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EXPERIENCE & REASON |
a Program in Medical Toxicology, Division of Emergency Medicine, Children’s Hospital Boston, Boston, Massachusetts
b Division of Medical Toxicology, University of Massachusetts Medical School, Boston, Massachusetts
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 buprenorphine’s 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. Confirmatory 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.
Key Words: buprenorphine • unintentional ingestion • respiratory depression • opioid • pediatric • exploratory behavior
Abbreviations: ED, emergency department • CNS, central nervous system
Buprenorphine, alone or in combination with naloxone, 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 physician’s 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 Administration’s approval in 2002. Treatment with buprenorphine has been demonstrated to decrease the number of opioid-related deaths and rivals methadone in efficacy.1
Although associated with respiratory depression when abused parenterally by adults, buprenorphine’s sublingual absorption may lead to toxicity in small children who merely place the medication in their mouth.2–7 Here we report 5 cases of buprenorphine toxicity in toddlers that required either naloxone therapy or mechanical ventilation.
CASE REPORTS
Patient1.
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 mmHg systolic) and was promptly intubated. On arrival at the emergency department (ED) his blood pressure was 124/44 mmHg, his heart rate was 144 beats per minute, and his respiratory rate was 24 breaths per minute on mechanical ventilation. The physical examination was significant 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.
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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.
Patient3.
A 20-month-old, 10-kg boy was found cyanotic and somnolent with shallow respirations next to an empty bottle of his father’s 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 boy’s 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 mmHg; respiratory rate, 20 breaths minute; temperature, 97.9°F; and oxygen saturation, 97% on room air. In the field 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.
Patient4.
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 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.
Patient5.
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 mother’s 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, 97.8°F; 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 difficult 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 findings 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 opioid dependence, agents such as buprenorphine preparations, clonidine patches, fentanyl patches, methadone, and L-
-acetyl-methadol may produce a similar clinical picture.11–16
The pharmacokinetics of buprenorphine have been well described. Buprenorphine is absorbed through the buccal or gastric mucosa; however, significant first-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 µ-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.24–26 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 µ-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 sufficient drug to become intoxicated, whereas a child who immediately swallows the tablet may not receive a sufficient 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 children.28,29 An animal study suggests that this effect may be mediated via µ receptors in the lung as well as central nervous system (CNS) µ receptors.22
Naloxone has been used to reverse buprenorphine-associated 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.30–32 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.30,33–35 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 field or in a community hospital ED, where treating physicians commonly use smaller doses of naloxone in adult opioid-dependent patients. Patient 5 was treated initially in a tertiary children’s 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 milligram-per-kilogram basis than adults, and large doses of naloxone generally are well tolerated in young children.33–35 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 established 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 definite 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 buprenorphine’s 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
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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 office 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 magnifies 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 (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.
FOOTNOTES
Accepted 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{at}hotmail.com
The authors have indicated they have no financial relationships relevant to this article to disclose.
REFERENCES
This article has been cited by other articles:
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  K. T. S. Pattinson Opioids and the control of respiration Br. J. Anaesth., June 1, 2008; 100(6): 747 - 758. [Abstract] [Full Text] [PDF]
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 B. D. Hayes, W. Klein-Schwartz, and S. Doyon Toxicity of Buprenorphine Overdoses in Children Pediatrics, April 1, 2008; 121(4): e782 - e786. [Abstract] [Full Text] [PDF]
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