s Hospital, Yale University School of Medicine, New Haven, Connecticut.
Article Information
Case Reports
Case Reports   |   August 2001
Intravenous Clonidine Use in a Neonate Experiencing Opioid-induced Myoclonus
Anesthesiology 8 2001, Vol.95, 549-550. doi:
Anesthesiology 8 2001, Vol.95, 549-550. doi:
USE of clonidine in the management of pain and opioid taper is well-established for adults. Various treatment modalities have been described, ranging from abrupt opioid cessation with clonidine substitution 1 to gradual taper with clonidine as an adjunct. 2 Oral administration of clonidine in neonatal abstinence syndrome has been cited as safe and effective. 3 Short-term use of intravenous clonidine for sedation in children has been recently reported in the literature. 4 This report describes prolonged and continuous use of intravenous clonidine in the management of opioid-induced myoclonus and opioid taper in a neonate.
Case Report
The patient is a 4.0-kg, 96-day-old male infant whose opioid requirements increased over the first 64 days of life from 0.05 to 25 mg · kg−1· d−1of morphine equivalents. The infant was born at 36 weeks’ gestation with a gastroschisis too large for complete closure at birth that consequently required staged repair. Mechanical ventilation via  an endotracheal tube had been required since birth. Episodes of hypoxia, agitation, and respiratory distress necessitated the intermittent administration of neuromuscular blockade for effective ventilation. The patient’s intolerance of mechanical ventilation persisted despite the addition of intravenous lorazepam at 0.1 mg/kg every 6 h. Ongoing agitation was assessed by an 11-point (0–10) Yale modification of the CRIES scale 5 (CRIES-Mod) for differentiating agitation from air hunger. By day 54 of life, the morphine dose was 21.5 mg · kg−1· d−1. The patient was switched to 20 mg methadone every 6 h, which was increased to 25 mg every 6 h on day 56 of life, but the patient remained agitated and had hourly bouts of desaturation to as low as 74%. The CRIES-Mod score was 9.
The Pediatric Pain Management Service was consulted on day 64 of life. At the time of consultation, the infant displayed bouts of clonic arm activity and facial twitching that temporally coincided with each mechanical breath. Ventilatory settings were as follows: peak inspiratory pressure = 40 cm H2O; positive end-expiratory pressure = 5 cm H2O; intermittent mandatory ventilation = 28; and fraction of inspired oxygen (Fio2) = 0.9. This achieved an oxygen saturation measured by pulse oximetry (Spo2) between 81 and 94%. Seizure activity was ruled out by electroencephalography.
The Pain Management Service proposed that the agitation was not likely to be due to withdrawal or opioid tolerance but represented opioid-induced myoclonus. The use of oral clonidine to decrease the patient’s opioid requirements was not an option because of persistent sanguineous drainage from the ileostomy. Informed consent for intravenous clonidine was obtained from the mother because this was our first use of Duraclon (Roxane Laboratories, Inc., Columbus, OH) as a parenteral agent. Pharmacokinetic data of intravenous clonidine in children and neonates are not available; therefore, the intravenous doses were based on the existing adult experience. 6 
A loading dose of 1 μg/kg injectable clonidine was administered to the patient, followed by a continuous infusion at 0.3 μg · kg−1· h−1. The infant was noted to have less facial grimacing and decreased agitation at 8 h after initiation of the infusion, and at hour 24 of the continuous clonidine infusion, he tolerated weaning of Fio2to 0.7. Next, methadone was reduced to 15 mg every 6 h for a 24-h period and was then further reduced to 10 mg every 6 h. On day 4 of the clonidine infusion, the infant became more agitated. A 0.5-μg/kg intravenous bolus of clonidine was administered, the infusion was increased to 0.35 μg · kg−1· h−1, and agitation decreased. On day 7 of the clonidine infusion, the infant’s heart rate decreased from 150 beats/min to 110 beats/min without significant change in blood pressure or level of alertness (fig. 1). On day 10 of clonidine treatment, tachycardia and diaphoresis developed approximately 48 h after the last reduction in methadone. A 1.0-μg/kg intravenous bolus of clonidine was administered over 30 min, and the clonidine infusion rate was increased to 0.4 μg · kg−1· h−1. The infant remained alert, his agitation subsided, heart rate and blood pressure normalized, and the diaphoretic episode resolved. Methadone taper continued every 3–5 days such that by day 89 of life, he was receiving 2.0 mg every 6 h intravenously, or 10% of the initial intravenous dose (fig. 2).
Fig. 1. The CRIES-Mod trend line displays ongoing overall decimation of agitation and pain behavior throughout the methadone taper.
Fig. 1. The CRIES-Mod trend line displays ongoing overall decimation of agitation and pain behavior throughout the methadone taper.
Fig. 1. The CRIES-Mod trend line displays ongoing overall decimation of agitation and pain behavior throughout the methadone taper.
×
Fig. 2. A methadone taper of 25% or greater was tolerated every 3–5 days without relapse or need for cessation of the opioid taper.
Fig. 2. A methadone taper of 25% or greater was tolerated every 3–5 days without relapse or need for cessation of the opioid taper.
Fig. 2. A methadone taper of 25% or greater was tolerated every 3–5 days without relapse or need for cessation of the opioid taper.
×
Gastrointestinal function improved, and the patient underwent extubation on day 90 of life. The sanguinous drainage from the ileostomy site resolved, enteral feeding was initiated and tolerated, and conversion to oral agents became possible. Because abrupt cessation of clonidine administration after prolonged exposure is not recommended, the clonidine infusion rate was reduced by 50% at the time of the initial oral clonidine dose of 10 μg. Oral clonidine was then scheduled for administration every 6 h. The clonidine infusion was stopped at the time of the second oral clonidine administration. Oral clonidine was gradually reduced until completion of the opioid taper.
Discussion
We have demonstrated the effective application of prolonged intravenous infusion of clonidine in the management of neonatal agitation and opioid-induced myoclonus. Clonidine, an α2agonist, acts at several locations, including the dorsal horn and cerebral cortex, and causes a central decrease in sympathetic outflow with subsequent dose-dependent sedation. The causes of agitation in infants with extended exposure to opioids are not clearly identified. Such presentation is often treated as evidence of withdrawal or inadequate analgesia. The physical signs of opioid abstinence syndrome and opioid-induced myoclonus with hyperalgesia are similar. Both syndromes present with signs of hyperexcitability. Therefore, further delineation of the etiology of myoclonus as seen in a neonatal intensive care setting is needed, especially in infants with prolonged opioid exposure. Withdrawal in the presence of increasing opioid doses can be excluded from the differential diagnosis. This should hold especially true for patients without prenatal opioid exposure.
Morphine-induced myoclonus is usually accompanied by hyperalgesia or a lowering of the pain threshold, presumably due to antalgesic effects of the metabolite morphine-3-glucuronide (M3G). 7,8 M3G leads to increased pain responsiveness to nonnoxious stimuli. Additionally, myoclonus and hyperalgesia have been described as adverse effects of pain management with chronic administration of other opioids, such as hydromorphone. 9 
The first aim in the management of myoclonus is to stop motor agitation. Next, reduction in opioid dose is performed. Suggested treatments of adverse effects seen with high opioid requirements include switching opioids, coadministration of benzodiazepines, or adding opioid-sparing agents, such as α2agonists (e.g.  , clonidine or dexmedetomidine). 3 
The use of oral clonidine in neonates has been established for the management of opioid withdrawal. 3 Intravenous clonidine is a viable alternative when oral intake is not possible. The use of intravenous clonidine in children was first described in the management of a child with severe burns. 10 Ambrose et al.  4 described the use of continuous infusions of clonidine and midazolam for sedation in critically ill children for up to 9 days. Our report corroborates these findings and demonstrates persistent cardiovascular tolerance for 26 days.
The continuous intravenous administration of clonidine allowed titration of sedation and facilitated execution of the methadone taper. In conclusion, we have demonstrated that clonidine is an effective treatment for recalcitrant agitation and myoclonus. Further study is needed to document the possible prevalence of opioid-induced hyperalgesia in neonates who experience prolonged opioid exposure.
References
Fishbain DA: Drug detoxification protocols, Handbook of Pain Management, 2nd edition. Edited by Tollison CD. Baltimore, Williams & Wilkins, 1994, pp 224–36
Spencer L, Gregory M: Clonidine transdermal patches for use in outpatient opiate withdrawal. J Subst Abuse Treat 1989; 6: 113–7Spencer, L Gregory, M
American Academy of Pediatrics Committee on Drugs: Neonatal drug withdrawal (RE9746). Pediatrics 1998; 101: 1079–88American Academy of Pediatrics Committee on Drugs:,
Ambrose C, Sale S, Howells R, Bevan C, Jenkins I, Weir P, Wolf A: Intravenous clonidine infusion in critically ill children: Dose-dependent sedative effects and cardiovascular stability. Br J Anaesth 2000; 84: 794–6Ambrose, C Sale, S Howells, R Bevan, C Jenkins, I Weir, P Wolf, A
Bildner J, Krechel SW: Increasing staff nurse awareness of postoperative pain management in the NICU. Neonatal Netw 1996; 15: 11–6Bildner, J Krechel, SW
Bernard JM, Lagarde D, Souron R: Balanced postoperative analgesia: Effect of intravenous clonidine on blood gases and pharmacokinetics of intravenous fentanyl. Anesth Analg 1994; 79: 1126–32Bernard, JM Lagarde, D Souron, R
Ferris David J: Controlling myoclonus after high-dosage morphine infusions. Am J Health Syst Pharm 1999; 56: 1009–10Ferris David, J
Faura CC, Olaso MJ, Cabanes CG, Horga JF: Lack of morphine-6-glucuronide antinociception after morphine treatment Is morphine-3-glucuronide involved? Pain 1996; 65: 25–30Faura, CC Olaso, MJ Cabanes, CG Horga, JF
Sylvester R, Levitt R, Steen P: Opioid-induced muscle activity: implications for managing chronic pain. Ann Pharmacother 1995; 29: 1118–21Sylvester, R Levitt, R Steen, P
Lyons B, Casey W, Doherty P, McHugh M, Moore KP: Pain relief with low-dose intravenous clonidine in a child with severe burns. Intensive Care Med 1996; 22: 249–51Lyons, B Casey, W Doherty, P McHugh, M Moore, KP
Fig. 1. The CRIES-Mod trend line displays ongoing overall decimation of agitation and pain behavior throughout the methadone taper.
Fig. 1. The CRIES-Mod trend line displays ongoing overall decimation of agitation and pain behavior throughout the methadone taper.
Fig. 1. The CRIES-Mod trend line displays ongoing overall decimation of agitation and pain behavior throughout the methadone taper.
×
Fig. 2. A methadone taper of 25% or greater was tolerated every 3–5 days without relapse or need for cessation of the opioid taper.
Fig. 2. A methadone taper of 25% or greater was tolerated every 3–5 days without relapse or need for cessation of the opioid taper.
Fig. 2. A methadone taper of 25% or greater was tolerated every 3–5 days without relapse or need for cessation of the opioid taper.
×