Adverse Effects in Children After Unintentional Buprenorphine Exposure Ann-Jeannette Geib, Kavita Babu, Michele Burns Ewald and

Edward W. Boyer Pediatrics 2006;118;1746 DOI: 10.1542/peds.2006-0948

The online version of this article, along with updated information and services, is located on the World Wide Web at:
http://pediatrics.aappublications.org/content/118/4/1746.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2006 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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EXPERIENCE & REASON

Short communications of factual material are published here. Comments and criticisms appear as Commentaries or Letters to the Editor.

In Medicine one must pay attention not to plausible theorizing but to experience and reason together. . . . I agree that theorizing is to be approved, provided that it is based on facts, and systematically makes its deductions from what is observed. . . . But conclusions drawn from unaided reason can hardly be serviceable; only those drawn from observed fact.
Hippocrates, Precepts

Adverse Effects in Children After Unintentional Buprenorphine Exposure

Ann-Jeannette Geib, MDa, Kavita Babu, MDb, Michele Burns Ewald, MDa, Edward W. Boyer, MD, PhDa,b
aProgram in Medical Toxicology, Division of Emergency Medicine, Childrens Hospital Boston, Boston, Massachusetts; bDivision of Medical Toxicology, University of Massachusetts Medical School, Boston, Massachusetts

The authors have indicated they have no nancial relationships relevant to this article to disclose.

ABSTRACT Buprenorphine in sublingual formulation was recently introduced to the American market for treatment of opioid dependence. We report a series of 5 toddlers with respiratory and mental-status depression after unintentional buprenorphine exposure. Despite buprenorphines partial agonist activity and ceiling effect on respiratory depression, all children required hospital admission and either opioid-antagonist therapy or mechanical ventilation. Results of routine urine toxicology screening for opioids were negative in all cases. Conrmatory testing was sent for 1 child and returned with a positive result. The increasing use of buprenorphine as a home-based therapy for opioid addiction in the United States raises public health concerns for the pediatric population.

oxone, has been approved in the United States for the treatment of opioid addiction. Unlike traditional methadone-maintenance therapy, buprenorphine is prescribed for outpatient administration under a physicians supervision and may not be directly observed. The thrice-weekly dosing regimen increases compliance, and its use in the United States has been rising steadily since the US Food and Drug Administrations approval in 2002. Treatment with buprenorphine has been demonstrated to decrease the number of opioid-related deaths and rivals methadone in efcacy.1 Although associated with respiratory depression when abused parenterally by adults, buprenorphines sublingual absorption may lead to toxicity in small children who merely place the medication in their mouth.27 Here we report 5 cases of buprenorphine toxicity in toddlers that required either naloxone therapy or mechanical ventilation.
1746 GEIB et al

UPRENORPHINE, ALONE OR in combination with nal-

CASE REPORTS
PATIENT 1. A 16-month-old, 12.5-kg boy was found with a

Suboxone tablet (buprenorphine 8 mg/naloxone 2 mg, prescribed for his father) in his mouth. Three hours later a caregiver found him unresponsive; 2 hours after that, he was frothing at the mouth. On emergency medical services arrival, nearly 5 hours after ingestion, he was gasping (with a respiratory rate of 2 breaths per minute and blood pressure of 60 mm Hg systolic) and
Key Words: buprenorphine, unintentional ingestion, respiratory depression, opioid, pediatric, exploratory behavior Abbreviations: ED, emergency department; CNS, central nervous system www.pediatrics.org/cgi/doi/10.1542/peds.2006-0948 doi:10.1542/peds.2006-0948
Accepted for publication May 24, 2006 Address correspondence to Ann-Jeannette Geib, MD, Pinnacle Health Toxicology Center, Harrisburg Hospital, PO Box 8700, Harrisburg, PA 17105-8700. E-mail: ajgeib@hotmail.com PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright 2006 by the American Academy of Pediatrics

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RR: 2 breaths per min; BP: 60 mm Hg systolic; O2 saturation: 70% on room air RR: 20 breaths per min; HR: 124 beats per min; BP: 101/69 mm Hg; O2 saturation: 98% on room air; temperature: 97.9F RR: 20 breaths per min; HR: 115 beats per min; BP: 100/89 mm Hg; O2 saturation: 97% on room air; temperature: 97.9F HR: 112 beats per min; BP: 146/86 mm Hg RR: 36 breaths per min; HR: 133 beats per min; O2 saturation: 98% on room air; temperature: 97.6F Gasping; unresponsive; perioral cyanosis Lethargic; cyanotic; respiratory failure 8 mg buprenorphine/2 mg naloxone (1 tablet) Female Male Male Male 16 20 22 15 1 3 2 4 PEDIATRICS Volume 118, Number 4, October 2006 5 16 Male 8 mg buprenorphine/2 mg naloxone (1 tablet) 4 mg buprenorphine/1 mg naloxone (2 tablets) 8 mg buprenorphine/2 mg naloxone (1 tablet) 10 mg buprenorphine ( 1 tablet) Somnolent Lethargic Drowsy

First Recorded Vital Signs

TABLE 1 Clinical Features

PATIENT 4. A 15-month-old, 12.7-kg boy presented to the ED with drowsiness. He had been found with orange pill residue in his mouth and on his hands. A family friend

Case

Age, mo

PATIENT 3. A 20-month-old, 10-kg boy was found cyanotic and somnolent with shallow respirations next to an empty bottle of his fathers Subutex (buprenorphine HCl 8 mg). According to his mother, 1 to 2 tablets had been left in the bottle. Paramedics arrived 45 minutes after the ingestion, administered intravenous naloxone 0.8 mg (0.08 mg/kg), and noted immediate improvement in the boys mental status, respiratory rate, and cyanosis. On arrival to the ED his vital signs were: heart rate, 115 beats per minute; blood pressure, 100/89 mm Hg; respiratory rate, 20 breaths minute; temperature, 97.9F; and oxygen saturation, 97% on room air. In the eld and the referring hospital, he had several episodes of emesis. He remained awake and playful before transfer to a tertiary care pediatric hospital. Before transport, he was given a second intravenous dose of naloxone for a decrease in heart rate (0.8 mg); no additional respiratory depression was documented. Serial examinations overnight revealed no other changes in clinical status. He was discharged the following day.

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RR indicates respiratory rate; BP, blood pressure; HR, heart rate; IV, intravenous; GC/MS/MS, gas chromatography/tandem mass spectroscopy.

PATIENT 2. A 22-month-old, 11-kg girl presented to the ED after ingestion of 1 tablet of Suboxone (buprenorphine 8 mg/naloxone 2 mg) that belonged to a relative. Her family transported her to the ED after she became difcult to arouse and her eyes rolled back. On presentation, her vital signs were: temperature, 97.9F; heart rate, 124 beats per minute; respiratory rate (reported), 20 breaths per minute; oxygen saturation, 98% on room air; and blood pressure, 101/69 mm Hg. Her physical examination was unremarkable except for somnolence and miotic pupils. Intravenous naloxone 0.8 mg (0.072 mg/kg) produced improvement in her level of consciousness. After 30 minutes, the patient again became lethargic. She then was started on a continuous infusion of naloxone at 0.5 mg/hour and transferred to a PICU for further management. She remained easily arousable on the naloxone infusion during the course of her PICU stay. The naloxone infusion was discontinued 25 hours after the exposure, and she was discharged on the second hospital day.

Negative

Gender

Estimated Dose

Presentation

Naloxone bolus: 0.2 mg 2 (0.016 mg/kg per dose) Naloxone bolus: 1 mg 5 (0.1 mg/kg per dose) 1747

Intubation; mechanical ventilation

Naloxone bolus: 0.4 mg IV 2 (0.072 mg/kg); naloxone infusion: 0.5 mg/h titrated over 17 h Naloxone bolus: 0.8 mg IV 2 (0.16 mg/kg)

Intervention

Negative

Negative; urine GC/MS/MS positive for buprenorphine and metabolite

Urine Opioid Toxicology Screen

was promptly intubated. On arrival at the emergency department (ED) his blood pressure was 124/44 mm Hg, his heart rate was 144 beats per minute, and his respiratory rate was 24 breaths per minute on mechanical ventilation. The physical examination was signicant for pinpoint pupils. Pertinent clinical data are presented in Table 1. He remained intubated overnight. His mental status improved, and he was extubated on the second hospital day. The remainder of his hospitalization was uneventful, and he was discharged on the third day.

Length of Stay, d

Negative

Negative

who was visiting the home was known to have dropped a Suboxone tablet (buprenorphine 8 mg/naloxone 2 mg) 30 minutes earlier. At the ED, the boy had pinpoint pupils and drowsiness. After receiving a total of 0.4 mg naloxone in divided doses (0.016 mg/kg per dose) he became more arousable and had 1 episode of emesis. He was transferred to a tertiary care pediatric hospital and underwent serial examinations. During overnight monitoring he was noted to have desaturations to 91% while sleeping without depression in respiratory rate. The next morning he was awake and playful and had stable vital signs. He was discharged to home that day.
PATIENT 5. A 16-month-old, 10-kg boy was found by his parent making funny faces. Approximately half of a Suboxone tablet (buprenorphine 2 mg/naloxone 0.5 mg) was found in his mouth and another tablet was unaccounted for. The tablets belonged to his mothers partner, who had left her daily dose unattended. After the parent contacted the poison control center, she took the child to a local hospital. He arrived 45 minutes after the exposure. His presenting vital signs were: heart rate, 133 beats per minute; respiratory rate, 36 breaths per minute; temperature, 97.8F; and oxygen saturation, 98% on room air. He was somnolent and had miotic pupils on arrival. Approximately 1 hour after ED presentation his respiratory rate decreased to 15 breaths per minute, and he became more difcult to arouse. He received 3 boluses of 0.1 mg/kg intravenous naloxone over 105 minutes for recurrent respiratory depression, and he was transferred to a tertiary pediatric hospital. There, he initially appeared well but developed recurrent respiratory depression (respiratory rate: 10 breaths per minute with oxygen saturations of 92%) at hours 8 and 18 after the exposure. On both occasions he received naloxone 0.1 mg/kg with full reversal. He underwent additional uneventful serial examinations and was discharged 30 hours after the exposure. Urine concentrations of buprenorphine and norbuprenorphine were 19 and 200 ng/mL, respectively.

DISCUSSION These data suggest that pediatric buprenorphine exposure produces the classic opioid toxidrome of apnea, mental-status depression, and miosis in children. Although previous reports have suggested a lack of significant toxicity in the pediatric population, our ndings indicate that buprenorphine exposure may produce serious adverse effects, including apnea, in toddlers.8,9 These observations are consistent with a report of respiratory depression in a 2-year-old exposed to 4 mg of buprenorphine10 and substantiate the public health risk of buprenorphine toxicity in the pediatric patient. The differential diagnosis of respiratory depression in children is broad. In settings in which young children have been exposed to an individual under treatment for opi1748 GEIB et al

oid dependence, agents such as buprenorphine preparations, clonidine patches, fentanyl patches, methadone, and L- -acetyl-methadol may produce a similar clinical picture.1116 The pharmacokinetics of buprenorphine have been well described. Buprenorphine is absorbed through the buccal or gastric mucosa; however, signicant rst-pass metabolism limits enteral bioavailability to 15%.17,18 Transbuccal bioavailability is 27.8%, and sublingual bioavailability is 51%.17,18 Thus, buprenorphine for opioid administration is typically dosed as a dissolving sublingual tablet. Buprenorphine is highly protein bound, with a volume of distribution of 97 to 187 L.19,20 Buprenorphine undergoes n-dealkylation via cytochrome P450 isoenzyme 3A4 to form norbuprenorphine.17,21,22 Conjugates of buprenorphine and norbuprenorphine are primarily excreted in the feces.17 The elimination half-life of buprenorphine is 37 hours after sublingual administration; the elimination half-life of norbuprenorphine is 34 hours.23,24 Enterohepatic recirculation has been theorized to result in the long terminal half-life and duration of action of buprenorphine.17,18 Buprenorphine produces partial -agonist and -antagonist activity. Coformulations of buprenorphine with naloxone (Suboxone; Reckitt Benckiser Pharmaceuticals, Richmond, VA) are intended to prevent the recreational misuse of buprenorphine by injection. Because of poor sublingual and enteral bioavailability of naloxone, however, patients experience no opioid antagonism when buprenorphine/naloxone formulations are administered sublingually.2426 Toddlers are likely to suck on or chew tablets, an exploratory behavior that may lead to buccal absorption of the drug. Despite the poor bioavailability of buprenorphine, children who merely suck on a tablet may, nonetheless, receive a toxic dose. Furthermore, opioid-naive children would be expected to have relatively greater -receptor sensitivity than an adult with opioid dependence and consequent receptor desensitization. Consequently, a child who places a buprenorphine-containing medication in his or her mouth may absorb sufcient drug to become intoxicated, whereas a child who immediately swallows the tablet may not receive a sufcient dose of buprenorphine to develop signs of opioid toxicity. In addition, buprenorphine may have an exaggerated effect on respiratory drive in children. A common pharmacologic effect of opioids is a decrease in tidal volume, which often precedes the decrease in respiratory rate classically associated with opioid toxicity.11 Clinical studies comparing the respiratory consequences of therapeutic buprenorphine and morphine administration have indicated that buprenorphine exhibited a greater effect on respiratory depression.27 Norbuprenorphine, the dealkylated primary metabolite of buprenorphine, also depresses respiratory rate and may contribute to the clinically observed ventilatory depressant effects of buprenorphine in

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FIGURE 1 Management of pediatric buprenorphine intoxication.

children.28,29 An animal study suggests that this effect may be mediated via receptors in the lung as well as central nervous system (CNS) receptors.22 Naloxone has been used to reverse buprenorphineassociated respiratory depression, although pediatric experience is lacking. Of 11 adults who presented with CNS and respiratory depression after buprenorphine overdose, 10 responded dramatically to doses of naloxone ranging from 0.2 to 0.8 mg.22 Reports of adult patients have suggested that higher doses of naloxone may be required to reverse the respiratory depression caused by buprenorphine.3032 Pediatric experience with naloxone suggests that doses of naloxone in excess of the recommended 0.1 mg/kg may be required, and the reversal of buprenorphine-induced respiratory depression by naloxone may be delayed relative to other opioids.30,3335 Of the children in this series who received naloxone, all had reversal of respiratory depression

within minutes of receiving the antidote. Patients 2, 3, and 4 received naloxone either in the eld or in a community hospital ED, where treating physicians commonly use smaller doses of naloxone in adult opioiddependent patients. Patient 5 was treated initially in a tertiary childrens hospital ED and received a full 0.1 mg/kg dose. Management of buprenorphine toxicity in children involves reversal of respiratory depression, airway protection, and supportive care. Pediatric patients have been observed to require more naloxone on a milligramper-kilogram basis than adults, and large doses of naloxone generally are well tolerated in young children.3335 We recommend that an initial dose of naloxone be 0.1 mg/kg, administered intravenously, with repeat dosing as needed every 2 minutes to achieve reversal, consistent with PALS (pediatric advanced life support) resuscitation guidelines.36 Adequate ventilation should be esPEDIATRICS Volume 118, Number 4, October 2006 1749

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tablished before reversal to prevent an adrenergic surge from naloxone administration. Recurrent respiratory depression after naloxone administration may require a continuous infusion of naloxone at an hourly rate of two thirds the naloxone reversal dose (ie, 0.067 mg/kg per hour), titrated to respiratory stimulation.37 We would not expect naloxone infusion to shorten recovery time, because naloxone neither enhances elimination nor induces buprenorphine metabolism. If naloxone fails to reverse respiratory and mental-status depression, orotracheal intubation should be performed to protect the airway and ensure adequate ventilation and oxygenation. Early, aggressive use of naloxone may avert having to undertake this invasive procedure. Toddlers with denite or suspected buprenorphine exposure deserve extended observation and serial examinations. Several reports, and our own experience, document the potential for delayed onset of CNS and respiratory depression.10,27,32,38,39 Given buprenorphines prolonged duration of action, we recommend that any young child with a suspected buprenorphine exposure be observed for a minimum of 24 hours (Fig 1). Any child who displays symptoms of opioid intoxication or requires naloxone therapy should be admitted to a monitored setting until respiratory and mental-status depression have resolved in the absence of naloxone. These recommendations are concordant with those for other opioids (eg, diphenoxylate) that may not produce toxicity until several hours after ingestion.21,33 Buprenorphine will not produce a positive result on the opioid portion of the drugs-of-abuse urine screen.21 Conrmation of buprenorphine exposure is feasible with drug-specic radioimmunoassay, gas chromatography/ tandem mass spectroscopy, or enzyme-linked immunosorbency assay.9,40 Quantication of buprenorphine, and its metabolite norbuprenorphine, concentrations may be performed in reference laboratories, but results likely will not return in sufcient time to affect clinical decisions.9 Therefore, treatment of the pediatric patient exhibiting clinical signs consistent with opioid intoxication should not await laboratory testing results. Because buprenorphine-naloxone formulations are thought to have minimal abuse liability, they are approved for outpatient treatment of opioid dependence. Although administration may be directly observed in an ofce setting, physicians often prefer to prescribe buprenorphine as a home-based therapy. Recent increases in the incidence of opioid addiction, coupled with relaxed restrictions on the number of patients treated by a single clinician, suggest greater opportunity for buprenorphine-based opioid-replacement therapy. The increased use of buprenorphine magnies the risk to children in homes in which it is used. Between 2003 and 2004, there was a 7-fold increase in the number of buprenorphine-containing tablets distributed by US pharmacies, with a 1.8-fold increase anticipated in 2005
1750 GEIB et al

(N. Reuter, MPH, written communication, 2005). Anticipatory guidance for parents in homes where buprenorphine is used should include a warning of the risks of pediatric exposure. CONCLUSIONS We have reported respiratory and CNS depression in young children exposed to buprenorphine. Because this drug is becoming more widely prescribed, clinicians should remain vigilant for occult exposures, which may cause delayed, persistent respiratory depression in toddlers. Children with known or suspected buprenorphine exposure should be monitored in an inpatient setting for at least 24 hours; those with respiratory depression should receive intravenous naloxone, 0.1 mg/kg, as a minimum reversal dose. Patients receiving buprenorphine on an outpatient basis should take steps to ensure that this drug will not be accessible to any young children in their homes. REFERENCES
1. Cook S, Indig D, Gray J, McGrath D. Opiate overdose and health treatment options for opiate users in New South Wales, 1999 2002. N S W Public Health Bull. 2004;15:125131 2. Boyd J, Randell T, Luurila H, Kuisma M. Serious overdoses involving buprenorphine in Helsinki. Acta Anaesthesiol Scand. 2003;47:10311033 3. Gaulier JM, Marquet P, Lacassie E, Dupuy JL, Lachatre G. Fatal intoxication following self-administration of a massive dose of buprenorphine. J Forensic Sci. 2000;45:226 228 4. Gueye PN, Megarbane B, Borron SW, et al. Trends in opiate and opioid poisonings in addicts in north-east Paris and suburbs, 199599. Addiction. 2002;97:12951304 5. Kintz P. Deaths involving buprenorphine: a compendium of French cases. Forensic Sci Int. 2001;121:65 69 6. Kintz P. A new series of 13 buprenorphine-related deaths. Clin Biochem. 2002;35:513516 7. Tracqui A, Kintz P, Ludes B. Buprenorphine-related deaths among drug addicts in France: a report on 20 fatalities. J Anal Toxicol. 1998;22:430 434 8. Doyon S, Klein-Schwartz W, Welsh C. Toxicity following buprenorphine ingestions. Clin Toxicol. 2005;43:640 9. Gaulier JM, Charvier F, Monceaux F, Marquet P, Lachatre G. Ingestion of high-dose buprenorphine by a 4 year-old child. J Toxicol Clin Toxicol. 2004;42:993995 10. Spadari M, Arditti J, Affaton MF, David JM, Valli M. Accidental narcotic and buprenorphine poisoning in children notied at the Marseille Poison Center between 1993 and 1999 [in French] [published correction appears in Therapie. 2001;56: 73]. Therapie. 2000;55:705708 11. Brooks DE, Roberge RJ, Spear A. Clinical nuances of pediatric methadone intoxication. Vet Hum Toxicol. 1999;41:388 390 12. Schwab J, Caggiano AO. Pediatric methadone poisoning revisited. Clin Pediatr (Phila). 2001;40:119 120 13. Hardwick WE Jr, King WD, Palmisano PA. Respiratory depression in a child unintentionally exposed to transdermal fentanyl patch. South Med J. 1997;90:962963 14. Hoffman RJ, Nelson LS, Hoffman RS. Life-threatening levo-aacetylmethadol (LAAM) overdose. J Toxicol Clin Toxicol. 2000; 38:188 189 15. Horowitz R, Mazor SS, Aks SE, Leikin JB. Accidental clonidine patch ingestion in a child. Am J Ther. 2005;12:272274

Downloaded from pediatrics.aappublications.org by guest on March 8, 2012

16. Kraft ME. A 9-month-old with bradycardia and periodic apnea. J Emerg Nurs. 1998;24:457 459 17. Chiang NC, Hawks RL. Pharmacokinetics of the combination tablet of buprenorphine and naloxone. Drug Alcohol Depend. 2003;70(suppl):S39 S47 18. Kuhlman JJ Jr, Lalani S, Magluilo J Jr, Levine B, Darwin WD. Human pharmacokinetics of intravenous, sublingual, and buccal buprenorphine. J Anal Toxicol. 1996;20:369 378 19. Heel RC, Brogden RN, Speight TM, Avery GS. Buprenorphine: a review of its pharmacological properties and therapeutic efcacy. Drugs. 1979;17:81110 20. Bullingham RE, McQuay HJ, Dwyer D, Allen MC, Moore RA. Sublingual buprenorphine used postoperatively: clinical observations and preliminary pharmacokinetic analysis. Br J Clin Pharmacol. 1981;12:117122 21. Sporer KA. Buprenorphine: a primer for emergency physicians. Ann Emerg Med. 2004;43:580 584 22. Ohtani M, Kotaki H, Nishitateno K, Sawada Y, Iga T. Kinetics of respiratory depression in rats induced by buprenorphine and its metabolite, norbuprenorphine. J Pharmacol Exp Ther. 1997; 281:428 433 23. Suboxone (buprenorphine HCl/naloxone HCl dihydrate sublingual tablets)/Subutex (buprenorphine HCl sublingual tablets) [prescribing information]. Richmond, VA; Reckitt Benckiser Pharmaceuticals, Inc; 2005 24. Harris DS, Jones RT, Welm S, Upton RA, Lin E, Mendelson J. Buprenorphine and naloxone co-administration in opiatedependent patients stabilized on sublingual buprenorphine. Drug Alcohol Depend. 2000;61:8594 25. Mendelson J, Jones RT. Clinical and pharmacological evaluation of buprenorphine and naloxone combinations: why the 4:1 ratio for treatment? Drug Alcohol Depend. 2003;70(suppl): S29 S37 26. Walsh SL, Eissenberg T. The clinical pharmacology of buprenorphine: extrapolating from the laboratory to the clinic. Drug Alcohol Depend. 2003;70(2 suppl):S13S27 27. Olkkola KT, Leijala MA, Maunuksela EL. Paediatric ventilatory effects of morphine and buprenorphine revisited. Paediatr Anaesth. 1995;5:303305 28. Megarbane B, Marie N, Pirnay S, et al. Buprenorphine is pro-

29. 30. 31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

tective against the depressive effects of norbuprenorphine on ventilation. Toxicol Appl Pharmacol. 2006;212:256 267 Cowan A. Buprenorphine: new pharmacological aspects. Int J Clin Pract Suppl. 2003;(133):3 8; discussion 2324 Gal TJ. Naloxone reversal of buprenorphine-induced respiratory depression. Clin Pharmacol Ther. 1989;45:66 71 Knape JT. Early respiratory depression resistant to naloxone following epidural buprenorphine. Anesthesiology. 1986;64: 382384 Thorn SE, Rawal N, Wennhager M. Prolonged respiratory depression caused by sublingual buprenorphine. Lancet. 1988; 1(8578):179 180 McCarron MM, Challoner KR, Thompson GA. Diphenoxylateatropine (Lomotil) overdose in children: an update (report of eight cases and review of the literature). Pediatrics. 1991;87: 694 700 Lewis JM, Klein-Schwartz W, Benson BE, Oderda GM, Takai S. Continuous naloxone infusion in pediatric narcotic overdose. Am J Dis Child. 1984;138:944 946 Gourlay GK, Coulthard K. The role of naloxone infusions in the treatment of overdoses of long half-life narcotic agonists: application to nor-methadone. Br J Clin Pharmacol. 1983;15: 269 271 Subcommittee on Pediatric Resuscitation. Toxicology. In: American Heart Association, ed. PALS Provider Manual. Dallas, TX: American Heart Association; 2002:319 321 Goldfrank L, Weisman RS, Errick JK, Lo MW. A dosing nomogram for continuous infusion intravenous naloxone. Ann Emerg Med. 1986;15:566 570 Jain PN, Shah SC. Respiratory depression following combination of epidural buprenorphine and intramuscular ketorolac. Anaesthesia. 1993;48:898 899 McQuay HJ, Bullingham RE, Bennett MR, Moore RA. Delayed respiratory depression: a case report and a new hypothesis. Acta Anaesthesiol Belg. 1979;30(suppl):245247 Simpson D, Braithwaite RA, Jarvie DR, et al. Screening for drugs of abuse (II): cannabinoids, lysergic acid diethylamide, buprenorphine, methadone, barbiturates, benzodiazepines and other drugs. Ann Clin Biochem. 1997;34:460 510

Downloaded from pediatrics.aappublications.org by guest on March 8, 2012

PEDIATRICS Volume 118, Number 4, October 2006

1751

Adverse Effects in Children After Unintentional Buprenorphine Exposure Ann-Jeannette Geib, Kavita Babu, Michele Burns Ewald and Edward W. Boyer Pediatrics 2006;118;1746 DOI: 10.1542/peds.2006-0948
Updated Information & Services References including high resolution figures, can be found at: http://pediatrics.aappublications.org/content/118/4/1746.full.h tml This article cites 35 articles, 6 of which can be accessed free at: http://pediatrics.aappublications.org/content/118/4/1746.full.h tml#ref-list-1 This article has been cited by 4 HighWire-hosted articles: http://pediatrics.aappublications.org/content/118/4/1746.full.h tml#related-urls This article, along with others on similar topics, appears in the following collection(s): Therapeutics & Toxicology http://pediatrics.aappublications.org/cgi/collection/therapeutic s_and_toxicology Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://pediatrics.aappublications.org/site/misc/Permissions.xht ml Information about ordering reprints can be found online: http://pediatrics.aappublications.org/site/misc/reprints.xhtml

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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2006 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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